Running title (full title to be decided):



Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer’s diseaseNatalie S Ryana, Geert-Jan Biesselsb, Lois Kimc, Jennifer M Nicholasa,d, Philip A Barbera, Phoebe Walshe, Priya Gamie, Huw R Morrisf, Ant?nio J Bastos-Leiteg, Jonathan M Schotta, Jon Beckh, Simon Meadh, Lucia Chavez-Gutierrezi,j, Bart de Strooperi,j, Martin N Rossora, Tamas Revesze, Tammaryn Lashleye *, Nick C Foxa *aDementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. bDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Centre, Utrecht, The Netherlands. cDepartment of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel St, London. WC1E 7HT, UK. dDepartment of Medical Statistics, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel St, London, WC1E 7HT, UK. eQueen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK. fDepartment of Clinical Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. gDepartment of Medical Imaging, University of Porto Faculty of Medicine, Alameda do Professor Hern?ni Monteiro, 4200-319 Porto, Portugal. hMRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. iVIB Center for the Biology of Disease, Leuven, Belgium. jCenter for Human Genetics and Leuven Institute for Neurodegenerative Diseases, University of Leuven, Leuven, Belgium.* Authors contributed equally to the workCorresponding author: Natalie S Ryan, Dementia Research Centre, Box 16 – The National Hospital for Neurology and Neurosugery, Queen Square, London WC1N 3BG, UK. Tel: +44 (0) 203 4483856 Fax: +44 (0) 203 4483104 E-mail: natalie.ryan@ucl.ac.ukAbstract Familial Alzheimer’s disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with post-codon 200 PSEN1 mutations and Aβ coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on MRI, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 pre-codon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (five pre-codon 200) had post-mortem examination. Increased WMH were observed in the PSEN1 post-codon 200 group and in the single APP patient with an Aβ coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The pre-codon 200 group had younger ages at onset, decreased axonal density/integrity and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD. Keywords: Familial Alzheimer’s disease, Presenilin 1 (PSEN1, PS1), amyloid precursor protein (APP), white matter hyperintensities, cerebral amyloid angiopathy1. IntroductionAD is the most common cause of dementia, which affects around 36 million people worldwide with numbers predicted to double every twenty years unless effective disease modifying therapies are found PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmluY2U8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

ZWNOdW0+MzIwPC9SZWNOdW0+PERpc3BsYXlUZXh0PihGb3ggYW5kIFBldGVyc2VuLCAyMDEzLFBy

aW5jZSwgZXQgYWwuLCAyMDEzKTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMjA8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQy

OXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTQxOTI1ODgzMyI+MzIwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QcmluY2UsIE0uPC9hdXRob3I+

PGF1dGhvcj5CcnljZSwgUi48L2F1dGhvcj48YXV0aG9yPkFsYmFuZXNlLCBFLjwvYXV0aG9yPjxh

dXRob3I+V2ltbywgQS48L2F1dGhvcj48YXV0aG9yPlJpYmVpcm8sIFcuPC9hdXRob3I+PGF1dGhv

cj5GZXJyaSwgQy4gUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5JbnN0aXR1dGUgb2YgUHN5Y2hpYXRyeSwgS2luZyZhcG9zO3MgQ29sbGVnZSBMb25kb24s

IExvbmRvbiwgVUsuIE1hcnRpbi5QcmluY2VAa2NsLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+VGhlIGdsb2JhbCBwcmV2YWxlbmNlIG9mIGRlbWVudGlhOiBhIHN5c3RlbWF0aWMg

cmV2aWV3IGFuZCBtZXRhYW5hbHlzaXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVy

cyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkFsemhlaW1lciZhcG9zO3MgJmFt

cDsgZGVtZW50aWEgOiB0aGUgam91cm5hbCBvZiB0aGUgQWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lh

dGlvbjwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFsemhlaW1l

cnMgRGVtZW50PC9mdWxsLXRpdGxlPjxhYmJyLTE+QWx6aGVpbWVyJmFwb3M7cyAmYW1wOyBkZW1l

bnRpYSA6IHRoZSBqb3VybmFsIG9mIHRoZSBBbHpoZWltZXImYXBvcztzIEFzc29jaWF0aW9uPC9h

YmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbHpoZWltZXJz

IERlbWVudDwvZnVsbC10aXRsZT48YWJici0xPkFsemhlaW1lciZhcG9zO3MgJmFtcDsgZGVtZW50

aWEgOiB0aGUgam91cm5hbCBvZiB0aGUgQWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lhdGlvbjwvYWJi

ci0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjYzLTc1IGUyPC9wYWdlcz48dm9sdW1lPjk8L3Zv

bHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48

a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5EZW1lbnRpYS8qZXBp

ZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HbG9i

YWwgSGVhbHRoLyp0cmVuZHM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPkxpZmUgRXhwZWN0YW5jeS90cmVuZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QcmV2YWxlbmNlPC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5K

YW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMp

JiN4RDsxNTUyLTUyNjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIzMzA1ODIzPC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzIzMzA1ODIzPC91cmw+PHVybD5odHRwOi8vd3d3LmFsemhlaW1lcnNh

bmRkZW1lbnRpYS5jb20vYXJ0aWNsZS9TMTU1Mi01MjYwKDEyKTAyNTMxLTkvcGRmPC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouamFs

ei4yMDEyLjExLjAwNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxD

aXRlPjxBdXRob3I+Rm94PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjMxOTwvUmVj

TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzE5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjE0MTkyNTg4MDUiPjMxOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+Rm94LCBOLiBDLjwvYXV0aG9yPjxhdXRob3I+UGV0ZXJzZW4sIFIuIEMuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBHOCBEZW1lbnRp

YSBSZXNlYXJjaCBTdW1taXQtLWEgc3RhcnRlciBmb3IgZWlnaHQ/PC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkxhbmNldDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+TGFuY2V0PC9hbHQtdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TGFuY2V0PC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TGFuY2V0PC9mdWxsLXRpdGxl

PjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjE5NjgtOTwvcGFnZXM+PHZvbHVtZT4zODI8L3ZvbHVt

ZT48bnVtYmVyPjk5MDk8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QmlvbWVkaWNhbCBSZXNl

YXJjaC8qb3JnYW5pemF0aW9uICZhbXA7IGFkbWluaXN0cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

PkRlbWVudGlhLypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+R2xv

YmFsIEhlYWx0aDwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+Kklu

dGVybmF0aW9uYWwgQ29vcGVyYXRpb248L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYyAxNDwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjE0NzQtNTQ3WCAoRWxlY3Ryb25pYykmI3hEOzAxNDAtNjczNiAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQzMzIzMDY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQzMzIzMDY8

L3VybD48dXJsPmh0dHA6Ly93d3cuc2NpZW5jZWRpcmVjdC5jb20vc2NpZW5jZS9hcnRpY2xlL3Bp

aS9TMDE0MDY3MzYxMzYyNDI2NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMDE0MC02NzM2KDEzKTYyNDI2LTU8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmluY2U8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

ZWNOdW0+MzIwPC9SZWNOdW0+PERpc3BsYXlUZXh0PihGb3ggYW5kIFBldGVyc2VuLCAyMDEzLFBy

aW5jZSwgZXQgYWwuLCAyMDEzKTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMjA8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQy

OXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTQxOTI1ODgzMyI+MzIwPC9r

ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl

Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5QcmluY2UsIE0uPC9hdXRob3I+

PGF1dGhvcj5CcnljZSwgUi48L2F1dGhvcj48YXV0aG9yPkFsYmFuZXNlLCBFLjwvYXV0aG9yPjxh

dXRob3I+V2ltbywgQS48L2F1dGhvcj48YXV0aG9yPlJpYmVpcm8sIFcuPC9hdXRob3I+PGF1dGhv

cj5GZXJyaSwgQy4gUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5JbnN0aXR1dGUgb2YgUHN5Y2hpYXRyeSwgS2luZyZhcG9zO3MgQ29sbGVnZSBMb25kb24s

IExvbmRvbiwgVUsuIE1hcnRpbi5QcmluY2VAa2NsLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+VGhlIGdsb2JhbCBwcmV2YWxlbmNlIG9mIGRlbWVudGlhOiBhIHN5c3RlbWF0aWMg

cmV2aWV3IGFuZCBtZXRhYW5hbHlzaXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6aGVpbWVy

cyBEZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkFsemhlaW1lciZhcG9zO3MgJmFt

cDsgZGVtZW50aWEgOiB0aGUgam91cm5hbCBvZiB0aGUgQWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lh

dGlvbjwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFsemhlaW1l

cnMgRGVtZW50PC9mdWxsLXRpdGxlPjxhYmJyLTE+QWx6aGVpbWVyJmFwb3M7cyAmYW1wOyBkZW1l

bnRpYSA6IHRoZSBqb3VybmFsIG9mIHRoZSBBbHpoZWltZXImYXBvcztzIEFzc29jaWF0aW9uPC9h

YmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbHpoZWltZXJz

IERlbWVudDwvZnVsbC10aXRsZT48YWJici0xPkFsemhlaW1lciZhcG9zO3MgJmFtcDsgZGVtZW50

aWEgOiB0aGUgam91cm5hbCBvZiB0aGUgQWx6aGVpbWVyJmFwb3M7cyBBc3NvY2lhdGlvbjwvYWJi

ci0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjYzLTc1IGUyPC9wYWdlcz48dm9sdW1lPjk8L3Zv

bHVtZT48bnVtYmVyPjE8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48

a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5EZW1lbnRpYS8qZXBp

ZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HbG9i

YWwgSGVhbHRoLyp0cmVuZHM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPkxpZmUgRXhwZWN0YW5jeS90cmVuZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QcmV2YWxlbmNlPC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5K

YW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTUyLTUyNzkgKEVsZWN0cm9uaWMp

JiN4RDsxNTUyLTUyNjAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIzMzA1ODIzPC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzIzMzA1ODIzPC91cmw+PHVybD5odHRwOi8vd3d3LmFsemhlaW1lcnNh

bmRkZW1lbnRpYS5jb20vYXJ0aWNsZS9TMTU1Mi01MjYwKDEyKTAyNTMxLTkvcGRmPC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouamFs

ei4yMDEyLjExLjAwNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxD

aXRlPjxBdXRob3I+Rm94PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjMxOTwvUmVj

TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzE5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjE0MTkyNTg4MDUiPjMxOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+Rm94LCBOLiBDLjwvYXV0aG9yPjxhdXRob3I+UGV0ZXJzZW4sIFIuIEMuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBHOCBEZW1lbnRp

YSBSZXNlYXJjaCBTdW1taXQtLWEgc3RhcnRlciBmb3IgZWlnaHQ/PC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkxhbmNldDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+TGFuY2V0PC9hbHQtdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TGFuY2V0PC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TGFuY2V0PC9mdWxsLXRpdGxl

PjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjE5NjgtOTwvcGFnZXM+PHZvbHVtZT4zODI8L3ZvbHVt

ZT48bnVtYmVyPjk5MDk8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QmlvbWVkaWNhbCBSZXNl

YXJjaC8qb3JnYW5pemF0aW9uICZhbXA7IGFkbWluaXN0cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

PkRlbWVudGlhLypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+R2xv

YmFsIEhlYWx0aDwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+Kklu

dGVybmF0aW9uYWwgQ29vcGVyYXRpb248L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYyAxNDwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjE0NzQtNTQ3WCAoRWxlY3Ryb25pYykmI3hEOzAxNDAtNjczNiAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQzMzIzMDY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQzMzIzMDY8

L3VybD48dXJsPmh0dHA6Ly93d3cuc2NpZW5jZWRpcmVjdC5jb20vc2NpZW5jZS9hcnRpY2xlL3Bp

aS9TMDE0MDY3MzYxMzYyNDI2NTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMDE0MC02NzM2KDEzKTYyNDI2LTU8L2VsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA (Fox and Petersen, 2013,Prince, et al., 2013). FAD, caused by autosomal dominantly inherited mutations in APP, PSEN1, PSEN2 and APP duplications, accounts for a small minority of AD cases. However, insights revealed through studying FAD have contributed to our understanding of AD pathophysiology, and therapies with the potential for disease modification have been developed in animal models harbouring FAD gene mutations. An emerging view is that therapeutic success may only be possible with intervention very early in the disease course. This has motivated the development of treatment trials specifically for FAD, which offers the possibility of treating individuals at a preclinical disease stage PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWltYW48L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MTQ4PC9SZWNOdW0+PERpc3BsYXlUZXh0PihCYXRlbWFuLCBldCBhbC4sIDIwMTEsUmVp

bWFuLCBldCBhbC4sIDIwMTApPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE0ODwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5

cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNDg8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlJlaW1hbixFLk0uPC9hdXRob3I+

PGF1dGhvcj5MYW5nYmF1bSxKLkIuPC9hdXRob3I+PGF1dGhvcj5UYXJpb3QsUC5OLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlRoZSBCYW5uZXIgQWx6aGVp

bWVyJmFwb3M7cyBJbnN0aXR1dGUsIFBob2VuaXgsIEFaIDg1MDA2LCBVU0EuIGVyaWMucmVpbWFu

QGJhbm5lcmhlYWx0aC5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbHpoZWltZXIm

YXBvcztzIHByZXZlbnRpb24gaW5pdGlhdGl2ZTogYSBwcm9wb3NhbCB0byBldmFsdWF0ZSBwcmVz

eW1wdG9tYXRpYyB0cmVhdG1lbnRzIGFzIHF1aWNrbHkgYXMgcG9zc2libGU8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+QmlvbWFyay5NZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5CaW9tYXJrLk1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBh

Z2VzPjMtMTQ8L3BhZ2VzPjx2b2x1bWU+NDwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXBy

aW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48

a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJv

dGVpbiBFNDwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2FsIE1hcmtlcnM8L2tleXdvcmQ+PGtl

eXdvcmQ+Y2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5kaWFnbm9zaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+ZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFu

Y2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk5v

b3Ryb3BpYyBBZ2VudHM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPlBvc2l0cm9uLUVtaXNzaW9uIFRvbW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+cHJldmVu

dGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlB1YmxpYyBQb2xpY3k8L2tleXdv

cmQ+PGtleXdvcmQ+UmFuZG9taXplZCBDb250cm9sbGVkIFRyaWFscyBhcyBUb3BpYzwva2V5d29y

ZD48a2V5d29yZD50YXUgUHJvdGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+dGhlcmFwZXV0aWMgdXNl

PC9rZXl3b3JkPjxrZXl3b3JkPlVuaXRlZCBTdGF0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIvMjAxMDwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD4xODM8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwMzgzMzE5PC91cmw+PHVybD5odHRw

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzI4NTA0NDYvcGRmL25paG1z

LTE4MDYyNy5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxD

aXRlPjxBdXRob3I+QmF0ZW1hbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051bT4xNjA8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjE2MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkJhdGVtYW4sUi5KLjwvYXV0aG9yPjxhdXRob3I+QWlzZW4sUC5TLjwvYXV0

aG9yPjxhdXRob3I+RGUgU3Ryb29wZXIsQi48L2F1dGhvcj48YXV0aG9yPkZveCxOLkMuPC9hdXRo

b3I+PGF1dGhvcj5MZW1lcmUsQy5BLjwvYXV0aG9yPjxhdXRob3I+UmluZ21hbixKLk0uPC9hdXRo

b3I+PGF1dGhvcj5TYWxsb3dheSxTLjwvYXV0aG9yPjxhdXRob3I+U3BlcmxpbmcsUi5BLjwvYXV0

aG9yPjxhdXRob3I+V2luZGlzY2gsTS48L2F1dGhvcj48YXV0aG9yPlhpb25nLEMuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVy

b2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIDY2MCBTLCBF

dWNsaWQsIENhbXB1cyBCb3ggODExMSwgU3QgTG91aXMsIE1PIDYzMTEwLCBVU0EuIGJhdGVtYW5y

QHd1c3RsLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkF1dG9zb21hbC1kb21pbmFu

dCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IGEgcmV2aWV3IGFuZCBwcm9wb3NhbCBmb3IgdGhl

IHByZXZlbnRpb24gb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkFsemhlaW1lcnMuUmVzLlRoZXIuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl

cmlvZGljYWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycy5SZXMuVGhlci48L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz4xPC9wYWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjE8L251

bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9sb2d5PC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzYv

MjAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xOTU8L2xhYmVsPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxMjEx

MDcwPC91cmw+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BN

QzMxMDk0MTAvcGRmL2FsenJ0NTkucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVj

b3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWltYW48L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MTQ4PC9SZWNOdW0+PERpc3BsYXlUZXh0PihCYXRlbWFuLCBldCBhbC4sIDIwMTEsUmVp

bWFuLCBldCBhbC4sIDIwMTApPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE0ODwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5

cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNDg8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlJlaW1hbixFLk0uPC9hdXRob3I+

PGF1dGhvcj5MYW5nYmF1bSxKLkIuPC9hdXRob3I+PGF1dGhvcj5UYXJpb3QsUC5OLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlRoZSBCYW5uZXIgQWx6aGVp

bWVyJmFwb3M7cyBJbnN0aXR1dGUsIFBob2VuaXgsIEFaIDg1MDA2LCBVU0EuIGVyaWMucmVpbWFu

QGJhbm5lcmhlYWx0aC5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbHpoZWltZXIm

YXBvcztzIHByZXZlbnRpb24gaW5pdGlhdGl2ZTogYSBwcm9wb3NhbCB0byBldmFsdWF0ZSBwcmVz

eW1wdG9tYXRpYyB0cmVhdG1lbnRzIGFzIHF1aWNrbHkgYXMgcG9zc2libGU8L3RpdGxlPjxzZWNv

bmRhcnktdGl0bGU+QmlvbWFyay5NZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5CaW9tYXJrLk1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBh

Z2VzPjMtMTQ8L3BhZ2VzPjx2b2x1bWU+NDwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXBy

aW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48

a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJv

dGVpbiBFNDwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2FsIE1hcmtlcnM8L2tleXdvcmQ+PGtl

eXdvcmQ+Y2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29yZD48a2V5d29yZD5kaWFnbm9zaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+ZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFu

Y2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk5v

b3Ryb3BpYyBBZ2VudHM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPlBvc2l0cm9uLUVtaXNzaW9uIFRvbW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+cHJldmVu

dGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlB1YmxpYyBQb2xpY3k8L2tleXdv

cmQ+PGtleXdvcmQ+UmFuZG9taXplZCBDb250cm9sbGVkIFRyaWFscyBhcyBUb3BpYzwva2V5d29y

ZD48a2V5d29yZD50YXUgUHJvdGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+dGhlcmFwZXV0aWMgdXNl

PC9rZXl3b3JkPjxrZXl3b3JkPlVuaXRlZCBTdGF0ZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIvMjAxMDwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD4xODM8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwMzgzMzE5PC91cmw+PHVybD5odHRw

Oi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzI4NTA0NDYvcGRmL25paG1z

LTE4MDYyNy5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxD

aXRlPjxBdXRob3I+QmF0ZW1hbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051bT4xNjA8

L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjE2MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkJhdGVtYW4sUi5KLjwvYXV0aG9yPjxhdXRob3I+QWlzZW4sUC5TLjwvYXV0

aG9yPjxhdXRob3I+RGUgU3Ryb29wZXIsQi48L2F1dGhvcj48YXV0aG9yPkZveCxOLkMuPC9hdXRo

b3I+PGF1dGhvcj5MZW1lcmUsQy5BLjwvYXV0aG9yPjxhdXRob3I+UmluZ21hbixKLk0uPC9hdXRo

b3I+PGF1dGhvcj5TYWxsb3dheSxTLjwvYXV0aG9yPjxhdXRob3I+U3BlcmxpbmcsUi5BLjwvYXV0

aG9yPjxhdXRob3I+V2luZGlzY2gsTS48L2F1dGhvcj48YXV0aG9yPlhpb25nLEMuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVy

b2xvZ3ksIFdhc2hpbmd0b24gVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIDY2MCBTLCBF

dWNsaWQsIENhbXB1cyBCb3ggODExMSwgU3QgTG91aXMsIE1PIDYzMTEwLCBVU0EuIGJhdGVtYW5y

QHd1c3RsLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkF1dG9zb21hbC1kb21pbmFu

dCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U6IGEgcmV2aWV3IGFuZCBwcm9wb3NhbCBmb3IgdGhl

IHByZXZlbnRpb24gb2YgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkFsemhlaW1lcnMuUmVzLlRoZXIuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl

cmlvZGljYWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycy5SZXMuVGhlci48L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz4xPC9wYWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjE8L251

bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9sb2d5PC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzYv

MjAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xOTU8L2xhYmVsPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxMjEx

MDcwPC91cmw+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BN

QzMxMDk0MTAvcGRmL2FsenJ0NTkucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVj

b3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA (Bateman, et al., 2011,Reiman, et al., 2010). Furthermore, the young age of patients with FAD, which typically manifests in the 30s-50s, means that co-morbidities such as atherosclerotic cerebrovascular disease that can complicate clinical trials in sporadic AD are rare. However, the launch of FAD treatment trials necessitates a deeper understanding of the heterogeneity that exists within FAD, particularly with regards to CAA, which appears to be an important factor in amyloid-modifying therapeutic trials PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NoZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4xMzE8L1JlY051bT48RGlzcGxheVRleHQ+KEJvY2hlLCBldCBhbC4sIDIwMDgsU2FrYWks

IGV0IGFsLiwgMjAxNCxTcGVybGluZywgZXQgYWwuLCAyMDExKTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMzE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0i

MTM5MjM3MjcxNSI+MTMxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5C

b2NoZSxELjwvYXV0aG9yPjxhdXRob3I+Wm90b3ZhLEUuPC9hdXRob3I+PGF1dGhvcj5XZWxsZXIs

Ui5PLjwvYXV0aG9yPjxhdXRob3I+TG92ZSxTLjwvYXV0aG9yPjxhdXRob3I+TmVhbCxKLlcuPC9h

dXRob3I+PGF1dGhvcj5QaWNrZXJpbmcsUi5NLjwvYXV0aG9yPjxhdXRob3I+V2lsa2luc29uLEQu

PC9hdXRob3I+PGF1dGhvcj5Ib2xtZXMsQy48L2F1dGhvcj48YXV0aG9yPk5pY29sbCxKLkEuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2Yg

Q2xpbmljYWwgTmV1cm9zY2llbmNlcywgVW5pdmVyc2l0eSBvZiBTb3V0aGFtcHRvbiwgU291dGhh

bXB0b24gR2VuZXJhbCBIb3NwaXRhbCwgU291dGhhbXB0b24sIFVLLiBELkJvY2hlQHNvdG9uLmFj

LnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q29uc2VxdWVuY2Ugb2YgQWJldGEgaW1t

dW5pemF0aW9uIG9uIHRoZSB2YXNjdWxhdHVyZSBvZiBodW1hbiBBbHpoZWltZXImYXBvcztzIGRp

c2Vhc2UgYnJhaW48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRsZT48L3Bl

cmlvZGljYWw+PHBhZ2VzPjMyOTktMzMxMDwvcGFnZXM+PHZvbHVtZT4xMzE8L3ZvbHVtZT48bnVt

YmVyPlB0IDEyPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1l

ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsODAg

YW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtl

eXdvcmQ+QWx6aGVpbWVyIFZhY2NpbmVzPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdv

cmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJv

ZGllczwva2V5d29yZD48a2V5d29yZD5ibG9vZDwva2V5d29yZD48a2V5d29yZD5ibG9vZCBzdXBw

bHk8L2tleXdvcmQ+PGtleXdvcmQ+Qmxvb2QgVmVzc2Vsczwva2V5d29yZD48a2V5d29yZD5CcmFp

bjwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHk8L2tleXdvcmQ+

PGtleXdvcmQ+Q2VyZWJyYWwgQ29ydGV4PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEhlbW9y

cmhhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl

PC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu

b3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vdGhlcmFweSxBY3RpdmU8L2tleXdvcmQ+

PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW5pbmdlczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+

TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlBlcHRpZGUgRnJhZ21lbnRzPC9rZXl3b3JkPjxrZXl3b3JkPlNvbHViaWxpdHk8L2tleXdvcmQ+

PGtleXdvcmQ+dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdv

cmQ+PGtleXdvcmQ+VmFjY2luZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAw

ODwveWVhcj48cHViLWRhdGVzPjxkYXRlPjEyLzIwMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48bGFiZWw+MTY2PC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xODk1MzA1NjwvdXJsPjx1cmw+aHR0cDovL2JyYWluLm94

Zm9yZGpvdXJuYWxzLm9yZy9jb250ZW50LzEzMS8xMi8zMjk5LmZ1bGwucGRmPC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNwZXJsaW5nPC9B

dXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVtPjE4NDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1u

dW1iZXI+MTg0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0i

MnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3

MTUiPjE4NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3Blcmxpbmcs

Ui5BLjwvYXV0aG9yPjxhdXRob3I+SmFjayxDLlIuLEpyLjwvYXV0aG9yPjxhdXRob3I+QmxhY2ss

Uy5FLjwvYXV0aG9yPjxhdXRob3I+RnJvc2NoLE0uUC48L2F1dGhvcj48YXV0aG9yPkdyZWVuYmVy

ZyxTLk0uPC9hdXRob3I+PGF1dGhvcj5IeW1hbixCLlQuPC9hdXRob3I+PGF1dGhvcj5TY2hlbHRl

bnMsUC48L2F1dGhvcj48YXV0aG9yPkNhcnJpbGxvLE0uQy48L2F1dGhvcj48YXV0aG9yPlRoaWVz

LFcuPC9hdXRob3I+PGF1dGhvcj5CZWRuYXIsTS5NLjwvYXV0aG9yPjxhdXRob3I+QmxhY2ssUi5T

LjwvYXV0aG9yPjxhdXRob3I+QnJhc2hlYXIsSC5SLjwvYXV0aG9yPjxhdXRob3I+R3J1bmRtYW4s

TS48L2F1dGhvcj48YXV0aG9yPlNpZW1lcnMsRS5SLjwvYXV0aG9yPjxhdXRob3I+RmVsZG1hbixI

LkguPC9hdXRob3I+PGF1dGhvcj5TY2hpbmRsZXIsUi5KLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoIGFu

ZCBUcmVhdG1lbnQsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBCcmlnaGFtIGFuZCBXb21lbiZh

cG9zO3MgSG9zcGl0YWwsIEJvc3RvbiwgTUEsIFVTQTsgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ks

IE1hc3NhY2h1c2V0dHMgR2VuZXJhbCBIb3NwaXRhbCwgSGFydmFyZCBNZWRpY2FsIFNjaG9vbCwg

Qm9zdG9uLCBNQSwgVVNBPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZC1yZWxh

dGVkIGltYWdpbmcgYWJub3JtYWxpdGllcyBpbiBhbXlsb2lkLW1vZGlmeWluZyB0aGVyYXBldXRp

YyB0cmlhbHM6IFJlY29tbWVuZGF0aW9ucyBmcm9tIHRoZSBBbHpoZWltZXImYXBvcztzIEFzc29j

aWF0aW9uIFJlc2VhcmNoIFJvdW5kdGFibGUgV29ya2dyb3VwPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkFsemhlaW1lcnMuRGVtZW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycy5EZW1lbnQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4zNjctMzg1PC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJl

cj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRz

PjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+TmV1cm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Ny8yMDExPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjIxODwvbGFiZWw+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE3ODQzNDg8L3Vy

bD48dXJsPmh0dHA6Ly9hYy5lbHMtY2RuLmNvbS9TMTU1MjUyNjAxMTAyNTA2NC8xLXMyLjAtUzE1

NTI1MjYwMTEwMjUwNjQtbWFpbi5wZGY/X3RpZD0yZDM2ZGQzOC1hMDc5LTExZTMtOWVlNC0wMDAw

MGFhY2IzNjImYW1wO2FjZG5hdD0xMzkzNTkyOTg2X2Q1ZDA2Yzk0NzNjMDdlZTYzNGEzMzQ5ZjI2

YWY3OGY5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPlNha2FpPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjQ3NjwvUmVjTnVt

PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDc2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1l

c3RhbXA9IjE0MjY3NjI2NjUiPjQ3Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+U2FrYWksIEsuPC9hdXRob3I+PGF1dGhvcj5Cb2NoZSwgRC48L2F1dGhvcj48YXV0aG9y

PkNhcmFyZSwgUi48L2F1dGhvcj48YXV0aG9yPkpvaG5zdG9uLCBELjwvYXV0aG9yPjxhdXRob3I+

SG9sbWVzLCBDLjwvYXV0aG9yPjxhdXRob3I+TG92ZSwgUy48L2F1dGhvcj48YXV0aG9yPk5pY29s

bCwgSi4gQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5D

bGluaWNhbCBOZXVyb3NjaWVuY2VzLCBDbGluaWNhbCBhbmQgRXhwZXJpbWVudGFsIFNjaWVuY2Vz

LCBGYWN1bHR5IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIFNvdXRoYW1wdG9uLCBTb3V0aGFt

cHRvbiwgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QWJldGEgaW1tdW5vdGhlcmFw

eSBmb3IgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiBlZmZlY3RzIG9uIGFwb0UgYW5kIGNlcmVi

cmFsIHZhc2N1bG9wYXRoeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0aG9s

PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5BY3RhIG5ldXJvcGF0aG9sb2dpY2E8L2FsdC10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5ldXJvcGF0aG9sPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+Nzc3LTg5PC9wYWdlcz48dm9sdW1lPjEyODwv

dm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQzMi0wNTMzIChF

bGVjdHJvbmljKSYjeEQ7MDAwMS02MzIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

NTE5NTA2MTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTE5NTA2MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA0MDEtMDE0LTEzNDAtOTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NoZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4xMzE8L1JlY051bT48RGlzcGxheVRleHQ+KEJvY2hlLCBldCBhbC4sIDIwMDgsU2FrYWks

IGV0IGFsLiwgMjAxNCxTcGVybGluZywgZXQgYWwuLCAyMDExKTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMzE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0i

MTM5MjM3MjcxNSI+MTMxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5C

b2NoZSxELjwvYXV0aG9yPjxhdXRob3I+Wm90b3ZhLEUuPC9hdXRob3I+PGF1dGhvcj5XZWxsZXIs

Ui5PLjwvYXV0aG9yPjxhdXRob3I+TG92ZSxTLjwvYXV0aG9yPjxhdXRob3I+TmVhbCxKLlcuPC9h

dXRob3I+PGF1dGhvcj5QaWNrZXJpbmcsUi5NLjwvYXV0aG9yPjxhdXRob3I+V2lsa2luc29uLEQu

PC9hdXRob3I+PGF1dGhvcj5Ib2xtZXMsQy48L2F1dGhvcj48YXV0aG9yPk5pY29sbCxKLkEuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2Yg

Q2xpbmljYWwgTmV1cm9zY2llbmNlcywgVW5pdmVyc2l0eSBvZiBTb3V0aGFtcHRvbiwgU291dGhh

bXB0b24gR2VuZXJhbCBIb3NwaXRhbCwgU291dGhhbXB0b24sIFVLLiBELkJvY2hlQHNvdG9uLmFj

LnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q29uc2VxdWVuY2Ugb2YgQWJldGEgaW1t

dW5pemF0aW9uIG9uIHRoZSB2YXNjdWxhdHVyZSBvZiBodW1hbiBBbHpoZWltZXImYXBvcztzIGRp

c2Vhc2UgYnJhaW48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRsZT48L3Bl

cmlvZGljYWw+PHBhZ2VzPjMyOTktMzMxMDwvcGFnZXM+PHZvbHVtZT4xMzE8L3ZvbHVtZT48bnVt

YmVyPlB0IDEyPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1l

ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsODAg

YW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtl

eXdvcmQ+QWx6aGVpbWVyIFZhY2NpbmVzPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdv

cmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJv

ZGllczwva2V5d29yZD48a2V5d29yZD5ibG9vZDwva2V5d29yZD48a2V5d29yZD5ibG9vZCBzdXBw

bHk8L2tleXdvcmQ+PGtleXdvcmQ+Qmxvb2QgVmVzc2Vsczwva2V5d29yZD48a2V5d29yZD5CcmFp

bjwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHk8L2tleXdvcmQ+

PGtleXdvcmQ+Q2VyZWJyYWwgQ29ydGV4PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEhlbW9y

cmhhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl

PC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu

b3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vdGhlcmFweSxBY3RpdmU8L2tleXdvcmQ+

PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW5pbmdlczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+

TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlBlcHRpZGUgRnJhZ21lbnRzPC9rZXl3b3JkPjxrZXl3b3JkPlNvbHViaWxpdHk8L2tleXdvcmQ+

PGtleXdvcmQ+dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdv

cmQ+PGtleXdvcmQ+VmFjY2luZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAw

ODwveWVhcj48cHViLWRhdGVzPjxkYXRlPjEyLzIwMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48bGFiZWw+MTY2PC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5u

Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xODk1MzA1NjwvdXJsPjx1cmw+aHR0cDovL2JyYWluLm94

Zm9yZGpvdXJuYWxzLm9yZy9jb250ZW50LzEzMS8xMi8zMjk5LmZ1bGwucGRmPC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNwZXJsaW5nPC9B

dXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVtPjE4NDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1u

dW1iZXI+MTg0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0i

MnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3

MTUiPjE4NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3Blcmxpbmcs

Ui5BLjwvYXV0aG9yPjxhdXRob3I+SmFjayxDLlIuLEpyLjwvYXV0aG9yPjxhdXRob3I+QmxhY2ss

Uy5FLjwvYXV0aG9yPjxhdXRob3I+RnJvc2NoLE0uUC48L2F1dGhvcj48YXV0aG9yPkdyZWVuYmVy

ZyxTLk0uPC9hdXRob3I+PGF1dGhvcj5IeW1hbixCLlQuPC9hdXRob3I+PGF1dGhvcj5TY2hlbHRl

bnMsUC48L2F1dGhvcj48YXV0aG9yPkNhcnJpbGxvLE0uQy48L2F1dGhvcj48YXV0aG9yPlRoaWVz

LFcuPC9hdXRob3I+PGF1dGhvcj5CZWRuYXIsTS5NLjwvYXV0aG9yPjxhdXRob3I+QmxhY2ssUi5T

LjwvYXV0aG9yPjxhdXRob3I+QnJhc2hlYXIsSC5SLjwvYXV0aG9yPjxhdXRob3I+R3J1bmRtYW4s

TS48L2F1dGhvcj48YXV0aG9yPlNpZW1lcnMsRS5SLjwvYXV0aG9yPjxhdXRob3I+RmVsZG1hbixI

LkguPC9hdXRob3I+PGF1dGhvcj5TY2hpbmRsZXIsUi5KLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgQWx6aGVpbWVyIFJlc2VhcmNoIGFu

ZCBUcmVhdG1lbnQsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBCcmlnaGFtIGFuZCBXb21lbiZh

cG9zO3MgSG9zcGl0YWwsIEJvc3RvbiwgTUEsIFVTQTsgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ks

IE1hc3NhY2h1c2V0dHMgR2VuZXJhbCBIb3NwaXRhbCwgSGFydmFyZCBNZWRpY2FsIFNjaG9vbCwg

Qm9zdG9uLCBNQSwgVVNBPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZC1yZWxh

dGVkIGltYWdpbmcgYWJub3JtYWxpdGllcyBpbiBhbXlsb2lkLW1vZGlmeWluZyB0aGVyYXBldXRp

YyB0cmlhbHM6IFJlY29tbWVuZGF0aW9ucyBmcm9tIHRoZSBBbHpoZWltZXImYXBvcztzIEFzc29j

aWF0aW9uIFJlc2VhcmNoIFJvdW5kdGFibGUgV29ya2dyb3VwPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPkFsemhlaW1lcnMuRGVtZW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QWx6aGVpbWVycy5EZW1lbnQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4zNjctMzg1PC9wYWdlcz48dm9sdW1lPjc8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJl

cj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRz

PjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+TmV1cm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Ny8yMDExPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjIxODwvbGFiZWw+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE3ODQzNDg8L3Vy

bD48dXJsPmh0dHA6Ly9hYy5lbHMtY2RuLmNvbS9TMTU1MjUyNjAxMTAyNTA2NC8xLXMyLjAtUzE1

NTI1MjYwMTEwMjUwNjQtbWFpbi5wZGY/X3RpZD0yZDM2ZGQzOC1hMDc5LTExZTMtOWVlNC0wMDAw

MGFhY2IzNjImYW1wO2FjZG5hdD0xMzkzNTkyOTg2X2Q1ZDA2Yzk0NzNjMDdlZTYzNGEzMzQ5ZjI2

YWY3OGY5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPlNha2FpPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjQ3NjwvUmVjTnVt

PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDc2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1l

c3RhbXA9IjE0MjY3NjI2NjUiPjQ3Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+U2FrYWksIEsuPC9hdXRob3I+PGF1dGhvcj5Cb2NoZSwgRC48L2F1dGhvcj48YXV0aG9y

PkNhcmFyZSwgUi48L2F1dGhvcj48YXV0aG9yPkpvaG5zdG9uLCBELjwvYXV0aG9yPjxhdXRob3I+

SG9sbWVzLCBDLjwvYXV0aG9yPjxhdXRob3I+TG92ZSwgUy48L2F1dGhvcj48YXV0aG9yPk5pY29s

bCwgSi4gQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5D

bGluaWNhbCBOZXVyb3NjaWVuY2VzLCBDbGluaWNhbCBhbmQgRXhwZXJpbWVudGFsIFNjaWVuY2Vz

LCBGYWN1bHR5IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIFNvdXRoYW1wdG9uLCBTb3V0aGFt

cHRvbiwgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QWJldGEgaW1tdW5vdGhlcmFw

eSBmb3IgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlOiBlZmZlY3RzIG9uIGFwb0UgYW5kIGNlcmVi

cmFsIHZhc2N1bG9wYXRoeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJvcGF0aG9s

PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5BY3RhIG5ldXJvcGF0aG9sb2dpY2E8L2FsdC10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5ldXJvcGF0aG9sPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+Nzc3LTg5PC9wYWdlcz48dm9sdW1lPjEyODwv

dm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQzMi0wNTMzIChF

bGVjdHJvbmljKSYjeEQ7MDAwMS02MzIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y

NTE5NTA2MTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTE5NTA2MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA0MDEtMDE0LTEzNDAtOTwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA (Boche, et al., 2008,Sakai, et al., 2014,Sperling, et al., 2011). Heterogeneity within FAD is apparent in the clinical phenotype and is also present at a molecular and histopathological level. Clinically, although most patients present with progressive amnesia, behavioural and language presentations can occur, and there may be additional neurological features such as seizures, myoclonus, spastic paraparesis, cerebellar and extrapyramidal syndromes ADDIN EN.CITE <EndNote><Cite><Author>Ryan</Author><Year>2010</Year><RecNum>146</RecNum><DisplayText>(Ryan and Rossor, 2010)</DisplayText><record><rec-number>146</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">146</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ryan,N.S.</author><author>Rossor,M.N.</author></authors></contributors><auth-address>Dementia Research Centre, Department of Neurodegenerative Diseases, University College London, Institute of Neurology, London, UK. ryan@drc.ion.ucl.ac.uk</auth-address><titles><title>Correlating familial Alzheimer&apos;s disease gene mutations with clinical phenotype</title><secondary-title>Biomark.Med</secondary-title></titles><periodical><full-title>Biomark.Med</full-title></periodical><pages>99-112</pages><volume>4</volume><number>1</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Alzheimer Disease</keyword><keyword>Amino Acid Sequence</keyword><keyword>Amyloid</keyword><keyword>Amyloid beta-Protein</keyword><keyword>Amyloid beta-Protein Precursor</keyword><keyword>chemistry</keyword><keyword>Dementia</keyword><keyword>Genetic Markers</keyword><keyword>genetics</keyword><keyword>Humans</keyword><keyword>Models,Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Mutation</keyword><keyword>Neurodegenerative Diseases</keyword><keyword>Neurology</keyword><keyword>Phenotype</keyword><keyword>physiopathology</keyword><keyword>Presenilin-1</keyword><keyword>Presenilin-2</keyword><keyword>Protein Structure,Tertiary</keyword><keyword>psychology</keyword></keywords><dates><year>2010</year><pub-dates><date>2/2010</date></pub-dates></dates><label>181</label><urls><related-urls><url>;(Ryan and Rossor, 2010). Furthermore, different mutations influence amyloid production and deposition in a variety of ways. Some increase Aβ42 concentrations, others increase the ratio of Aβ42/40 but some do neither, increasing instead the propensity to form protofibrils, which may accelerate Aβ deposition PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWxzYmVydGg8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFy

PjxSZWNOdW0+MTEyPC9SZWNOdW0+PERpc3BsYXlUZXh0PihOaWxzYmVydGgsIGV0IGFsLiwgMjAw

MSk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTEyPC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1

MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjExMjwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+Tmlsc2JlcnRoLEMuPC9hdXRob3I+PGF1dGhvcj5XZXN0bGlu

ZC1EYW5pZWxzc29uLEEuPC9hdXRob3I+PGF1dGhvcj5FY2ttYW4sQy5CLjwvYXV0aG9yPjxhdXRo

b3I+Q29uZHJvbixNLk0uPC9hdXRob3I+PGF1dGhvcj5BeGVsbWFuLEsuPC9hdXRob3I+PGF1dGhv

cj5Gb3JzZWxsLEMuPC9hdXRob3I+PGF1dGhvcj5TdGVuaCxDLjwvYXV0aG9yPjxhdXRob3I+THV0

aG1hbixKLjwvYXV0aG9yPjxhdXRob3I+VGVwbG93LEQuQi48L2F1dGhvcj48YXV0aG9yPllvdW5r

aW4sUy5HLjwvYXV0aG9yPjxhdXRob3I+TmFzbHVuZCxKLjwvYXV0aG9yPjxhdXRob3I+TGFubmZl

bHQsTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5LYXJv

bGluc2thIEluc3RpdHV0ZXQsIERlcGFydG1lbnQgb2YgTmV1cm90ZWMsIEdlcmlhdHJpYyBNZWRp

Y2luZSwgTm92dW0gS0ZDLCBTLTE0MSA4NiBIdWRkaW5nZSwgU3dlZGVuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+VGhlICZhcG9zO0FyY3RpYyZhcG9zOyBBUFAgbXV0YXRpb24gKEU2OTNH

KSBjYXVzZXMgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGJ5IGVuaGFuY2VkIEFiZXRhIHByb3Rv

ZmlicmlsIGZvcm1hdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQuTmV1cm9zY2k8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXQuTmV1cm9z

Y2k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz44ODctODkzPC9wYWdlcz48dm9sdW1l

PjQ8L3ZvbHVtZT48bnVtYmVyPjk8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBy

b3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yPC9r

ZXl3b3JkPjxrZXl3b3JkPmJsb29kPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgTGluZTwva2V5d29y

ZD48a2V5d29yZD5jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+Q29kb248L2tleXdvcmQ+PGtl

eXdvcmQ+Q3VsdHVyZSBNZWRpYTwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48

a2V5d29yZD5IZXRlcm96eWdvdGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr

ZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+TXV0YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+UGVkaWdyZWU8L2tleXdvcmQ+PGtl

eXdvcmQ+UGVwdGlkZSBGcmFnbWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvbG9neTwva2V5

d29yZD48a2V5d29yZD5Td2VkZW48L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAw

MTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjkvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

PjxsYWJlbD4xNDc8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzExNTI4NDE5PC91cmw+PHVybD5odHRwOi8vd3d3Lm5hdHVy

ZS5jb20vbmV1cm8vam91cm5hbC92NC9uOS9wZGYvbm4wOTAxLTg4Ny5wZGY8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWxzYmVydGg8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFy

PjxSZWNOdW0+MTEyPC9SZWNOdW0+PERpc3BsYXlUZXh0PihOaWxzYmVydGgsIGV0IGFsLiwgMjAw

MSk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTEyPC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1

MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjExMjwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+Tmlsc2JlcnRoLEMuPC9hdXRob3I+PGF1dGhvcj5XZXN0bGlu

ZC1EYW5pZWxzc29uLEEuPC9hdXRob3I+PGF1dGhvcj5FY2ttYW4sQy5CLjwvYXV0aG9yPjxhdXRo

b3I+Q29uZHJvbixNLk0uPC9hdXRob3I+PGF1dGhvcj5BeGVsbWFuLEsuPC9hdXRob3I+PGF1dGhv

cj5Gb3JzZWxsLEMuPC9hdXRob3I+PGF1dGhvcj5TdGVuaCxDLjwvYXV0aG9yPjxhdXRob3I+THV0

aG1hbixKLjwvYXV0aG9yPjxhdXRob3I+VGVwbG93LEQuQi48L2F1dGhvcj48YXV0aG9yPllvdW5r

aW4sUy5HLjwvYXV0aG9yPjxhdXRob3I+TmFzbHVuZCxKLjwvYXV0aG9yPjxhdXRob3I+TGFubmZl

bHQsTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5LYXJv

bGluc2thIEluc3RpdHV0ZXQsIERlcGFydG1lbnQgb2YgTmV1cm90ZWMsIEdlcmlhdHJpYyBNZWRp

Y2luZSwgTm92dW0gS0ZDLCBTLTE0MSA4NiBIdWRkaW5nZSwgU3dlZGVuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+VGhlICZhcG9zO0FyY3RpYyZhcG9zOyBBUFAgbXV0YXRpb24gKEU2OTNH

KSBjYXVzZXMgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGJ5IGVuaGFuY2VkIEFiZXRhIHByb3Rv

ZmlicmlsIGZvcm1hdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OYXQuTmV1cm9zY2k8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXQuTmV1cm9z

Y2k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz44ODctODkzPC9wYWdlcz48dm9sdW1l

PjQ8L3ZvbHVtZT48bnVtYmVyPjk8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBy

b3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJlY3Vyc29yPC9r

ZXl3b3JkPjxrZXl3b3JkPmJsb29kPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgTGluZTwva2V5d29y

ZD48a2V5d29yZD5jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+Q29kb248L2tleXdvcmQ+PGtl

eXdvcmQ+Q3VsdHVyZSBNZWRpYTwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48

a2V5d29yZD5IZXRlcm96eWdvdGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr

ZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+TXV0YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+UGVkaWdyZWU8L2tleXdvcmQ+PGtl

eXdvcmQ+UGVwdGlkZSBGcmFnbWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvbG9neTwva2V5

d29yZD48a2V5d29yZD5Td2VkZW48L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAw

MTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjkvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

PjxsYWJlbD4xNDc8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzExNTI4NDE5PC91cmw+PHVybD5odHRwOi8vd3d3Lm5hdHVy

ZS5jb20vbmV1cm8vam91cm5hbC92NC9uOS9wZGYvbm4wOTAxLTg4Ny5wZGY8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Nilsberth, et al., 2001). Increasingly, it appears to be the qualitative shifts in Aβ profile production caused by FAD mutations that underlies their pathogenicity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGF2ZXotR3V0aWVycmV6PC9BdXRob3I+PFllYXI+MjAx

MjwvWWVhcj48UmVjTnVtPjI3NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oQ2hhdmV6LUd1dGllcnJl

eiwgZXQgYWwuLCAyMDEyKTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNzc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBl

dWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTQxMTQ4MDg5MiI+Mjc3PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DaGF2ZXotR3V0aWVycmV6LCBMLjwv

YXV0aG9yPjxhdXRob3I+QmFtbWVucywgTC48L2F1dGhvcj48YXV0aG9yPkJlbmlsb3ZhLCBJLjwv

YXV0aG9yPjxhdXRob3I+VmFuZGVyc3RlZW4sIEEuPC9hdXRob3I+PGF1dGhvcj5CZW51cndhciwg

TS48L2F1dGhvcj48YXV0aG9yPkJvcmdlcnMsIE0uPC9hdXRob3I+PGF1dGhvcj5MaXNtb250LCBT

LjwvYXV0aG9yPjxhdXRob3I+WmhvdSwgTC48L2F1dGhvcj48YXV0aG9yPlZhbiBDbGV5bmVuYnJl

dWdlbCwgUy48L2F1dGhvcj48YXV0aG9yPkVzc2VsbWFubiwgSC48L2F1dGhvcj48YXV0aG9yPldp

bHRmYW5nLCBKLjwvYXV0aG9yPjxhdXRob3I+U2VybmVlbHMsIEwuPC9hdXRob3I+PGF1dGhvcj5L

YXJyYW4sIEUuPC9hdXRob3I+PGF1dGhvcj5HaWpzZW4sIEguPC9hdXRob3I+PGF1dGhvcj5TY2h5

bWtvd2l0eiwgSi48L2F1dGhvcj48YXV0aG9yPlJvdXNzZWF1LCBGLjwvYXV0aG9yPjxhdXRob3I+

QnJvZXJzZW4sIEsuPC9hdXRob3I+PGF1dGhvcj5EZSBTdHJvb3BlciwgQi48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5WSUIgQ2VudGVyIGZvciB0aGUgQmlv

bG9neSBvZiBEaXNlYXNlLCBMZXV2ZW4sIEJlbGdpdW0uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+VGhlIG1lY2hhbmlzbSBvZiBnYW1tYS1TZWNyZXRhc2UgZHlzZnVuY3Rpb24gaW4gZmFt

aWxpYWwgQWx6aGVpbWVyIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RU1CTyBKPC9z

ZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5UaGUgRU1CTyBqb3VybmFsPC9hbHQtdGl0bGU+PC90

aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+RU1CTyBKPC9mdWxsLXRpdGxlPjxhYmJyLTE+

VGhlIEVNQk8gam91cm5hbDwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+RU1CTyBKPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIEVNQk8gam91cm5hbDwvYWJi

ci0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjIyNjEtNzQ8L3BhZ2VzPjx2b2x1bWU+MzE8L3Zv

bHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlLyplbnp5bW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBQcmVjdXJzb3IgUHJvdGVpbiBTZWNyZXRhc2VzLyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlnZW5zLCBDRC9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkNhZGhlcmlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPktpbmV0aWNz

PC9rZXl3b3JkPjxrZXl3b3JkPlByZXNlbmlsaW4tMS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5SZWNlcHRvciwgRXBpZGVybWFsIEdyb3d0aCBGYWN0b3IvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5SZWNlcHRvciwgTm90Y2gxL21ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heSAxNjwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NjAtMjA3NSAoRWxlY3Ryb25pYykmI3hEOzAyNjEt

NDE4OSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjI1MDUwMjU8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjI1MDUwMjU8L3VybD48dXJsPmh0dHA6Ly9lbWJvai5lbWJvcHJlc3Mub3JnL2NvbnRl

bnQvZW1ib2pubC8zMS8xMC8yMjYxLmZ1bGwucGRmPC91cmw+PHVybD5odHRwOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzMzNjQ3NDcvcGRmL2VtYm9qMjAxMjc5YS5wZGY8

L3VybD48dXJsPmh0dHA6Ly9lbWJvai5lbWJvcHJlc3Mub3JnL2NvbnRlbnQvMzEvMTAvMjI2MS5s

b25nPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPjMzNjQ3NDc8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMzgvZW1ib2ouMjAxMi43OTwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGF2ZXotR3V0aWVycmV6PC9BdXRob3I+PFllYXI+MjAx

MjwvWWVhcj48UmVjTnVtPjI3NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oQ2hhdmV6LUd1dGllcnJl

eiwgZXQgYWwuLCAyMDEyKTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNzc8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBl

dWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTQxMTQ4MDg5MiI+Mjc3PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DaGF2ZXotR3V0aWVycmV6LCBMLjwv

YXV0aG9yPjxhdXRob3I+QmFtbWVucywgTC48L2F1dGhvcj48YXV0aG9yPkJlbmlsb3ZhLCBJLjwv

YXV0aG9yPjxhdXRob3I+VmFuZGVyc3RlZW4sIEEuPC9hdXRob3I+PGF1dGhvcj5CZW51cndhciwg

TS48L2F1dGhvcj48YXV0aG9yPkJvcmdlcnMsIE0uPC9hdXRob3I+PGF1dGhvcj5MaXNtb250LCBT

LjwvYXV0aG9yPjxhdXRob3I+WmhvdSwgTC48L2F1dGhvcj48YXV0aG9yPlZhbiBDbGV5bmVuYnJl

dWdlbCwgUy48L2F1dGhvcj48YXV0aG9yPkVzc2VsbWFubiwgSC48L2F1dGhvcj48YXV0aG9yPldp

bHRmYW5nLCBKLjwvYXV0aG9yPjxhdXRob3I+U2VybmVlbHMsIEwuPC9hdXRob3I+PGF1dGhvcj5L

YXJyYW4sIEUuPC9hdXRob3I+PGF1dGhvcj5HaWpzZW4sIEguPC9hdXRob3I+PGF1dGhvcj5TY2h5

bWtvd2l0eiwgSi48L2F1dGhvcj48YXV0aG9yPlJvdXNzZWF1LCBGLjwvYXV0aG9yPjxhdXRob3I+

QnJvZXJzZW4sIEsuPC9hdXRob3I+PGF1dGhvcj5EZSBTdHJvb3BlciwgQi48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5WSUIgQ2VudGVyIGZvciB0aGUgQmlv

bG9neSBvZiBEaXNlYXNlLCBMZXV2ZW4sIEJlbGdpdW0uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+VGhlIG1lY2hhbmlzbSBvZiBnYW1tYS1TZWNyZXRhc2UgZHlzZnVuY3Rpb24gaW4gZmFt

aWxpYWwgQWx6aGVpbWVyIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RU1CTyBKPC9z

ZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5UaGUgRU1CTyBqb3VybmFsPC9hbHQtdGl0bGU+PC90

aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+RU1CTyBKPC9mdWxsLXRpdGxlPjxhYmJyLTE+

VGhlIEVNQk8gam91cm5hbDwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1

bGwtdGl0bGU+RU1CTyBKPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIEVNQk8gam91cm5hbDwvYWJi

ci0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjIyNjEtNzQ8L3BhZ2VzPjx2b2x1bWU+MzE8L3Zv

bHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlLyplbnp5bW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBQcmVjdXJzb3IgUHJvdGVpbiBTZWNyZXRhc2VzLyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlnZW5zLCBDRC9tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPkNhZGhlcmlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPktpbmV0aWNz

PC9rZXl3b3JkPjxrZXl3b3JkPlByZXNlbmlsaW4tMS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5SZWNlcHRvciwgRXBpZGVybWFsIEdyb3d0aCBGYWN0b3IvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5SZWNlcHRvciwgTm90Y2gxL21ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heSAxNjwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NjAtMjA3NSAoRWxlY3Ryb25pYykmI3hEOzAyNjEt

NDE4OSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjI1MDUwMjU8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjI1MDUwMjU8L3VybD48dXJsPmh0dHA6Ly9lbWJvai5lbWJvcHJlc3Mub3JnL2NvbnRl

bnQvZW1ib2pubC8zMS8xMC8yMjYxLmZ1bGwucGRmPC91cmw+PHVybD5odHRwOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzMzNjQ3NDcvcGRmL2VtYm9qMjAxMjc5YS5wZGY8

L3VybD48dXJsPmh0dHA6Ly9lbWJvai5lbWJvcHJlc3Mub3JnL2NvbnRlbnQvMzEvMTAvMjI2MS5s

b25nPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPjMzNjQ3NDc8L2N1c3RvbTI+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMzgvZW1ib2ouMjAxMi43OTwvZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA (Chavez-Gutierrez, et al., 2012). Pathological findings in PSEN1 mutation carriers have revealed considerable heterogeneity in terms of neuronal loss; the type, number and distribution of amyloid plaques; and the amount and distribution of neurofibrillary tangles PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWFyb3VmPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

UmVjTnVtPjE0OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oR29tZXotSXNsYSwgZXQgYWwuLCAxOTk5

LE1hYXJvdWYsIGV0IGFsLiwgMjAwOCxTaGVwaGVyZCwgZXQgYWwuLCAyMDA5KTwvRGlzcGxheVRl

eHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRp

bWVzdGFtcD0iMTM5MjM3MjcxNSI+MTQ5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYWFyb3VmLEMuTC48L2F1dGhvcj48YXV0aG9yPkRhdWdzLEkuRC48L2F1dGhvcj48

YXV0aG9yPlNwaW5hLFMuPC9hdXRob3I+PGF1dGhvcj5WaWRhbCxSLjwvYXV0aG9yPjxhdXRob3I+

S29ram9obixULkEuPC9hdXRob3I+PGF1dGhvcj5QYXR0b24sUi5MLjwvYXV0aG9yPjxhdXRob3I+

S2FsYmFjayxXLk0uPC9hdXRob3I+PGF1dGhvcj5MdWVocnMsRC5DLjwvYXV0aG9yPjxhdXRob3I+

V2Fsa2VyLEQuRy48L2F1dGhvcj48YXV0aG9yPkNhc3Rhbm8sRS5NLjwvYXV0aG9yPjxhdXRob3I+

QmVhY2gsVC5HLjwvYXV0aG9yPjxhdXRob3I+R2hldHRpLEIuPC9hdXRob3I+PGF1dGhvcj5Sb2hl

cixBLkUuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+VGhl

IExvbmd0aW5lIENlbnRlciBmb3IgTW9sZWN1bGFyIEJpb2xvZ3kgYW5kIEdlbmV0aWNzLCBTdW4g

SGVhbHRoIFJlc2VhcmNoIEluc3RpdHV0ZSwgU3VuIENpdHksIEFaIDg1MzUxLCBVU0EuIGFsZXgu

cm9oZXJAYmFubmVyaGVhbHRoLmNvbTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkhpc3Rv

cGF0aG9sb2dpY2FsIGFuZCBtb2xlY3VsYXIgaGV0ZXJvZ2VuZWl0eSBhbW9uZyBpbmRpdmlkdWFs

cyB3aXRoIGRlbWVudGlhIGFzc29jaWF0ZWQgd2l0aCBQcmVzZW5pbGluIG11dGF0aW9uczwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5Nb2wuTmV1cm9kZWdlbmVyLjwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk1vbC5OZXVyb2RlZ2VuZXIuPC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjA8L3BhZ2VzPjx2b2x1bWU+Mzwvdm9sdW1lPjxyZXBy

aW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5EZW1lbnRpYTwva2V5d29yZD48a2V5d29yZD5H

ZW5lczwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5Nb2xlY3Vs

YXIgQmlvbG9neTwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5O

ZXVyb2ZpYnJpbGxhcnkgVGFuZ2xlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAwODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

PjxsYWJlbD4xODQ8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzE5MDIxOTA1PC91cmw+PHVybD5odHRwOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzI2MDA3ODQvcGRmLzE3NTAtMTMyNi0zLTIwLnBk

ZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv

cj5Hb21lei1Jc2xhPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVjTnVtPjkzPC9SZWNOdW0+

PHJlY29yZD48cmVjLW51bWJlcj45MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0

YW1wPSIxMzkyMzcyNzE1Ij45Mzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+R29tZXotSXNsYSxULjwvYXV0aG9yPjxhdXRob3I+R3Jvd2RvbixXLkIuPC9hdXRob3I+PGF1

dGhvcj5NY05hbWFyYSxNLkouPC9hdXRob3I+PGF1dGhvcj5Ob2NobGluLEQuPC9hdXRob3I+PGF1

dGhvcj5CaXJkLFQuRC48L2F1dGhvcj48YXV0aG9yPkFyYW5nbyxKLkMuPC9hdXRob3I+PGF1dGhv

cj5Mb3BlcmEsRi48L2F1dGhvcj48YXV0aG9yPktvc2lrLEsuUy48L2F1dGhvcj48YXV0aG9yPkxh

bnRvcyxQLkwuPC9hdXRob3I+PGF1dGhvcj5DYWlybnMsTi5KLjwvYXV0aG9yPjxhdXRob3I+SHlt

YW4sQi5ULjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk5l

dXJvbG9neSBTZXJ2aWNlLCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIE5ldXJvbG9n

eSBTZXJ2aWNlLCBCcmlnaGFtIGFuZCBXb21lbiZhcG9zO3MgSG9zcGl0YWwsIEJvc3RvbiwgVVNB

LiBnb21lejAxMEB0Yy51bW4uZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGlt

cGFjdCBvZiBkaWZmZXJlbnQgcHJlc2VuaWxpbiAxIGFuZHByZXNlbmlsaW4gMiBtdXRhdGlvbnMg

b24gYW15bG9pZCBkZXBvc2l0aW9uLCBuZXVyb2ZpYnJpbGxhcnkgY2hhbmdlcyBhbmQgbmV1cm9u

YWwgbG9zcyBpbiB0aGUgZmFtaWxpYWwgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGJyYWluOiBl

dmlkZW5jZSBmb3Igb3RoZXIgcGhlbm90eXBlLW1vZGlmeWluZyBmYWN0b3JzPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkJyYWluPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+QnJhaW48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xNzA5LTE3

MTk8L3BhZ2VzPjx2b2x1bWU+MTIyICggUHQgOSk8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5v

dCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZSBvZiBPbnNl

dDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFtaW5vIEFjaWQgU3Vic3RpdHV0aW9uPC9rZXl3b3JkPjxr

ZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tl

eXdvcmQ+PGtleXdvcmQ+YW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW48L2tleXdvcmQ+

PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPk1lbWJyYW5lIFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248L2tleXdv

cmQ+PGtleXdvcmQ+TmV1cm9maWJyaWxsYXJ5IFRhbmdsZXM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBlZGlncmVlPC9rZXl3b3JkPjxrZXl3b3JkPlBoZW5vdHlw

ZTwva2V5d29yZD48a2V5d29yZD5Qb2ludCBNdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5QcmVz

ZW5pbGluLTE8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0yPC9rZXl3b3JkPjxrZXl3b3Jk

PlJlZ3Jlc3Npb24gQW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+U2VuaWxlIFBsYXF1ZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+VGVtcG9yYWwgTG9iZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4xOTk5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OS8xOTk5PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGxhYmVsPjEyODwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTA0Njg1MTA8L3VybD48L3JlbGF0ZWQtdXJs

cz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2hlcGhlcmQ8L0F1dGhvcj48

WWVhcj4yMDA5PC9ZZWFyPjxSZWNOdW0+MTQzPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4x

NDM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVy

ZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTQz

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TaGVwaGVyZCxDLjwvYXV0

aG9yPjxhdXRob3I+TWNDYW5uLEguPC9hdXRob3I+PGF1dGhvcj5IYWxsaWRheSxHLk0uPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+UHJpbmNlIG9mIFdhbGVz

IE1lZGljYWwgUmVzZWFyY2ggSW5zdGl0dXRlLCBCYXJrZXIgU3RyZWV0LCBSYW5kd2ljaywgTlNX

LCAyMDMxLCBBdXN0cmFsaWE8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5WYXJpYXRpb25z

IGluIHRoZSBuZXVyb3BhdGhvbG9neSBvZiBmYW1pbGlhbCBBbHpoZWltZXImYXBvcztzIGRpc2Vh

c2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWN0YSBOZXVyb3BhdGhvbDwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4zNy01MjwvcGFnZXM+PHZvbHVtZT4xMTg8L3Zv

bHVtZT48bnVtYmVyPjE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXBy

aW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48

L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BdHJvcGh5PC9rZXl3

b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgRGVhdGg8L2tleXdvcmQ+

PGtleXdvcmQ+ZGlhZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkV4b25zPC9rZXl3b3JkPjxrZXl3

b3JkPkdlbmVzPC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvZmlicmlsbGFyeSBUYW5nbGVzPC9rZXl3b3JkPjxr

ZXl3b3JkPk5ldXJvaW1tdW5vbW9kdWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXVyb25zPC9r

ZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QaG9zcGhvcnlsYXRp

b248L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5QcmVzZW5p

bGluLTE8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0yPC9rZXl3b3JkPjxrZXl3b3JkPlBy

ZXNlbmlsaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlNlbmlsZSBQbGFxdWVzPC9rZXl3b3JkPjxrZXl3

b3JkPnRhdSBQcm90ZWluczwva2V5d29yZD48a2V5d29yZD5UYXVvcGF0aGllczwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Ny8yMDA5

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjE3ODwvbGFiZWw+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTkzMDYwOTg8

L3VybD48dXJsPmh0dHA6Ly9kb3dubG9hZC5zcHJpbmdlci5jb20vc3RhdGljL3BkZi8zMTgvYXJ0

JTI1M0ExMC4xMDA3JTI1MkZzMDA0MDEtMDA5LTA1MjEtNC5wZGY/YXV0aDY2PTEzOTM3NjU1NTVf

M2E5Mzg5NGNhOThmNzg3NzU3YTU2OGM5YWE4MDFlYTUmYW1wO2V4dD0ucGRmPC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWFyb3VmPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

UmVjTnVtPjE0OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oR29tZXotSXNsYSwgZXQgYWwuLCAxOTk5

LE1hYXJvdWYsIGV0IGFsLiwgMjAwOCxTaGVwaGVyZCwgZXQgYWwuLCAyMDA5KTwvRGlzcGxheVRl

eHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRp

bWVzdGFtcD0iMTM5MjM3MjcxNSI+MTQ5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYWFyb3VmLEMuTC48L2F1dGhvcj48YXV0aG9yPkRhdWdzLEkuRC48L2F1dGhvcj48

YXV0aG9yPlNwaW5hLFMuPC9hdXRob3I+PGF1dGhvcj5WaWRhbCxSLjwvYXV0aG9yPjxhdXRob3I+

S29ram9obixULkEuPC9hdXRob3I+PGF1dGhvcj5QYXR0b24sUi5MLjwvYXV0aG9yPjxhdXRob3I+

S2FsYmFjayxXLk0uPC9hdXRob3I+PGF1dGhvcj5MdWVocnMsRC5DLjwvYXV0aG9yPjxhdXRob3I+

V2Fsa2VyLEQuRy48L2F1dGhvcj48YXV0aG9yPkNhc3Rhbm8sRS5NLjwvYXV0aG9yPjxhdXRob3I+

QmVhY2gsVC5HLjwvYXV0aG9yPjxhdXRob3I+R2hldHRpLEIuPC9hdXRob3I+PGF1dGhvcj5Sb2hl

cixBLkUuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+VGhl

IExvbmd0aW5lIENlbnRlciBmb3IgTW9sZWN1bGFyIEJpb2xvZ3kgYW5kIEdlbmV0aWNzLCBTdW4g

SGVhbHRoIFJlc2VhcmNoIEluc3RpdHV0ZSwgU3VuIENpdHksIEFaIDg1MzUxLCBVU0EuIGFsZXgu

cm9oZXJAYmFubmVyaGVhbHRoLmNvbTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkhpc3Rv

cGF0aG9sb2dpY2FsIGFuZCBtb2xlY3VsYXIgaGV0ZXJvZ2VuZWl0eSBhbW9uZyBpbmRpdmlkdWFs

cyB3aXRoIGRlbWVudGlhIGFzc29jaWF0ZWQgd2l0aCBQcmVzZW5pbGluIG11dGF0aW9uczwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5Nb2wuTmV1cm9kZWdlbmVyLjwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk1vbC5OZXVyb2RlZ2VuZXIuPC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjA8L3BhZ2VzPjx2b2x1bWU+Mzwvdm9sdW1lPjxyZXBy

aW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5EZW1lbnRpYTwva2V5d29yZD48a2V5d29yZD5H

ZW5lczwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5Nb2xlY3Vs

YXIgQmlvbG9neTwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5O

ZXVyb2ZpYnJpbGxhcnkgVGFuZ2xlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAwODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

PjxsYWJlbD4xODQ8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5j

YmkubmxtLm5paC5nb3YvcHVibWVkLzE5MDIxOTA1PC91cmw+PHVybD5odHRwOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzI2MDA3ODQvcGRmLzE3NTAtMTMyNi0zLTIwLnBk

ZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv

cj5Hb21lei1Jc2xhPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVjTnVtPjkzPC9SZWNOdW0+

PHJlY29yZD48cmVjLW51bWJlcj45MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0

YW1wPSIxMzkyMzcyNzE1Ij45Mzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+R29tZXotSXNsYSxULjwvYXV0aG9yPjxhdXRob3I+R3Jvd2RvbixXLkIuPC9hdXRob3I+PGF1

dGhvcj5NY05hbWFyYSxNLkouPC9hdXRob3I+PGF1dGhvcj5Ob2NobGluLEQuPC9hdXRob3I+PGF1

dGhvcj5CaXJkLFQuRC48L2F1dGhvcj48YXV0aG9yPkFyYW5nbyxKLkMuPC9hdXRob3I+PGF1dGhv

cj5Mb3BlcmEsRi48L2F1dGhvcj48YXV0aG9yPktvc2lrLEsuUy48L2F1dGhvcj48YXV0aG9yPkxh

bnRvcyxQLkwuPC9hdXRob3I+PGF1dGhvcj5DYWlybnMsTi5KLjwvYXV0aG9yPjxhdXRob3I+SHlt

YW4sQi5ULjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk5l

dXJvbG9neSBTZXJ2aWNlLCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIE5ldXJvbG9n

eSBTZXJ2aWNlLCBCcmlnaGFtIGFuZCBXb21lbiZhcG9zO3MgSG9zcGl0YWwsIEJvc3RvbiwgVVNB

LiBnb21lejAxMEB0Yy51bW4uZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGlt

cGFjdCBvZiBkaWZmZXJlbnQgcHJlc2VuaWxpbiAxIGFuZHByZXNlbmlsaW4gMiBtdXRhdGlvbnMg

b24gYW15bG9pZCBkZXBvc2l0aW9uLCBuZXVyb2ZpYnJpbGxhcnkgY2hhbmdlcyBhbmQgbmV1cm9u

YWwgbG9zcyBpbiB0aGUgZmFtaWxpYWwgQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGJyYWluOiBl

dmlkZW5jZSBmb3Igb3RoZXIgcGhlbm90eXBlLW1vZGlmeWluZyBmYWN0b3JzPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkJyYWluPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+QnJhaW48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xNzA5LTE3

MTk8L3BhZ2VzPjx2b2x1bWU+MTIyICggUHQgOSk8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5v

dCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZSBvZiBPbnNl

dDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFtaW5vIEFjaWQgU3Vic3RpdHV0aW9uPC9rZXl3b3JkPjxr

ZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tl

eXdvcmQ+PGtleXdvcmQ+YW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW48L2tleXdvcmQ+

PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPk1lbWJyYW5lIFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248L2tleXdv

cmQ+PGtleXdvcmQ+TmV1cm9maWJyaWxsYXJ5IFRhbmdsZXM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1

cm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBlZGlncmVlPC9rZXl3b3JkPjxrZXl3b3JkPlBoZW5vdHlw

ZTwva2V5d29yZD48a2V5d29yZD5Qb2ludCBNdXRhdGlvbjwva2V5d29yZD48a2V5d29yZD5QcmVz

ZW5pbGluLTE8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0yPC9rZXl3b3JkPjxrZXl3b3Jk

PlJlZ3Jlc3Npb24gQW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+U2VuaWxlIFBsYXF1ZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+VGVtcG9yYWwgTG9iZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4xOTk5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OS8xOTk5PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGxhYmVsPjEyODwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6

Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTA0Njg1MTA8L3VybD48L3JlbGF0ZWQtdXJs

cz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+U2hlcGhlcmQ8L0F1dGhvcj48

WWVhcj4yMDA5PC9ZZWFyPjxSZWNOdW0+MTQzPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4x

NDM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVy

ZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTQz

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TaGVwaGVyZCxDLjwvYXV0

aG9yPjxhdXRob3I+TWNDYW5uLEguPC9hdXRob3I+PGF1dGhvcj5IYWxsaWRheSxHLk0uPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+UHJpbmNlIG9mIFdhbGVz

IE1lZGljYWwgUmVzZWFyY2ggSW5zdGl0dXRlLCBCYXJrZXIgU3RyZWV0LCBSYW5kd2ljaywgTlNX

LCAyMDMxLCBBdXN0cmFsaWE8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5WYXJpYXRpb25z

IGluIHRoZSBuZXVyb3BhdGhvbG9neSBvZiBmYW1pbGlhbCBBbHpoZWltZXImYXBvcztzIGRpc2Vh

c2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWN0YSBOZXVyb3BhdGhvbDwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4zNy01MjwvcGFnZXM+PHZvbHVtZT4xMTg8L3Zv

bHVtZT48bnVtYmVyPjE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXBy

aW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48

L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BdHJvcGh5PC9rZXl3

b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgRGVhdGg8L2tleXdvcmQ+

PGtleXdvcmQ+ZGlhZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkV4b25zPC9rZXl3b3JkPjxrZXl3

b3JkPkdlbmVzPC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvZmlicmlsbGFyeSBUYW5nbGVzPC9rZXl3b3JkPjxr

ZXl3b3JkPk5ldXJvaW1tdW5vbW9kdWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXVyb25zPC9r

ZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QaG9zcGhvcnlsYXRp

b248L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5QcmVzZW5p

bGluLTE8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0yPC9rZXl3b3JkPjxrZXl3b3JkPlBy

ZXNlbmlsaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlNlbmlsZSBQbGFxdWVzPC9rZXl3b3JkPjxrZXl3

b3JkPnRhdSBQcm90ZWluczwva2V5d29yZD48a2V5d29yZD5UYXVvcGF0aGllczwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Ny8yMDA5

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjE3ODwvbGFiZWw+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTkzMDYwOTg8

L3VybD48dXJsPmh0dHA6Ly9kb3dubG9hZC5zcHJpbmdlci5jb20vc3RhdGljL3BkZi8zMTgvYXJ0

JTI1M0ExMC4xMDA3JTI1MkZzMDA0MDEtMDA5LTA1MjEtNC5wZGY/YXV0aDY2PTEzOTM3NjU1NTVf

M2E5Mzg5NGNhOThmNzg3NzU3YTU2OGM5YWE4MDFlYTUmYW1wO2V4dD0ucGRmPC91cmw+PC9yZWxh

dGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA (Gomez-Isla, et al., 1999,Maarouf, et al., 2008,Shepherd, et al., 2009). Of particular importance, marked variability in the amount of CAA has been observed that may be driven by the location of the mutation within PSEN1. Mutations before codon 200 have been reported to be associated with many diffuse and cored plaques, few white matter plaques and only mild to moderate CAA, mainly confined to leptomeningeal blood vessels. By contrast, mutations beyond codon 200 have been described as demonstrating larger diffuse and cored plaques surrounding amyloid-laden arteries, with severe CAA that involves both leptomeningeal and intraparenchymal arteries PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PihNYW5uLCBldCBhbC4sIDIwMDEpPC9EaXNwbGF5

VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjU5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYW5uLEQuTS48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZy1Ccm93bixTLk0uPC9h

dXRob3I+PGF1dGhvcj5UYWtldWNoaSxBLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sVC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBOZXVy

b3NjaWVuY2UgUmVzZWFyY2ggR3JvdXAsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgTWFuY2hlc3RlciwgTWFuY2hlc3RlciwgVW5pdGVkIEtpbmdkb20uIGRhdmlkLm1hbm5A

bWFuLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBhbmdpb3BhdGh5

IGFuZCB2YXJpYWJpbGl0eSBpbiBhbXlsb2lkIGJldGEgZGVwb3NpdGlvbiBpcyBkZXRlcm1pbmVk

IGJ5IG11dGF0aW9uIHBvc2l0aW9uIGluIHByZXNlbmlsaW4tMS1saW5rZWQgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGF0aG9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjUtMjE3NTwvcGFnZXM+PHZvbHVtZT4x

NTg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29yZD48a2V5d29yZD5ibG9v

ZDwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYmVsbHVtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5Db2Rvbjwva2V5d29yZD48a2V5d29yZD5Db3MgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250YWwgTG9iZTwva2V5d29yZD48a2V5d29yZD5H

ZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQcm90ZWluczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5QZXB0aWRlIEZyYWdtZW50czwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdv

cmQ+PGtleXdvcmQ+dWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD45NjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTEzOTUzOTQ8L3VybD48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTg5MTk5My9wZGYvMjY4NS5wZGY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PihNYW5uLCBldCBhbC4sIDIwMDEpPC9EaXNwbGF5

VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjU5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYW5uLEQuTS48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZy1Ccm93bixTLk0uPC9h

dXRob3I+PGF1dGhvcj5UYWtldWNoaSxBLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sVC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBOZXVy

b3NjaWVuY2UgUmVzZWFyY2ggR3JvdXAsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgTWFuY2hlc3RlciwgTWFuY2hlc3RlciwgVW5pdGVkIEtpbmdkb20uIGRhdmlkLm1hbm5A

bWFuLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBhbmdpb3BhdGh5

IGFuZCB2YXJpYWJpbGl0eSBpbiBhbXlsb2lkIGJldGEgZGVwb3NpdGlvbiBpcyBkZXRlcm1pbmVk

IGJ5IG11dGF0aW9uIHBvc2l0aW9uIGluIHByZXNlbmlsaW4tMS1saW5rZWQgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGF0aG9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjUtMjE3NTwvcGFnZXM+PHZvbHVtZT4x

NTg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29yZD48a2V5d29yZD5ibG9v

ZDwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYmVsbHVtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5Db2Rvbjwva2V5d29yZD48a2V5d29yZD5Db3MgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250YWwgTG9iZTwva2V5d29yZD48a2V5d29yZD5H

ZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQcm90ZWluczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5QZXB0aWRlIEZyYWdtZW50czwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdv

cmQ+PGtleXdvcmQ+dWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD45NjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTEzOTUzOTQ8L3VybD48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTg5MTk5My9wZGYvMjY4NS5wZGY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Mann, et al., 2001). Certain APP mutations are also associated with very severe CAA, particularly those that lie within the Aβ coding sequence PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGVwaGVyZDwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4xNDM8L1JlY051bT48RGlzcGxheVRleHQ+KFJldmVzeiwgZXQgYWwuLCAyMDAzLFJl

dmVzeiwgZXQgYWwuLCAyMDA5LFNoZXBoZXJkLCBldCBhbC4sIDIwMDkpPC9EaXNwbGF5VGV4dD48

cmVjb3JkPjxyZWMtbnVtYmVyPjE0MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0

YW1wPSIxMzkyMzcyNzE1Ij4xNDM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlNoZXBoZXJkLEMuPC9hdXRob3I+PGF1dGhvcj5NY0Nhbm4sSC48L2F1dGhvcj48YXV0aG9y

PkhhbGxpZGF5LEcuTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5QcmluY2Ugb2YgV2FsZXMgTWVkaWNhbCBSZXNlYXJjaCBJbnN0aXR1dGUsIEJhcmtlciBT

dHJlZXQsIFJhbmR3aWNrLCBOU1csIDIwMzEsIEF1c3RyYWxpYTwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPlZhcmlhdGlvbnMgaW4gdGhlIG5ldXJvcGF0aG9sb2d5IG9mIGZhbWlsaWFsIEFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJv

cGF0aG9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

QWN0YSBOZXVyb3BhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM3LTUyPC9w

YWdlcz48dm9sdW1lPjExODwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXByaW50LWVkaXRp

b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVp

bWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5B

bXlsb2lkIGJldGEtUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPkF0cm9waHk8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW48L2tleXdvcmQ+PGtleXdvcmQ+

Q2VsbCBEZWF0aDwva2V5d29yZD48a2V5d29yZD5kaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+

RXhvbnM8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXM8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9maWJyaWxsYXJ5

IFRhbmdsZXM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9pbW11bm9tb2R1bGF0aW9uPC9rZXl3b3Jk

PjxrZXl3b3JkPk5ldXJvbnM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPlBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5waHlzaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPlByZXNlbmlsaW4tMTwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTI8

L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbnM8L2tleXdvcmQ+PGtleXdvcmQ+U2VuaWxlIFBs

YXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlRh

dW9wYXRoaWVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT43LzIwMDk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MTc4

PC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8xOTMwNjA5ODwvdXJsPjx1cmw+aHR0cDovL2Rvd25sb2FkLnNwcmluZ2VyLmNv

bS9zdGF0aWMvcGRmLzMxOC9hcnQlMjUzQTEwLjEwMDclMjUyRnMwMDQwMS0wMDktMDUyMS00LnBk

Zj9hdXRoNjY9MTM5Mzc2NTU1NV8zYTkzODk0Y2E5OGY3ODc3NTdhNTY4YzlhYTgwMWVhNSZhbXA7

ZXh0PS5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl

PjxBdXRob3I+UmV2ZXN6PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVjTnVtPjE4MTwvUmVj

TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTgxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjE4MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+UmV2ZXN6LFQuPC9hdXRob3I+PGF1dGhvcj5HaGlzbyxKLjwvYXV0aG9yPjxhdXRo

b3I+TGFzaGxleSxULjwvYXV0aG9yPjxhdXRob3I+UGxhbnQsRy48L2F1dGhvcj48YXV0aG9yPlJv

c3RhZ25vLEEuPC9hdXRob3I+PGF1dGhvcj5GcmFuZ2lvbmUsQi48L2F1dGhvcj48YXV0aG9yPkhv

bHRvbixKLkwuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

UXVlZW4gU3F1YXJlIEJyYWluIEJhbmssIERlcGFydG1lbnQgb2YgTW9sZWN1bGFyIE5ldXJvc2Np

ZW5jZSBhbmQgRGl2aXNpb24gb2YgTmV1cm9wYXRob2xvZ3ksIEluc3RpdHV0ZSBvZiBOZXVyb2xv

Z3ksIFVuaXZlcnNpdHkgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgVW5pdGVkIEtpbmdkb20uIHQu

cmV2ZXN6QGlvbi51Y2wuYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DZXJlYnJh

bCBhbXlsb2lkIGFuZ2lvcGF0aGllczogYSBwYXRob2xvZ2ljLCBiaW9jaGVtaWNhbCwgYW5kIGdl

bmV0aWMgdmlldzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvcGF0aG9sIEV4cC5OZXVy

b2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIE5l

dXJvcGF0aG9sIEV4cC5OZXVyb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz44ODUt

ODk4PC9wYWdlcz48dm9sdW1lPjYyPC92b2x1bWU+PG51bWJlcj45PC9udW1iZXI+PHJlcHJpbnQt

ZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5B

bHpoZWltZXIgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbWlubyBBY2lkIFNlcXVlbmNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZG9zaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48

a2V5d29yZD5DYXBpbGxhcmllczwva2V5d29yZD48a2V5d29yZD5DZW50cmFsIE5lcnZvdXMgU3lz

dGVtPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29y

ZD48a2V5d29yZD5DZXJlYnJhbCBIZW1vcnJoYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlh

PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmVzPC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPk1vbGVjdWxhciBTZXF1ZW5jZSBEYXRhPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0xPC9rZXl3b3JkPjxrZXl3b3JkPlByb3Rl

aW5zPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT45LzIwMDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MjE1PC9sYWJl

bD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8xNDUzMzc3ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+

PENpdGU+PEF1dGhvcj5SZXZlc3o8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxSZWNOdW0+MzE0

PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2

MDIiIHRpbWVzdGFtcD0iMTQxNzQzMzg4OCI+MzE0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10

eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1

dGhvcnM+PGF1dGhvcj5SZXZlc3osIFQuPC9hdXRob3I+PGF1dGhvcj5Ib2x0b24sIEouIEwuPC9h

dXRob3I+PGF1dGhvcj5MYXNobGV5LCBULjwvYXV0aG9yPjxhdXRob3I+UGxhbnQsIEcuPC9hdXRo

b3I+PGF1dGhvcj5GcmFuZ2lvbmUsIEIuPC9hdXRob3I+PGF1dGhvcj5Sb3N0YWdubywgQS48L2F1

dGhvcj48YXV0aG9yPkdoaXNvLCBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

YXV0aC1hZGRyZXNzPlF1ZWVuIFNxdWFyZSBCcmFpbiBCYW5rIGZvciBOZXVyb2xvZ2ljYWwgRGlz

b3JkZXJzLCBEZXBhcnRtZW50IG9mIE1vbGVjdWxhciBOZXVyb3NjaWVuY2UsIFVDTCBJbnN0aXR1

dGUgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IENvbGxlZ2UgTG9uZG9uLCBRdWVlbiBTcXVhcmUs

IExvbmRvbiBXQzFOM0JHLCBVSy4gdC5yZXZlc3pAaW9uLnVjbC5hYy51azwvYXV0aC1hZGRyZXNz

Pjx0aXRsZXM+PHRpdGxlPkdlbmV0aWNzIGFuZCBtb2xlY3VsYXIgcGF0aG9nZW5lc2lzIG9mIHNw

b3JhZGljIGFuZCBoZXJlZGl0YXJ5IGNlcmVicmFsIGFteWxvaWQgYW5naW9wYXRoaWVzPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPkFjdGEgbmV1cm9wYXRob2xvZ2ljYTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4xMTUtMzA8L3BhZ2VzPjx2b2x1bWU+MTE4PC92b2x1bWU+PG51bWJlcj4xPC9udW1i

ZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2NvbXBsaWNhdGlvbnMvdGhl

cmFweTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5BbXlsb2lkb3Npcy9jb21wbGljYXRpb25zL2dlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKmJsb29kIHN1cHBs

eS9tZXRhYm9saXNtL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5LypnZW5ldGljcy8qcGF0aG9sb2d5L3BoeXNpb3Bh

dGhvbG9neS90aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEhlbW9ycmhhZ2UvY29t

cGxpY2F0aW9ucy9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5DeXN0YXRpbiBDL2dlbmV0aWNz

PC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlhL2NvbXBsaWNhdGlvbnMvZ2VuZXRpY3M8L2tleXdv

cmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5HZW5l

dGljIFByZWRpc3Bvc2l0aW9uIHRvIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPkltbXVub3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248

L2tleXdvcmQ+PGtleXdvcmQ+UHJlYWxidW1pbi9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PlByaW9uIERpc2Vhc2VzL2NvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE0MzItMDUzMyAoRWxlY3Ryb25pYykmI3hEOzAwMDEtNjMyMiAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTkyMjU3ODk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTkyMjU3

ODk8L3VybD48dXJsPmh0dHA6Ly9kb3dubG9hZC5zcHJpbmdlci5jb20vc3RhdGljL3BkZi83NDAv

YXJ0JTI1M0ExMC4xMDA3JTI1MkZzMDA0MDEtMDA5LTA1MDEtOC5wZGY/YXV0aDY2PTE0MTc0MzM5

NzNfNDE4MzhhZDkxY2JjZjYzODk3YWE1YTdlZjJhODJmYjEmYW1wO2V4dD0ucGRmPC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPjI4NDQwOTI8L2N1c3RvbTI+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjEwMDcvczAwNDAxLTAwOS0wNTAxLTg8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGVwaGVyZDwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4xNDM8L1JlY051bT48RGlzcGxheVRleHQ+KFJldmVzeiwgZXQgYWwuLCAyMDAzLFJl

dmVzeiwgZXQgYWwuLCAyMDA5LFNoZXBoZXJkLCBldCBhbC4sIDIwMDkpPC9EaXNwbGF5VGV4dD48

cmVjb3JkPjxyZWMtbnVtYmVyPjE0MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0

YW1wPSIxMzkyMzcyNzE1Ij4xNDM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlNoZXBoZXJkLEMuPC9hdXRob3I+PGF1dGhvcj5NY0Nhbm4sSC48L2F1dGhvcj48YXV0aG9y

PkhhbGxpZGF5LEcuTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5QcmluY2Ugb2YgV2FsZXMgTWVkaWNhbCBSZXNlYXJjaCBJbnN0aXR1dGUsIEJhcmtlciBT

dHJlZXQsIFJhbmR3aWNrLCBOU1csIDIwMzEsIEF1c3RyYWxpYTwvYXV0aC1hZGRyZXNzPjx0aXRs

ZXM+PHRpdGxlPlZhcmlhdGlvbnMgaW4gdGhlIG5ldXJvcGF0aG9sb2d5IG9mIGZhbWlsaWFsIEFs

emhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BY3RhIE5ldXJv

cGF0aG9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

QWN0YSBOZXVyb3BhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM3LTUyPC9w

YWdlcz48dm9sdW1lPjExODwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXByaW50LWVkaXRp

b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVp

bWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5B

bXlsb2lkIGJldGEtUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPkF0cm9waHk8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW48L2tleXdvcmQ+PGtleXdvcmQ+

Q2VsbCBEZWF0aDwva2V5d29yZD48a2V5d29yZD5kaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+

RXhvbnM8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXM8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8

L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9maWJyaWxsYXJ5

IFRhbmdsZXM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9pbW11bm9tb2R1bGF0aW9uPC9rZXl3b3Jk

PjxrZXl3b3JkPk5ldXJvbnM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPlBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5waHlzaW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPlByZXNlbmlsaW4tMTwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTI8

L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbnM8L2tleXdvcmQ+PGtleXdvcmQ+U2VuaWxlIFBs

YXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1IFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlRh

dW9wYXRoaWVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT43LzIwMDk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MTc4

PC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWgu

Z292L3B1Ym1lZC8xOTMwNjA5ODwvdXJsPjx1cmw+aHR0cDovL2Rvd25sb2FkLnNwcmluZ2VyLmNv

bS9zdGF0aWMvcGRmLzMxOC9hcnQlMjUzQTEwLjEwMDclMjUyRnMwMDQwMS0wMDktMDUyMS00LnBk

Zj9hdXRoNjY9MTM5Mzc2NTU1NV8zYTkzODk0Y2E5OGY3ODc3NTdhNTY4YzlhYTgwMWVhNSZhbXA7

ZXh0PS5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl

PjxBdXRob3I+UmV2ZXN6PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVjTnVtPjE4MTwvUmVj

TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTgxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjE4MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+UmV2ZXN6LFQuPC9hdXRob3I+PGF1dGhvcj5HaGlzbyxKLjwvYXV0aG9yPjxhdXRo

b3I+TGFzaGxleSxULjwvYXV0aG9yPjxhdXRob3I+UGxhbnQsRy48L2F1dGhvcj48YXV0aG9yPlJv

c3RhZ25vLEEuPC9hdXRob3I+PGF1dGhvcj5GcmFuZ2lvbmUsQi48L2F1dGhvcj48YXV0aG9yPkhv

bHRvbixKLkwuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

UXVlZW4gU3F1YXJlIEJyYWluIEJhbmssIERlcGFydG1lbnQgb2YgTW9sZWN1bGFyIE5ldXJvc2Np

ZW5jZSBhbmQgRGl2aXNpb24gb2YgTmV1cm9wYXRob2xvZ3ksIEluc3RpdHV0ZSBvZiBOZXVyb2xv

Z3ksIFVuaXZlcnNpdHkgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgVW5pdGVkIEtpbmdkb20uIHQu

cmV2ZXN6QGlvbi51Y2wuYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DZXJlYnJh

bCBhbXlsb2lkIGFuZ2lvcGF0aGllczogYSBwYXRob2xvZ2ljLCBiaW9jaGVtaWNhbCwgYW5kIGdl

bmV0aWMgdmlldzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvcGF0aG9sIEV4cC5OZXVy

b2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIE5l

dXJvcGF0aG9sIEV4cC5OZXVyb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz44ODUt

ODk4PC9wYWdlcz48dm9sdW1lPjYyPC92b2x1bWU+PG51bWJlcj45PC9udW1iZXI+PHJlcHJpbnQt

ZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5B

bHpoZWltZXIgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbWlubyBBY2lkIFNlcXVlbmNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZG9zaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48

a2V5d29yZD5DYXBpbGxhcmllczwva2V5d29yZD48a2V5d29yZD5DZW50cmFsIE5lcnZvdXMgU3lz

dGVtPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29y

ZD48a2V5d29yZD5DZXJlYnJhbCBIZW1vcnJoYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlh

PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmVzPC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3Jk

PjxrZXl3b3JkPk1vbGVjdWxhciBTZXF1ZW5jZSBEYXRhPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5wYXRob2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0xPC9rZXl3b3JkPjxrZXl3b3JkPlByb3Rl

aW5zPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT45LzIwMDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MjE1PC9sYWJl

bD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC8xNDUzMzc3ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+

PENpdGU+PEF1dGhvcj5SZXZlc3o8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxSZWNOdW0+MzE0

PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zMTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5

cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2

MDIiIHRpbWVzdGFtcD0iMTQxNzQzMzg4OCI+MzE0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10

eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1

dGhvcnM+PGF1dGhvcj5SZXZlc3osIFQuPC9hdXRob3I+PGF1dGhvcj5Ib2x0b24sIEouIEwuPC9h

dXRob3I+PGF1dGhvcj5MYXNobGV5LCBULjwvYXV0aG9yPjxhdXRob3I+UGxhbnQsIEcuPC9hdXRo

b3I+PGF1dGhvcj5GcmFuZ2lvbmUsIEIuPC9hdXRob3I+PGF1dGhvcj5Sb3N0YWdubywgQS48L2F1

dGhvcj48YXV0aG9yPkdoaXNvLCBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48

YXV0aC1hZGRyZXNzPlF1ZWVuIFNxdWFyZSBCcmFpbiBCYW5rIGZvciBOZXVyb2xvZ2ljYWwgRGlz

b3JkZXJzLCBEZXBhcnRtZW50IG9mIE1vbGVjdWxhciBOZXVyb3NjaWVuY2UsIFVDTCBJbnN0aXR1

dGUgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IENvbGxlZ2UgTG9uZG9uLCBRdWVlbiBTcXVhcmUs

IExvbmRvbiBXQzFOM0JHLCBVSy4gdC5yZXZlc3pAaW9uLnVjbC5hYy51azwvYXV0aC1hZGRyZXNz

Pjx0aXRsZXM+PHRpdGxlPkdlbmV0aWNzIGFuZCBtb2xlY3VsYXIgcGF0aG9nZW5lc2lzIG9mIHNw

b3JhZGljIGFuZCBoZXJlZGl0YXJ5IGNlcmVicmFsIGFteWxvaWQgYW5naW9wYXRoaWVzPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPkFjdGEgbmV1cm9wYXRob2xvZ2ljYTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4xMTUtMzA8L3BhZ2VzPjx2b2x1bWU+MTE4PC92b2x1bWU+PG51bWJlcj4xPC9udW1i

ZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2NvbXBsaWNhdGlvbnMvdGhl

cmFweTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5BbXlsb2lkb3Npcy9jb21wbGljYXRpb25zL2dlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKmJsb29kIHN1cHBs

eS9tZXRhYm9saXNtL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5LypnZW5ldGljcy8qcGF0aG9sb2d5L3BoeXNpb3Bh

dGhvbG9neS90aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEhlbW9ycmhhZ2UvY29t

cGxpY2F0aW9ucy9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5DeXN0YXRpbiBDL2dlbmV0aWNz

PC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlhL2NvbXBsaWNhdGlvbnMvZ2VuZXRpY3M8L2tleXdv

cmQ+PGtleXdvcmQ+RGlzZWFzZSBNb2RlbHMsIEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5HZW5l

dGljIFByZWRpc3Bvc2l0aW9uIHRvIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPkltbXVub3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248

L2tleXdvcmQ+PGtleXdvcmQ+UHJlYWxidW1pbi9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk

PlByaW9uIERpc2Vhc2VzL2NvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjE0MzItMDUzMyAoRWxlY3Ryb25pYykmI3hEOzAwMDEtNjMyMiAoTGlua2lu

Zyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTkyMjU3ODk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJl

bGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTkyMjU3

ODk8L3VybD48dXJsPmh0dHA6Ly9kb3dubG9hZC5zcHJpbmdlci5jb20vc3RhdGljL3BkZi83NDAv

YXJ0JTI1M0ExMC4xMDA3JTI1MkZzMDA0MDEtMDA5LTA1MDEtOC5wZGY/YXV0aDY2PTE0MTc0MzM5

NzNfNDE4MzhhZDkxY2JjZjYzODk3YWE1YTdlZjJhODJmYjEmYW1wO2V4dD0ucGRmPC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPjI4NDQwOTI8L2N1c3RvbTI+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjEwMDcvczAwNDAxLTAwOS0wNTAxLTg8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA (Revesz, et al., 2003,Revesz, et al., 2009,Shepherd, et al., 2009) including the Dutch (p.Glu693Gln), Flemish (p.Ala692Gly) Arctic (p.Glu693Gly) and Iowa (p.Asp694Asn) mutations. Whilst all these mutations cause prominent CAA, the occurrence of plaques and tangles varies, as does the clinical phenotype ADDIN EN.CITE <EndNote><Cite><Author>Ryan</Author><Year>2010</Year><RecNum>146</RecNum><DisplayText>(Ryan and Rossor, 2010)</DisplayText><record><rec-number>146</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">146</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ryan,N.S.</author><author>Rossor,M.N.</author></authors></contributors><auth-address>Dementia Research Centre, Department of Neurodegenerative Diseases, University College London, Institute of Neurology, London, UK. ryan@drc.ion.ucl.ac.uk</auth-address><titles><title>Correlating familial Alzheimer&apos;s disease gene mutations with clinical phenotype</title><secondary-title>Biomark.Med</secondary-title></titles><periodical><full-title>Biomark.Med</full-title></periodical><pages>99-112</pages><volume>4</volume><number>1</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Alzheimer Disease</keyword><keyword>Amino Acid Sequence</keyword><keyword>Amyloid</keyword><keyword>Amyloid beta-Protein</keyword><keyword>Amyloid beta-Protein Precursor</keyword><keyword>chemistry</keyword><keyword>Dementia</keyword><keyword>Genetic Markers</keyword><keyword>genetics</keyword><keyword>Humans</keyword><keyword>Models,Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Mutation</keyword><keyword>Neurodegenerative Diseases</keyword><keyword>Neurology</keyword><keyword>Phenotype</keyword><keyword>physiopathology</keyword><keyword>Presenilin-1</keyword><keyword>Presenilin-2</keyword><keyword>Protein Structure,Tertiary</keyword><keyword>psychology</keyword></keywords><dates><year>2010</year><pub-dates><date>2/2010</date></pub-dates></dates><label>181</label><urls><related-urls><url>;(Ryan and Rossor, 2010). The Dutch mutation typically presents with recurrent cerebral haemorrhage, usually followed by dementia; the Flemish mutation presents with haemorrhages or dementia and the Arctic and Iowa mutations present with dementia only. Post-mortem studies of AD patients who participated in the initial, active, Aβ42 AN1792 immunotherapy (vaccination) trial have revealed that parenchymal amyloid removal may be accompanied by an increase in CAA, thought to be secondary to Aβ42 accumulation via perivascular drainage pathways PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NoZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4xMzE8L1JlY051bT48RGlzcGxheVRleHQ+KEJvY2hlLCBldCBhbC4sIDIwMDgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEzMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xMzE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkJvY2hlLEQuPC9hdXRob3I+PGF1dGhvcj5ab3RvdmEsRS48L2F1dGhvcj48

YXV0aG9yPldlbGxlcixSLk8uPC9hdXRob3I+PGF1dGhvcj5Mb3ZlLFMuPC9hdXRob3I+PGF1dGhv

cj5OZWFsLEouVy48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZyxSLk0uPC9hdXRob3I+PGF1dGhv

cj5XaWxraW5zb24sRC48L2F1dGhvcj48YXV0aG9yPkhvbG1lcyxDLjwvYXV0aG9yPjxhdXRob3I+

Tmljb2xsLEouQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EaXZpc2lvbiBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFNvdXRo

YW1wdG9uLCBTb3V0aGFtcHRvbiBHZW5lcmFsIEhvc3BpdGFsLCBTb3V0aGFtcHRvbiwgVUsuIEQu

Qm9jaGVAc290b24uYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Db25zZXF1ZW5j

ZSBvZiBBYmV0YSBpbW11bml6YXRpb24gb24gdGhlIHZhc2N1bGF0dXJlIG9mIGh1bWFuIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZSBicmFpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFpbjwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWluPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzI5OS0zMzEwPC9wYWdlcz48dm9sdW1lPjEz

MTwvdm9sdW1lPjxudW1iZXI+UHQgMTI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgVmFjY2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5BbnRpYm9kaWVzPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kPC9rZXl3b3JkPjxrZXl3

b3JkPmJsb29kIHN1cHBseTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBWZXNzZWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9w

YXRoeTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXg8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VyZWJyYWwgSGVtb3JyaGFnZTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rm9sbG93LVVwIFN0dWRpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPmltbXVub2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5LEFj

dGl2ZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VzPC9r

ZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5

d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+U29sdWJp

bGl0eTwva2V5d29yZD48a2V5d29yZD50aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5WYWNjaW5lczwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTIvMjAwODwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xNjY8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE4OTUzMDU2PC91cmw+PHVybD5o

dHRwOi8vYnJhaW4ub3hmb3Jkam91cm5hbHMub3JnL2NvbnRlbnQvMTMxLzEyLzMyOTkuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NoZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4xMzE8L1JlY051bT48RGlzcGxheVRleHQ+KEJvY2hlLCBldCBhbC4sIDIwMDgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEzMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xMzE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkJvY2hlLEQuPC9hdXRob3I+PGF1dGhvcj5ab3RvdmEsRS48L2F1dGhvcj48

YXV0aG9yPldlbGxlcixSLk8uPC9hdXRob3I+PGF1dGhvcj5Mb3ZlLFMuPC9hdXRob3I+PGF1dGhv

cj5OZWFsLEouVy48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZyxSLk0uPC9hdXRob3I+PGF1dGhv

cj5XaWxraW5zb24sRC48L2F1dGhvcj48YXV0aG9yPkhvbG1lcyxDLjwvYXV0aG9yPjxhdXRob3I+

Tmljb2xsLEouQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EaXZpc2lvbiBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFNvdXRo

YW1wdG9uLCBTb3V0aGFtcHRvbiBHZW5lcmFsIEhvc3BpdGFsLCBTb3V0aGFtcHRvbiwgVUsuIEQu

Qm9jaGVAc290b24uYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Db25zZXF1ZW5j

ZSBvZiBBYmV0YSBpbW11bml6YXRpb24gb24gdGhlIHZhc2N1bGF0dXJlIG9mIGh1bWFuIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZSBicmFpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFpbjwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWluPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzI5OS0zMzEwPC9wYWdlcz48dm9sdW1lPjEz

MTwvdm9sdW1lPjxudW1iZXI+UHQgMTI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgVmFjY2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5BbnRpYm9kaWVzPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kPC9rZXl3b3JkPjxrZXl3

b3JkPmJsb29kIHN1cHBseTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBWZXNzZWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9w

YXRoeTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXg8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VyZWJyYWwgSGVtb3JyaGFnZTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rm9sbG93LVVwIFN0dWRpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPmltbXVub2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5LEFj

dGl2ZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VzPC9r

ZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5

d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+U29sdWJp

bGl0eTwva2V5d29yZD48a2V5d29yZD50aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5WYWNjaW5lczwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTIvMjAwODwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xNjY8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE4OTUzMDU2PC91cmw+PHVybD5o

dHRwOi8vYnJhaW4ub3hmb3Jkam91cm5hbHMub3JnL2NvbnRlbnQvMTMxLzEyLzMyOTkuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Boche, et al., 2008). The era of disease-modifying treatment trials for FAD therefore necessitates better characterisation and understanding of the variable occurrence of CAA in individuals with APP and PSEN1 mutations. Radiological features of CAA include WMH on T2-weighted MRI; cortico-subcortical intracerebral haemorrhages including microbleeds on gradient echo imaging; and atrophy best seen on T1-weighted imaging ADDIN EN.CITE <EndNote><Cite><Author>Chao</Author><Year>2006</Year><RecNum>155</RecNum><DisplayText>(Chao, et al., 2006)</DisplayText><record><rec-number>155</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">155</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chao,C.P.</author><author>Kotsenas,A.L.</author><author>Broderick,D.F.</author></authors></contributors><auth-address>Department of Radiology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA</auth-address><titles><title>Cerebral amyloid angiopathy: CT and MR imaging findings</title><secondary-title>Radiographics</secondary-title></titles><periodical><full-title>Radiographics</full-title></periodical><pages>1517-1531</pages><volume>26</volume><number>5</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Amyloid</keyword><keyword>Brain</keyword><keyword>Cerebral Amyloid Angiopathy</keyword><keyword>Cerebral Angiography</keyword><keyword>Cerebrovascular Disorders</keyword><keyword>diagnosis</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Image Enhancement</keyword><keyword>Magnetic Resonance Angiography</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>methods</keyword><keyword>pathology</keyword><keyword>Physician&apos;s Practice Patterns</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>radiography</keyword><keyword>Tomography,X-Ray Computed</keyword></keywords><dates><year>2006</year><pub-dates><date>9/2006</date></pub-dates></dates><label>190</label><urls><related-urls><url>;(Chao, et al., 2006). Whilst WMH on MRI are common in the elderly, in whom they may represent multiple pathologies, the young age of patients with FAD makes them less likely to have significant conventional vascular risk factors and MRI manifestations of atherosclerotic small vessel disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3BraW5zPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48

UmVjTnVtPjMyMjwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oSG9wa2lucywgZXQgYWwuLCAyMDA2KTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMjI8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTQyMDcxNjkzMiI+MzIyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5Ib3BraW5zLCBSLiBPLjwvYXV0aG9yPjxhdXRob3I+QmVjaywgQy4g

Si48L2F1dGhvcj48YXV0aG9yPkJ1cm5ldHQsIEQuIEwuPC9hdXRob3I+PGF1dGhvcj5XZWF2ZXIs

IEwuIEsuPC9hdXRob3I+PGF1dGhvcj5WaWN0b3JvZmYsIEouPC9hdXRob3I+PGF1dGhvcj5CaWds

ZXIsIEUuIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

UHN5Y2hvbG9neSBEZXBhcnRtZW50LCBCcmlnaGFtIFlvdW5nIFVuaXZlcnNpdHksIFByb3ZvLCBV

VCA4NDYwMiwgVVNBLiBtb25hLmhvcGtpbnNAYnl1LmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+

PHRpdGxlPlByZXZhbGVuY2Ugb2Ygd2hpdGUgbWF0dGVyIGh5cGVyaW50ZW5zaXRpZXMgaW4gYSB5

b3VuZyBoZWFsdGh5IHBvcHVsYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBOZXVyb2lt

YWdpbmc8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkpvdXJuYWwgb2YgbmV1cm9pbWFnaW5n

IDogb2ZmaWNpYWwgam91cm5hbCBvZiB0aGUgQW1lcmljYW4gU29jaWV0eSBvZiBOZXVyb2ltYWdp

bmc8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIE5ldXJvaW1h

Z2luZzwvZnVsbC10aXRsZT48YWJici0xPkpvdXJuYWwgb2YgbmV1cm9pbWFnaW5nIDogb2ZmaWNp

YWwgam91cm5hbCBvZiB0aGUgQW1lcmljYW4gU29jaWV0eSBvZiBOZXVyb2ltYWdpbmc8L2FiYnIt

MT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9pbWFnaW5n

PC9mdWxsLXRpdGxlPjxhYmJyLTE+Sm91cm5hbCBvZiBuZXVyb2ltYWdpbmcgOiBvZmZpY2lhbCBq

b3VybmFsIG9mIHRoZSBBbWVyaWNhbiBTb2NpZXR5IG9mIE5ldXJvaW1hZ2luZzwvYWJici0xPjwv

YWx0LXBlcmlvZGljYWw+PHBhZ2VzPjI0My01MTwvcGFnZXM+PHZvbHVtZT4xNjwvdm9sdW1lPjxu

dW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxr

ZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdp

bmcvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLypwYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZy8qbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5N

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByZXZh

bGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDA2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVsPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA1MS0yMjg0IChQcmludCkmI3hEOzEwNTEtMjI4

NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTY4MDg4MjY8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMTY4MDg4MjY8L3VybD48dXJsPmh0dHA6Ly9vbmxpbmVsaWJyYXJ5LndpbGV5LmNvbS9zdG9y

ZS8xMC4xMTExL2ouMTU1Mi02NTY5LjIwMDYuMDAwNDcueC9hc3NldC9qLjE1NTItNjU2OS4yMDA2

LjAwMDQ3LngucGRmP3Y9MSZhbXA7dD1pNHkyZ3ppYiZhbXA7cz1jODNkYjQ3MDZmODE5ODM5ODM2

MjI0YTFhZDI2NzdkNmEyYWY3ZjNkPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMTExL2ouMTU1Mi02NTY5LjIwMDYuMDAwNDcueDwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3BraW5zPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48

UmVjTnVtPjMyMjwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oSG9wa2lucywgZXQgYWwuLCAyMDA2KTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMjI8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTQyMDcxNjkzMiI+MzIyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5Ib3BraW5zLCBSLiBPLjwvYXV0aG9yPjxhdXRob3I+QmVjaywgQy4g

Si48L2F1dGhvcj48YXV0aG9yPkJ1cm5ldHQsIEQuIEwuPC9hdXRob3I+PGF1dGhvcj5XZWF2ZXIs

IEwuIEsuPC9hdXRob3I+PGF1dGhvcj5WaWN0b3JvZmYsIEouPC9hdXRob3I+PGF1dGhvcj5CaWds

ZXIsIEUuIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

UHN5Y2hvbG9neSBEZXBhcnRtZW50LCBCcmlnaGFtIFlvdW5nIFVuaXZlcnNpdHksIFByb3ZvLCBV

VCA4NDYwMiwgVVNBLiBtb25hLmhvcGtpbnNAYnl1LmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+

PHRpdGxlPlByZXZhbGVuY2Ugb2Ygd2hpdGUgbWF0dGVyIGh5cGVyaW50ZW5zaXRpZXMgaW4gYSB5

b3VuZyBoZWFsdGh5IHBvcHVsYXRpb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBOZXVyb2lt

YWdpbmc8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkpvdXJuYWwgb2YgbmV1cm9pbWFnaW5n

IDogb2ZmaWNpYWwgam91cm5hbCBvZiB0aGUgQW1lcmljYW4gU29jaWV0eSBvZiBOZXVyb2ltYWdp

bmc8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIE5ldXJvaW1h

Z2luZzwvZnVsbC10aXRsZT48YWJici0xPkpvdXJuYWwgb2YgbmV1cm9pbWFnaW5nIDogb2ZmaWNp

YWwgam91cm5hbCBvZiB0aGUgQW1lcmljYW4gU29jaWV0eSBvZiBOZXVyb2ltYWdpbmc8L2FiYnIt

MT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9pbWFnaW5n

PC9mdWxsLXRpdGxlPjxhYmJyLTE+Sm91cm5hbCBvZiBuZXVyb2ltYWdpbmcgOiBvZmZpY2lhbCBq

b3VybmFsIG9mIHRoZSBBbWVyaWNhbiBTb2NpZXR5IG9mIE5ldXJvaW1hZ2luZzwvYWJici0xPjwv

YWx0LXBlcmlvZGljYWw+PHBhZ2VzPjI0My01MTwvcGFnZXM+PHZvbHVtZT4xNjwvdm9sdW1lPjxu

dW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxr

ZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdp

bmcvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLypwYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZy8qbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5N

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByZXZh

bGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDA2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVsPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA1MS0yMjg0IChQcmludCkmI3hEOzEwNTEtMjI4

NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTY4MDg4MjY8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMTY4MDg4MjY8L3VybD48dXJsPmh0dHA6Ly9vbmxpbmVsaWJyYXJ5LndpbGV5LmNvbS9zdG9y

ZS8xMC4xMTExL2ouMTU1Mi02NTY5LjIwMDYuMDAwNDcueC9hc3NldC9qLjE1NTItNjU2OS4yMDA2

LjAwMDQ3LngucGRmP3Y9MSZhbXA7dD1pNHkyZ3ppYiZhbXA7cz1jODNkYjQ3MDZmODE5ODM5ODM2

MjI0YTFhZDI2NzdkNmEyYWY3ZjNkPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv

bmljLXJlc291cmNlLW51bT4xMC4xMTExL2ouMTU1Mi02NTY5LjIwMDYuMDAwNDcueDwvZWxlY3Ry

b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Hopkins, et al., 2006). Prominent WMH in this population are therefore much more likely to be indicative of an aspect of FAD pathology. The aim of this study was to investigate the degree and location of WMH in symptomatic APP and PSEN1 mutation carriers, together with age-matched controls, and to explore whether the reports of increased CAA in intra-domain APP mutations and PSEN1 mutations located beyond codon 200 are reflected in greater WMH burden on MRI. Pathological investigations were also carried out in 10 cases who had post-mortem examination.2. Materials and methods2.1. Study SubjectsThe study was conducted at the Dementia Research Centre, University College London (UCL) Institute of Neurology at the National Hospital for Neurology and Neurosurgery. Individuals with FAD have been participating in research with our group for over two decades and all symptomatic subjects with a confirmed APP or PSEN1 mutation and appropriate imaging were included in this retrospective study. Fifty-two patients were studied: 13 with APP mutations and 39 with PSEN1 mutations. In the PSEN1 cohort, 18 subjects had pre-codon 200 mutations; 21 had post-codon 200 mutations. All FAD subjects were clinically affected and met criteria for probable AD at the time of MRI acquisition. Twenty-five healthy control subjects, mainly spouses and mutation-negative siblings, were also recruited. All subjects gave informed consent and approval was received from the local ethics committee. Mutation analysis was conducted on genomic DNA and APOE genotype was established for all patients (excluding controls). All subjects with FAD underwent clinical assessment. In most cases, a comprehensive medical history was recorded and from this, the presence or absence of hypertension, diabetes, hyperlipidaemia, stroke, transient ischaemic attack (TIA) and coronary artery disease was assessed to create a composite score for vascular risk that was the sum of the factors present, ranging from 0 to 6 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZUNhcmxpPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48

UmVjTnVtPjE2NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oRGVDYXJsaSwgZXQgYWwuLCAyMDA0KTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTY0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5EZUNhcmxpLEMuPC9hdXRob3I+PGF1dGhvcj5NdW5nYXMsRC48L2F1

dGhvcj48YXV0aG9yPkhhcnZleSxELjwvYXV0aG9yPjxhdXRob3I+UmVlZCxCLjwvYXV0aG9yPjxh

dXRob3I+V2VpbmVyLE0uPC9hdXRob3I+PGF1dGhvcj5DaHVpLEguPC9hdXRob3I+PGF1dGhvcj5K

YWd1c3QsVy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5E

ZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhIGF0IFNhbiBG

cmFuY2lzY28sIFVTQS4gY2RlY2FybGlAdWNkYXZpcy5lZHU8L2F1dGgtYWRkcmVzcz48dGl0bGVz

Pjx0aXRsZT5NZW1vcnkgaW1wYWlybWVudCwgYnV0IG5vdCBjZXJlYnJvdmFzY3VsYXIgZGlzZWFz

ZSwgcHJlZGljdHMgcHJvZ3Jlc3Npb24gb2YgTUNJIHRvIGRlbWVudGlhPC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIy

MC0yMjc8L3BhZ2VzPjx2b2x1bWU+NjM8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmlu

dC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y

ZD5BZ2luZzwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5d29yZD48a2V5

d29yZD5hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29y

ZD48a2V5d29yZD5DYXJkaW92YXNjdWxhciBEaXNlYXNlczwva2V5d29yZD48a2V5d29yZD5DZXJl

YnJvdmFzY3VsYXIgRGlzb3JkZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRl

cnM8L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWE8L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMg

TWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48

a2V5d29yZD5lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48

a2V5d29yZD5IeXBlcmxpcGlkZW1pYXM8L2tleXdvcmQ+PGtleXdvcmQ+TGlmZSBUYWJsZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+TG9uZ2l0dWRpbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+TWFn

bmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48

a2V5d29yZD5NZW1vcnk8L2tleXdvcmQ+PGtleXdvcmQ+TWVtb3J5IERpc29yZGVyczwva2V5d29y

ZD48a2V5d29yZD5tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3Jk

PjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwg

VGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByb3Nw

ZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+cHN5Y2hvbG9neTwva2V5d29yZD48a2V5

d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+U3Ryb2tlPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT43LzI3LzIwMDQ8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MTk5PC9sYWJlbD48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNTI3NzYxMjwv

dXJsPjx1cmw+aHR0cDovL3d3dy5uZXVyb2xvZ3kub3JnL2NvbnRlbnQvNjMvMi8yMjAuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZUNhcmxpPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48

UmVjTnVtPjE2NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oRGVDYXJsaSwgZXQgYWwuLCAyMDA0KTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTY0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5EZUNhcmxpLEMuPC9hdXRob3I+PGF1dGhvcj5NdW5nYXMsRC48L2F1

dGhvcj48YXV0aG9yPkhhcnZleSxELjwvYXV0aG9yPjxhdXRob3I+UmVlZCxCLjwvYXV0aG9yPjxh

dXRob3I+V2VpbmVyLE0uPC9hdXRob3I+PGF1dGhvcj5DaHVpLEguPC9hdXRob3I+PGF1dGhvcj5K

YWd1c3QsVy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5E

ZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhIGF0IFNhbiBG

cmFuY2lzY28sIFVTQS4gY2RlY2FybGlAdWNkYXZpcy5lZHU8L2F1dGgtYWRkcmVzcz48dGl0bGVz

Pjx0aXRsZT5NZW1vcnkgaW1wYWlybWVudCwgYnV0IG5vdCBjZXJlYnJvdmFzY3VsYXIgZGlzZWFz

ZSwgcHJlZGljdHMgcHJvZ3Jlc3Npb24gb2YgTUNJIHRvIGRlbWVudGlhPC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIy

MC0yMjc8L3BhZ2VzPjx2b2x1bWU+NjM8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmlu

dC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y

ZD5BZ2luZzwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5d29yZD48a2V5

d29yZD5hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29y

ZD48a2V5d29yZD5DYXJkaW92YXNjdWxhciBEaXNlYXNlczwva2V5d29yZD48a2V5d29yZD5DZXJl

YnJvdmFzY3VsYXIgRGlzb3JkZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRl

cnM8L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWE8L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMg

TWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48

a2V5d29yZD5lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48

a2V5d29yZD5IeXBlcmxpcGlkZW1pYXM8L2tleXdvcmQ+PGtleXdvcmQ+TGlmZSBUYWJsZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+TG9uZ2l0dWRpbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+TWFn

bmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48

a2V5d29yZD5NZW1vcnk8L2tleXdvcmQ+PGtleXdvcmQ+TWVtb3J5IERpc29yZGVyczwva2V5d29y

ZD48a2V5d29yZD5tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3Jk

PjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwg

VGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByb3Nw

ZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+cHN5Y2hvbG9neTwva2V5d29yZD48a2V5

d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+U3Ryb2tlPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT43LzI3LzIwMDQ8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MTk5PC9sYWJlbD48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNTI3NzYxMjwv

dXJsPjx1cmw+aHR0cDovL3d3dy5uZXVyb2xvZ3kub3JnL2NvbnRlbnQvNjMvMi8yMjAuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (DeCarli, et al., 2004). This information was not available for some of the historical cases and controls but could be analysed for a large subset (Table 1). 2.2. ImagingAll subjects underwent T2-weighted (T2 or FLAIR) and volumetric T1-weighted MRI. As this study was a retrospective analysis of individuals scanned over almost twenty years, images acquired on 1.5Tesla and 3Tesla scanners were included and there was also some variability in the parameters of the sequences used. However, an equivalent proportion of individuals were scanned at each magnetic field strength in each group. An experienced neurologist (G-JB), blinded to clinical diagnosis, visually assessed all scans. The scans were rated using the age-related white matter change (ARWMC) scale PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48

UmVjTnVtPjE1MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oV2FobHVuZCwgZXQgYWwuLCAyMDAxKTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNTI8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTUyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5XYWhsdW5kLEwuTy48L2F1dGhvcj48YXV0aG9yPkJhcmtob2YsRi48

L2F1dGhvcj48YXV0aG9yPkZhemVrYXMsRi48L2F1dGhvcj48YXV0aG9yPkJyb25nZSxMLjwvYXV0

aG9yPjxhdXRob3I+QXVndXN0aW4sTS48L2F1dGhvcj48YXV0aG9yPlNqb2dyZW4sTS48L2F1dGhv

cj48YXV0aG9yPldhbGxpbixBLjwvYXV0aG9yPjxhdXRob3I+QWRlcixILjwvYXV0aG9yPjxhdXRo

b3I+TGV5cyxELjwvYXV0aG9yPjxhdXRob3I+UGFudG9uaSxMLjwvYXV0aG9yPjxhdXRob3I+UGFz

cXVpZXIsRi48L2F1dGhvcj48YXV0aG9yPkVya2luanVudHRpLFQuPC9hdXRob3I+PGF1dGhvcj5T

Y2hlbHRlbnMsUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EZXBhcnRtZW50IG9mIENsaW5pY2FsIE5ldXJvc2NpZW5jZSwgTkVVUk9URUMsIEthcm9saW5z

a2EgSW5zdGl0dXRldCBhdCBIdWRkaW5nZSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwg

U3dlZGVuLiBsYXJzLW9sb2Yud2FobHVuZEBuZXVyb3RlYy5raS5zZTwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkEgbmV3IHJhdGluZyBzY2FsZSBmb3IgYWdlLXJlbGF0ZWQgd2hpdGUgbWF0

dGVyIGNoYW5nZXMgYXBwbGljYWJsZSB0byBNUkkgYW5kIENUPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPlN0cm9rZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPlN0cm9rZTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEzMTgtMTMyMjwvcGFn

ZXM+PHZvbHVtZT4zMjwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+

Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWdpbmc8L2tl

eXdvcmQ+PGtleXdvcmQ+QmFzYWwgR2FuZ2xpYTwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5

d29yZD48a2V5d29yZD5CcmFpbiBEaXNlYXNlczwva2V5d29yZD48a2V5d29yZD5Db2duaXRpb24g

RGlzb3JkZXJzPC9rZXl3b3JkPjxrZXl3b3JkPmNvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdv

cmQ+ZGlhZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkV1cm9wZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0

aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWVtb3J5IERpc29yZGVyczwv

a2V5d29yZD48a2V5d29yZD5tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk15ZWxpbiBTaGVhdGg8

L2tleXdvcmQ+PGtleXdvcmQ+T2JzZXJ2ZXIgVmFyaWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QcmVkaWN0aXZlIFZhbHVlIG9mIFRlc3RzPC9rZXl3

b3JkPjxrZXl3b3JkPnJhZGlvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPlJlcHJvZHVjaWJpbGl0

eSBvZiBSZXN1bHRzPC9rZXl3b3JkPjxrZXl3b3JkPlNlbnNpdGl2aXR5IGFuZCBTcGVjaWZpY2l0

eTwva2V5d29yZD48a2V5d29yZD5zdGFuZGFyZHM8L2tleXdvcmQ+PGtleXdvcmQ+U3dlZGVuPC9r

ZXl3b3JkPjxrZXl3b3JkPlRvbW9ncmFwaHksWC1SYXkgQ29tcHV0ZWQ8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xODc8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzExMzg3NDkzPC91cmw+

PHVybD5odHRwOi8vc3Ryb2tlLmFoYWpvdXJuYWxzLm9yZy9jb250ZW50LzMyLzYvMTMxOC5mdWxs

LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

PgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48

UmVjTnVtPjE1MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oV2FobHVuZCwgZXQgYWwuLCAyMDAxKTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNTI8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTUyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5XYWhsdW5kLEwuTy48L2F1dGhvcj48YXV0aG9yPkJhcmtob2YsRi48

L2F1dGhvcj48YXV0aG9yPkZhemVrYXMsRi48L2F1dGhvcj48YXV0aG9yPkJyb25nZSxMLjwvYXV0

aG9yPjxhdXRob3I+QXVndXN0aW4sTS48L2F1dGhvcj48YXV0aG9yPlNqb2dyZW4sTS48L2F1dGhv

cj48YXV0aG9yPldhbGxpbixBLjwvYXV0aG9yPjxhdXRob3I+QWRlcixILjwvYXV0aG9yPjxhdXRo

b3I+TGV5cyxELjwvYXV0aG9yPjxhdXRob3I+UGFudG9uaSxMLjwvYXV0aG9yPjxhdXRob3I+UGFz

cXVpZXIsRi48L2F1dGhvcj48YXV0aG9yPkVya2luanVudHRpLFQuPC9hdXRob3I+PGF1dGhvcj5T

Y2hlbHRlbnMsUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EZXBhcnRtZW50IG9mIENsaW5pY2FsIE5ldXJvc2NpZW5jZSwgTkVVUk9URUMsIEthcm9saW5z

a2EgSW5zdGl0dXRldCBhdCBIdWRkaW5nZSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIdWRkaW5nZSwg

U3dlZGVuLiBsYXJzLW9sb2Yud2FobHVuZEBuZXVyb3RlYy5raS5zZTwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkEgbmV3IHJhdGluZyBzY2FsZSBmb3IgYWdlLXJlbGF0ZWQgd2hpdGUgbWF0

dGVyIGNoYW5nZXMgYXBwbGljYWJsZSB0byBNUkkgYW5kIENUPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPlN0cm9rZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPlN0cm9rZTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEzMTgtMTMyMjwvcGFn

ZXM+PHZvbHVtZT4zMjwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+

Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWdpbmc8L2tl

eXdvcmQ+PGtleXdvcmQ+QmFzYWwgR2FuZ2xpYTwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5

d29yZD48a2V5d29yZD5CcmFpbiBEaXNlYXNlczwva2V5d29yZD48a2V5d29yZD5Db2duaXRpb24g

RGlzb3JkZXJzPC9rZXl3b3JkPjxrZXl3b3JkPmNvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdv

cmQ+ZGlhZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkV1cm9wZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0

aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWVtb3J5IERpc29yZGVyczwv

a2V5d29yZD48a2V5d29yZD5tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk15ZWxpbiBTaGVhdGg8

L2tleXdvcmQ+PGtleXdvcmQ+T2JzZXJ2ZXIgVmFyaWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QcmVkaWN0aXZlIFZhbHVlIG9mIFRlc3RzPC9rZXl3

b3JkPjxrZXl3b3JkPnJhZGlvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPlJlcHJvZHVjaWJpbGl0

eSBvZiBSZXN1bHRzPC9rZXl3b3JkPjxrZXl3b3JkPlNlbnNpdGl2aXR5IGFuZCBTcGVjaWZpY2l0

eTwva2V5d29yZD48a2V5d29yZD5zdGFuZGFyZHM8L2tleXdvcmQ+PGtleXdvcmQ+U3dlZGVuPC9r

ZXl3b3JkPjxrZXl3b3JkPlRvbW9ncmFwaHksWC1SYXkgQ29tcHV0ZWQ8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xODc8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzExMzg3NDkzPC91cmw+

PHVybD5odHRwOi8vc3Ryb2tlLmFoYWpvdXJuYWxzLm9yZy9jb250ZW50LzMyLzYvMTMxOC5mdWxs

LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

PgB=

ADDIN EN.CITE.DATA (Wahlund, et al., 2001). The ARWMC scale (range 0-30) rates the degree of WMH on a four point scale for five different brain regions (frontal, parieto-occipital, temporal, infratentorial and basal ganglia including thalamus) for the right and left cerebral hemispheres separately. The ARWMC scale was chosen as it has been shown to provide robust results when applied to both CT and MRI, and therefore would be applicable to the T2-weighted MR images available in this study, which were acquired on a variety of different scanners and field strengths. T2*-weighted imaging sensitive to microbleeds was only available in the 12 most recently scanned patients (one APP and 11 PSEN1 mutation carriers) and has been reported elsewhere ADDIN EN.CITE <EndNote><Cite><Author>Ryan</Author><Year>2011</Year><RecNum>166</RecNum><DisplayText>(Ryan, et al., 2011)</DisplayText><record><rec-number>166</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">166</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ryan,N.S.</author><author>Bastos-Leite,A.J.</author><author>Rohrer,J.D.</author><author>Werring,D.J.</author><author>Fox,N.C.</author><author>Rossor,M.N.</author><author>Schott,J.M.</author></authors></contributors><auth-address>1 Dementia Research Centre, Department of Neurodegeneration, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK</auth-address><titles><title>Cerebral microbleeds in familial Alzheimer&apos;s disease</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>e201</pages><volume>135</volume><number>Pt 1</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Dementia</keyword><keyword>Neurology</keyword></keywords><dates><year>2011</year><pub-dates><date>6/17/2011</date></pub-dates></dates><label>201</label><urls><related-urls><url>;(Ryan, et al., 2011) so was not included in the current study.2.3. PathologyBrains were donated to the Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology. The protocol used for brain donation was approved by a London Research Ethics Committee and tissue is stored for research under a license from the Human Tissue Authority. Tissue sections (7-?m) from a number of brain regions were immunostained using commercially available antibodies as described previously and in Supplementary Information PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYXNobGV5PC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

UmVjTnVtPjIwMjwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oTGFzaGxleSwgZXQgYWwuLCAyMDA4KTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDI8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3NTg2MyI+MjAyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5MYXNobGV5LCBULjwvYXV0aG9yPjxhdXRob3I+SG9sdG9uLCBKLiBM

LjwvYXV0aG9yPjxhdXRob3I+R3JheSwgRS48L2F1dGhvcj48YXV0aG9yPktpcmtoYW0sIEsuPC9h

dXRob3I+PGF1dGhvcj5PJmFwb3M7U3VsbGl2YW4sIFMuIFMuPC9hdXRob3I+PGF1dGhvcj5IaWxi

aWcsIEEuPC9hdXRob3I+PGF1dGhvcj5Xb29kLCBOLiBXLjwvYXV0aG9yPjxhdXRob3I+TGVlcywg

QS4gSi48L2F1dGhvcj48YXV0aG9yPlJldmVzeiwgVC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5RdWVlbiBTcXVhcmUgQnJhaW4gQmFuayBmb3IgTmV1cm9s

b2dpY2FsIERpc29yZGVycywgRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgTmV1cm9zY2llbmNlLCBV

Q0wgSW5zdGl0dXRlIG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBDb2xsZWdlIExvbmRvbiwgUXVl

ZW4gU3F1YXJlLCBMb25kb24gV0MxTiAzQkcsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPkNvcnRpY2FsIGFscGhhLXN5bnVjbGVpbiBsb2FkIGlzIGFzc29jaWF0ZWQgd2l0aCBhbXls

b2lkLWJldGEgcGxhcXVlIGJ1cmRlbiBpbiBhIHN1YnNldCBvZiBQYXJraW5zb24mYXBvcztzIGRp

c2Vhc2UgcGF0aWVudHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWN0YSBOZXVyb3BhdGhvbDwv

c2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QWN0YSBuZXVyb3BhdGhvbG9naWNhPC9hbHQtdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0YSBOZXVyb3BhdGhvbDwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQxNy0yNTwvcGFnZXM+PHZvbHVtZT4xMTU8L3Zv

bHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDA4LzAxLzExPC9lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0

aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXgvKm1ldGFi

b2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TGV3eSBCb2RpZXMvcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+KlBhcmtpbnNvbiBEaXNlYXNlL2NsYXNzaWZpY2F0aW9uL21ldGFib2xpc20vcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBsYXF1ZSwgQW15bG9pZC8qcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPlN0YXRpc3RpY3MsIE5vbnBhcmFtZXRyaWM8L2tleXdvcmQ+PGtleXdvcmQ+YWxw

aGEtU3ludWNsZWluLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMDg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4wMDAxLTYzMjIgKFByaW50KSYjeEQ7MDAwMS02MzIyIChMaW5raW5nKTwvaXNibj48

YWNjZXNzaW9uLW51bT4xODE4NTk0MDwvYWNjZXNzaW9uLW51bT48d29yay10eXBlPlJlc2VhcmNo

IFN1cHBvcnQsIE5vbi1VLlMuIEdvdiZhcG9zO3Q8L3dvcmstdHlwZT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xODE4NTk0MDwvdXJs

Pjx1cmw+aHR0cDovL2Rvd25sb2FkLnNwcmluZ2VyLmNvbS9zdGF0aWMvcGRmLzY0Ni9hcnQlMjUz

QTEwLjEwMDclMjUyRnMwMDQwMS0wMDctMDMzNi0wLnBkZj9hdXRoNjY9MTM5Mzc2NTE2OF8yYzI3

YTI5YzNmNjRlMmYyZTNmZGJhMjIyNTU4NmY5ZiZhbXA7ZXh0PS5wZGY8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczAwNDAxLTAwNy0w

MzM2LTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYXNobGV5PC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

UmVjTnVtPjIwMjwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oTGFzaGxleSwgZXQgYWwuLCAyMDA4KTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDI8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3NTg2MyI+MjAyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5MYXNobGV5LCBULjwvYXV0aG9yPjxhdXRob3I+SG9sdG9uLCBKLiBM

LjwvYXV0aG9yPjxhdXRob3I+R3JheSwgRS48L2F1dGhvcj48YXV0aG9yPktpcmtoYW0sIEsuPC9h

dXRob3I+PGF1dGhvcj5PJmFwb3M7U3VsbGl2YW4sIFMuIFMuPC9hdXRob3I+PGF1dGhvcj5IaWxi

aWcsIEEuPC9hdXRob3I+PGF1dGhvcj5Xb29kLCBOLiBXLjwvYXV0aG9yPjxhdXRob3I+TGVlcywg

QS4gSi48L2F1dGhvcj48YXV0aG9yPlJldmVzeiwgVC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5RdWVlbiBTcXVhcmUgQnJhaW4gQmFuayBmb3IgTmV1cm9s

b2dpY2FsIERpc29yZGVycywgRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgTmV1cm9zY2llbmNlLCBV

Q0wgSW5zdGl0dXRlIG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBDb2xsZWdlIExvbmRvbiwgUXVl

ZW4gU3F1YXJlLCBMb25kb24gV0MxTiAzQkcsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp

dGxlPkNvcnRpY2FsIGFscGhhLXN5bnVjbGVpbiBsb2FkIGlzIGFzc29jaWF0ZWQgd2l0aCBhbXls

b2lkLWJldGEgcGxhcXVlIGJ1cmRlbiBpbiBhIHN1YnNldCBvZiBQYXJraW5zb24mYXBvcztzIGRp

c2Vhc2UgcGF0aWVudHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWN0YSBOZXVyb3BhdGhvbDwv

c2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QWN0YSBuZXVyb3BhdGhvbG9naWNhPC9hbHQtdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0YSBOZXVyb3BhdGhvbDwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQxNy0yNTwvcGFnZXM+PHZvbHVtZT4xMTU8L3Zv

bHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDA4LzAxLzExPC9lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0

aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXgvKm1ldGFi

b2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TGV3eSBCb2RpZXMvcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+KlBhcmtpbnNvbiBEaXNlYXNlL2NsYXNzaWZpY2F0aW9uL21ldGFib2xpc20vcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBsYXF1ZSwgQW15bG9pZC8qcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPlN0YXRpc3RpY3MsIE5vbnBhcmFtZXRyaWM8L2tleXdvcmQ+PGtleXdvcmQ+YWxw

aGEtU3ludWNsZWluLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMDg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4wMDAxLTYzMjIgKFByaW50KSYjeEQ7MDAwMS02MzIyIChMaW5raW5nKTwvaXNibj48

YWNjZXNzaW9uLW51bT4xODE4NTk0MDwvYWNjZXNzaW9uLW51bT48d29yay10eXBlPlJlc2VhcmNo

IFN1cHBvcnQsIE5vbi1VLlMuIEdvdiZhcG9zO3Q8L3dvcmstdHlwZT48dXJscz48cmVsYXRlZC11

cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xODE4NTk0MDwvdXJs

Pjx1cmw+aHR0cDovL2Rvd25sb2FkLnNwcmluZ2VyLmNvbS9zdGF0aWMvcGRmLzY0Ni9hcnQlMjUz

QTEwLjEwMDclMjUyRnMwMDQwMS0wMDctMDMzNi0wLnBkZj9hdXRoNjY9MTM5Mzc2NTE2OF8yYzI3

YTI5YzNmNjRlMmYyZTNmZGJhMjIyNTU4NmY5ZiZhbXA7ZXh0PS5wZGY8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczAwNDAxLTAwNy0w

MzM2LTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA (Lashley, et al., 2008). Quantitation of Aβ-positive mature and diffuse plaques was performed based on Consortium to Establish a Registry for AD (CERAD) recommendations ADDIN EN.CITE <EndNote><Cite><Author>Mirra</Author><Year>1991</Year><RecNum>206</RecNum><DisplayText>(Mirra, et al., 1991)</DisplayText><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392377331">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mirra, S. S.</author><author>Heyman, A.</author><author>McKeel, D.</author><author>Sumi, S. M.</author><author>Crain, B. J.</author><author>Brownlee, L. M.</author><author>Vogel, F. S.</author><author>Hughes, J. P.</author><author>van Belle, G.</author><author>Berg, L.</author></authors></contributors><auth-address>VA Medical Center, Department of Pathology and Laboratory Medicine, Decatur, GA 30033.</auth-address><titles><title>The Consortium to Establish a Registry for Alzheimer&apos;s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer&apos;s disease</title><secondary-title>Neurology</secondary-title><alt-title>Neurology</alt-title></titles><periodical><full-title>Neurology</full-title></periodical><alt-periodical><full-title>Neurology</full-title></alt-periodical><pages>479-86</pages><volume>41</volume><number>4</number><edition>1991/04/01</edition><keywords><keyword>Aged</keyword><keyword>Alzheimer Disease/complications/metabolism/*pathology</keyword><keyword>Amyloid/metabolism</keyword><keyword>Brain/metabolism/*pathology</keyword><keyword>Cadaver</keyword><keyword>Cognition Disorders/etiology</keyword><keyword>Humans</keyword><keyword>Reference Values</keyword><keyword>*Registries</keyword></keywords><dates><year>1991</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0028-3878 (Print)&#xD;0028-3878 (Linking)</isbn><accession-num>2011243</accession-num><work-type>Research Support, U.S. Gov&apos;t, Non-P.H.S.&#xD;Research Support, U.S. Gov&apos;t, P.H.S.</work-type><urls><related-urls><url>;(Mirra, et al., 1991). Alzheimer-type neurofibrillary tangle pathology was assessed using Braak and Braak staging PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmFhazwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4yMDk8L1JlY051bT48RGlzcGxheVRleHQ+KEJyYWFrLCBldCBhbC4sIDIwMDYpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIwOTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzc3ODE3Ij4yMDk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkJyYWFrLCBILjwvYXV0aG9yPjxhdXRob3I+QWxhZnV6b2ZmLCBJLjwvYXV0

aG9yPjxhdXRob3I+QXJ6YmVyZ2VyLCBULjwvYXV0aG9yPjxhdXRob3I+S3JldHpzY2htYXIsIEgu

PC9hdXRob3I+PGF1dGhvcj5EZWwgVHJlZGljaSwgSy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgZm9yIENsaW5pY2FsIE5ldXJvYW5hdG9t

eSwgSi5XLiBHb2V0aGUgVW5pdmVyc2l0eSBDbGluaWMsIFRoZW9kb3IgU3Rlcm4gS2FpIDcsIDYw

NTkwIEZyYW5rZnVydC9NYWluLCBHZXJtYW55LiBCcmFha0BlbS51bmktZnJhbmtmdXJ0LmRlPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U3RhZ2luZyBvZiBBbHpoZWltZXIgZGlzZWFzZS1h

c3NvY2lhdGVkIG5ldXJvZmlicmlsbGFyeSBwYXRob2xvZ3kgdXNpbmcgcGFyYWZmaW4gc2VjdGlv

bnMgYW5kIGltbXVub2N5dG9jaGVtaXN0cnk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWN0YSBO

ZXVyb3BhdGhvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QWN0YSBuZXVyb3BhdGhvbG9n

aWNhPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0YSBOZXVy

b3BhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM4OS00MDQ8L3BhZ2VzPjx2

b2x1bWU+MTEyPC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGVkaXRpb24+MjAwNi8wOC8xNTwv

ZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvbWV0YWJvbGlzbS8q

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9tZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPipEaXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3

b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeS8qbWV0aG9k

czwva2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbGxhcnkgVGFuZ2xlcy9tZXRhYm9saXNtLypw

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UGFyYWZmaW4gRW1iZWRkaW5nLyptZXRob2RzPC9r

ZXl3b3JkPjxrZXl3b3JkPlRpc3N1ZSBGaXhhdGlvbi9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3Jk

PnRhdSBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3Q8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4wMDAxLTYzMjIgKFByaW50KSYjeEQ7MDAwMS02MzIyIChMaW5raW5nKTwvaXNibj48

YWNjZXNzaW9uLW51bT4xNjkwNjQyNjwvYWNjZXNzaW9uLW51bT48d29yay10eXBlPlJlc2VhcmNo

IFN1cHBvcnQsIE5vbi1VLlMuIEdvdiZhcG9zO3QmI3hEO1RlY2huaWNhbCBSZXBvcnQ8L3dvcmst

dHlwZT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC8xNjkwNjQyNjwvdXJsPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3Bt

Yy9hcnRpY2xlcy9QTUMzOTA2NzA5L3BkZi80MDFfMjAwNl9BcnRpY2xlXzEyNy5wZGY8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+MzkwNjcwOTwvY3VzdG9tMj48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA0MDEtMDA2LTAxMjctejwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmFhazwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4yMDk8L1JlY051bT48RGlzcGxheVRleHQ+KEJyYWFrLCBldCBhbC4sIDIwMDYpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIwOTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzc3ODE3Ij4yMDk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkJyYWFrLCBILjwvYXV0aG9yPjxhdXRob3I+QWxhZnV6b2ZmLCBJLjwvYXV0

aG9yPjxhdXRob3I+QXJ6YmVyZ2VyLCBULjwvYXV0aG9yPjxhdXRob3I+S3JldHpzY2htYXIsIEgu

PC9hdXRob3I+PGF1dGhvcj5EZWwgVHJlZGljaSwgSy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgZm9yIENsaW5pY2FsIE5ldXJvYW5hdG9t

eSwgSi5XLiBHb2V0aGUgVW5pdmVyc2l0eSBDbGluaWMsIFRoZW9kb3IgU3Rlcm4gS2FpIDcsIDYw

NTkwIEZyYW5rZnVydC9NYWluLCBHZXJtYW55LiBCcmFha0BlbS51bmktZnJhbmtmdXJ0LmRlPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U3RhZ2luZyBvZiBBbHpoZWltZXIgZGlzZWFzZS1h

c3NvY2lhdGVkIG5ldXJvZmlicmlsbGFyeSBwYXRob2xvZ3kgdXNpbmcgcGFyYWZmaW4gc2VjdGlv

bnMgYW5kIGltbXVub2N5dG9jaGVtaXN0cnk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWN0YSBO

ZXVyb3BhdGhvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QWN0YSBuZXVyb3BhdGhvbG9n

aWNhPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0YSBOZXVy

b3BhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM4OS00MDQ8L3BhZ2VzPjx2

b2x1bWU+MTEyPC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGVkaXRpb24+MjAwNi8wOC8xNTwv

ZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvbWV0YWJvbGlzbS8q

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9tZXRhYm9s

aXNtPC9rZXl3b3JkPjxrZXl3b3JkPipEaXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3

b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeS8qbWV0aG9k

czwva2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbGxhcnkgVGFuZ2xlcy9tZXRhYm9saXNtLypw

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UGFyYWZmaW4gRW1iZWRkaW5nLyptZXRob2RzPC9r

ZXl3b3JkPjxrZXl3b3JkPlRpc3N1ZSBGaXhhdGlvbi9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3Jk

PnRhdSBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5PY3Q8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4wMDAxLTYzMjIgKFByaW50KSYjeEQ7MDAwMS02MzIyIChMaW5raW5nKTwvaXNibj48

YWNjZXNzaW9uLW51bT4xNjkwNjQyNjwvYWNjZXNzaW9uLW51bT48d29yay10eXBlPlJlc2VhcmNo

IFN1cHBvcnQsIE5vbi1VLlMuIEdvdiZhcG9zO3QmI3hEO1RlY2huaWNhbCBSZXBvcnQ8L3dvcmst

dHlwZT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC8xNjkwNjQyNjwvdXJsPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3Bt

Yy9hcnRpY2xlcy9QTUMzOTA2NzA5L3BkZi80MDFfMjAwNl9BcnRpY2xlXzEyNy5wZGY8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+MzkwNjcwOTwvY3VzdG9tMj48ZWxlY3Ryb25p

Yy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA0MDEtMDA2LTAxMjctejwvZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Braak, et al., 2006). The extent and severity of CAA was determined based on a four-tier grading system PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PbGljaG5leTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+

PFJlY051bT4yMDc8L1JlY051bT48RGlzcGxheVRleHQ+KExhc2hsZXksIGV0IGFsLiwgMjAwOCxP

bGljaG5leSwgZXQgYWwuLCAxOTk2KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4y

MDc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVy

ZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3Nzc5OCI+MjA3

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5PbGljaG5leSwgSi4gTS48

L2F1dGhvcj48YXV0aG9yPkhhbnNlbiwgTC4gQS48L2F1dGhvcj48YXV0aG9yPkdhbGFza28sIEQu

PC9hdXRob3I+PGF1dGhvcj5TYWl0b2gsIFQuPC9hdXRob3I+PGF1dGhvcj5Ib2ZzdGV0dGVyLCBD

LiBSLjwvYXV0aG9yPjxhdXRob3I+S2F0em1hbiwgUi48L2F1dGhvcj48YXV0aG9yPlRoYWwsIEwu

IEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0

bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIFNhbiBEaWVn

bywgTGEgSm9sbGEsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgYXBvbGlw

b3Byb3RlaW4gRSBlcHNpbG9uIDQgYWxsZWxlIGlzIGFzc29jaWF0ZWQgd2l0aCBpbmNyZWFzZWQg

bmV1cml0aWMgcGxhcXVlcyBhbmQgY2VyZWJyYWwgYW15bG9pZCBhbmdpb3BhdGh5IGluIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZSBhbmQgTGV3eSBib2R5IHZhcmlhbnQ8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+TmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5OZXVyb2xvZ3k8

L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xvZ3k8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xv

Z3k8L2Z1bGwtdGl0bGU+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MTkwLTY8L3BhZ2VzPjx2b2x1

bWU+NDc8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4xOTk2LzA3LzAxPC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFu

ZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypnZW5ldGljczwva2V5

d29yZD48a2V5d29yZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5BcG9s

aXBvcHJvdGVpbnMgRS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9p

ZCBBbmdpb3BhdGh5LypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+

PGtleXdvcmQ+R2Vub3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPkxld3kgQm9kaWVzLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI4LTM4NzggKFByaW50KSYjeEQ7MDAy

OC0zODc4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT44NzEwMDc2PC9hY2Nlc3Npb24t

bnVtPjx3b3JrLXR5cGU+UmVzZWFyY2ggU3VwcG9ydCwgVS5TLiBHb3YmYXBvczt0LCBOb24tUC5I

LlMuJiN4RDtSZXNlYXJjaCBTdXBwb3J0LCBVLlMuIEdvdiZhcG9zO3QsIFAuSC5TLjwvd29yay10

eXBlPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzg3MTAwNzY8L3VybD48dXJsPmh0dHA6Ly9ncmFwaGljcy50eC5vdmlkLmNvbS9vdmZ0

cGRmcy9GUERETkNHQ0pCSUtBRzAwL2ZzMDQ3L292ZnQvbGl2ZS9ndjAzMS8wMDAwNjExNC8wMDAw

NjExNC0xOTk2MDcwMDAtMDAwMzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVj

b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkxhc2hsZXk8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFy

PjxSZWNOdW0+MjAyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4yMDI8L3JlYy1udW1iZXI+

PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4

ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3NTg2MyI+MjAyPC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MYXNobGV5LCBULjwvYXV0aG9yPjxhdXRob3I+SG9s

dG9uLCBKLiBMLjwvYXV0aG9yPjxhdXRob3I+R3JheSwgRS48L2F1dGhvcj48YXV0aG9yPktpcmto

YW0sIEsuPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7U3VsbGl2YW4sIFMuIFMuPC9hdXRob3I+PGF1

dGhvcj5IaWxiaWcsIEEuPC9hdXRob3I+PGF1dGhvcj5Xb29kLCBOLiBXLjwvYXV0aG9yPjxhdXRo

b3I+TGVlcywgQS4gSi48L2F1dGhvcj48YXV0aG9yPlJldmVzeiwgVC48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5RdWVlbiBTcXVhcmUgQnJhaW4gQmFuayBm

b3IgTmV1cm9sb2dpY2FsIERpc29yZGVycywgRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgTmV1cm9z

Y2llbmNlLCBVQ0wgSW5zdGl0dXRlIG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBDb2xsZWdlIExv

bmRvbiwgUXVlZW4gU3F1YXJlLCBMb25kb24gV0MxTiAzQkcsIFVLLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkNvcnRpY2FsIGFscGhhLXN5bnVjbGVpbiBsb2FkIGlzIGFzc29jaWF0ZWQg

d2l0aCBhbXlsb2lkLWJldGEgcGxhcXVlIGJ1cmRlbiBpbiBhIHN1YnNldCBvZiBQYXJraW5zb24m

YXBvcztzIGRpc2Vhc2UgcGF0aWVudHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWN0YSBOZXVy

b3BhdGhvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QWN0YSBuZXVyb3BhdGhvbG9naWNh

PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0YSBOZXVyb3Bh

dGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQxNy0yNTwvcGFnZXM+PHZvbHVt

ZT4xMTU8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDA4LzAxLzExPC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQg

YmV0YS1QZXB0aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0

ZXgvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TGV3eSBCb2RpZXMvcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tl

eXdvcmQ+PGtleXdvcmQ+KlBhcmtpbnNvbiBEaXNlYXNlL2NsYXNzaWZpY2F0aW9uL21ldGFib2xp

c20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBsYXF1ZSwgQW15bG9pZC8qcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPlN0YXRpc3RpY3MsIE5vbnBhcmFtZXRyaWM8L2tleXdvcmQ+PGtl

eXdvcmQ+YWxwaGEtU3ludWNsZWluLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMDg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0

ZXM+PC9kYXRlcz48aXNibj4wMDAxLTYzMjIgKFByaW50KSYjeEQ7MDAwMS02MzIyIChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4xODE4NTk0MDwvYWNjZXNzaW9uLW51bT48d29yay10eXBl

PlJlc2VhcmNoIFN1cHBvcnQsIE5vbi1VLlMuIEdvdiZhcG9zO3Q8L3dvcmstdHlwZT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xODE4

NTk0MDwvdXJsPjx1cmw+aHR0cDovL2Rvd25sb2FkLnNwcmluZ2VyLmNvbS9zdGF0aWMvcGRmLzY0

Ni9hcnQlMjUzQTEwLjEwMDclMjUyRnMwMDQwMS0wMDctMDMzNi0wLnBkZj9hdXRoNjY9MTM5Mzc2

NTE2OF8yYzI3YTI5YzNmNjRlMmYyZTNmZGJhMjIyNTU4NmY5ZiZhbXA7ZXh0PS5wZGY8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczAw

NDAxLTAwNy0wMzM2LTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PbGljaG5leTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+

PFJlY051bT4yMDc8L1JlY051bT48RGlzcGxheVRleHQ+KExhc2hsZXksIGV0IGFsLiwgMjAwOCxP

bGljaG5leSwgZXQgYWwuLCAxOTk2KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4y

MDc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVy

ZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3Nzc5OCI+MjA3

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5PbGljaG5leSwgSi4gTS48

L2F1dGhvcj48YXV0aG9yPkhhbnNlbiwgTC4gQS48L2F1dGhvcj48YXV0aG9yPkdhbGFza28sIEQu

PC9hdXRob3I+PGF1dGhvcj5TYWl0b2gsIFQuPC9hdXRob3I+PGF1dGhvcj5Ib2ZzdGV0dGVyLCBD

LiBSLjwvYXV0aG9yPjxhdXRob3I+S2F0em1hbiwgUi48L2F1dGhvcj48YXV0aG9yPlRoYWwsIEwu

IEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0

bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENhbGlmb3JuaWEsIFNhbiBEaWVn

bywgTGEgSm9sbGEsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgYXBvbGlw

b3Byb3RlaW4gRSBlcHNpbG9uIDQgYWxsZWxlIGlzIGFzc29jaWF0ZWQgd2l0aCBpbmNyZWFzZWQg

bmV1cml0aWMgcGxhcXVlcyBhbmQgY2VyZWJyYWwgYW15bG9pZCBhbmdpb3BhdGh5IGluIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZSBhbmQgTGV3eSBib2R5IHZhcmlhbnQ8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+TmV1cm9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5OZXVyb2xvZ3k8

L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xvZ3k8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xv

Z3k8L2Z1bGwtdGl0bGU+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MTkwLTY8L3BhZ2VzPjx2b2x1

bWU+NDc8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4xOTk2LzA3LzAxPC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFu

ZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypnZW5ldGljczwva2V5

d29yZD48a2V5d29yZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5BcG9s

aXBvcHJvdGVpbnMgRS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9p

ZCBBbmdpb3BhdGh5LypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+

PGtleXdvcmQ+R2Vub3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPkxld3kgQm9kaWVzLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI4LTM4NzggKFByaW50KSYjeEQ7MDAy

OC0zODc4IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT44NzEwMDc2PC9hY2Nlc3Npb24t

bnVtPjx3b3JrLXR5cGU+UmVzZWFyY2ggU3VwcG9ydCwgVS5TLiBHb3YmYXBvczt0LCBOb24tUC5I

LlMuJiN4RDtSZXNlYXJjaCBTdXBwb3J0LCBVLlMuIEdvdiZhcG9zO3QsIFAuSC5TLjwvd29yay10

eXBlPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv

cHVibWVkLzg3MTAwNzY8L3VybD48dXJsPmh0dHA6Ly9ncmFwaGljcy50eC5vdmlkLmNvbS9vdmZ0

cGRmcy9GUERETkNHQ0pCSUtBRzAwL2ZzMDQ3L292ZnQvbGl2ZS9ndjAzMS8wMDAwNjExNC8wMDAw

NjExNC0xOTk2MDcwMDAtMDAwMzQucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVj

b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkxhc2hsZXk8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFy

PjxSZWNOdW0+MjAyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4yMDI8L3JlYy1udW1iZXI+

PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4

ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3NTg2MyI+MjAyPC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MYXNobGV5LCBULjwvYXV0aG9yPjxhdXRob3I+SG9s

dG9uLCBKLiBMLjwvYXV0aG9yPjxhdXRob3I+R3JheSwgRS48L2F1dGhvcj48YXV0aG9yPktpcmto

YW0sIEsuPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7U3VsbGl2YW4sIFMuIFMuPC9hdXRob3I+PGF1

dGhvcj5IaWxiaWcsIEEuPC9hdXRob3I+PGF1dGhvcj5Xb29kLCBOLiBXLjwvYXV0aG9yPjxhdXRo

b3I+TGVlcywgQS4gSi48L2F1dGhvcj48YXV0aG9yPlJldmVzeiwgVC48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5RdWVlbiBTcXVhcmUgQnJhaW4gQmFuayBm

b3IgTmV1cm9sb2dpY2FsIERpc29yZGVycywgRGVwYXJ0bWVudCBvZiBNb2xlY3VsYXIgTmV1cm9z

Y2llbmNlLCBVQ0wgSW5zdGl0dXRlIG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBDb2xsZWdlIExv

bmRvbiwgUXVlZW4gU3F1YXJlLCBMb25kb24gV0MxTiAzQkcsIFVLLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkNvcnRpY2FsIGFscGhhLXN5bnVjbGVpbiBsb2FkIGlzIGFzc29jaWF0ZWQg

d2l0aCBhbXlsb2lkLWJldGEgcGxhcXVlIGJ1cmRlbiBpbiBhIHN1YnNldCBvZiBQYXJraW5zb24m

YXBvcztzIGRpc2Vhc2UgcGF0aWVudHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWN0YSBOZXVy

b3BhdGhvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QWN0YSBuZXVyb3BhdGhvbG9naWNh

PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QWN0YSBOZXVyb3Bh

dGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQxNy0yNTwvcGFnZXM+PHZvbHVt

ZT4xMTU8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDA4LzAxLzExPC9lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQg

YmV0YS1QZXB0aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0

ZXgvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29y

ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TGV3eSBCb2RpZXMvcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tl

eXdvcmQ+PGtleXdvcmQ+KlBhcmtpbnNvbiBEaXNlYXNlL2NsYXNzaWZpY2F0aW9uL21ldGFib2xp

c20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBsYXF1ZSwgQW15bG9pZC8qcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPlN0YXRpc3RpY3MsIE5vbnBhcmFtZXRyaWM8L2tleXdvcmQ+PGtl

eXdvcmQ+YWxwaGEtU3ludWNsZWluLyptZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMDg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0

ZXM+PC9kYXRlcz48aXNibj4wMDAxLTYzMjIgKFByaW50KSYjeEQ7MDAwMS02MzIyIChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4xODE4NTk0MDwvYWNjZXNzaW9uLW51bT48d29yay10eXBl

PlJlc2VhcmNoIFN1cHBvcnQsIE5vbi1VLlMuIEdvdiZhcG9zO3Q8L3dvcmstdHlwZT48dXJscz48

cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xODE4

NTk0MDwvdXJsPjx1cmw+aHR0cDovL2Rvd25sb2FkLnNwcmluZ2VyLmNvbS9zdGF0aWMvcGRmLzY0

Ni9hcnQlMjUzQTEwLjEwMDclMjUyRnMwMDQwMS0wMDctMDMzNi0wLnBkZj9hdXRoNjY9MTM5Mzc2

NTE2OF8yYzI3YTI5YzNmNjRlMmYyZTNmZGJhMjIyNTU4NmY5ZiZhbXA7ZXh0PS5wZGY8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMDcvczAw

NDAxLTAwNy0wMzM2LTA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA (Lashley, et al., 2008,Olichney, et al., 1996), described in Supplementary Information. Quantitation of the immunohistochemical stains was undertaken to assess any deep white matter changes in the occipital and parietal regions. Myelin loss was assessed using myelin basic protein (MBP) immunohistochemistry (SMI94R antibody) while changes in axonal density and/or integrity were investigated using the phosphorylation dependent anti-neurofilament antibody RT97. Iba1 and CD68 immunohistochemistry was used to assess microglial response and GFAP immunohistochemistry was employed to study astrocytic response. CD3 and CD20 immunohistochemical preparations were used to assess T and B lymphocytic response, respectively. A semi-quantitative assessment of myelin loss, gliosis and microglial expression was made, described in Supplementary Information. Stained slides were scanned using the Leica Slide Scanner SCN400 producing digital images of the whole section. Regions of interest were marked in the deep white matter and separately in the superficial U-fibres. The latter were used as an internal control on the basis that U-fibres are relatively spared in both subcortical arteriosclerotic encephalopathy ADDIN EN.CITE <EndNote><Cite><Author>Revesz</Author><Year>1989</Year><RecNum>204</RecNum><DisplayText>(Revesz, et al., 1989)</DisplayText><record><rec-number>204</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392377302">204</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Revesz, T.</author><author>Hawkins, C. P.</author><author>du Boulay, E. P.</author><author>Barnard, R. O.</author><author>McDonald, W. I.</author></authors></contributors><auth-address>Maida Vale Hospital for Nervous Diseases, London, England.</auth-address><titles><title>Pathological findings correlated with magnetic resonance imaging in subcortical arteriosclerotic encephalopathy (Binswanger&apos;s disease)</title><secondary-title>J Neurol Neurosurg Psychiatry</secondary-title><alt-title>Journal of neurology, neurosurgery, and psychiatry</alt-title></titles><periodical><full-title>J Neurol Neurosurg Psychiatry</full-title></periodical><pages>1337-44</pages><volume>52</volume><number>12</number><edition>1989/12/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Cerebral Cortex/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Intracranial Arteriosclerosis/*pathology</keyword><keyword>Magnetic Resonance Imaging/methods</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Multiple Sclerosis/pathology</keyword></keywords><dates><year>1989</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0022-3050 (Print)&#xD;0022-3050 (Linking)</isbn><accession-num>2614428</accession-num><work-type>Case Reports&#xD;Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>;(Revesz, et al., 1989) and in white matter damage due to CAA ADDIN EN.CITE <EndNote><Cite><Author>Plant</Author><Year>1990</Year><RecNum>203</RecNum><DisplayText>(Plant, et al., 1990)</DisplayText><record><rec-number>203</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392377271">203</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Plant, G. T.</author><author>Revesz, T.</author><author>Barnard, R. O.</author><author>Harding, A. E.</author><author>Gautier-Smith, P. C.</author></authors></contributors><auth-address>National Hospital for Nervous Diseases, Queen Square, London, UK.</auth-address><titles><title>Familial cerebral amyloid angiopathy with nonneuritic amyloid plaque formation</title><secondary-title>Brain</secondary-title><alt-title>Brain : a journal of neurology</alt-title></titles><periodical><full-title>Brain</full-title></periodical><pages>721-47</pages><volume>113 ( Pt 3)</volume><edition>1990/06/01</edition><keywords><keyword>Amyloidosis/*genetics/pathology</keyword><keyword>Blood Vessels/pathology</keyword><keyword>Brain/pathology</keyword><keyword>Cerebrovascular Circulation</keyword><keyword>Cerebrovascular Disorders/diagnosis/*genetics/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Microscopy, Electron</keyword><keyword>Middle Aged</keyword><keyword>Neurofibrils/pathology</keyword><keyword>Pedigree</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>1990</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0006-8950 (Print)&#xD;0006-8950 (Linking)</isbn><accession-num>2364266</accession-num><work-type>Case Reports</work-type><urls><related-urls><url>;(Plant, et al., 1990). Using x20 magnification, ten random fields from the marked areas were captured using PicPick software (). The density of immunohistochemical staining (% area stained) was accessed using Image J software (imagej.en.). Occipital white matter could not be analysed for the p.Arg377Met case due to an infarct and there was insufficient parietal deep white matter available for region of interest analysis for one intron 4 (g.23024delG) case.The proportion of blood vessels affected by amyloid deposition and the severity of amyloid deposition were also determined; occipital sections immunostained with an anti-Aβ antibody were scanned and 10 random fields digitally captured as described above. The number of vessels containing Aβ in the leptomeninges and cerebral cortical parenchyma were then counted and expressed as a percentage of the total number of vessels analysed. The number of vessels classed as ‘severely affected’ were also counted. The criteria for this was the presence of degenerative vascular changes known to be associated with CAA ADDIN EN.CITE <EndNote><Cite><Author>Revesz</Author><Year>2003</Year><RecNum>181</RecNum><DisplayText>(Revesz, et al., 2003)</DisplayText><record><rec-number>181</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">181</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Revesz,T.</author><author>Ghiso,J.</author><author>Lashley,T.</author><author>Plant,G.</author><author>Rostagno,A.</author><author>Frangione,B.</author><author>Holton,J.L.</author></authors></contributors><auth-address>Queen Square Brain Bank, Department of Molecular Neuroscience and Division of Neuropathology, Institute of Neurology, University College London, London, United Kingdom. t.revesz@ion.ucl.ac.uk</auth-address><titles><title>Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view</title><secondary-title>J Neuropathol Exp.Neurol</secondary-title></titles><periodical><full-title>J Neuropathol Exp.Neurol</full-title></periodical><pages>885-898</pages><volume>62</volume><number>9</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Alzheimer Disease</keyword><keyword>Amino Acid Sequence</keyword><keyword>Amyloid</keyword><keyword>Amyloidosis</keyword><keyword>Animals</keyword><keyword>Brain</keyword><keyword>Capillaries</keyword><keyword>Central Nervous System</keyword><keyword>Cerebral Amyloid Angiopathy</keyword><keyword>Cerebral Hemorrhage</keyword><keyword>Dementia</keyword><keyword>Genes</keyword><keyword>genetics</keyword><keyword>Humans</keyword><keyword>metabolism</keyword><keyword>Molecular Sequence Data</keyword><keyword>Mutation</keyword><keyword>Neurology</keyword><keyword>pathology</keyword><keyword>Presenilin-1</keyword><keyword>Proteins</keyword></keywords><dates><year>2003</year><pub-dates><date>9/2003</date></pub-dates></dates><label>215</label><urls><related-urls><url>;(Revesz, et al., 2003). In both the leptomeninges and parenchyma, the diameter of the blood vessel walls were measured and averaged in 10 random fields. 2.4. Statistical analysisAnalysis of the association between mutation group and ARWMC score on MRI was carried out using bootstrapped regression with samples stratified by group, using 2000 replications and bias-corrected confidence intervals, implemented in STATA 11 (Stata Corporation, College Station, Texas). Due to the use of bootstrapping, exact p-values are not provided; rather, p-value ranges were inferred from whether confidence intervals excluded zero. Mutation group was defined as either control, APP, PSEN1 pre-codon 200 or PSEN1 post-codon 200. Group differences in total ARWMC scores were assessed for each of the mutation groups compared to controls and for the two PSEN1 mutation groups compared to each other. Analyses were additionally adjusted for age at scan, presence of an APOE4 allele and vascular risk score. The vascular risk scores observed in this study ranged from only 0-2 and were therefore categorised as either low (score 0) or increased (score 1-2) risk. In the autopsy cohort, comparisons between the PSEN1 pre-codon 200 and PSEN1 post-codon 200 mutation groups were made for the immunohistochemical stains using t-tests for normally distributed variables and Wilcoxon rank sum testing for categorical data. Paired t-tests were used for within-subject comparisons of staining in the deep white matter and U-fibre regions of interest. In view of the skewed distribution of the ARWMC scale Kendall’s tau, a non-parametric correlation coefficient, was used to investigate correlations between total ARWMC score on MRI and pathological findings in the autopsy cohort as a whole. Correlations between age at onset and the pathological findings were investigated using Kendall’s tau for categorical and Pearson’s pairwise correlations for continuous data. Pathological differences between APOE4 carriers and non-carriers were explored using the same methods as were used to compare the PSEN1 pre and post-codon groups.3. Results3.1. Imaging cohortThe majority of the 52 FAD patients in this study had mutations that have previously been reported but several subjects with novel mutations were also included. The APP cohort comprised six p.Val717Ile, four p.Val717Gly and one each of p.Val717Leu, p.Ala692Gly (Flemish) and the novel p.Thr719Asn mutation. The PSEN1 pre-codon 200 cohort comprised six intron 4 (g.23024delG) mutations, six p.Met139Val and one each of p.Ile143Phe, p.Leu166del, p.Leu166Arg, p.Glu184Asp, p.Tyr115His and p.Glu120Lys. The PSEN1 post-codon 200 cohort comprised five p.Glu280Gly, three p.Arg278Ile, two each of p.Leu235Val and p.Pro264Leu, one each of p.Ile202Phe, p.Phe237Leu, p.Leu250Ser, p.Arg269His, p.Arg377Met, p.Gly394Val and the novel mutations p.Gln222Pro and p.Phe283Leu. The final subject had pathologically confirmed AD with two post-codon 200 PSEN1 substitutions; the novel p.Thr291Ala and the recently reported p.Ala434Thr mutation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KaWFvPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVj

TnVtPjI4NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oSmlhbywgZXQgYWwuLCAyMDE0KTwvRGlzcGxh

eVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yODQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIi

IHRpbWVzdGFtcD0iMTQxMzc5NjM4MCI+Mjg0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5KaWFvLCBCLjwvYXV0aG9yPjxhdXRob3I+VGFuZywgQi48L2F1dGhvcj48YXV0

aG9yPkxpdSwgWC48L2F1dGhvcj48YXV0aG9yPlh1LCBKLjwvYXV0aG9yPjxhdXRob3I+V2FuZywg

WS48L2F1dGhvcj48YXV0aG9yPlpob3UsIEwuPC9hdXRob3I+PGF1dGhvcj5aaGFuZywgRi48L2F1

dGhvcj48YXV0aG9yPllhbiwgWC48L2F1dGhvcj48YXV0aG9yPlpob3UsIFkuPC9hdXRob3I+PGF1

dGhvcj5TaGVuLCBMLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy

ZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBYaWFuZ3lhIEhvc3BpdGFsLCBDZW50cmFsIFNv

dXRoIFVuaXZlcnNpdHksIENoYW5nc2hhLCBDaGluYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9s

b2d5LCBYaWFuZ3lhIEhvc3BpdGFsLCBDZW50cmFsIFNvdXRoIFVuaXZlcnNpdHksIENoYW5nc2hh

LCBDaGluYTsgU3RhdGUgS2V5IExhYm9yYXRvcnkgb2YgTWVkaWNhbCBHZW5ldGljcywgQ2hhbmdz

aGEsIENoaW5hOyBLZXkgTGFib3JhdG9yeSBvZiBIdW5hbiBQcm92aW5jZSBpbiBOZXVyb2RlZ2Vu

ZXJhdGl2ZSBEaXNvcmRlcnMsIENlbnRyYWwgU291dGggVW5pdmVyc2l0eSwgQ2hhbmdzaGEsIENo

aW5hLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEppYW5nc3UgR2VyaWF0cmljIEhvc3Bp

dGFsLCBOYW5qaW5nLCBDaGluYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5IGFuZCBDZW50

ZXIgZm9yIENsaW5pY2FsIE5ldXJvc2NpZW5jZSwgRGFwaW5nIEhvc3BpdGFsLCBUaGlyZCBNaWxp

dGFyeSBNZWRpY2FsIFVuaXZlcnNpdHksIENob25ncWluZywgQ2hpbmEuJiN4RDtEZXBhcnRtZW50

IG9mIE5ldXJvbG9neSwgWGlhbmd5YSBIb3NwaXRhbCwgQ2VudHJhbCBTb3V0aCBVbml2ZXJzaXR5

LCBDaGFuZ3NoYSwgQ2hpbmE7IEtleSBMYWJvcmF0b3J5IG9mIEh1bmFuIFByb3ZpbmNlIGluIE5l

dXJvZGVnZW5lcmF0aXZlIERpc29yZGVycywgQ2VudHJhbCBTb3V0aCBVbml2ZXJzaXR5LCBDaGFu

Z3NoYSwgQ2hpbmEuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgWGlhbmd5YSBIb3NwaXRh

bCwgQ2VudHJhbCBTb3V0aCBVbml2ZXJzaXR5LCBDaGFuZ3NoYSwgQ2hpbmE7IFN0YXRlIEtleSBM

YWJvcmF0b3J5IG9mIE1lZGljYWwgR2VuZXRpY3MsIENoYW5nc2hhLCBDaGluYTsgS2V5IExhYm9y

YXRvcnkgb2YgSHVuYW4gUHJvdmluY2UgaW4gTmV1cm9kZWdlbmVyYXRpdmUgRGlzb3JkZXJzLCBD

ZW50cmFsIFNvdXRoIFVuaXZlcnNpdHksIENoYW5nc2hhLCBDaGluYS4gRWxlY3Ryb25pYyBhZGRy

ZXNzOiBzaGVubHUyNTA1QDEyNi5jb20uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TXV0

YXRpb25hbCBhbmFseXNpcyBpbiBlYXJseS1vbnNldCBmYW1pbGlhbCBBbHpoZWltZXImYXBvcztz

IGRpc2Vhc2UgaW4gTWFpbmxhbmQgQ2hpbmE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9i

aW9sIEFnaW5nPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgYWdp

bmc8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2Jpb2wg

QWdpbmc8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xOTU3IGUxLTY8L3BhZ2VzPjx2

b2x1bWU+MzU8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNDwveWVh

cj48cHViLWRhdGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1

NTgtMTQ5NyAoRWxlY3Ryb25pYykmI3hEOzAxOTctNDU4MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjQ2NTA3OTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ2NTA3OTQ8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jp

b2xhZ2luZy4yMDE0LjAyLjAxNDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KaWFvPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVj

TnVtPjI4NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oSmlhbywgZXQgYWwuLCAyMDE0KTwvRGlzcGxh

eVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yODQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIi

IHRpbWVzdGFtcD0iMTQxMzc5NjM4MCI+Mjg0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5KaWFvLCBCLjwvYXV0aG9yPjxhdXRob3I+VGFuZywgQi48L2F1dGhvcj48YXV0

aG9yPkxpdSwgWC48L2F1dGhvcj48YXV0aG9yPlh1LCBKLjwvYXV0aG9yPjxhdXRob3I+V2FuZywg

WS48L2F1dGhvcj48YXV0aG9yPlpob3UsIEwuPC9hdXRob3I+PGF1dGhvcj5aaGFuZywgRi48L2F1

dGhvcj48YXV0aG9yPllhbiwgWC48L2F1dGhvcj48YXV0aG9yPlpob3UsIFkuPC9hdXRob3I+PGF1

dGhvcj5TaGVuLCBMLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy

ZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBYaWFuZ3lhIEhvc3BpdGFsLCBDZW50cmFsIFNv

dXRoIFVuaXZlcnNpdHksIENoYW5nc2hhLCBDaGluYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9s

b2d5LCBYaWFuZ3lhIEhvc3BpdGFsLCBDZW50cmFsIFNvdXRoIFVuaXZlcnNpdHksIENoYW5nc2hh

LCBDaGluYTsgU3RhdGUgS2V5IExhYm9yYXRvcnkgb2YgTWVkaWNhbCBHZW5ldGljcywgQ2hhbmdz

aGEsIENoaW5hOyBLZXkgTGFib3JhdG9yeSBvZiBIdW5hbiBQcm92aW5jZSBpbiBOZXVyb2RlZ2Vu

ZXJhdGl2ZSBEaXNvcmRlcnMsIENlbnRyYWwgU291dGggVW5pdmVyc2l0eSwgQ2hhbmdzaGEsIENo

aW5hLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEppYW5nc3UgR2VyaWF0cmljIEhvc3Bp

dGFsLCBOYW5qaW5nLCBDaGluYS4mI3hEO0RlcGFydG1lbnQgb2YgTmV1cm9sb2d5IGFuZCBDZW50

ZXIgZm9yIENsaW5pY2FsIE5ldXJvc2NpZW5jZSwgRGFwaW5nIEhvc3BpdGFsLCBUaGlyZCBNaWxp

dGFyeSBNZWRpY2FsIFVuaXZlcnNpdHksIENob25ncWluZywgQ2hpbmEuJiN4RDtEZXBhcnRtZW50

IG9mIE5ldXJvbG9neSwgWGlhbmd5YSBIb3NwaXRhbCwgQ2VudHJhbCBTb3V0aCBVbml2ZXJzaXR5

LCBDaGFuZ3NoYSwgQ2hpbmE7IEtleSBMYWJvcmF0b3J5IG9mIEh1bmFuIFByb3ZpbmNlIGluIE5l

dXJvZGVnZW5lcmF0aXZlIERpc29yZGVycywgQ2VudHJhbCBTb3V0aCBVbml2ZXJzaXR5LCBDaGFu

Z3NoYSwgQ2hpbmEuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgWGlhbmd5YSBIb3NwaXRh

bCwgQ2VudHJhbCBTb3V0aCBVbml2ZXJzaXR5LCBDaGFuZ3NoYSwgQ2hpbmE7IFN0YXRlIEtleSBM

YWJvcmF0b3J5IG9mIE1lZGljYWwgR2VuZXRpY3MsIENoYW5nc2hhLCBDaGluYTsgS2V5IExhYm9y

YXRvcnkgb2YgSHVuYW4gUHJvdmluY2UgaW4gTmV1cm9kZWdlbmVyYXRpdmUgRGlzb3JkZXJzLCBD

ZW50cmFsIFNvdXRoIFVuaXZlcnNpdHksIENoYW5nc2hhLCBDaGluYS4gRWxlY3Ryb25pYyBhZGRy

ZXNzOiBzaGVubHUyNTA1QDEyNi5jb20uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TXV0

YXRpb25hbCBhbmFseXNpcyBpbiBlYXJseS1vbnNldCBmYW1pbGlhbCBBbHpoZWltZXImYXBvcztz

IGRpc2Vhc2UgaW4gTWFpbmxhbmQgQ2hpbmE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9i

aW9sIEFnaW5nPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5OZXVyb2Jpb2xvZ3kgb2YgYWdp

bmc8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2Jpb2wg

QWdpbmc8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xOTU3IGUxLTY8L3BhZ2VzPjx2

b2x1bWU+MzU8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAxNDwveWVh

cj48cHViLWRhdGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1

NTgtMTQ5NyAoRWxlY3Ryb25pYykmI3hEOzAxOTctNDU4MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vz

c2lvbi1udW0+MjQ2NTA3OTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs

Pmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ2NTA3OTQ8L3VybD48L3JlbGF0

ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5uZXVyb2Jp

b2xhZ2luZy4yMDE0LjAyLjAxNDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA (Jiao, et al., 2014). All novel sequence variants identified were absent from 100 healthy unrelated white control patients and none of the variants were found in the Exome Aggregate Consortium (ExAC) browser (). Baseline characteristics are shown in Table 1, including ARWMC scores. The groups were well matched for gender. The mean age of the control group (54y) was similar to the APP patient group (54y). The mean age of all PSEN1 subjects at 48 years was, as expected, younger than the APP group. The PSEN1 post-codon 200 group was significantly older than the PSEN1 pre-codon 200 group both at the time of scan (51 vs 44y; p < 0.001) and age at symptom onset (47 vs 39y; p < 0.001). The three patient groups had similar disease durations. None of the groups had clinically significant levels of conventional vascular risk factors. There was a borderline increased vascular risk score in the PSEN1 post-codon 200 compared with PSEN1 pre-codon 200 group (p=0.06), although neither group differed from controls (both p>0.1).3.1.1. White matter hyperintensities and mutation positionResults from analyses of ARWMC score are presented in Table 1, with the mean total ARWMC score at each mutation position shown in Table 2. The PSEN1 post-codon 200 group had a higher total ARWMC score than the PSEN1 pre-codon 200 group (estimated difference in score 2.1 (95% CI 0.4 to 3.8), p<0.01) and controls (estimated difference in score 2.8 (95% CI 1.4 to 4.4), p<0.005), after adjusting for age. The difference between the PSEN1 subgroups appeared to be driven by differences in the parieto-occipital ARWMC score (estimated difference in score 1.4 (95% CI 0.5 to 2.3), 0.005<p<0.01, after adjusting for age); there was no evidence of a difference in total score after excluding this component (p>0.1, after adjusting for age). There was no evidence that individuals with mutations in the APP gene or PSEN1 gene pre-codon 200 differed from controls in terms of their ARWMC score (both p>0.1, after adjusting for age). Only one APP subject had a mutation within the amyloid-β coding domain (p.Ala692Gly, Flemish). This individual’s total ARWMC score (14) was disproportionately higher than the median score for the APP group (0), the remainder of which had mutations at positions 717 and 719. Figure 1 shows representative MR images for subjects in the PSEN1 cohort; some of the WMHs had an atypical appearance, with U-fibre involvement.3.1.2. White matter hyperintensities and vascular risk Accounting for vascular risk weakened the difference in ARWMC score between the PSEN1 pre-codon 200 and PSEN1 post-codon 200 group (estimated difference in score 1.5 (95% CI -0.3 to 3.1), 0.09<p<0.1). However, there was still strong evidence for a difference between the PSEN1 post-codon 200 group and controls (estimated difference in score 2.8 (95% CI 1.5 to 4.4, p<0.005). The model provides evidence that vascular risk and mutation position were both independent predictors of ARWMC score. Increased vascular risk score was associated with an estimated difference in ARWMC score of 2.7 (95% CI 0.5 to 5.5, 0.01<p<0.05), after adjusting for age and mutation group.3.1.3. White matter hyperintensities and APOE4 statusThere was no evidence that APOE status was associated with ARWMC score (after adjusting for group and age, p>0.2) and there was no difference in the proportion of subjects carrying an APOE4 allele between the PSEN1 pre-codon 200 (22%) and PSEN1 post-codon 200 groups (38%, p=0.3). Only one subject in each patient group was APOE4 homozygous: these were individuals with an APP p.Val717Ile mutation (ARWMC score 0): a PSEN1 pre-codon 200 intron 4 (g.23024delG) mutation (ARWMC score 0): and a PSEN1 post-codon 200 p.Ile202Phe mutation ADDIN EN.CITE <EndNote><Cite><Author>Church</Author><Year>2011</Year><RecNum>167</RecNum><DisplayText>(Church, et al., 2011)</DisplayText><record><rec-number>167</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Church,A.</author><author>Prescott,J.</author><author>Lillis,S.</author><author>Rees,J.</author><author>Chance,P.</author><author>Williamson,K.</author><author>Morris,H.R.</author></authors></contributors><auth-address>Department of Neurology, Royal Gwent Hospital, Newport, Gwent, UK</auth-address><titles><title>A novel presenilin 1 mutation, I202F occurring at a previously predicted pathogenic site causing autosomal dominant Alzheimer&apos;s disease</title><secondary-title>Neurobiol Aging</secondary-title></titles><periodical><full-title>Neurobiol Aging</full-title></periodical><pages>556-2</pages><volume>32</volume><number>3</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Mutation</keyword><keyword>Neurology</keyword><keyword>Presenilin-1</keyword></keywords><dates><year>2011</year><pub-dates><date>3/2011</date></pub-dates></dates><label>202</label><urls><related-urls><url>;(Church, et al., 2011) (ARWMC score 8). It was the PSEN1 p.Ile202Phe patient’s baseline scan (shown in Figure 1) that was rated for this study. However, it should be noted that further imaging after a period of clinical deterioration three years later demonstrated floridly increased WMH with extension into the U-fibres and oedema suggesting CAA-related inflammation (CAA-ri), which was confirmed at post-mortem ADDIN EN.CITE <EndNote><Cite><Author>Ryan</Author><Year>2014</Year><RecNum>316</RecNum><DisplayText>(Ryan, et al., 2014)</DisplayText><record><rec-number>316</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1417445854">316</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ryan, N. S.</author><author>Lashley, T.</author><author>Revesz, T.</author><author>Dantu, K.</author><author>Fox, N. C.</author><author>Morris, H. R.</author></authors></contributors><auth-address>Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square, London, UK.&#xD;Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.&#xD;Department of Old Age Psychiatry, Ysbyty Ystrad Fawr Hospital, Hengoed, UK.&#xD;Department of Clinical Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.</auth-address><titles><title>Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer&apos;s Disease</title><secondary-title>J Alzheimers Dis</secondary-title><alt-title>Journal of Alzheimer&apos;s disease : JAD</alt-title></titles><periodical><full-title>J Alzheimers Dis</full-title><abbr-1>Journal of Alzheimer&apos;s disease : JAD</abbr-1></periodical><alt-periodical><full-title>J Alzheimers Dis</full-title><abbr-1>Journal of Alzheimer&apos;s disease : JAD</abbr-1></alt-periodical><dates><year>2014</year><pub-dates><date>Nov 18</date></pub-dates></dates><isbn>1875-8908 (Electronic)&#xD;1387-2877 (Linking)</isbn><accession-num>25408217</accession-num><urls><related-urls><url>;(Ryan, et al., 2014).3.2. Pathology cohortOf the 10 subjects in the imaging study who underwent post-mortem examination, five had PSEN1 pre-codon 200 mutations (p.Glu120Lys and four intron 4 (g.23024delG) mutations) and five had PSEN1 post-codon 200 mutations (p.Ile202Phe, p.Leu235Val, p.Arg278Ile, p.Arg377Met and the double substitution p.Thr291Ala & p.Ala434Thr). In the autopsy subgroup, as in the larger cohort, age at onset was significantly later for those with PSEN1 post-codon 200 compared to PSEN1 pre-codon 200 mutations (43.6 vs 36.6y, p=0.02), although disease duration was similar (Table 3). The mean interval between MRI and post-mortem was five years. Three subjects in the autopsy cohort had ARWMC scores greater than 0; all were in the post-codon 200 group.3.2.1. Amyloid and tau pathologyAll autopsy cases demonstrated Braak stage VI tau pathology. The severity of Aβ-positive mature, diffuse or cotton wool plaques did not differ between the PSEN1 pre-codon 200 and post-codon 200 groups. The grade of CAA showed little difference between the two groups for any region other than the cerebellum, where the median CAA score was marginally higher in the PSEN1 post-codon 200 than pre-codon 200 group (3 vs 2, p=0.05). However, it should be noted that the average CAA grade for each region was at least 2 or 3 in both groups, and that the post-codon 200 group had an average score of 3 for all regions, reflecting widespread CAA. The mean proportion of blood vessels affected by amyloid deposition was nominally higher in the PSEN1 post-codon 200 than pre-codon 200 group in cortical parenchyma (47.6% vs 28.6%) and leptomeninges (78.2% vs 72.2%). However, differences between the two mutation groups were not statistically significant for these, nor any other aspects of the blood vessel analysis (Table 3).3.2.2. White matter pathologySemi-quantitative assessment of myelin loss, gliosis and microglial expression in the deep white matter (Table 4) suggested a pattern, whereby cases with minimal or no white matter pallor tended to have more active microglia and gliosis, whereas cases with white matter pallor had minimal gliosis and activated microglia. There was some evidence that the PSEN1 pre-codon 200 group had more white matter pallor than the PSEN1 post-codon 200 group on HE staining of parietal (p=0.02) and occipital (p=0.07) sections, and more severe gliosis in the parietal white matter on GFAP immunohistochemistry (p=0.06).The mean density of staining (% area stained) for each immunohistochemical marker in parietal and occipital deep white matter and U-fibre regions of interest is presented in Figure 2. In the PSEN1 cohort as a whole, the only differences between deep white matter and U-fibres were in RT97, which demonstrated lower axonal density/integrity in the deep white matter compared to U-fibres in occipital (53.9% vs 78.7%, p=0.02) and parietal (52.5% vs 71.3%, p=0.04) areas. When the pre-codon 200 group was analysed separately, there were still trends for the density of RT97 to be lower in deep white matter compared to U-fibres in occipital (53.4% vs 78.9%, p=0.06) and, to a lesser extent, parietal (44.8% vs 64.3%, p=0.1) areas. There was also a slightly higher density of CD3-positive T-lymphocytes in occipital deep white matter compared to U-fibres (1.4% vs 0.7%, p=0.04) in the pre-codon 200 group. In the post-codon 200 group, none of the stains showed significant differences between deep white matter and U-fibres. However, there was weak evidence that the density of Iba1-positive microglia was somewhat higher in parietal U-fibres than deep white matter (4.3% vs 3.0%, p=0.07). In the pre-codon 200 group, Iba1 staining did not differ significantly between these regions but was on average higher in deep white matter. Direct comparisons between the pre and post-codon 200 groups for the overall density of staining in each region and the ratio of staining in deep white matter to U-fibres demonstrated no significant differences. 3.2.3. Pathological features and white matter hyperintensities In the autopsy cohort as a whole, there was a correlation between ARWMC score on MRI and grade of CAA severity in the temporal lobe (p=0.02) and to a lesser extent frontal and parietal lobes (both p=0.09). ARWMC score was associated with severity of cotton wool plaques in the occipital (p=0.03) and temporal, parietal and cerebellar (all p=0.04) regions (Figure 3). There was a trend towards a negative correlation between ARWMC score and mature plaque severity in the parietal lobe (p=0.06). ARWMC score was associated with leptomeningeal blood vessel diameter (p=0.03) with borderline associations between ARWMC score and the proportion of cortical blood vessels affected by amyloid deposition (p=0.07) and the proportion of leptomeningeal vessels that were classified as severely affected by CAA (p=0.09). There was some evidence that higher ARWMC scores were associated with a lower density of CD68-positive microglia in the parietal deep white matter (p=0.04) and U-fibres (p=0.09).3.2.4. Pathological features and APOE4 statusThree of the ten autopsy subjects carried an APOE4 allele; one (E44) in the pre-codon 200 group and two (one E44, one E34) in the post-codon 200 group. As in the larger cohort, there was no association between ARWMC score and APOE status. Although the APOE4 carrier group was very small and results should be interpreted with caution, the proportion of cortical blood vessels affected by amyloid deposition was significantly greater in APOE4 carriers than non-carriers (84.0% vs 18.4%, p<0.002), as was the proportion of cortical vessels classified as severely affected (66.0% vs 10.6%, p=0.02). The proportion of leptomeningeal blood vessels affected by amyloid deposition was higher than the proportion of cortical blood vessels affected in both APOE4 carriers (99%) and non-carriers (65%) and did not significantly differ between the two APOE groups (p=0.13). However, there was borderline evidence that the proportion of leptomeningeal blood vessels classified as severely affected was higher in APOE4 carriers than non-carriers (70.0% vs 33.7%, P=0.06). The degree of parietal or occipital capillary CAA showed no association with ARWMC score and did not differ between the pre and post-codon 200 groups, nor between APOE4 carriers and non-carriers. APOE4 carriers demonstrated an increased T lymphocytic response in the parietal U-fibres (3.8% vs 1.0%, p=0.01) and showed trends towards decreased myelin in the U-fibres in both parietal (64.2% vs 92.0%, p=0.09) and occipital (77.6% vs 90.8%, p=0.08) regions. In contrast, APOE4 non-carriers demonstrated higher staining of CD68 for activated microglia in occipital U-fibres (1.9% vs 1.0%, p=0.03). and parietal deep white matter (2.1% vs 1.0%, p=0.06). The ratio of Iba1 microglial staining between occipital deep white matter and U-fibres was also higher in non-carriers (1.5 vs 0.8, p=0.05), driven by increased Iba1 in the deep white matter.3.2.5. Pathological features and age at symptom onsetIn the pathology cohort as a whole, there was some evidence that younger ages at onset were associated with greater immune/inflammatory responses in the deep white matter. Negative correlations were found between age at onset and density of Iba1-positive microglia in parietal deep white matter (absolute counts and ratio compared to U-fibres, both r=-0.7, p=0.03) and of CD20-immunoreactive B cells in parietal and occipital deep white matter (both r=-0.7, p=0.06). The ratio of CD20-immunoreactive B cells in occipital deep white matter compared to U-fibres also negatively correlated with age at onset (r=0.7, p=0.04) although CD20 staining was minimal in all cases. Younger ages at onset were associated with more severe gliosis on HE staining of parietal deep white matter (r=-0.5, p=0.02) and with lower axonal density/integrity in parietal deep white matter (r=0.6, p=0.06) and U-fibres (r=0.7, p=0.04) on RT97 immunohistochemistry.4. Discussion We have demonstrated that individuals with PSEN1 post-codon 200 mutations have significantly more parieto-occipital WMH on T2-weighted MRI and a later age at onset than those with PSEN1 pre-codon 200 mutations. WMH may be caused by a variety of pathological processes including ischaemia, infarction, demyelination and oedema. In older patients, they commonly result from the ischaemia caused by cerebrovascular disease secondary to conventional vascular risk factors ADDIN EN.CITE <EndNote><Cite><Author>Prins</Author><Year>2015</Year><RecNum>426</RecNum><DisplayText>(Prins and Scheltens, 2015)</DisplayText><record><rec-number>426</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1425291894">426</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Prins, N. D.</author><author>Scheltens, P.</author></authors></contributors><auth-address>Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands.</auth-address><titles><title>White matter hyperintensities, cognitive impairment and dementia: an update</title><secondary-title>Nat Rev Neurol</secondary-title><alt-title>Nature reviews. Neurology</alt-title></titles><periodical><full-title>Nat Rev Neurol</full-title><abbr-1>Nature reviews. Neurology</abbr-1></periodical><alt-periodical><full-title>Nat Rev Neurol</full-title><abbr-1>Nature reviews. Neurology</abbr-1></alt-periodical><dates><year>2015</year><pub-dates><date>Feb 17</date></pub-dates></dates><isbn>1759-4766 (Electronic)&#xD;1759-4758 (Linking)</isbn><accession-num>25686760</accession-num><urls><related-urls><url>;(Prins and Scheltens, 2015). Given the young age and relative lack of co-morbidities or vascular risk factors in the subjects in this study, their WMH are much more likely to reflect an aspect of FAD pathology. It has previously been reported that PSEN1 mutations beyond codon 200 show more prominent CAA than mutations situated pre-codon 200 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PihNYW5uLCBldCBhbC4sIDIwMDEpPC9EaXNwbGF5

VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjU5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYW5uLEQuTS48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZy1Ccm93bixTLk0uPC9h

dXRob3I+PGF1dGhvcj5UYWtldWNoaSxBLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sVC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBOZXVy

b3NjaWVuY2UgUmVzZWFyY2ggR3JvdXAsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgTWFuY2hlc3RlciwgTWFuY2hlc3RlciwgVW5pdGVkIEtpbmdkb20uIGRhdmlkLm1hbm5A

bWFuLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBhbmdpb3BhdGh5

IGFuZCB2YXJpYWJpbGl0eSBpbiBhbXlsb2lkIGJldGEgZGVwb3NpdGlvbiBpcyBkZXRlcm1pbmVk

IGJ5IG11dGF0aW9uIHBvc2l0aW9uIGluIHByZXNlbmlsaW4tMS1saW5rZWQgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGF0aG9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjUtMjE3NTwvcGFnZXM+PHZvbHVtZT4x

NTg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29yZD48a2V5d29yZD5ibG9v

ZDwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYmVsbHVtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5Db2Rvbjwva2V5d29yZD48a2V5d29yZD5Db3MgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250YWwgTG9iZTwva2V5d29yZD48a2V5d29yZD5H

ZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQcm90ZWluczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5QZXB0aWRlIEZyYWdtZW50czwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdv

cmQ+PGtleXdvcmQ+dWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD45NjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTEzOTUzOTQ8L3VybD48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTg5MTk5My9wZGYvMjY4NS5wZGY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PihNYW5uLCBldCBhbC4sIDIwMDEpPC9EaXNwbGF5

VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjU5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYW5uLEQuTS48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZy1Ccm93bixTLk0uPC9h

dXRob3I+PGF1dGhvcj5UYWtldWNoaSxBLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sVC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBOZXVy

b3NjaWVuY2UgUmVzZWFyY2ggR3JvdXAsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgTWFuY2hlc3RlciwgTWFuY2hlc3RlciwgVW5pdGVkIEtpbmdkb20uIGRhdmlkLm1hbm5A

bWFuLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBhbmdpb3BhdGh5

IGFuZCB2YXJpYWJpbGl0eSBpbiBhbXlsb2lkIGJldGEgZGVwb3NpdGlvbiBpcyBkZXRlcm1pbmVk

IGJ5IG11dGF0aW9uIHBvc2l0aW9uIGluIHByZXNlbmlsaW4tMS1saW5rZWQgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGF0aG9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjUtMjE3NTwvcGFnZXM+PHZvbHVtZT4x

NTg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29yZD48a2V5d29yZD5ibG9v

ZDwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYmVsbHVtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5Db2Rvbjwva2V5d29yZD48a2V5d29yZD5Db3MgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250YWwgTG9iZTwva2V5d29yZD48a2V5d29yZD5H

ZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQcm90ZWluczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5QZXB0aWRlIEZyYWdtZW50czwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdv

cmQ+PGtleXdvcmQ+dWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD45NjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTEzOTUzOTQ8L3VybD48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTg5MTk5My9wZGYvMjY4NS5wZGY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Mann, et al., 2001). MRI manifestations of CAA include WMH, cortico-subcortical intracerebral haemorrhages including microbleeds and atrophy ADDIN EN.CITE <EndNote><Cite><Author>Chao</Author><Year>2006</Year><RecNum>155</RecNum><DisplayText>(Chao, et al., 2006)</DisplayText><record><rec-number>155</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">155</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chao,C.P.</author><author>Kotsenas,A.L.</author><author>Broderick,D.F.</author></authors></contributors><auth-address>Department of Radiology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA</auth-address><titles><title>Cerebral amyloid angiopathy: CT and MR imaging findings</title><secondary-title>Radiographics</secondary-title></titles><periodical><full-title>Radiographics</full-title></periodical><pages>1517-1531</pages><volume>26</volume><number>5</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Amyloid</keyword><keyword>Brain</keyword><keyword>Cerebral Amyloid Angiopathy</keyword><keyword>Cerebral Angiography</keyword><keyword>Cerebrovascular Disorders</keyword><keyword>diagnosis</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Image Enhancement</keyword><keyword>Magnetic Resonance Angiography</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>methods</keyword><keyword>pathology</keyword><keyword>Physician&apos;s Practice Patterns</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>radiography</keyword><keyword>Tomography,X-Ray Computed</keyword></keywords><dates><year>2006</year><pub-dates><date>9/2006</date></pub-dates></dates><label>190</label><urls><related-urls><url>;(Chao, et al., 2006). Our finding of a greater WMH ‘burden’ on MRI in the PSEN1 post-codon 200 mutation group is therefore consistent with at least a proportion of these individuals having more severe CAA. The predominantly parieto-occipital location of the WMH further supports the hypothesis that they relate to CAA. CAA, which is present to at least some degree in 70%-100% of AD brains at post-mortem PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbGxpczwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl

Y051bT4xNzg8L1JlY051bT48RGlzcGxheVRleHQ+KEJlcmdlcm9uLCBldCBhbC4sIDE5ODcsRWxs

aXMsIGV0IGFsLiwgMTk5Nik8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTc4PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0Mjlw

ZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjE3ODwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RWxsaXMsUi5KLjwvYXV0aG9yPjxh

dXRob3I+T2xpY2huZXksSi5NLjwvYXV0aG9yPjxhdXRob3I+VGhhbCxMLkouPC9hdXRob3I+PGF1

dGhvcj5NaXJyYSxTLlMuPC9hdXRob3I+PGF1dGhvcj5Nb3JyaXMsSi5DLjwvYXV0aG9yPjxhdXRo

b3I+QmVla2x5LEQuPC9hdXRob3I+PGF1dGhvcj5IZXltYW4sQS48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVz

ZWFyY2ggQ2VudGVyICgwOTQ4KSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhIChTYW4gRGllZ28p

LCBMYSBKb2xsYSA5MjA5MywgVVNBPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2VyZWJy

YWwgYW15bG9pZCBhbmdpb3BhdGh5IGluIHRoZSBicmFpbnMgb2YgcGF0aWVudHMgd2l0aCBBbHpo

ZWltZXImYXBvcztzIGRpc2Vhc2U6IHRoZSBDRVJBRCBleHBlcmllbmNlLCBQYXJ0IFhWPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PHBhZ2VzPjE1OTItMTU5NjwvcGFnZXM+PHZvbHVtZT40Njwvdm9sdW1lPjxudW1iZXI+NjwvbnVt

YmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29y

ZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5

d29yZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxrZXl3b3JkPkFydGVyaW9zY2xlcm9zaXM8

L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW48L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4gSXNjaGVtaWE8

L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5PC9rZXl3b3JkPjxr

ZXl3b3JkPkNlcmVicmFsIEhlbW9ycmhhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+Q29tb3JiaWRpdHk8

L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5EZW1lbnRp

YTwva2V5d29yZD48a2V5d29yZD5lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5

d29yZD48a2V5d29yZD5IeXBlcnRlbnNpb248L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5Vbml0ZWQg

U3RhdGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT42LzE5OTY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MjEyPC9s

YWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC84NjQ5NTU0PC91cmw+PHVybD5odHRwOi8vZ3JhcGhpY3MudHgub3ZpZC5jb20vb3Zm

dHBkZnMvRlBERE5DR0NKQklLQUcwMC9mczA0Ny9vdmZ0L2xpdmUvZ3YwMjQvMDAwMDYxMTQvMDAw

MDYxMTQtMTk5NjA2MDAwLTAwMDE4LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3Jl

Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5CZXJnZXJvbjwvQXV0aG9yPjxZZWFyPjE5ODc8L1ll

YXI+PFJlY051bT4xNzk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjE3OTwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVw

ZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNzk8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJlcmdlcm9uLEMuPC9hdXRob3I+PGF1dGhvcj5S

YW5hbGxpLFAuSi48L2F1dGhvcj48YXV0aG9yPk1pY2VsaSxQLk4uPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQYXRob2xvZ3ksIChO

ZXVyb3BhdGhvbG9neSksIEZhY3VsdHkgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgVG9yb250

bywgT250YXJpbywgQ2FuYWRhPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBh

bmdpb3BhdGh5IGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5DYW4uSiBOZXVyb2wgU2NpLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkNhbi5KIE5ldXJvbCBTY2kuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+NTY0LTU2OTwvcGFnZXM+PHZvbHVtZT4xNDwvdm9sdW1lPjxudW1iZXI+NDwvbnVt

YmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29y

ZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29y

ZD5BZ2VkLDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZG9zaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+QnJhaW48L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBB

bmdpb3BhdGh5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFydGVyaWVzPC9rZXl3b3JkPjxr

ZXl3b3JkPkNlcmVicm92YXNjdWxhciBEaXNvcmRlcnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z

PC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9maWJyaWxzPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD51bHRyYXN0cnVjdHVyZTwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4xOTg3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMTk4NzwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMTM8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzM2OTA0MjY8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbGxpczwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl

Y051bT4xNzg8L1JlY051bT48RGlzcGxheVRleHQ+KEJlcmdlcm9uLCBldCBhbC4sIDE5ODcsRWxs

aXMsIGV0IGFsLiwgMTk5Nik8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTc4PC9y

ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0Mjlw

ZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjE3ODwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RWxsaXMsUi5KLjwvYXV0aG9yPjxh

dXRob3I+T2xpY2huZXksSi5NLjwvYXV0aG9yPjxhdXRob3I+VGhhbCxMLkouPC9hdXRob3I+PGF1

dGhvcj5NaXJyYSxTLlMuPC9hdXRob3I+PGF1dGhvcj5Nb3JyaXMsSi5DLjwvYXV0aG9yPjxhdXRo

b3I+QmVla2x5LEQuPC9hdXRob3I+PGF1dGhvcj5IZXltYW4sQS48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5BbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVz

ZWFyY2ggQ2VudGVyICgwOTQ4KSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhIChTYW4gRGllZ28p

LCBMYSBKb2xsYSA5MjA5MywgVVNBPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2VyZWJy

YWwgYW15bG9pZCBhbmdpb3BhdGh5IGluIHRoZSBicmFpbnMgb2YgcGF0aWVudHMgd2l0aCBBbHpo

ZWltZXImYXBvcztzIGRpc2Vhc2U6IHRoZSBDRVJBRCBleHBlcmllbmNlLCBQYXJ0IFhWPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PHBhZ2VzPjE1OTItMTU5NjwvcGFnZXM+PHZvbHVtZT40Njwvdm9sdW1lPjxudW1iZXI+NjwvbnVt

YmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29y

ZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5

d29yZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxrZXl3b3JkPkFydGVyaW9zY2xlcm9zaXM8

L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW48L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4gSXNjaGVtaWE8

L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5PC9rZXl3b3JkPjxr

ZXl3b3JkPkNlcmVicmFsIEhlbW9ycmhhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+Q29tb3JiaWRpdHk8

L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5EZW1lbnRp

YTwva2V5d29yZD48a2V5d29yZD5lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5

d29yZD48a2V5d29yZD5IeXBlcnRlbnNpb248L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5Vbml0ZWQg

U3RhdGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT42LzE5OTY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MjEyPC9s

YWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC84NjQ5NTU0PC91cmw+PHVybD5odHRwOi8vZ3JhcGhpY3MudHgub3ZpZC5jb20vb3Zm

dHBkZnMvRlBERE5DR0NKQklLQUcwMC9mczA0Ny9vdmZ0L2xpdmUvZ3YwMjQvMDAwMDYxMTQvMDAw

MDYxMTQtMTk5NjA2MDAwLTAwMDE4LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3Jl

Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5CZXJnZXJvbjwvQXV0aG9yPjxZZWFyPjE5ODc8L1ll

YXI+PFJlY051bT4xNzk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjE3OTwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVw

ZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNzk8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJlcmdlcm9uLEMuPC9hdXRob3I+PGF1dGhvcj5S

YW5hbGxpLFAuSi48L2F1dGhvcj48YXV0aG9yPk1pY2VsaSxQLk4uPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBQYXRob2xvZ3ksIChO

ZXVyb3BhdGhvbG9neSksIEZhY3VsdHkgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgVG9yb250

bywgT250YXJpbywgQ2FuYWRhPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBh

bmdpb3BhdGh5IGluIEFsemhlaW1lciZhcG9zO3MgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5DYW4uSiBOZXVyb2wgU2NpLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkNhbi5KIE5ldXJvbCBTY2kuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+NTY0LTU2OTwvcGFnZXM+PHZvbHVtZT4xNDwvdm9sdW1lPjxudW1iZXI+NDwvbnVt

YmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29y

ZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29y

ZD5BZ2VkLDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZG9zaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+QnJhaW48L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBB

bmdpb3BhdGh5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFydGVyaWVzPC9rZXl3b3JkPjxr

ZXl3b3JkPkNlcmVicm92YXNjdWxhciBEaXNvcmRlcnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z

PC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9maWJyaWxzPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD51bHRyYXN0cnVjdHVyZTwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4xOTg3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMTk4NzwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMTM8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzM2OTA0MjY8L3VybD48L3Jl

bGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Bergeron, et al., 1987,Ellis, et al., 1996), has a particular predilection for the occipital lobes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGFmdXpvZmY8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFy

PjxSZWNOdW0+MTc2PC9SZWNOdW0+PERpc3BsYXlUZXh0PihBbGFmdXpvZmYsIGV0IGFsLiwgMjAw

OSxUaGFsLCBldCBhbC4sIDIwMDIpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE3

NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJm

NDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNzY8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkFsYWZ1em9mZixJLjwvYXV0

aG9yPjxhdXRob3I+VGhhbCxELlIuPC9hdXRob3I+PGF1dGhvcj5BcnpiZXJnZXIsVC48L2F1dGhv

cj48YXV0aG9yPkJvZ2Rhbm92aWMsTi48L2F1dGhvcj48YXV0aG9yPkFsIFNhcnJhaixTLjwvYXV0

aG9yPjxhdXRob3I+Qm9kaSxJLjwvYXV0aG9yPjxhdXRob3I+Qm9sdWRhLFMuPC9hdXRob3I+PGF1

dGhvcj5CdWdpYW5pLE8uPC9hdXRob3I+PGF1dGhvcj5EdXlja2FlcnRzLEMuPC9hdXRob3I+PGF1

dGhvcj5HZWxwaSxFLjwvYXV0aG9yPjxhdXRob3I+R2VudGxlbWFuLFMuPC9hdXRob3I+PGF1dGhv

cj5HaWFjY29uZSxHLjwvYXV0aG9yPjxhdXRob3I+R3JhZWJlcixNLjwvYXV0aG9yPjxhdXRob3I+

SG9ydG9iYWd5aSxULjwvYXV0aG9yPjxhdXRob3I+SG9mdGJlcmdlcixSLjwvYXV0aG9yPjxhdXRo

b3I+SW5jZSxQLjwvYXV0aG9yPjxhdXRob3I+SXJvbnNpZGUsSi5XLjwvYXV0aG9yPjxhdXRob3I+

S2F2YW50emFzLE4uPC9hdXRob3I+PGF1dGhvcj5LaW5nLEEuPC9hdXRob3I+PGF1dGhvcj5Lb3Jr

b2xvcG91bG91LFAuPC9hdXRob3I+PGF1dGhvcj5Lb3ZhY3MsRy5HLjwvYXV0aG9yPjxhdXRob3I+

TWV5cm9uZXQsRC48L2F1dGhvcj48YXV0aG9yPk1vbm9yYW51LEMuPC9hdXRob3I+PGF1dGhvcj5O

aWxzc29uLFQuPC9hdXRob3I+PGF1dGhvcj5QYXJjaGksUC48L2F1dGhvcj48YXV0aG9yPlBhdHNv

dXJpcyxFLjwvYXV0aG9yPjxhdXRob3I+UGlra2FyYWluZW4sTS48L2F1dGhvcj48YXV0aG9yPlJl

dmVzeixULjwvYXV0aG9yPjxhdXRob3I+Um96ZW11bGxlcixBLjwvYXV0aG9yPjxhdXRob3I+U2Vp

bGhlYW4sRC48L2F1dGhvcj48YXV0aG9yPlNjaHVsei1TY2hhZWZmZXIsVy48L2F1dGhvcj48YXV0

aG9yPlN0cmVpY2hlbmJlcmdlcixOLjwvYXV0aG9yPjxhdXRob3I+V2hhcnRvbixTLkIuPC9hdXRo

b3I+PGF1dGhvcj5LcmV0enNjaG1hcixILjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2xpbmljYWwgTWVkaWNpbmUsIEt1b3BpbyBV

bml2ZXJzaXR5LCBGaW5sYW5kLiBpcmluYS5hbGFmdXpvZmZAdWt1LmZpPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+QXNzZXNzbWVudCBvZiBiZXRhLWFteWxvaWQgZGVwb3NpdHMgaW4gaHVt

YW4gYnJhaW46IGEgc3R1ZHkgb2YgdGhlIEJyYWluTmV0IEV1cm9wZSBDb25zb3J0aXVtPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5ldXJvcGF0aG9sPC9mdWxsLXRpdGxl

PjwvcGVyaW9kaWNhbD48cGFnZXM+MzA5LTMyMDwvcGFnZXM+PHZvbHVtZT4xMTc8L3ZvbHVtZT48

bnVtYmVyPjM8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVk

aXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBh

bmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5hbHBoYS1TeW51Y2xlaW48L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48

a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXM8L2tleXdvcmQ+PGtleXdvcmQ+Ymlvc3ludGhl

c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmViZWxsdW08

L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5PC9rZXl3b3JkPjxr

ZXl3b3JkPkNlcmVicmFsIEFydGVyaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgUHJvZ3Jl

c3Npb248L2tleXdvcmQ+PGtleXdvcmQ+RXVyb3BlPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwv

a2V5d29yZD48a2V5d29yZD5GaW5sYW5kPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y

ZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBoZW5vdHlwZTwv

a2V5d29yZD48a2V5d29yZD5waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmVmZXJl

bmNlIFZhbHVlczwva2V5d29yZD48a2V5d29yZD5SZXByb2R1Y2liaWxpdHkgb2YgUmVzdWx0czwv

a2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjMvMjAwOTwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMTA8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE5MTg0NjY2PC91cmw+PHVy

bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzI5MTA4ODkvcGRm

LzQwMV8yMDA5X0FydGljbGVfNDg1LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3Jl

Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5UaGFsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48

UmVjTnVtPjE3NzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTc3PC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3

c3A1MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjE3Nzwva2V5PjwvZm9yZWlnbi1r

ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp

YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VGhhbCxELlIuPC9hdXRob3I+PGF1dGhvcj5HaGVicmVt

ZWRoaW4sRS48L2F1dGhvcj48YXV0aG9yPlJ1YixVLjwvYXV0aG9yPjxhdXRob3I+WWFtYWd1Y2hp

LEguPC9hdXRob3I+PGF1dGhvcj5EZWwgVHJlZGljaSxLLjwvYXV0aG9yPjxhdXRob3I+QnJhYWss

SC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRt

ZW50IG9mIENsaW5pY2FsIE5ldXJvYW5hdG9teSwgSi5XLiBHb2V0aGUgVW5pdmVyc2l0eSwgRnJh

bmtmdXJ0IGFtIE1haW4sIEdlcm1hbnk8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Ud28g

dHlwZXMgb2Ygc3BvcmFkaWMgY2VyZWJyYWwgYW15bG9pZCBhbmdpb3BhdGh5PC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkogTmV1cm9wYXRob2wgRXhwLk5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9wYXRob2wgRXhwLk5ldXJvbDwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI4Mi0yOTM8L3BhZ2VzPjx2b2x1bWU+NjE8

L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y

ZD5BZ2luZzwva2V5d29yZD48a2V5d29yZD5BbGxlbGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhl

aW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZCBiZXRhLVBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90

ZWluPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWRvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xp

cG9wcm90ZWlucyBFPC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kIFZlc3NlbHM8L2tleXdvcmQ+PGtl

eXdvcmQ+QnJhaW4gRGlzZWFzZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FwaWxsYXJpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5PC9rZXl3b3JkPjxrZXl3b3Jk

PkNlcmVicmFsIEluZmFyY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyb3Zhc2N1bGFyIENp

cmN1bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmNsYXNzaWZpY2F0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPmNvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPkdlbmUgRnJlcXVlbmN5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJlZGlzcG9zaXRp

b24gdG8gRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5d29y

ZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5HZXJtYW55PC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvbG9n

eTwva2V5d29yZD48a2V5d29yZD5waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmVm

ZXJlbmNlIFZhbHVlczwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtl

eXdvcmQ+U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDAyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+My8yMDAyPC9kYXRlPjwvcHViLWRh

dGVzPjwvZGF0ZXM+PGxhYmVsPjIxMTwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTE4OTUwNDM8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGFmdXpvZmY8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFy

PjxSZWNOdW0+MTc2PC9SZWNOdW0+PERpc3BsYXlUZXh0PihBbGFmdXpvZmYsIGV0IGFsLiwgMjAw

OSxUaGFsLCBldCBhbC4sIDIwMDIpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE3

NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJm

NDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNzY8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkFsYWZ1em9mZixJLjwvYXV0

aG9yPjxhdXRob3I+VGhhbCxELlIuPC9hdXRob3I+PGF1dGhvcj5BcnpiZXJnZXIsVC48L2F1dGhv

cj48YXV0aG9yPkJvZ2Rhbm92aWMsTi48L2F1dGhvcj48YXV0aG9yPkFsIFNhcnJhaixTLjwvYXV0

aG9yPjxhdXRob3I+Qm9kaSxJLjwvYXV0aG9yPjxhdXRob3I+Qm9sdWRhLFMuPC9hdXRob3I+PGF1

dGhvcj5CdWdpYW5pLE8uPC9hdXRob3I+PGF1dGhvcj5EdXlja2FlcnRzLEMuPC9hdXRob3I+PGF1

dGhvcj5HZWxwaSxFLjwvYXV0aG9yPjxhdXRob3I+R2VudGxlbWFuLFMuPC9hdXRob3I+PGF1dGhv

cj5HaWFjY29uZSxHLjwvYXV0aG9yPjxhdXRob3I+R3JhZWJlcixNLjwvYXV0aG9yPjxhdXRob3I+

SG9ydG9iYWd5aSxULjwvYXV0aG9yPjxhdXRob3I+SG9mdGJlcmdlcixSLjwvYXV0aG9yPjxhdXRo

b3I+SW5jZSxQLjwvYXV0aG9yPjxhdXRob3I+SXJvbnNpZGUsSi5XLjwvYXV0aG9yPjxhdXRob3I+

S2F2YW50emFzLE4uPC9hdXRob3I+PGF1dGhvcj5LaW5nLEEuPC9hdXRob3I+PGF1dGhvcj5Lb3Jr

b2xvcG91bG91LFAuPC9hdXRob3I+PGF1dGhvcj5Lb3ZhY3MsRy5HLjwvYXV0aG9yPjxhdXRob3I+

TWV5cm9uZXQsRC48L2F1dGhvcj48YXV0aG9yPk1vbm9yYW51LEMuPC9hdXRob3I+PGF1dGhvcj5O

aWxzc29uLFQuPC9hdXRob3I+PGF1dGhvcj5QYXJjaGksUC48L2F1dGhvcj48YXV0aG9yPlBhdHNv

dXJpcyxFLjwvYXV0aG9yPjxhdXRob3I+UGlra2FyYWluZW4sTS48L2F1dGhvcj48YXV0aG9yPlJl

dmVzeixULjwvYXV0aG9yPjxhdXRob3I+Um96ZW11bGxlcixBLjwvYXV0aG9yPjxhdXRob3I+U2Vp

bGhlYW4sRC48L2F1dGhvcj48YXV0aG9yPlNjaHVsei1TY2hhZWZmZXIsVy48L2F1dGhvcj48YXV0

aG9yPlN0cmVpY2hlbmJlcmdlcixOLjwvYXV0aG9yPjxhdXRob3I+V2hhcnRvbixTLkIuPC9hdXRo

b3I+PGF1dGhvcj5LcmV0enNjaG1hcixILjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2xpbmljYWwgTWVkaWNpbmUsIEt1b3BpbyBV

bml2ZXJzaXR5LCBGaW5sYW5kLiBpcmluYS5hbGFmdXpvZmZAdWt1LmZpPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+QXNzZXNzbWVudCBvZiBiZXRhLWFteWxvaWQgZGVwb3NpdHMgaW4gaHVt

YW4gYnJhaW46IGEgc3R1ZHkgb2YgdGhlIEJyYWluTmV0IEV1cm9wZSBDb25zb3J0aXVtPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPkFjdGEgTmV1cm9wYXRob2w8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BY3RhIE5ldXJvcGF0aG9sPC9mdWxsLXRpdGxl

PjwvcGVyaW9kaWNhbD48cGFnZXM+MzA5LTMyMDwvcGFnZXM+PHZvbHVtZT4xMTc8L3ZvbHVtZT48

bnVtYmVyPjM8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVk

aXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBh

bmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5hbHBoYS1TeW51Y2xlaW48L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48

a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXM8L2tleXdvcmQ+PGtleXdvcmQ+Ymlvc3ludGhl

c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmViZWxsdW08

L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5PC9rZXl3b3JkPjxr

ZXl3b3JkPkNlcmVicmFsIEFydGVyaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgUHJvZ3Jl

c3Npb248L2tleXdvcmQ+PGtleXdvcmQ+RXVyb3BlPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwv

a2V5d29yZD48a2V5d29yZD5GaW5sYW5kPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29y

ZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9r

ZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBoZW5vdHlwZTwv

a2V5d29yZD48a2V5d29yZD5waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmVmZXJl

bmNlIFZhbHVlczwva2V5d29yZD48a2V5d29yZD5SZXByb2R1Y2liaWxpdHkgb2YgUmVzdWx0czwv

a2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjMvMjAwOTwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMTA8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE5MTg0NjY2PC91cmw+PHVy

bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzI5MTA4ODkvcGRm

LzQwMV8yMDA5X0FydGljbGVfNDg1LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3Jl

Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5UaGFsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48

UmVjTnVtPjE3NzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTc3PC9yZWMtbnVtYmVyPjxm

b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3

c3A1MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjE3Nzwva2V5PjwvZm9yZWlnbi1r

ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp

YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+VGhhbCxELlIuPC9hdXRob3I+PGF1dGhvcj5HaGVicmVt

ZWRoaW4sRS48L2F1dGhvcj48YXV0aG9yPlJ1YixVLjwvYXV0aG9yPjxhdXRob3I+WWFtYWd1Y2hp

LEguPC9hdXRob3I+PGF1dGhvcj5EZWwgVHJlZGljaSxLLjwvYXV0aG9yPjxhdXRob3I+QnJhYWss

SC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRt

ZW50IG9mIENsaW5pY2FsIE5ldXJvYW5hdG9teSwgSi5XLiBHb2V0aGUgVW5pdmVyc2l0eSwgRnJh

bmtmdXJ0IGFtIE1haW4sIEdlcm1hbnk8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Ud28g

dHlwZXMgb2Ygc3BvcmFkaWMgY2VyZWJyYWwgYW15bG9pZCBhbmdpb3BhdGh5PC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkogTmV1cm9wYXRob2wgRXhwLk5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9wYXRob2wgRXhwLk5ldXJvbDwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI4Mi0yOTM8L3BhZ2VzPjx2b2x1bWU+NjE8

L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y

ZD5BZ2luZzwva2V5d29yZD48a2V5d29yZD5BbGxlbGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhl

aW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZCBiZXRhLVBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90

ZWluPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWRvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xp

cG9wcm90ZWlucyBFPC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kIFZlc3NlbHM8L2tleXdvcmQ+PGtl

eXdvcmQ+QnJhaW4gRGlzZWFzZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FwaWxsYXJpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5PC9rZXl3b3JkPjxrZXl3b3Jk

PkNlcmVicmFsIEluZmFyY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyb3Zhc2N1bGFyIENp

cmN1bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmNsYXNzaWZpY2F0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPmNvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPkdlbmUgRnJlcXVlbmN5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJlZGlzcG9zaXRp

b24gdG8gRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5d29y

ZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5HZXJtYW55PC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208

L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvbG9n

eTwva2V5d29yZD48a2V5d29yZD5waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmVm

ZXJlbmNlIFZhbHVlczwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtl

eXdvcmQ+U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDAyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+My8yMDAyPC9kYXRlPjwvcHViLWRh

dGVzPjwvZGF0ZXM+PGxhYmVsPjIxMTwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0

dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTE4OTUwNDM8L3VybD48L3JlbGF0ZWQt

dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Alafuzoff, et al., 2009,Thal, et al., 2002) and a posterior distribution of WMH has been shown to predict pathologically confirmed CAA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGFucHJhc2VydHN1azwvQXV0aG9yPjxZZWFyPjIwMTQ8

L1llYXI+PFJlY051bT4yNjI8L1JlY051bT48RGlzcGxheVRleHQ+KFRoYW5wcmFzZXJ0c3VrLCBl

dCBhbC4sIDIwMTQpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI2MjwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZk

MDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxNDA2NTU0NTk1Ij4yNjI8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlRoYW5wcmFzZXJ0c3VrLCBTLjwvYXV0aG9y

PjxhdXRob3I+TWFydGluZXotUmFtaXJleiwgUy48L2F1dGhvcj48YXV0aG9yPlBvbnRlcy1OZXRv

LCBPLiBNLjwvYXV0aG9yPjxhdXRob3I+TmksIEouPC9hdXRob3I+PGF1dGhvcj5BeXJlcywgQS48

L2F1dGhvcj48YXV0aG9yPlJlZWQsIEEuPC9hdXRob3I+PGF1dGhvcj5Td29yZHMsIEsuPC9hdXRo

b3I+PGF1dGhvcj5HdXJvbCwgTS4gRS48L2F1dGhvcj48YXV0aG9yPkdyZWVuYmVyZywgUy4gTS48

L2F1dGhvcj48YXV0aG9yPlZpc3dhbmF0aGFuLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkZyb20gdGhlIEouIFBoaWxpcCBLaXN0bGVyIFN0cm9rZSBS

ZXNlYXJjaCBDZW50ZXIgKFMuVC4sIFMuTS4tUi4sIE8uTS5QLi1OLiwgSi5OLiwgQS5BLiwgQS5S

LiwgTS5FLkcuLCBTLk0uRy4sIEEuVi4pLCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWws

IEJvc3RvbjsgRmFjdWx0eSBvZiBNZWRpY2luZSAoUy5ULiksIENodWxhbG9uZ2tvcm4gVW5pdmVy

c2l0eSwgQmFuZ2tvaywgVGhhaWxhbmQ7IGFuZCBFc2NvbGEgZGUgUG9zdGdyYXUgKFMuTS4tUi4p

LCBVbml2ZXJzaXRhdCBBdXRvbm9tYSBkZSBCYXJjZWxvbmEsIEVkaWNpZmkgVSwgQ2FtcHVzIFVB

QiwgQmVsbGF0ZXJyYSAoQ2VyZGFueW9sYSBkZWwgVmFsbGVzKSwgU3BhaW4uJiN4RDtGcm9tIHRo

ZSBKLiBQaGlsaXAgS2lzdGxlciBTdHJva2UgUmVzZWFyY2ggQ2VudGVyIChTLlQuLCBTLk0uLVIu

LCBPLk0uUC4tTi4sIEouTi4sIEEuQS4sIEEuUi4sIE0uRS5HLiwgUy5NLkcuLCBBLlYuKSwgTWFz

c2FjaHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCBCb3N0b247IEZhY3VsdHkgb2YgTWVkaWNpbmUg

KFMuVC4pLCBDaHVsYWxvbmdrb3JuIFVuaXZlcnNpdHksIEJhbmdrb2ssIFRoYWlsYW5kOyBhbmQg

RXNjb2xhIGRlIFBvc3RncmF1IChTLk0uLVIuKSwgVW5pdmVyc2l0YXQgQXV0b25vbWEgZGUgQmFy

Y2Vsb25hLCBFZGljaWZpIFUsIENhbXB1cyBVQUIsIEJlbGxhdGVycmEgKENlcmRhbnlvbGEgZGVs

IFZhbGxlcyksIFNwYWluLiBhdmlzd2FuYXRoYW4xQHBhcnRuZXJzLm9yZy48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5Qb3N0ZXJpb3Igd2hpdGUgbWF0dGVyIGRpc2Vhc2UgZGlzdHJpYnV0

aW9uIGFzIGEgcHJlZGljdG9yIG9mIGFteWxvaWQgYW5naW9wYXRoeTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5OZXVyb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPk5ldXJvbG9neTwv

YWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9n

eTwvZnVsbC10aXRsZT48L2FsdC1wZXJpb2RpY2FsPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+SnVsIDI1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUy

Ni02MzJYIChFbGVjdHJvbmljKSYjeEQ7MDAyOC0zODc4IChMaW5raW5nKTwvaXNibj48YWNjZXNz

aW9uLW51bT4yNTA2Mzc1OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+

aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTA2Mzc1OTwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTIxMi9XTkwuMDAwMDAw

MDAwMDAwMDczMjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k

Tm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGFucHJhc2VydHN1azwvQXV0aG9yPjxZZWFyPjIwMTQ8

L1llYXI+PFJlY051bT4yNjI8L1JlY051bT48RGlzcGxheVRleHQ+KFRoYW5wcmFzZXJ0c3VrLCBl

dCBhbC4sIDIwMTQpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI2MjwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZk

MDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxNDA2NTU0NTk1Ij4yNjI8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlRoYW5wcmFzZXJ0c3VrLCBTLjwvYXV0aG9y

PjxhdXRob3I+TWFydGluZXotUmFtaXJleiwgUy48L2F1dGhvcj48YXV0aG9yPlBvbnRlcy1OZXRv

LCBPLiBNLjwvYXV0aG9yPjxhdXRob3I+TmksIEouPC9hdXRob3I+PGF1dGhvcj5BeXJlcywgQS48

L2F1dGhvcj48YXV0aG9yPlJlZWQsIEEuPC9hdXRob3I+PGF1dGhvcj5Td29yZHMsIEsuPC9hdXRo

b3I+PGF1dGhvcj5HdXJvbCwgTS4gRS48L2F1dGhvcj48YXV0aG9yPkdyZWVuYmVyZywgUy4gTS48

L2F1dGhvcj48YXV0aG9yPlZpc3dhbmF0aGFuLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkZyb20gdGhlIEouIFBoaWxpcCBLaXN0bGVyIFN0cm9rZSBS

ZXNlYXJjaCBDZW50ZXIgKFMuVC4sIFMuTS4tUi4sIE8uTS5QLi1OLiwgSi5OLiwgQS5BLiwgQS5S

LiwgTS5FLkcuLCBTLk0uRy4sIEEuVi4pLCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWws

IEJvc3RvbjsgRmFjdWx0eSBvZiBNZWRpY2luZSAoUy5ULiksIENodWxhbG9uZ2tvcm4gVW5pdmVy

c2l0eSwgQmFuZ2tvaywgVGhhaWxhbmQ7IGFuZCBFc2NvbGEgZGUgUG9zdGdyYXUgKFMuTS4tUi4p

LCBVbml2ZXJzaXRhdCBBdXRvbm9tYSBkZSBCYXJjZWxvbmEsIEVkaWNpZmkgVSwgQ2FtcHVzIFVB

QiwgQmVsbGF0ZXJyYSAoQ2VyZGFueW9sYSBkZWwgVmFsbGVzKSwgU3BhaW4uJiN4RDtGcm9tIHRo

ZSBKLiBQaGlsaXAgS2lzdGxlciBTdHJva2UgUmVzZWFyY2ggQ2VudGVyIChTLlQuLCBTLk0uLVIu

LCBPLk0uUC4tTi4sIEouTi4sIEEuQS4sIEEuUi4sIE0uRS5HLiwgUy5NLkcuLCBBLlYuKSwgTWFz

c2FjaHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCBCb3N0b247IEZhY3VsdHkgb2YgTWVkaWNpbmUg

KFMuVC4pLCBDaHVsYWxvbmdrb3JuIFVuaXZlcnNpdHksIEJhbmdrb2ssIFRoYWlsYW5kOyBhbmQg

RXNjb2xhIGRlIFBvc3RncmF1IChTLk0uLVIuKSwgVW5pdmVyc2l0YXQgQXV0b25vbWEgZGUgQmFy

Y2Vsb25hLCBFZGljaWZpIFUsIENhbXB1cyBVQUIsIEJlbGxhdGVycmEgKENlcmRhbnlvbGEgZGVs

IFZhbGxlcyksIFNwYWluLiBhdmlzd2FuYXRoYW4xQHBhcnRuZXJzLm9yZy48L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5Qb3N0ZXJpb3Igd2hpdGUgbWF0dGVyIGRpc2Vhc2UgZGlzdHJpYnV0

aW9uIGFzIGEgcHJlZGljdG9yIG9mIGFteWxvaWQgYW5naW9wYXRoeTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5OZXVyb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPk5ldXJvbG9neTwv

YWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9n

eTwvZnVsbC10aXRsZT48L2FsdC1wZXJpb2RpY2FsPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+SnVsIDI1PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUy

Ni02MzJYIChFbGVjdHJvbmljKSYjeEQ7MDAyOC0zODc4IChMaW5raW5nKTwvaXNibj48YWNjZXNz

aW9uLW51bT4yNTA2Mzc1OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+

aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNTA2Mzc1OTwvdXJsPjwvcmVsYXRl

ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTIxMi9XTkwuMDAwMDAw

MDAwMDAwMDczMjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k

Tm90ZT4A

ADDIN EN.CITE.DATA (Thanprasertsuk, et al., 2014). Although only one of the APP subjects had a mutation within the amyloid-β coding domain, their ARWMC score was considerably higher than the median for the APP group, consistent with pathological reports of severe CAA in cases with intradomain APP mutations. There was also one outlier in the PSEN1 pre-codon 200 group (p.Leu116Arg), whose total ARWMC score of 8 was considerably higher than the median for the group (0). This subject also carried the p.Arg62His PSEN2 variant. It was previously unclear whether this variant represents a novel mutation or non-pathogenic polymorphism PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcnV0czwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+PFJl

Y051bT4xNjI8L1JlY051bT48RGlzcGxheVRleHQ+KENydXRzLCBldCBhbC4sIDE5OTgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE2MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNjI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkNydXRzLE0uPC9hdXRob3I+PGF1dGhvcj52YW4gRHVpam4sQy5NLjwvYXV0

aG9yPjxhdXRob3I+QmFja2hvdmVucyxILjwvYXV0aG9yPjxhdXRob3I+VmFuIGRlbixCcm9lY2sg

TS48L2F1dGhvcj48YXV0aG9yPldlaG5lcnQsQS48L2F1dGhvcj48YXV0aG9yPlNlcm5lZWxzLFMu

PC9hdXRob3I+PGF1dGhvcj5TaGVycmluZ3RvbixSLjwvYXV0aG9yPjxhdXRob3I+SHV0dG9uLE0u

PC9hdXRob3I+PGF1dGhvcj5IYXJkeSxKLjwvYXV0aG9yPjxhdXRob3I+R2VvcmdlLUh5c2xvcCxQ

LkguPC9hdXRob3I+PGF1dGhvcj5Ib2ZtYW4sQS48L2F1dGhvcj48YXV0aG9yPlZhbiBCcm9lY2to

b3ZlbixDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkxh

Ym9yYXRvcnkgb2YgTmV1cm9nZW5ldGljcywgRmxhbmRlcnMgSW50ZXJ1bml2ZXJzaXR5IEluc3Rp

dHV0ZSBmb3IgQmlvdGVjaG5vbG9neSAoVklCKSwgQm9ybi1CdW5nZSBGb3VuZGF0aW9uIChCQlMp

LCBVbml2ZXJzaXR5IG9mIEFudHdlcnAgKFVJQSksIERlcGFydG1lbnQgb2YgQmlvY2hlbWlzdHJ5

LCBBbnR3ZXJwZW4sIEJlbGdpdW08L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Fc3RpbWF0

aW9uIG9mIHRoZSBnZW5ldGljIGNvbnRyaWJ1dGlvbiBvZiBwcmVzZW5pbGluLTEgYW5kIC0yIG11

dGF0aW9ucyBpbiBhIHBvcHVsYXRpb24tYmFzZWQgc3R1ZHkgb2YgcHJlc2VuaWxlIEFsemhlaW1l

ciBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkh1bS5Nb2wuR2VuZXQuPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SHVtLk1vbC5HZW5ldC48

L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40My01MTwvcGFnZXM+PHZvbHVtZT43PC92

b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVw

cmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdv

cmQ+YW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+QmVsZ2l1bTwva2V5d29yZD48a2V5d29yZD5F

eG9uczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWVtYnJhbmUgUHJvdGVpbnM8L2tleXdv

cmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248L2tleXdv

cmQ+PGtleXdvcmQ+UG9seW1vcnBoaXNtLEdlbmV0aWM8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2Vu

aWxpbi0xPC9rZXl3b3JkPjxrZXl3b3JkPlByZXNlbmlsaW4tMjwva2V5d29yZD48a2V5d29yZD5Q

cmVzZW5pbGluczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk4PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+MS8xOTk4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjE5

NzwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmlo

Lmdvdi9wdWJtZWQvOTM4NDYwMjwvdXJsPjx1cmw+aHR0cDovL2htZy5veGZvcmRqb3VybmFscy5v

cmcvY29udGVudC83LzEvNDMuZnVsbC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcnV0czwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+PFJl

Y051bT4xNjI8L1JlY051bT48RGlzcGxheVRleHQ+KENydXRzLCBldCBhbC4sIDE5OTgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE2MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNjI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkNydXRzLE0uPC9hdXRob3I+PGF1dGhvcj52YW4gRHVpam4sQy5NLjwvYXV0

aG9yPjxhdXRob3I+QmFja2hvdmVucyxILjwvYXV0aG9yPjxhdXRob3I+VmFuIGRlbixCcm9lY2sg

TS48L2F1dGhvcj48YXV0aG9yPldlaG5lcnQsQS48L2F1dGhvcj48YXV0aG9yPlNlcm5lZWxzLFMu

PC9hdXRob3I+PGF1dGhvcj5TaGVycmluZ3RvbixSLjwvYXV0aG9yPjxhdXRob3I+SHV0dG9uLE0u

PC9hdXRob3I+PGF1dGhvcj5IYXJkeSxKLjwvYXV0aG9yPjxhdXRob3I+R2VvcmdlLUh5c2xvcCxQ

LkguPC9hdXRob3I+PGF1dGhvcj5Ib2ZtYW4sQS48L2F1dGhvcj48YXV0aG9yPlZhbiBCcm9lY2to

b3ZlbixDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkxh

Ym9yYXRvcnkgb2YgTmV1cm9nZW5ldGljcywgRmxhbmRlcnMgSW50ZXJ1bml2ZXJzaXR5IEluc3Rp

dHV0ZSBmb3IgQmlvdGVjaG5vbG9neSAoVklCKSwgQm9ybi1CdW5nZSBGb3VuZGF0aW9uIChCQlMp

LCBVbml2ZXJzaXR5IG9mIEFudHdlcnAgKFVJQSksIERlcGFydG1lbnQgb2YgQmlvY2hlbWlzdHJ5

LCBBbnR3ZXJwZW4sIEJlbGdpdW08L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Fc3RpbWF0

aW9uIG9mIHRoZSBnZW5ldGljIGNvbnRyaWJ1dGlvbiBvZiBwcmVzZW5pbGluLTEgYW5kIC0yIG11

dGF0aW9ucyBpbiBhIHBvcHVsYXRpb24tYmFzZWQgc3R1ZHkgb2YgcHJlc2VuaWxlIEFsemhlaW1l

ciBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkh1bS5Nb2wuR2VuZXQuPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SHVtLk1vbC5HZW5ldC48

L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40My01MTwvcGFnZXM+PHZvbHVtZT43PC92

b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVw

cmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdv

cmQ+YW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+QmVsZ2l1bTwva2V5d29yZD48a2V5d29yZD5F

eG9uczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWVtYnJhbmUgUHJvdGVpbnM8L2tleXdv

cmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TXV0YXRpb248L2tleXdv

cmQ+PGtleXdvcmQ+UG9seW1vcnBoaXNtLEdlbmV0aWM8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2Vu

aWxpbi0xPC9rZXl3b3JkPjxrZXl3b3JkPlByZXNlbmlsaW4tMjwva2V5d29yZD48a2V5d29yZD5Q

cmVzZW5pbGluczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk4PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+MS8xOTk4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjE5

NzwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmlo

Lmdvdi9wdWJtZWQvOTM4NDYwMjwvdXJsPjx1cmw+aHR0cDovL2htZy5veGZvcmRqb3VybmFscy5v

cmcvY29udGVudC83LzEvNDMuZnVsbC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA (Cruts, et al., 1998). Although it seems increasingly likely that it is not pathogenic PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdWVycmVpcm88L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy

PjxSZWNOdW0+MTYxPC9SZWNOdW0+PERpc3BsYXlUZXh0PihHdWVycmVpcm8sIGV0IGFsLiwgMjAx

MCk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTYxPC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1

MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjE2MTwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+R3VlcnJlaXJvLFIuSi48L2F1dGhvcj48YXV0aG9yPkJhcXVl

cm8sTS48L2F1dGhvcj48YXV0aG9yPkJsZXNhLFIuPC9hdXRob3I+PGF1dGhvcj5Cb2FkYSxNLjwv

YXV0aG9yPjxhdXRob3I+QnJhcyxKLk0uPC9hdXRob3I+PGF1dGhvcj5CdWxsaWRvLE0uSi48L2F1

dGhvcj48YXV0aG9yPkNhbGFkbyxBLjwvYXV0aG9yPjxhdXRob3I+Q3Jvb2ssUi48L2F1dGhvcj48

YXV0aG9yPkZlcnJlaXJhLEMuPC9hdXRob3I+PGF1dGhvcj5GcmFuayxBLjwvYXV0aG9yPjxhdXRo

b3I+R29tZXotSXNsYSxULjwvYXV0aG9yPjxhdXRob3I+SGVybmFuZGV6LEkuPC9hdXRob3I+PGF1

dGhvcj5MbGVvLEEuPC9hdXRob3I+PGF1dGhvcj5NYWNoYWRvLEEuPC9hdXRob3I+PGF1dGhvcj5N

YXJ0aW5lei1MYWdlLFAuPC9hdXRob3I+PGF1dGhvcj5NYXNkZXUsSi48L2F1dGhvcj48YXV0aG9y

Pk1vbGluYS1Qb3JjZWwsTC48L2F1dGhvcj48YXV0aG9yPk1vbGludWV2byxKLkwuPC9hdXRob3I+

PGF1dGhvcj5QYXN0b3IsUC48L2F1dGhvcj48YXV0aG9yPlBlcmV6LVR1cixKLjwvYXV0aG9yPjxh

dXRob3I+UmVsdmFzLFIuPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSxDLlIuPC9hdXRob3I+PGF1

dGhvcj5SaWJlaXJvLE0uSC48L2F1dGhvcj48YXV0aG9yPlJvZ2FldmEsRS48L2F1dGhvcj48YXV0

aG9yPlNhLEEuPC9hdXRob3I+PGF1dGhvcj5TYW1hcmFuY2gsTC48L2F1dGhvcj48YXV0aG9yPlNh

bmNoZXotVmFsbGUsUi48L2F1dGhvcj48YXV0aG9yPlNhbnRhbmEsSS48L2F1dGhvcj48YXV0aG9y

PlRhcnJhZ2EsTC48L2F1dGhvcj48YXV0aG9yPlZhbGRpdmllc28sRi48L2F1dGhvcj48YXV0aG9y

PlNpbmdsZXRvbixBLjwvYXV0aG9yPjxhdXRob3I+SGFyZHksSi48L2F1dGhvcj48YXV0aG9yPkNs

YXJpbW9uLEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

TGFib3JhdG9yeSBvZiBOZXVyb2dlbmV0aWNzLCBOYXRpb25hbCBJbnN0aXR1dGUgb24gQWdpbmcs

IE5hdGlvbmFsIEluc3RpdHV0ZXMgb2YgSGVhbHRoLCBCZXRoZXNkYSwgTUQsIFVTQTwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkdlbmV0aWMgc2NyZWVuaW5nIG9mIEFsemhlaW1lciZhcG9z

O3MgZGlzZWFzZSBnZW5lcyBpbiBJYmVyaWFuIGFuZCBBZnJpY2FuIHNhbXBsZXMgeWllbGRzIG5v

dmVsIG11dGF0aW9ucyBpbiBwcmVzZW5pbGlucyBhbmQgQVBQPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk5ldXJvYmlvbCBBZ2luZzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBh

Z2VzPjcyNS03MzE8L3BhZ2VzPjx2b2x1bWU+MzE8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48

cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFmcmljYTwva2V5d29yZD48a2V5d29yZD5B

Z2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBE

aXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9p

ZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJl

Y3Vyc29yPC9rZXl3b3JkPjxrZXl3b3JkPmFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPmRpYWdu

b3Npczwva2V5d29yZD48a2V5d29yZD5FeG9uczwva2V5d29yZD48a2V5d29yZD5HZW5lczwva2V5

d29yZD48a2V5d29yZD5HZW5ldGljIFByZWRpc3Bvc2l0aW9uIHRvIERpc2Vhc2U8L2tleXdvcmQ+

PGtleXdvcmQ+R2VuZXRpYyBTY3JlZW5pbmc8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBUZXN0

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UG9ydHVnYWw8L2tl

eXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0xPC9rZXl3b3JkPjxrZXl3b3JkPlByZXNlbmlsaW4t

Mjwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluczwva2V5d29yZD48a2V5d29yZD5TcGFpbjwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+NS8yMDEwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjE5NjwvbGFiZWw+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQv

MTg2NjcyNTg8L3VybD48dXJsPmh0dHA6Ly9hYy5lbHMtY2RuLmNvbS9TMDE5NzQ1ODAwODAwMjE5

NC8xLXMyLjAtUzAxOTc0NTgwMDgwMDIxOTQtbWFpbi5wZGY/X3RpZD1kZWQ3YWQyNi1hMDc3LTEx

ZTMtOWE4MS0wMDAwMGFhY2IzNjEmYW1wO2FjZG5hdD0xMzkzNTkyNDI1XzI2ZjhiZjAyZmRlNTY5

NDI0Y2IzMDI3OWIzM2UzNmRiPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdWVycmVpcm88L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy

PjxSZWNOdW0+MTYxPC9SZWNOdW0+PERpc3BsYXlUZXh0PihHdWVycmVpcm8sIGV0IGFsLiwgMjAx

MCk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTYxPC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1

MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjE2MTwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+R3VlcnJlaXJvLFIuSi48L2F1dGhvcj48YXV0aG9yPkJhcXVl

cm8sTS48L2F1dGhvcj48YXV0aG9yPkJsZXNhLFIuPC9hdXRob3I+PGF1dGhvcj5Cb2FkYSxNLjwv

YXV0aG9yPjxhdXRob3I+QnJhcyxKLk0uPC9hdXRob3I+PGF1dGhvcj5CdWxsaWRvLE0uSi48L2F1

dGhvcj48YXV0aG9yPkNhbGFkbyxBLjwvYXV0aG9yPjxhdXRob3I+Q3Jvb2ssUi48L2F1dGhvcj48

YXV0aG9yPkZlcnJlaXJhLEMuPC9hdXRob3I+PGF1dGhvcj5GcmFuayxBLjwvYXV0aG9yPjxhdXRo

b3I+R29tZXotSXNsYSxULjwvYXV0aG9yPjxhdXRob3I+SGVybmFuZGV6LEkuPC9hdXRob3I+PGF1

dGhvcj5MbGVvLEEuPC9hdXRob3I+PGF1dGhvcj5NYWNoYWRvLEEuPC9hdXRob3I+PGF1dGhvcj5N

YXJ0aW5lei1MYWdlLFAuPC9hdXRob3I+PGF1dGhvcj5NYXNkZXUsSi48L2F1dGhvcj48YXV0aG9y

Pk1vbGluYS1Qb3JjZWwsTC48L2F1dGhvcj48YXV0aG9yPk1vbGludWV2byxKLkwuPC9hdXRob3I+

PGF1dGhvcj5QYXN0b3IsUC48L2F1dGhvcj48YXV0aG9yPlBlcmV6LVR1cixKLjwvYXV0aG9yPjxh

dXRob3I+UmVsdmFzLFIuPC9hdXRob3I+PGF1dGhvcj5PbGl2ZWlyYSxDLlIuPC9hdXRob3I+PGF1

dGhvcj5SaWJlaXJvLE0uSC48L2F1dGhvcj48YXV0aG9yPlJvZ2FldmEsRS48L2F1dGhvcj48YXV0

aG9yPlNhLEEuPC9hdXRob3I+PGF1dGhvcj5TYW1hcmFuY2gsTC48L2F1dGhvcj48YXV0aG9yPlNh

bmNoZXotVmFsbGUsUi48L2F1dGhvcj48YXV0aG9yPlNhbnRhbmEsSS48L2F1dGhvcj48YXV0aG9y

PlRhcnJhZ2EsTC48L2F1dGhvcj48YXV0aG9yPlZhbGRpdmllc28sRi48L2F1dGhvcj48YXV0aG9y

PlNpbmdsZXRvbixBLjwvYXV0aG9yPjxhdXRob3I+SGFyZHksSi48L2F1dGhvcj48YXV0aG9yPkNs

YXJpbW9uLEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

TGFib3JhdG9yeSBvZiBOZXVyb2dlbmV0aWNzLCBOYXRpb25hbCBJbnN0aXR1dGUgb24gQWdpbmcs

IE5hdGlvbmFsIEluc3RpdHV0ZXMgb2YgSGVhbHRoLCBCZXRoZXNkYSwgTUQsIFVTQTwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkdlbmV0aWMgc2NyZWVuaW5nIG9mIEFsemhlaW1lciZhcG9z

O3MgZGlzZWFzZSBnZW5lcyBpbiBJYmVyaWFuIGFuZCBBZnJpY2FuIHNhbXBsZXMgeWllbGRzIG5v

dmVsIG11dGF0aW9ucyBpbiBwcmVzZW5pbGlucyBhbmQgQVBQPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk5ldXJvYmlvbCBBZ2luZzwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPk5ldXJvYmlvbCBBZ2luZzwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBh

Z2VzPjcyNS03MzE8L3BhZ2VzPjx2b2x1bWU+MzE8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48

cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFmcmljYTwva2V5d29yZD48a2V5d29yZD5B

Z2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBE

aXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9p

ZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4gUHJl

Y3Vyc29yPC9rZXl3b3JkPjxrZXl3b3JkPmFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPmRpYWdu

b3Npczwva2V5d29yZD48a2V5d29yZD5FeG9uczwva2V5d29yZD48a2V5d29yZD5HZW5lczwva2V5

d29yZD48a2V5d29yZD5HZW5ldGljIFByZWRpc3Bvc2l0aW9uIHRvIERpc2Vhc2U8L2tleXdvcmQ+

PGtleXdvcmQ+R2VuZXRpYyBTY3JlZW5pbmc8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBUZXN0

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv

a2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NdXRhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UG9ydHVnYWw8L2tl

eXdvcmQ+PGtleXdvcmQ+UHJlc2VuaWxpbi0xPC9rZXl3b3JkPjxrZXl3b3JkPlByZXNlbmlsaW4t

Mjwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluczwva2V5d29yZD48a2V5d29yZD5TcGFpbjwv

a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRh

dGU+NS8yMDEwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjE5NjwvbGFiZWw+PHVy

bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQv

MTg2NjcyNTg8L3VybD48dXJsPmh0dHA6Ly9hYy5lbHMtY2RuLmNvbS9TMDE5NzQ1ODAwODAwMjE5

NC8xLXMyLjAtUzAxOTc0NTgwMDgwMDIxOTQtbWFpbi5wZGY/X3RpZD1kZWQ3YWQyNi1hMDc3LTEx

ZTMtOWE4MS0wMDAwMGFhY2IzNjEmYW1wO2FjZG5hdD0xMzkzNTkyNDI1XzI2ZjhiZjAyZmRlNTY5

NDI0Y2IzMDI3OWIzM2UzNmRiPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA (Guerreiro, et al., 2010), the possibility remains that it may have an influence on the clinico-pathological phenotype. The pathology results in the patients who came to post-mortem offer some support that the WMH are related to CAA, as there was a positive correlation between ARWMC score on MRI and severity of CAA in the temporal and to a lesser extent frontal and parietal lobe. Occipital CAA was the maximum grade of severity in all cases, preventing detection of any association with ARWMC score. Although the actual grade of CAA showed little difference between the pre and post-codon 200 groups for any region other than the cerebellum, where it was marginally higher in the PSEN1 post-codon 200 group, it should be noted that in the small number of subjects with post-mortem examination, CAA was relatively severe in the majority of cases. An alternative explanation for the increased WMH in the PSEN1 post-codon 200 cohort is that they reflect another aspect of FAD pathology, independent of or related to CAA, which also varies according to mutation position such as inflammatory mediated pathology. Vascular amyloid may be associated with a variety of inflammatory reactions PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaHVuZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

Y051bT4xNzQ8L1JlY051bT48RGlzcGxheVRleHQ+KENodW5nLCBldCBhbC4sIDIwMTEsTWlhbywg

ZXQgYWwuLCAyMDA1KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNzQ8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVm

ZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTc0PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DaHVuZyxLLksuPC9hdXRob3I+PGF1dGhv

cj5BbmRlcnNvbixOLkUuPC9hdXRob3I+PGF1dGhvcj5IdXRjaGluc29uLEQuPC9hdXRob3I+PGF1

dGhvcj5TeW5layxCLjwvYXV0aG9yPjxhdXRob3I+QmFyYmVyLFAuQS48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvbG9neSwg

QXVja2xhbmQgSG9zcGl0YWwsIEF1Y2tsYW5kLCBOZXcgWmVhbGFuZDwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkNlcmVicmFsIGFteWxvaWQgYW5naW9wYXRoeSByZWxhdGVkIGluZmxhbW1h

dGlvbjogdGhyZWUgY2FzZSByZXBvcnRzIGFuZCBhIHJldmlldzwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5KIE5ldXJvbCBOZXVyb3N1cmcgUHN5Y2hpYXRyeTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9sIE5ldXJvc3VyZyBQc3ljaGlhdHJ5

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjAtMjY8L3BhZ2VzPjx2b2x1bWU+ODI8

L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y

ZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxr

ZXl3b3JkPkFudGktSW5mbGFtbWF0b3J5IEFnZW50czwva2V5d29yZD48a2V5d29yZD5CbG9vZCBW

ZXNzZWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFs

IEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXg8L2tl

eXdvcmQ+PGtleXdvcmQ+Q3ljbG9waG9zcGhhbWlkZTwva2V5d29yZD48a2V5d29yZD5EZXhhbWV0

aGFzb25lPC9rZXl3b3JkPjxrZXl3b3JkPmRpYWdub3Npczwva2V5d29yZD48a2V5d29yZD5kcnVn

IHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmF0

YWwgT3V0Y29tZTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SGVh

ZGFjaGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub3N1

cHByZXNzaXZlIEFnZW50czwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+TWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NZXRoeWxwcmVkbmlzb2xvbmU8L2tleXdvcmQ+PGtleXdvcmQ+

TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlBhcmVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBy

b2dub3Npczwva2V5d29yZD48a2V5d29yZD5TZWl6dXJlczwva2V5d29yZD48a2V5d29yZD50aGVy

YXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5U

b21vZ3JhcGh5LFgtUmF5IENvbXB1dGVkPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzIwMTE8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48bGFiZWw+MjA4PC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDkzNTMyODwvdXJsPjx1cmw+aHR0cDovL2pubnAu

Ym1qLmNvbS9jb250ZW50LzgyLzEvMjAuZnVsbC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TWlhbzwvQXV0aG9yPjxZZWFyPjIwMDU8

L1llYXI+PFJlY051bT4xNzM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjE3MzwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZk

MDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNzM8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1pYW8sSi48L2F1dGhvcj48YXV0aG9yPlh1

LEYuPC9hdXRob3I+PGF1dGhvcj5EYXZpcyxKLjwvYXV0aG9yPjxhdXRob3I+T3R0ZS1Ib2xsZXIs

SS48L2F1dGhvcj48YXV0aG9yPlZlcmJlZWssTS5NLjwvYXV0aG9yPjxhdXRob3I+VmFuIE5vc3Ry

YW5kLFcuRS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5E

ZXBhcnRtZW50IG9mIE1lZGljaW5lLCBIU0MsIFN0b255IEJyb29rIFVuaXZlcnNpdHksIFN0b255

IEJyb29rLCBOWSAxMTc5NC04MTUzLCBVU0E8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5D

ZXJlYnJhbCBtaWNyb3Zhc2N1bGFyIGFteWxvaWQgYmV0YSBwcm90ZWluIGRlcG9zaXRpb24gaW5k

dWNlcyB2YXNjdWxhciBkZWdlbmVyYXRpb24gYW5kIG5ldXJvaW5mbGFtbWF0aW9uIGluIHRyYW5z

Z2VuaWMgbWljZSBleHByZXNzaW5nIGh1bWFuIHZhc2N1bG90cm9waWMgbXV0YW50IGFteWxvaWQg

YmV0YSBwcmVjdXJzb3IgcHJvdGVpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbSBKIFBhdGhv

bC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBK

IFBhdGhvbC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz41MDUtNTE1PC9wYWdlcz48

dm9sdW1lPjE2Nzwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90

IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW15bG9pZDwva2V5

d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXM8L2tleXdvcmQ+PGtleXdvcmQ+QW15

bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4g

UHJlY3Vyc29yPC9rZXl3b3JkPjxrZXl3b3JkPmFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkFu

aW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXBvcHRvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkFzdHJv

Y3l0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW48L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJlbGx1

bTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHk8L2tleXdvcmQ+

PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5LEZhbWlsaWFsPC9rZXl3b3JkPjxr

ZXl3b3JkPkNlcmVicm92YXNjdWxhciBDaXJjdWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5EZW1l

bnRpYTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5nZW5ldGlj

czwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+aW1tdW5vbG9neTwv

a2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVr

aW4tMTwva2V5d29yZD48a2V5d29yZD5JbnRlcmxldWtpbi02PC9rZXl3b3JkPjxrZXl3b3JkPklv

d2E8L2tleXdvcmQ+PGtleXdvcmQ+bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pY2UsSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2Us

VHJhbnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5NaWNyb2NpcmN1bGF0aW9uPC9rZXl3b3JkPjxr

ZXl3b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnM8L2tleXdvcmQ+PGtleXdv

cmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRyYW5zZ2VuZXM8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjgvMjAwNTwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMDc8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE2MDQ5MzM1PC91cmw+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzE2MDM1NzQv

cGRmL0pQQVRIMTY3MDAwNTA1LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaHVuZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

Y051bT4xNzQ8L1JlY051bT48RGlzcGxheVRleHQ+KENodW5nLCBldCBhbC4sIDIwMTEsTWlhbywg

ZXQgYWwuLCAyMDA1KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNzQ8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVm

ZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTc0PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DaHVuZyxLLksuPC9hdXRob3I+PGF1dGhv

cj5BbmRlcnNvbixOLkUuPC9hdXRob3I+PGF1dGhvcj5IdXRjaGluc29uLEQuPC9hdXRob3I+PGF1

dGhvcj5TeW5layxCLjwvYXV0aG9yPjxhdXRob3I+QmFyYmVyLFAuQS48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvbG9neSwg

QXVja2xhbmQgSG9zcGl0YWwsIEF1Y2tsYW5kLCBOZXcgWmVhbGFuZDwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkNlcmVicmFsIGFteWxvaWQgYW5naW9wYXRoeSByZWxhdGVkIGluZmxhbW1h

dGlvbjogdGhyZWUgY2FzZSByZXBvcnRzIGFuZCBhIHJldmlldzwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5KIE5ldXJvbCBOZXVyb3N1cmcgUHN5Y2hpYXRyeTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9sIE5ldXJvc3VyZyBQc3ljaGlhdHJ5

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjAtMjY8L3BhZ2VzPjx2b2x1bWU+ODI8

L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y

ZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxr

ZXl3b3JkPkFudGktSW5mbGFtbWF0b3J5IEFnZW50czwva2V5d29yZD48a2V5d29yZD5CbG9vZCBW

ZXNzZWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFs

IEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXg8L2tl

eXdvcmQ+PGtleXdvcmQ+Q3ljbG9waG9zcGhhbWlkZTwva2V5d29yZD48a2V5d29yZD5EZXhhbWV0

aGFzb25lPC9rZXl3b3JkPjxrZXl3b3JkPmRpYWdub3Npczwva2V5d29yZD48a2V5d29yZD5kcnVn

IHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmF0

YWwgT3V0Y29tZTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SGVh

ZGFjaGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub3N1

cHByZXNzaXZlIEFnZW50czwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+TWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFs

ZTwva2V5d29yZD48a2V5d29yZD5NZXRoeWxwcmVkbmlzb2xvbmU8L2tleXdvcmQ+PGtleXdvcmQ+

TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlBhcmVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBy

b2dub3Npczwva2V5d29yZD48a2V5d29yZD5TZWl6dXJlczwva2V5d29yZD48a2V5d29yZD50aGVy

YXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5U

b21vZ3JhcGh5LFgtUmF5IENvbXB1dGVkPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzIwMTE8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48bGFiZWw+MjA4PC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDkzNTMyODwvdXJsPjx1cmw+aHR0cDovL2pubnAu

Ym1qLmNvbS9jb250ZW50LzgyLzEvMjAuZnVsbC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3Vy

bHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TWlhbzwvQXV0aG9yPjxZZWFyPjIwMDU8

L1llYXI+PFJlY051bT4xNzM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjE3MzwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZk

MDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNzM8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1pYW8sSi48L2F1dGhvcj48YXV0aG9yPlh1

LEYuPC9hdXRob3I+PGF1dGhvcj5EYXZpcyxKLjwvYXV0aG9yPjxhdXRob3I+T3R0ZS1Ib2xsZXIs

SS48L2F1dGhvcj48YXV0aG9yPlZlcmJlZWssTS5NLjwvYXV0aG9yPjxhdXRob3I+VmFuIE5vc3Ry

YW5kLFcuRS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5E

ZXBhcnRtZW50IG9mIE1lZGljaW5lLCBIU0MsIFN0b255IEJyb29rIFVuaXZlcnNpdHksIFN0b255

IEJyb29rLCBOWSAxMTc5NC04MTUzLCBVU0E8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5D

ZXJlYnJhbCBtaWNyb3Zhc2N1bGFyIGFteWxvaWQgYmV0YSBwcm90ZWluIGRlcG9zaXRpb24gaW5k

dWNlcyB2YXNjdWxhciBkZWdlbmVyYXRpb24gYW5kIG5ldXJvaW5mbGFtbWF0aW9uIGluIHRyYW5z

Z2VuaWMgbWljZSBleHByZXNzaW5nIGh1bWFuIHZhc2N1bG90cm9waWMgbXV0YW50IGFteWxvaWQg

YmV0YSBwcmVjdXJzb3IgcHJvdGVpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbSBKIFBhdGhv

bC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBK

IFBhdGhvbC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz41MDUtNTE1PC9wYWdlcz48

dm9sdW1lPjE2Nzwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90

IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW15bG9pZDwva2V5

d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXM8L2tleXdvcmQ+PGtleXdvcmQ+QW15

bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW4g

UHJlY3Vyc29yPC9rZXl3b3JkPjxrZXl3b3JkPmFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkFu

aW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXBvcHRvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkFzdHJv

Y3l0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW48L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJlbGx1

bTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHk8L2tleXdvcmQ+

PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5LEZhbWlsaWFsPC9rZXl3b3JkPjxr

ZXl3b3JkPkNlcmVicm92YXNjdWxhciBDaXJjdWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5EZW1l

bnRpYTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5nZW5ldGlj

czwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+aW1tdW5vbG9neTwv

a2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVr

aW4tMTwva2V5d29yZD48a2V5d29yZD5JbnRlcmxldWtpbi02PC9rZXl3b3JkPjxrZXl3b3JkPklv

d2E8L2tleXdvcmQ+PGtleXdvcmQ+bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pY2UsSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2Us

VHJhbnNnZW5pYzwva2V5d29yZD48a2V5d29yZD5NaWNyb2NpcmN1bGF0aW9uPC9rZXl3b3JkPjxr

ZXl3b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbnM8L2tleXdvcmQ+PGtleXdv

cmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRyYW5zZ2VuZXM8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjgvMjAwNTwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMDc8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVy

bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE2MDQ5MzM1PC91cmw+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcG1jL2FydGljbGVzL1BNQzE2MDM1NzQv

cGRmL0pQQVRIMTY3MDAwNTA1LnBkZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA (Chung, et al., 2011,Miao, et al., 2005) including perivascular inflammation surrounding amyloid-laden blood vessels and granulomatous or non-granulomatous angiitis in which there is also inflammation and necrosis within the vessel wall PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fbmc8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO

dW0+MTU2PC9SZWNOdW0+PERpc3BsYXlUZXh0PihFbmcsIGV0IGFsLiwgMjAwNCxIYXJrbmVzcywg

ZXQgYWwuLCAyMDA0LFNjb2xkaW5nLCBldCBhbC4sIDIwMDUpPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjE1NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIx

MzkyMzcyNzE1Ij4xNTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkVu

ZyxKLkEuPC9hdXRob3I+PGF1dGhvcj5Gcm9zY2gsTS5QLjwvYXV0aG9yPjxhdXRob3I+Q2hvaSxL

LjwvYXV0aG9yPjxhdXRob3I+UmViZWNrLEcuVy48L2F1dGhvcj48YXV0aG9yPkdyZWVuYmVyZyxT

Lk0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIE1hc3NhY2h1c2V0dHMgR2VuZXJhbCBIb3NwaXRhbCBhbmQgSGFy

dmFyZCBNZWRpY2FsIFNjaG9vbCwgQm9zdG9uLCBNQSAwMjExNCwgVVNBPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+Q2xpbmljYWwgbWFuaWZlc3RhdGlvbnMgb2YgY2VyZWJyYWwgYW15bG9p

ZCBhbmdpb3BhdGh5LXJlbGF0ZWQgaW5mbGFtbWF0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkFubiBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5Bbm4gTmV1cm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjUwLTI1Njwv

cGFnZXM+PHZvbHVtZT41NTwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxyZXByaW50LWVkaXRp

b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWRyZW5h

bCBDb3J0ZXggSG9ybW9uZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIEZhY3RvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxrZXl3b3Jk

PkFteWxvaWQgYmV0YS1QZXB0aWRlczwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMg

RTwva2V5d29yZD48a2V5d29yZD5ibG9vZCBzdXBwbHk8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW48

L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5PC9rZXl3b3JkPjxr

ZXl3b3JkPkNlcmVicmFsIEhlbW9ycmhhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uIERp

c29yZGVyczwva2V5d29yZD48a2V5d29yZD5jb21wbGljYXRpb25zPC9rZXl3b3JkPjxrZXl3b3Jk

PkN5Y2xvcGhvc3BoYW1pZGU8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1ZyB0aGVyYXB5PC9rZXl3b3Jk

PjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+

PGtleXdvcmQ+SW1tdW5vc3VwcHJlc3NpdmUgQWdlbnRzPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxh

bW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5

d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5waHlzaW9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlNlaXp1cmVzPC9r

ZXl3b3JkPjxrZXl3b3JkPnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5UcmVhdG1l

bnQgT3V0Y29tZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA0PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+Mi8yMDA0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjE5

MTwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmlo

Lmdvdi9wdWJtZWQvMTQ3NTU3Mjk8L3VybD48dXJsPmh0dHA6Ly9vbmxpbmVsaWJyYXJ5LndpbGV5

LmNvbS9zdG9yZS8xMC4xMDAyL2FuYS4xMDgxMC9hc3NldC8xMDgxMF9mdHAucGRmP3Y9MSZhbXA7

dD1oczdncjY4aSZhbXA7cz1lNWYzYmU4ZGRkMzE2YTkyNDAzYjI5YTY5MWMwYzJjMTA5MDc2MDg3

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9y

PlNjb2xkaW5nPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVjTnVtPjE2ODwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTY4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1lc3Rh

bXA9IjEzOTIzNzI3MTUiPjE2ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+U2NvbGRpbmcsTi5KLjwvYXV0aG9yPjxhdXRob3I+Sm9zZXBoLEYuPC9hdXRob3I+PGF1dGhv

cj5LaXJieSxQLkEuPC9hdXRob3I+PGF1dGhvcj5NYXphbnRpLEkuPC9hdXRob3I+PGF1dGhvcj5H

cmF5LEYuPC9hdXRob3I+PGF1dGhvcj5NaWtvbCxKLjwvYXV0aG9yPjxhdXRob3I+RWxsaXNvbixE

LjwvYXV0aG9yPjxhdXRob3I+SGlsdG9uLEQuQS48L2F1dGhvcj48YXV0aG9yPldpbGxpYW1zLFQu

TC48L2F1dGhvcj48YXV0aG9yPk1hY0tlbnppZSxKLk0uPC9hdXRob3I+PGF1dGhvcj5YdWVyZWIs

Si5ILjwvYXV0aG9yPjxhdXRob3I+TG92ZSxTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBJbnN0aXR1dGUgb2Yg

Q2xpbmljYWwgTmV1cm9zY2llbmNlcywgVW5pdmVyc2l0eSBvZiBCcmlzdG9sLCBGcmVuY2hheSBI

b3NwaXRhbCwgQnJpc3RvbCwgVUs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BYmV0YS1y

ZWxhdGVkIGFuZ2lpdGlzOiBwcmltYXJ5IGFuZ2lpdGlzIG9mIHRoZSBjZW50cmFsIG5lcnZvdXMg

c3lzdGVtIGFzc29jaWF0ZWQgd2l0aCBjZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjUw

MC01MTU8L3BhZ2VzPjx2b2x1bWU+MTI4PC92b2x1bWU+PG51bWJlcj5QdCAzPC9udW1iZXI+PHJl

cHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5

d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtl

eXdvcmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+YW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+Ymxvb2Q8L2tleXdvcmQ+

PGtleXdvcmQ+Qmxvb2QgVmVzc2Vsczwva2V5d29yZD48a2V5d29yZD5DZW50cmFsIE5lcnZvdXMg

U3lzdGVtPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5

d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbmdpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5DZXJl

YnJhbCBDb3J0ZXg8L2tleXdvcmQ+PGtleXdvcmQ+Y2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29y

ZD48a2V5d29yZD5jb21wbGljYXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPmRpYWdub3Npczwva2V5

d29yZD48a2V5d29yZD5FbGVjdHJvZW5jZXBoYWxvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkZl

bWFsZTwva2V5d29yZD48a2V5d29yZD5HbGlvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkhhbGx1Y2lu

YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmZsYW1t

YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdv

cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48

a2V5d29yZD5OZXVyb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvZ25vc2lzPC9rZXl3b3JkPjxr

ZXl3b3JkPlNlaXp1cmVzPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtleXdv

cmQ+VG9tb2dyYXBoeSxYLVJheSBDb21wdXRlZDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQg

T3V0Y29tZTwva2V5d29yZD48a2V5d29yZD5WYXNjdWxpdGlzLENlbnRyYWwgTmVydm91cyBTeXN0

ZW08L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNTwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjMvMjAwNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMDM8L2xhYmVs

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi

bWVkLzE1NjU5NDI4PC91cmw+PHVybD5odHRwOi8vYnJhaW4ub3hmb3Jkam91cm5hbHMub3JnL2Nv

bnRlbnQvMTI4LzMvNTAwLmZ1bGwucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVj

b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhhcmtuZXNzPC9BdXRob3I+PFllYXI+MjAwNDwvWWVh

cj48UmVjTnVtPjE1NDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTU0PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBl

eGY3c3A1MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjE1NDwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGFya25lc3MsSy5BLjwvYXV0aG9yPjxhdXRob3I+

Q29sZXMsQS48L2F1dGhvcj48YXV0aG9yPlBvaGwsVS48L2F1dGhvcj48YXV0aG9yPlh1ZXJlYixK

LkguPC9hdXRob3I+PGF1dGhvcj5CYXJvbixKLkMuPC9hdXRob3I+PGF1dGhvcj5MZW5ub3gsRy5H

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBBZGRlbmJyb29rZSZhcG9zO3MgVW5pdmVyc2l0eSBIb3NwaXRhbCwg

SGlsbHMgUm9hZCwgQ2FtYnJpZGdlLCBVSy4ga2lyc3R5aGFya25lc3NAeWFob28uY29tPC9hdXRo

LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UmFwaWRseSByZXZlcnNpYmxlIGRlbWVudGlhIGluIGNl

cmVicmFsIGFteWxvaWQgaW5mbGFtbWF0b3J5IHZhc2N1bG9wYXRoeTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5FdXIgSiBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5FdXIgSiBOZXVyb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz41OS02MjwvcGFnZXM+PHZvbHVtZT4xMTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXBy

aW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QWRyZW5hbCBDb3J0ZXggSG9ybW9uZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29y

ZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kIHN1cHBseTwva2V5d29y

ZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lv

cGF0aHk8L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5E

ZW1lbnRpYTwva2V5d29yZD48a2V5d29yZD5EZXhhbWV0aGFzb25lPC9rZXl3b3JkPjxrZXl3b3Jk

PmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48a2V5d29y

ZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu

b2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbjwva2V5d29yZD48

a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5OZXVy

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNp

b3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD50aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtl

eXdvcmQ+VmFzY3VsaXRpcyxDZW50cmFsIE5lcnZvdXMgU3lzdGVtPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMDQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzIwMDQ8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MTg5PC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNDY5Mjg5MDwvdXJsPjx1

cmw+aHR0cDovL29ubGluZWxpYnJhcnkud2lsZXkuY29tL3N0b3JlLzEwLjEwNDYvai4xMzUxLTUx

MDEuMjAwMy4wMDcwNy54L2Fzc2V0L2ouMTM1MS01MTAxLjIwMDMuMDA3MDcueC5wZGY/dj0xJmFt

cDt0PWhzN2d1bWkwJmFtcDtzPTgwMGExNjg1MzU3OWU1ZTczZWJkZTEyNGM5MjM0NmZhZWZhNDFl

Njg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRo

b3I+SGFya25lc3M8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNOdW0+MTU0PC9SZWNOdW0+

PHJlY29yZD48cmVjLW51bWJlcj4xNTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVz

dGFtcD0iMTM5MjM3MjcxNSI+MTU0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5IYXJrbmVzcyxLLkEuPC9hdXRob3I+PGF1dGhvcj5Db2xlcyxBLjwvYXV0aG9yPjxhdXRo

b3I+UG9obCxVLjwvYXV0aG9yPjxhdXRob3I+WHVlcmViLEouSC48L2F1dGhvcj48YXV0aG9yPkJh

cm9uLEouQy48L2F1dGhvcj48YXV0aG9yPkxlbm5veCxHLkcuPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEFkZGVu

YnJvb2tlJmFwb3M7cyBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIaWxscyBSb2FkLCBDYW1icmlkZ2Us

IFVLLiBraXJzdHloYXJrbmVzc0B5YWhvby5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5SYXBpZGx5IHJldmVyc2libGUgZGVtZW50aWEgaW4gY2VyZWJyYWwgYW15bG9pZCBpbmZsYW1t

YXRvcnkgdmFzY3Vsb3BhdGh5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ciBKIE5ldXJvbDwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkV1ciBKIE5l

dXJvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU5LTYyPC9wYWdlcz48dm9sdW1l

PjExPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmls

ZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZHJlbmFsIENvcnRleCBIb3Jt

b25lczwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tl

eXdvcmQ+PGtleXdvcmQ+Ymxvb2Qgc3VwcGx5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3

b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29y

ZD5jb21wbGljYXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlhPC9rZXl3b3JkPjxrZXl3

b3JkPkRleGFtZXRoYXNvbmU8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1ZyB0aGVyYXB5PC9rZXl3b3Jk

PjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdv

cmQ+PGtleXdvcmQ+SW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJlc29u

YW5jZSBJbWFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29y

ZD5wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5WYXNjdWxpdGlzLENlbnRy

YWwgTmVydm91cyBTeXN0ZW08L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNDwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjEvMjAwNDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxs

YWJlbD4xODk8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcHVibWVkLzE0NjkyODkwPC91cmw+PHVybD5odHRwOi8vb25saW5lbGlicmFy

eS53aWxleS5jb20vc3RvcmUvMTAuMTA0Ni9qLjEzNTEtNTEwMS4yMDAzLjAwNzA3LngvYXNzZXQv

ai4xMzUxLTUxMDEuMjAwMy4wMDcwNy54LnBkZj92PTEmYW1wO3Q9aHM3Z3VtaTAmYW1wO3M9ODAw

YTE2ODUzNTc5ZTVlNzNlYmRlMTI0YzkyMzQ2ZmFlZmE0MWU2ODwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fbmc8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO

dW0+MTU2PC9SZWNOdW0+PERpc3BsYXlUZXh0PihFbmcsIGV0IGFsLiwgMjAwNCxIYXJrbmVzcywg

ZXQgYWwuLCAyMDA0LFNjb2xkaW5nLCBldCBhbC4sIDIwMDUpPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjE1NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIx

MzkyMzcyNzE1Ij4xNTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkVu

ZyxKLkEuPC9hdXRob3I+PGF1dGhvcj5Gcm9zY2gsTS5QLjwvYXV0aG9yPjxhdXRob3I+Q2hvaSxL

LjwvYXV0aG9yPjxhdXRob3I+UmViZWNrLEcuVy48L2F1dGhvcj48YXV0aG9yPkdyZWVuYmVyZyxT

Lk0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIE1hc3NhY2h1c2V0dHMgR2VuZXJhbCBIb3NwaXRhbCBhbmQgSGFy

dmFyZCBNZWRpY2FsIFNjaG9vbCwgQm9zdG9uLCBNQSAwMjExNCwgVVNBPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+Q2xpbmljYWwgbWFuaWZlc3RhdGlvbnMgb2YgY2VyZWJyYWwgYW15bG9p

ZCBhbmdpb3BhdGh5LXJlbGF0ZWQgaW5mbGFtbWF0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkFubiBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5Bbm4gTmV1cm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjUwLTI1Njwv

cGFnZXM+PHZvbHVtZT41NTwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxyZXByaW50LWVkaXRp

b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWRyZW5h

bCBDb3J0ZXggSG9ybW9uZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIEZhY3RvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxrZXl3b3Jk

PkFteWxvaWQgYmV0YS1QZXB0aWRlczwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMg

RTwva2V5d29yZD48a2V5d29yZD5ibG9vZCBzdXBwbHk8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW48

L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5PC9rZXl3b3JkPjxr

ZXl3b3JkPkNlcmVicmFsIEhlbW9ycmhhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uIERp

c29yZGVyczwva2V5d29yZD48a2V5d29yZD5jb21wbGljYXRpb25zPC9rZXl3b3JkPjxrZXl3b3Jk

PkN5Y2xvcGhvc3BoYW1pZGU8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1ZyB0aGVyYXB5PC9rZXl3b3Jk

PjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29y

ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+

PGtleXdvcmQ+SW1tdW5vc3VwcHJlc3NpdmUgQWdlbnRzPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxh

bW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5

d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5waHlzaW9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlNlaXp1cmVzPC9r

ZXl3b3JkPjxrZXl3b3JkPnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5UcmVhdG1l

bnQgT3V0Y29tZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA0PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+Mi8yMDA0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjE5

MTwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmlo

Lmdvdi9wdWJtZWQvMTQ3NTU3Mjk8L3VybD48dXJsPmh0dHA6Ly9vbmxpbmVsaWJyYXJ5LndpbGV5

LmNvbS9zdG9yZS8xMC4xMDAyL2FuYS4xMDgxMC9hc3NldC8xMDgxMF9mdHAucGRmP3Y9MSZhbXA7

dD1oczdncjY4aSZhbXA7cz1lNWYzYmU4ZGRkMzE2YTkyNDAzYjI5YTY5MWMwYzJjMTA5MDc2MDg3

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9y

PlNjb2xkaW5nPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVjTnVtPjE2ODwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTY4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1lc3Rh

bXA9IjEzOTIzNzI3MTUiPjE2ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+U2NvbGRpbmcsTi5KLjwvYXV0aG9yPjxhdXRob3I+Sm9zZXBoLEYuPC9hdXRob3I+PGF1dGhv

cj5LaXJieSxQLkEuPC9hdXRob3I+PGF1dGhvcj5NYXphbnRpLEkuPC9hdXRob3I+PGF1dGhvcj5H

cmF5LEYuPC9hdXRob3I+PGF1dGhvcj5NaWtvbCxKLjwvYXV0aG9yPjxhdXRob3I+RWxsaXNvbixE

LjwvYXV0aG9yPjxhdXRob3I+SGlsdG9uLEQuQS48L2F1dGhvcj48YXV0aG9yPldpbGxpYW1zLFQu

TC48L2F1dGhvcj48YXV0aG9yPk1hY0tlbnppZSxKLk0uPC9hdXRob3I+PGF1dGhvcj5YdWVyZWIs

Si5ILjwvYXV0aG9yPjxhdXRob3I+TG92ZSxTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBJbnN0aXR1dGUgb2Yg

Q2xpbmljYWwgTmV1cm9zY2llbmNlcywgVW5pdmVyc2l0eSBvZiBCcmlzdG9sLCBGcmVuY2hheSBI

b3NwaXRhbCwgQnJpc3RvbCwgVUs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BYmV0YS1y

ZWxhdGVkIGFuZ2lpdGlzOiBwcmltYXJ5IGFuZ2lpdGlzIG9mIHRoZSBjZW50cmFsIG5lcnZvdXMg

c3lzdGVtIGFzc29jaWF0ZWQgd2l0aCBjZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k

aWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjUw

MC01MTU8L3BhZ2VzPjx2b2x1bWU+MTI4PC92b2x1bWU+PG51bWJlcj5QdCAzPC9udW1iZXI+PHJl

cHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5

d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtl

eXdvcmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+YW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+Ymxvb2Q8L2tleXdvcmQ+

PGtleXdvcmQ+Qmxvb2QgVmVzc2Vsczwva2V5d29yZD48a2V5d29yZD5DZW50cmFsIE5lcnZvdXMg

U3lzdGVtPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5

d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbmdpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5DZXJl

YnJhbCBDb3J0ZXg8L2tleXdvcmQ+PGtleXdvcmQ+Y2VyZWJyb3NwaW5hbCBmbHVpZDwva2V5d29y

ZD48a2V5d29yZD5jb21wbGljYXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPmRpYWdub3Npczwva2V5

d29yZD48a2V5d29yZD5FbGVjdHJvZW5jZXBoYWxvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkZl

bWFsZTwva2V5d29yZD48a2V5d29yZD5HbGlvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkhhbGx1Y2lu

YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmZsYW1t

YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdv

cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48

a2V5d29yZD5OZXVyb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvZ25vc2lzPC9rZXl3b3JkPjxr

ZXl3b3JkPlNlaXp1cmVzPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtleXdv

cmQ+VG9tb2dyYXBoeSxYLVJheSBDb21wdXRlZDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQg

T3V0Y29tZTwva2V5d29yZD48a2V5d29yZD5WYXNjdWxpdGlzLENlbnRyYWwgTmVydm91cyBTeXN0

ZW08L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNTwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjMvMjAwNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMDM8L2xhYmVs

Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi

bWVkLzE1NjU5NDI4PC91cmw+PHVybD5odHRwOi8vYnJhaW4ub3hmb3Jkam91cm5hbHMub3JnL2Nv

bnRlbnQvMTI4LzMvNTAwLmZ1bGwucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVj

b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhhcmtuZXNzPC9BdXRob3I+PFllYXI+MjAwNDwvWWVh

cj48UmVjTnVtPjE1NDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTU0PC9yZWMtbnVtYmVy

Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBl

eGY3c3A1MnBwZGR2djAyIiB0aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjE1NDwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGFya25lc3MsSy5BLjwvYXV0aG9yPjxhdXRob3I+

Q29sZXMsQS48L2F1dGhvcj48YXV0aG9yPlBvaGwsVS48L2F1dGhvcj48YXV0aG9yPlh1ZXJlYixK

LkguPC9hdXRob3I+PGF1dGhvcj5CYXJvbixKLkMuPC9hdXRob3I+PGF1dGhvcj5MZW5ub3gsRy5H

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBBZGRlbmJyb29rZSZhcG9zO3MgVW5pdmVyc2l0eSBIb3NwaXRhbCwg

SGlsbHMgUm9hZCwgQ2FtYnJpZGdlLCBVSy4ga2lyc3R5aGFya25lc3NAeWFob28uY29tPC9hdXRo

LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UmFwaWRseSByZXZlcnNpYmxlIGRlbWVudGlhIGluIGNl

cmVicmFsIGFteWxvaWQgaW5mbGFtbWF0b3J5IHZhc2N1bG9wYXRoeTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5FdXIgSiBOZXVyb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5FdXIgSiBOZXVyb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz41OS02MjwvcGFnZXM+PHZvbHVtZT4xMTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXBy

aW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QWRyZW5hbCBDb3J0ZXggSG9ybW9uZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29y

ZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kIHN1cHBseTwva2V5d29y

ZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lv

cGF0aHk8L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5E

ZW1lbnRpYTwva2V5d29yZD48a2V5d29yZD5EZXhhbWV0aGFzb25lPC9rZXl3b3JkPjxrZXl3b3Jk

PmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48a2V5d29y

ZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu

b2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbjwva2V5d29yZD48

a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5OZXVy

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNp

b3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD50aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtl

eXdvcmQ+VmFzY3VsaXRpcyxDZW50cmFsIE5lcnZvdXMgU3lzdGVtPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMDQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzIwMDQ8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MTg5PC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxz

Pjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNDY5Mjg5MDwvdXJsPjx1

cmw+aHR0cDovL29ubGluZWxpYnJhcnkud2lsZXkuY29tL3N0b3JlLzEwLjEwNDYvai4xMzUxLTUx

MDEuMjAwMy4wMDcwNy54L2Fzc2V0L2ouMTM1MS01MTAxLjIwMDMuMDA3MDcueC5wZGY/dj0xJmFt

cDt0PWhzN2d1bWkwJmFtcDtzPTgwMGExNjg1MzU3OWU1ZTczZWJkZTEyNGM5MjM0NmZhZWZhNDFl

Njg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRo

b3I+SGFya25lc3M8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNOdW0+MTU0PC9SZWNOdW0+

PHJlY29yZD48cmVjLW51bWJlcj4xNTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVz

dGFtcD0iMTM5MjM3MjcxNSI+MTU0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5IYXJrbmVzcyxLLkEuPC9hdXRob3I+PGF1dGhvcj5Db2xlcyxBLjwvYXV0aG9yPjxhdXRo

b3I+UG9obCxVLjwvYXV0aG9yPjxhdXRob3I+WHVlcmViLEouSC48L2F1dGhvcj48YXV0aG9yPkJh

cm9uLEouQy48L2F1dGhvcj48YXV0aG9yPkxlbm5veCxHLkcuPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEFkZGVu

YnJvb2tlJmFwb3M7cyBVbml2ZXJzaXR5IEhvc3BpdGFsLCBIaWxscyBSb2FkLCBDYW1icmlkZ2Us

IFVLLiBraXJzdHloYXJrbmVzc0B5YWhvby5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5SYXBpZGx5IHJldmVyc2libGUgZGVtZW50aWEgaW4gY2VyZWJyYWwgYW15bG9pZCBpbmZsYW1t

YXRvcnkgdmFzY3Vsb3BhdGh5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ciBKIE5ldXJvbDwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkV1ciBKIE5l

dXJvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU5LTYyPC9wYWdlcz48dm9sdW1l

PjExPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmls

ZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZHJlbmFsIENvcnRleCBIb3Jt

b25lczwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tl

eXdvcmQ+PGtleXdvcmQ+Ymxvb2Qgc3VwcGx5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3

b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29y

ZD5jb21wbGljYXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkRlbWVudGlhPC9rZXl3b3JkPjxrZXl3

b3JkPkRleGFtZXRoYXNvbmU8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1ZyB0aGVyYXB5PC9rZXl3b3Jk

PjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdv

cmQ+PGtleXdvcmQ+SW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJlc29u

YW5jZSBJbWFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29y

ZD5wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5WYXNjdWxpdGlzLENlbnRy

YWwgTmVydm91cyBTeXN0ZW08L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNDwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjEvMjAwNDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxs

YWJlbD4xODk8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmku

bmxtLm5paC5nb3YvcHVibWVkLzE0NjkyODkwPC91cmw+PHVybD5odHRwOi8vb25saW5lbGlicmFy

eS53aWxleS5jb20vc3RvcmUvMTAuMTA0Ni9qLjEzNTEtNTEwMS4yMDAzLjAwNzA3LngvYXNzZXQv

ai4xMzUxLTUxMDEuMjAwMy4wMDcwNy54LnBkZj92PTEmYW1wO3Q9aHM3Z3VtaTAmYW1wO3M9ODAw

YTE2ODUzNTc5ZTVlNzNlYmRlMTI0YzkyMzQ2ZmFlZmE0MWU2ODwvdXJsPjwvcmVsYXRlZC11cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA (Eng, et al., 2004,Harkness, et al., 2004,Scolding, et al., 2005). The clinical and neuroradiological manifestations of these inflammatory responses do, however, appear to be relatively consistent with WMH a common feature. WMH typically spare the U-fibres when they are caused by ischaemic cerebrovascular disease secondary to either arteriolosclerosis or CAA ADDIN EN.CITE <EndNote><Cite><Author>Chao</Author><Year>2006</Year><RecNum>155</RecNum><DisplayText>(Chao, et al., 2006)</DisplayText><record><rec-number>155</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">155</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chao,C.P.</author><author>Kotsenas,A.L.</author><author>Broderick,D.F.</author></authors></contributors><auth-address>Department of Radiology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA</auth-address><titles><title>Cerebral amyloid angiopathy: CT and MR imaging findings</title><secondary-title>Radiographics</secondary-title></titles><periodical><full-title>Radiographics</full-title></periodical><pages>1517-1531</pages><volume>26</volume><number>5</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Amyloid</keyword><keyword>Brain</keyword><keyword>Cerebral Amyloid Angiopathy</keyword><keyword>Cerebral Angiography</keyword><keyword>Cerebrovascular Disorders</keyword><keyword>diagnosis</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Image Enhancement</keyword><keyword>Magnetic Resonance Angiography</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>methods</keyword><keyword>pathology</keyword><keyword>Physician&apos;s Practice Patterns</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>radiography</keyword><keyword>Tomography,X-Ray Computed</keyword></keywords><dates><year>2006</year><pub-dates><date>9/2006</date></pub-dates></dates><label>190</label><urls><related-urls><url>;(Chao, et al., 2006). However, WMH extending into the U-fibres have been described in cases of CAA-ri ADDIN EN.CITE <EndNote><Cite><Author>Chao</Author><Year>2006</Year><RecNum>155</RecNum><DisplayText>(Chao, et al., 2006)</DisplayText><record><rec-number>155</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">155</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chao,C.P.</author><author>Kotsenas,A.L.</author><author>Broderick,D.F.</author></authors></contributors><auth-address>Department of Radiology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA</auth-address><titles><title>Cerebral amyloid angiopathy: CT and MR imaging findings</title><secondary-title>Radiographics</secondary-title></titles><periodical><full-title>Radiographics</full-title></periodical><pages>1517-1531</pages><volume>26</volume><number>5</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Amyloid</keyword><keyword>Brain</keyword><keyword>Cerebral Amyloid Angiopathy</keyword><keyword>Cerebral Angiography</keyword><keyword>Cerebrovascular Disorders</keyword><keyword>diagnosis</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Image Enhancement</keyword><keyword>Magnetic Resonance Angiography</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>methods</keyword><keyword>pathology</keyword><keyword>Physician&apos;s Practice Patterns</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>radiography</keyword><keyword>Tomography,X-Ray Computed</keyword></keywords><dates><year>2006</year><pub-dates><date>9/2006</date></pub-dates></dates><label>190</label><urls><related-urls><url>;(Chao, et al., 2006). In some of the PSEN1 post-codon 200 cases in our study, the WMH showed a degree of extension into the U-fibres, including those with the p.Arg278Ile mutation, as demonstrated in Figure 1. The p.Arg278Ile mutation is associated with selective overproduction of Aβ43 and mice carrying this mutation show accelerated Aβ pathology, accompanied by an inflammatory response with massive astrocytosis surrounding amyloid plaques ADDIN EN.CITE <EndNote><Cite><Author>Saito</Author><Year>2011</Year><RecNum>169</RecNum><DisplayText>(Saito, et al., 2011)</DisplayText><record><rec-number>169</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">169</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saito,T.</author><author>Suemoto,T.</author><author>Brouwers,N.</author><author>Sleegers,K.</author><author>Funamoto,S.</author><author>Mihira,N.</author><author>Matsuba,Y.</author><author>Yamada,K.</author><author>Nilsson,P.</author><author>Takano,J.</author><author>Nishimura,M.</author><author>Iwata,N.</author><author>Van Broeckhoven,C.</author><author>Ihara,Y.</author><author>Saido,T.C.</author></authors></contributors><auth-address>1] Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan. [2]</auth-address><titles><title>Potent amyloidogenicity and pathogenicity of Abeta43</title><secondary-title>Nat.Neurosci</secondary-title></titles><periodical><full-title>Nat.Neurosci</full-title></periodical><pages>1023-32</pages><volume>14</volume><number>8</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Amyloid</keyword><keyword>Brain</keyword><keyword>Japan</keyword><keyword>Memory</keyword><keyword>Mice</keyword><keyword>Mutation</keyword><keyword>pathology</keyword><keyword>Presenilin-1</keyword></keywords><dates><year>2011</year><pub-dates><date>7/3/2011</date></pub-dates></dates><label>204</label><urls><related-urls><url>;(Saito, et al., 2011). Our alternative hypothesis that WMH may reflect secondary inflammatory mediated pathology led us to investigate microglial, astrocytic and lymphocytic responses in the autopsy cases. At a group level, there was weak evidence that the density of Iba1-stained microglia was higher in the U-fibres than deep white matter in the PSEN1 post-codon 200 group and the autopsy cohort included the p.Ile202Phe case with CAA-ri that has been reported elsewhere ADDIN EN.CITE <EndNote><Cite><Author>Ryan</Author><Year>2014</Year><RecNum>316</RecNum><DisplayText>(Ryan, et al., 2014)</DisplayText><record><rec-number>316</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1417445854">316</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ryan, N. S.</author><author>Lashley, T.</author><author>Revesz, T.</author><author>Dantu, K.</author><author>Fox, N. C.</author><author>Morris, H. R.</author></authors></contributors><auth-address>Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square, London, UK.&#xD;Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.&#xD;Department of Old Age Psychiatry, Ysbyty Ystrad Fawr Hospital, Hengoed, UK.&#xD;Department of Clinical Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.</auth-address><titles><title>Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer&apos;s Disease</title><secondary-title>J Alzheimers Dis</secondary-title><alt-title>Journal of Alzheimer&apos;s disease : JAD</alt-title></titles><periodical><full-title>J Alzheimers Dis</full-title><abbr-1>Journal of Alzheimer&apos;s disease : JAD</abbr-1></periodical><alt-periodical><full-title>J Alzheimers Dis</full-title><abbr-1>Journal of Alzheimer&apos;s disease : JAD</abbr-1></alt-periodical><dates><year>2014</year><pub-dates><date>Nov 18</date></pub-dates></dates><isbn>1875-8908 (Electronic)&#xD;1387-2877 (Linking)</isbn><accession-num>25408217</accession-num><urls><related-urls><url>;(Ryan, et al., 2014). However, the pathological analysis suggested that inflammatory responses might if anything be more prominent in the PSEN1 pre-codon 200 cohort and that this may be related to the younger ages at onset. The pre-codon 200 group had more severe gliosis and a greater T lymphocytic response and decreased axonal density in deep white matter compared to U-fibres. In the pathology cohort as a whole, younger ages at onset were associated with greater immune/inflammatory responses and lower axonal density/integrity. Furthermore, higher ARWMC scores were associated with a lower density of microglia in parietal deep white matter and, on semi-quantitative assessment, cases with white matter pallor were noted to have minimal activated microglia. ARWMC scores also showed positive correlations with the severity of cotton wool plaques in occipital, parietal, temporal and cerebellar regions and a negative correlation with mature plaque severity in the parietal lobe. These observations require corroboration in larger studies but may all be connected. Cotton wool plaques are immunoreactive for A but lack the dense amyloid cores, neuritic responses or microglial associations seen with mature plaques PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Dcm9vazwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+PFJl

Y051bT4yODY8L1JlY051bT48RGlzcGxheVRleHQ+KENyb29rLCBldCBhbC4sIDE5OTgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI4NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxNDE0NjYzNTM0Ij4yODY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkNyb29rLCBSLjwvYXV0aG9yPjxhdXRob3I+VmVya2tvbmllbWksIEEuPC9h

dXRob3I+PGF1dGhvcj5QZXJlei1UdXIsIEouPC9hdXRob3I+PGF1dGhvcj5NZWh0YSwgTi48L2F1

dGhvcj48YXV0aG9yPkJha2VyLCBNLjwvYXV0aG9yPjxhdXRob3I+SG91bGRlbiwgSC48L2F1dGhv

cj48YXV0aG9yPkZhcnJlciwgTS48L2F1dGhvcj48YXV0aG9yPkh1dHRvbiwgTS48L2F1dGhvcj48

YXV0aG9yPkxpbmNvbG4sIFMuPC9hdXRob3I+PGF1dGhvcj5IYXJkeSwgSi48L2F1dGhvcj48YXV0

aG9yPkd3aW5uLCBLLjwvYXV0aG9yPjxhdXRob3I+U29tZXIsIE0uPC9hdXRob3I+PGF1dGhvcj5Q

YWV0YXUsIEEuPC9hdXRob3I+PGF1dGhvcj5LYWxpbW8sIEguPC9hdXRob3I+PGF1dGhvcj5ZbGlr

b3NraSwgUi48L2F1dGhvcj48YXV0aG9yPlBveWhvbmVuLCBNLjwvYXV0aG9yPjxhdXRob3I+S3Vj

ZXJhLCBTLjwvYXV0aG9yPjxhdXRob3I+SGFsdGlhLCBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk1heW8gQ2xpbmljIEphY2tzb252aWxsZSwgRmxvcmlk

YSAzMjA4NCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkEgdmFyaWFudCBvZiBB

bHpoZWltZXImYXBvcztzIGRpc2Vhc2Ugd2l0aCBzcGFzdGljIHBhcmFwYXJlc2lzIGFuZCB1bnVz

dWFsIHBsYXF1ZXMgZHVlIHRvIGRlbGV0aW9uIG9mIGV4b24gOSBvZiBwcmVzZW5pbGluIDE8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+

TmF0dXJlIG1lZGljaW5lPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0

bGU+TmF0IE1lZDwvZnVsbC10aXRsZT48YWJici0xPk5hdHVyZSBtZWRpY2luZTwvYWJici0xPjwv

cGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0IE1lZDwvZnVsbC10aXRs

ZT48YWJici0xPk5hdHVyZSBtZWRpY2luZTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2Vz

PjQ1Mi01PC9wYWdlcz48dm9sdW1lPjQ8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29y

ZHM+PGtleXdvcmQ+QWdlIG9mIE9uc2V0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvY29tcGxpY2F0aW9ucy8qZ2VuZXRpY3MvcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC8qcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkV4b25zPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5GaW5sYW5kPC9rZXl3b3JkPjxrZXl3b3JkPipHZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48

a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW50cm9uczwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJyYW5lIFByb3RlaW5zLypnZW5ldGljczwva2V5

d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbGxh

cnkgVGFuZ2xlcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UGVkaWdyZWU8L2tleXdvcmQ+

PGtleXdvcmQ+UGxhcXVlLCBBbXlsb2lkLypnZW5ldGljcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+UG9seW1lcmFzZSBDaGFpbiBSZWFjdGlvbjwva2V5d29yZD48a2V5d29yZD5QcmVzZW5p

bGluLTE8L2tleXdvcmQ+PGtleXdvcmQ+Uk5BLCBNZXNzZW5nZXIvYmlvc3ludGhlc2lzPC9rZXl3

b3JkPjxrZXl3b3JkPipTZXF1ZW5jZSBEZWxldGlvbjwva2V5d29yZD48a2V5d29yZD5TcGFzdGlj

IFBhcmFwbGVnaWEsIEhlcmVkaXRhcnkvY29tcGxpY2F0aW9ucy8qZ2VuZXRpY3MvcGF0aG9sb2d5

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTg8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDc4LTg5NTYgKFByaW50

KSYjeEQ7MTA3OC04OTU2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT45NTQ2NzkyPC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzk1NDY3OTI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNv

cmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Dcm9vazwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+PFJl

Y051bT4yODY8L1JlY051bT48RGlzcGxheVRleHQ+KENyb29rLCBldCBhbC4sIDE5OTgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI4NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxNDE0NjYzNTM0Ij4yODY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkNyb29rLCBSLjwvYXV0aG9yPjxhdXRob3I+VmVya2tvbmllbWksIEEuPC9h

dXRob3I+PGF1dGhvcj5QZXJlei1UdXIsIEouPC9hdXRob3I+PGF1dGhvcj5NZWh0YSwgTi48L2F1

dGhvcj48YXV0aG9yPkJha2VyLCBNLjwvYXV0aG9yPjxhdXRob3I+SG91bGRlbiwgSC48L2F1dGhv

cj48YXV0aG9yPkZhcnJlciwgTS48L2F1dGhvcj48YXV0aG9yPkh1dHRvbiwgTS48L2F1dGhvcj48

YXV0aG9yPkxpbmNvbG4sIFMuPC9hdXRob3I+PGF1dGhvcj5IYXJkeSwgSi48L2F1dGhvcj48YXV0

aG9yPkd3aW5uLCBLLjwvYXV0aG9yPjxhdXRob3I+U29tZXIsIE0uPC9hdXRob3I+PGF1dGhvcj5Q

YWV0YXUsIEEuPC9hdXRob3I+PGF1dGhvcj5LYWxpbW8sIEguPC9hdXRob3I+PGF1dGhvcj5ZbGlr

b3NraSwgUi48L2F1dGhvcj48YXV0aG9yPlBveWhvbmVuLCBNLjwvYXV0aG9yPjxhdXRob3I+S3Vj

ZXJhLCBTLjwvYXV0aG9yPjxhdXRob3I+SGFsdGlhLCBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk1heW8gQ2xpbmljIEphY2tzb252aWxsZSwgRmxvcmlk

YSAzMjA4NCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkEgdmFyaWFudCBvZiBB

bHpoZWltZXImYXBvcztzIGRpc2Vhc2Ugd2l0aCBzcGFzdGljIHBhcmFwYXJlc2lzIGFuZCB1bnVz

dWFsIHBsYXF1ZXMgZHVlIHRvIGRlbGV0aW9uIG9mIGV4b24gOSBvZiBwcmVzZW5pbGluIDE8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+

TmF0dXJlIG1lZGljaW5lPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0

bGU+TmF0IE1lZDwvZnVsbC10aXRsZT48YWJici0xPk5hdHVyZSBtZWRpY2luZTwvYWJici0xPjwv

cGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0IE1lZDwvZnVsbC10aXRs

ZT48YWJici0xPk5hdHVyZSBtZWRpY2luZTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2Vz

PjQ1Mi01PC9wYWdlcz48dm9sdW1lPjQ8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29y

ZHM+PGtleXdvcmQ+QWdlIG9mIE9uc2V0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvY29tcGxpY2F0aW9ucy8qZ2VuZXRpY3MvcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC8qcGF0aG9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPkV4b25zPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y

ZD5GaW5sYW5kPC9rZXl3b3JkPjxrZXl3b3JkPipHZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48

a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW50cm9uczwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbWJyYW5lIFByb3RlaW5zLypnZW5ldGljczwva2V5

d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbGxh

cnkgVGFuZ2xlcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UGVkaWdyZWU8L2tleXdvcmQ+

PGtleXdvcmQ+UGxhcXVlLCBBbXlsb2lkLypnZW5ldGljcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+UG9seW1lcmFzZSBDaGFpbiBSZWFjdGlvbjwva2V5d29yZD48a2V5d29yZD5QcmVzZW5p

bGluLTE8L2tleXdvcmQ+PGtleXdvcmQ+Uk5BLCBNZXNzZW5nZXIvYmlvc3ludGhlc2lzPC9rZXl3

b3JkPjxrZXl3b3JkPipTZXF1ZW5jZSBEZWxldGlvbjwva2V5d29yZD48a2V5d29yZD5TcGFzdGlj

IFBhcmFwbGVnaWEsIEhlcmVkaXRhcnkvY29tcGxpY2F0aW9ucy8qZ2VuZXRpY3MvcGF0aG9sb2d5

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTg8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDc4LTg5NTYgKFByaW50

KSYjeEQ7MTA3OC04OTU2IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT45NTQ2NzkyPC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxt

Lm5paC5nb3YvcHVibWVkLzk1NDY3OTI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNv

cmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA (Crook, et al., 1998). Their aetiology remains unknown but it has been speculated that they may result from the combination of particularly high A production PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3VsZGVuPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48

UmVjTnVtPjEwNzwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oSG91bGRlbiwgZXQgYWwuLCAyMDAwKTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMDc8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5Ib3VsZGVuLEguPC9hdXRob3I+PGF1dGhvcj5CYWtlcixNLjwvYXV0

aG9yPjxhdXRob3I+TWNHb3dhbixFLjwvYXV0aG9yPjxhdXRob3I+TGV3aXMsUC48L2F1dGhvcj48

YXV0aG9yPkh1dHRvbixNLjwvYXV0aG9yPjxhdXRob3I+Q3Jvb2ssUi48L2F1dGhvcj48YXV0aG9y

Pldvb2QsTi5XLjwvYXV0aG9yPjxhdXRob3I+S3VtYXItU2luZ2gsUy48L2F1dGhvcj48YXV0aG9y

PkdlZGRlcyxKLjwvYXV0aG9yPjxhdXRob3I+U3dhc2gsTS48L2F1dGhvcj48YXV0aG9yPlNjYXJh

dmlsbGksRi48L2F1dGhvcj48YXV0aG9yPkhvbHRvbixKLkwuPC9hdXRob3I+PGF1dGhvcj5MYXNo

bGV5LFQuPC9hdXRob3I+PGF1dGhvcj5Ub21pdGEsVC48L2F1dGhvcj48YXV0aG9yPkhhc2hpbW90

byxULjwvYXV0aG9yPjxhdXRob3I+VmVya2tvbmllbWksQS48L2F1dGhvcj48YXV0aG9yPkthbGlt

byxILjwvYXV0aG9yPjxhdXRob3I+U29tZXIsTS48L2F1dGhvcj48YXV0aG9yPlBhZXRhdSxBLjwv

YXV0aG9yPjxhdXRob3I+TWFydGluLEouSi48L2F1dGhvcj48YXV0aG9yPlZhbiBCcm9lY2tob3Zl

bixDLjwvYXV0aG9yPjxhdXRob3I+R29sZGUsVC48L2F1dGhvcj48YXV0aG9yPkhhcmR5LEouPC9h

dXRob3I+PGF1dGhvcj5IYWx0aWEsTS48L2F1dGhvcj48YXV0aG9yPlJldmVzeixULjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2xp

bmljYWwgTmV1cm9sb2d5IGFuZCBOZXVyb3BhdGhvbG9neSwgSW5zdGl0dXRlIG9mIE5ldXJvbG9n

eSwgTG9uZG9uLCBVSzwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlZhcmlhbnQgQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlIHdpdGggc3Bhc3RpYyBwYXJhcGFyZXNpcyBhbmQgY290dG9uIHdv

b2wgcGxhcXVlcyBpcyBjYXVzZWQgYnkgUFMtMSBtdXRhdGlvbnMgdGhhdCBsZWFkIHRvIGV4Y2Vw

dGlvbmFsbHkgaGlnaCBhbXlsb2lkLWJldGEgY29uY2VudHJhdGlvbnM8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QW5uIE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPkFubiBOZXVyb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz44

MDYtODA4PC9wYWdlcz48dm9sdW1lPjQ4PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PHJlcHJp

bnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29y

ZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxr

ZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90ZWluPC9rZXl3b3JkPjxrZXl3b3JkPmFuYWx5c2lzPC9r

ZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPmNvbXBsaWNhdGlvbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+RG5hPC9rZXl3b3JkPjxrZXl3b3JkPkZpbmxhbmQ8L2tleXdvcmQ+PGtl

eXdvcmQ+R2VuZXM8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+

SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJv

bG9neTwva2V5d29yZD48a2V5d29yZD5QYXJhcGFyZXNpcyxTcGFzdGljPC9rZXl3b3JkPjxrZXl3

b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjExLzIwMDA8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MTQyPC9sYWJlbD48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMTA3OTU0ODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3VsZGVuPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48

UmVjTnVtPjEwNzwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oSG91bGRlbiwgZXQgYWwuLCAyMDAwKTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMDc8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5Ib3VsZGVuLEguPC9hdXRob3I+PGF1dGhvcj5CYWtlcixNLjwvYXV0

aG9yPjxhdXRob3I+TWNHb3dhbixFLjwvYXV0aG9yPjxhdXRob3I+TGV3aXMsUC48L2F1dGhvcj48

YXV0aG9yPkh1dHRvbixNLjwvYXV0aG9yPjxhdXRob3I+Q3Jvb2ssUi48L2F1dGhvcj48YXV0aG9y

Pldvb2QsTi5XLjwvYXV0aG9yPjxhdXRob3I+S3VtYXItU2luZ2gsUy48L2F1dGhvcj48YXV0aG9y

PkdlZGRlcyxKLjwvYXV0aG9yPjxhdXRob3I+U3dhc2gsTS48L2F1dGhvcj48YXV0aG9yPlNjYXJh

dmlsbGksRi48L2F1dGhvcj48YXV0aG9yPkhvbHRvbixKLkwuPC9hdXRob3I+PGF1dGhvcj5MYXNo

bGV5LFQuPC9hdXRob3I+PGF1dGhvcj5Ub21pdGEsVC48L2F1dGhvcj48YXV0aG9yPkhhc2hpbW90

byxULjwvYXV0aG9yPjxhdXRob3I+VmVya2tvbmllbWksQS48L2F1dGhvcj48YXV0aG9yPkthbGlt

byxILjwvYXV0aG9yPjxhdXRob3I+U29tZXIsTS48L2F1dGhvcj48YXV0aG9yPlBhZXRhdSxBLjwv

YXV0aG9yPjxhdXRob3I+TWFydGluLEouSi48L2F1dGhvcj48YXV0aG9yPlZhbiBCcm9lY2tob3Zl

bixDLjwvYXV0aG9yPjxhdXRob3I+R29sZGUsVC48L2F1dGhvcj48YXV0aG9yPkhhcmR5LEouPC9h

dXRob3I+PGF1dGhvcj5IYWx0aWEsTS48L2F1dGhvcj48YXV0aG9yPlJldmVzeixULjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2xp

bmljYWwgTmV1cm9sb2d5IGFuZCBOZXVyb3BhdGhvbG9neSwgSW5zdGl0dXRlIG9mIE5ldXJvbG9n

eSwgTG9uZG9uLCBVSzwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlZhcmlhbnQgQWx6aGVp

bWVyJmFwb3M7cyBkaXNlYXNlIHdpdGggc3Bhc3RpYyBwYXJhcGFyZXNpcyBhbmQgY290dG9uIHdv

b2wgcGxhcXVlcyBpcyBjYXVzZWQgYnkgUFMtMSBtdXRhdGlvbnMgdGhhdCBsZWFkIHRvIGV4Y2Vw

dGlvbmFsbHkgaGlnaCBhbXlsb2lkLWJldGEgY29uY2VudHJhdGlvbnM8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QW5uIE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPkFubiBOZXVyb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz44

MDYtODA4PC9wYWdlcz48dm9sdW1lPjQ4PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PHJlcHJp

bnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29y

ZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxr

ZXl3b3JkPkFteWxvaWQgYmV0YS1Qcm90ZWluPC9rZXl3b3JkPjxrZXl3b3JkPmFuYWx5c2lzPC9r

ZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPmNvbXBsaWNhdGlvbnM8L2tl

eXdvcmQ+PGtleXdvcmQ+RG5hPC9rZXl3b3JkPjxrZXl3b3JkPkZpbmxhbmQ8L2tleXdvcmQ+PGtl

eXdvcmQ+R2VuZXM8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+

SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJv

bG9neTwva2V5d29yZD48a2V5d29yZD5QYXJhcGFyZXNpcyxTcGFzdGljPC9rZXl3b3JkPjxrZXl3

b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjExLzIwMDA8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MTQyPC9sYWJlbD48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMTA3OTU0ODwv

dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA (Houlden, et al., 2000) and low clearance by the immune system ADDIN EN.CITE <EndNote><Cite><Author>Tabira</Author><Year>2002</Year><RecNum>109</RecNum><DisplayText>(Tabira, et al., 2002)</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">109</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tabira,T.</author><author>Chui,D.H.</author><author>Nakayama,H.</author><author>Kuroda,S.</author><author>Shibuya,M.</author></authors></contributors><auth-address>National Institute for Longevity Sciences, Obu, Aichi, Japan. tabira@nils.go.jp</auth-address><titles><title>Alzheimer&apos;s disease with spastic paresis and cotton wool type plaques</title><secondary-title>J Neurosci Res.</secondary-title></titles><periodical><full-title>J Neurosci Res.</full-title></periodical><pages>367-372</pages><volume>70</volume><number>3</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Adult</keyword><keyword>Alzheimer Disease</keyword><keyword>Amyloid</keyword><keyword>Amyloid beta-Protein</keyword><keyword>analysis</keyword><keyword>Basal Ganglia</keyword><keyword>Central Nervous System</keyword><keyword>complications</keyword><keyword>deficiency</keyword><keyword>Female</keyword><keyword>genetics</keyword><keyword>Humans</keyword><keyword>Japan</keyword><keyword>Male</keyword><keyword>Membrane Proteins</keyword><keyword>Middle Aged</keyword><keyword>Mutation</keyword><keyword>Paraparesis,Spastic</keyword><keyword>pathology</keyword><keyword>Peptide Fragments</keyword><keyword>physiopathology</keyword><keyword>Presenilin-1</keyword><keyword>Senile Plaques</keyword></keywords><dates><year>2002</year><pub-dates><date>11/1/2002</date></pub-dates></dates><label>144</label><urls><related-urls><url>;(Tabira, et al., 2002). Of potential relevance to the imaging findings, cotton wool plaques have sometimes been noted to encroach into superficial subcortical white matter PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaHJpbXB0b248L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFy

PjxSZWNOdW0+Mjg3PC9SZWNOdW0+PERpc3BsYXlUZXh0PihTaHJpbXB0b24sIGV0IGFsLiwgMjAw

Nyk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mjg3PC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1

MnBwZGR2djAyIiB0aW1lc3RhbXA9IjE0MTQ2NjQxNzkiPjI4Nzwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2hyaW1wdG9uLCBBLiBFLjwvYXV0aG9yPjxhdXRob3I+U2No

ZWxwZXIsIFIuIEwuPC9hdXRob3I+PGF1dGhvcj5MaW5rZSwgUi4gUC48L2F1dGhvcj48YXV0aG9y

PkhhcmR5LCBKLjwvYXV0aG9yPjxhdXRob3I+Q3Jvb2ssIFIuPC9hdXRob3I+PGF1dGhvcj5EaWNr

c29uLCBELiBXLjwvYXV0aG9yPjxhdXRob3I+SXNoaXphd2EsIFQuPC9hdXRob3I+PGF1dGhvcj5E

YXZpcywgUi4gTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EZXBhcnRtZW50IG9mIFBhdGhvbG9neSwgU1VOWSBVcHN0YXRlIE1lZGljYWwgVW5pdmVyc2l0

eSwgNzUwIEUgQWRhbXMgU3QsIFN5cmFjdXNlLCBOWSAxMzIxMCwgVVNBLiBzaHJpbXB0YUB1cHN0

YXRlLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkEgcHJlc2VuaWxpbiAxIG11dGF0

aW9uIChMNDIwUikgaW4gYSBmYW1pbHkgd2l0aCBlYXJseSBvbnNldCBBbHpoZWltZXIgZGlzZWFz

ZSwgc2VpenVyZXMgYW5kIGNvdHRvbiB3b29sIHBsYXF1ZXMsIGJ1dCBub3Qgc3Bhc3RpYyBwYXJh

cGFyZXNpczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb3BhdGhvbG9neTwvc2Vjb25kYXJ5

LXRpdGxlPjxhbHQtdGl0bGU+TmV1cm9wYXRob2xvZ3kgOiBvZmZpY2lhbCBqb3VybmFsIG9mIHRo

ZSBKYXBhbmVzZSBTb2NpZXR5IG9mIE5ldXJvcGF0aG9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+

PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9wYXRob2xvZ3k8L2Z1bGwtdGl0bGU+PGFiYnIt

MT5OZXVyb3BhdGhvbG9neSA6IG9mZmljaWFsIGpvdXJuYWwgb2YgdGhlIEphcGFuZXNlIFNvY2ll

dHkgb2YgTmV1cm9wYXRob2xvZ3k8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPk5ldXJvcGF0aG9sb2d5PC9mdWxsLXRpdGxlPjxhYmJyLTE+TmV1cm9wYXRo

b2xvZ3kgOiBvZmZpY2lhbCBqb3VybmFsIG9mIHRoZSBKYXBhbmVzZSBTb2NpZXR5IG9mIE5ldXJv

cGF0aG9sb2d5PC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MjI4LTMyPC9wYWdlcz48

dm9sdW1lPjI3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlLypnZW5ldGljcy9wYXRob2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

QnJhaW4vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkROQSBNdXRhdGlvbmFsIEFuYWx5c2lz

PC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBUeXBlIDIvcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SHlwZXJ0ZW5zaW9uL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5JbW11bm9o

aXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk11

dGF0aW9uLCBNaXNzZW5zZTwva2V5d29yZD48a2V5d29yZD5QYXJhcGFyZXNpcywgU3Bhc3RpYy8q

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBlZGlncmVlPC9rZXl3b3JkPjxrZXl3b3JkPlBs

YXF1ZSwgQW15bG9pZC8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBvaW50IE11dGF0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPlByZXNlbmlsaW4tMS9jaGVtaXN0cnkvKmdlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPlNlaXp1cmVzLypldGlvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDA3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGlzYm4+MDkxOS02NTQ0IChQcmludCkmI3hEOzA5MTktNjU0NCAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTc2NDUyMzY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTc2NDUyMzY8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaHJpbXB0b248L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFy

PjxSZWNOdW0+Mjg3PC9SZWNOdW0+PERpc3BsYXlUZXh0PihTaHJpbXB0b24sIGV0IGFsLiwgMjAw

Nyk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+Mjg3PC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1

MnBwZGR2djAyIiB0aW1lc3RhbXA9IjE0MTQ2NjQxNzkiPjI4Nzwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+U2hyaW1wdG9uLCBBLiBFLjwvYXV0aG9yPjxhdXRob3I+U2No

ZWxwZXIsIFIuIEwuPC9hdXRob3I+PGF1dGhvcj5MaW5rZSwgUi4gUC48L2F1dGhvcj48YXV0aG9y

PkhhcmR5LCBKLjwvYXV0aG9yPjxhdXRob3I+Q3Jvb2ssIFIuPC9hdXRob3I+PGF1dGhvcj5EaWNr

c29uLCBELiBXLjwvYXV0aG9yPjxhdXRob3I+SXNoaXphd2EsIFQuPC9hdXRob3I+PGF1dGhvcj5E

YXZpcywgUi4gTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EZXBhcnRtZW50IG9mIFBhdGhvbG9neSwgU1VOWSBVcHN0YXRlIE1lZGljYWwgVW5pdmVyc2l0

eSwgNzUwIEUgQWRhbXMgU3QsIFN5cmFjdXNlLCBOWSAxMzIxMCwgVVNBLiBzaHJpbXB0YUB1cHN0

YXRlLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkEgcHJlc2VuaWxpbiAxIG11dGF0

aW9uIChMNDIwUikgaW4gYSBmYW1pbHkgd2l0aCBlYXJseSBvbnNldCBBbHpoZWltZXIgZGlzZWFz

ZSwgc2VpenVyZXMgYW5kIGNvdHRvbiB3b29sIHBsYXF1ZXMsIGJ1dCBub3Qgc3Bhc3RpYyBwYXJh

cGFyZXNpczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb3BhdGhvbG9neTwvc2Vjb25kYXJ5

LXRpdGxlPjxhbHQtdGl0bGU+TmV1cm9wYXRob2xvZ3kgOiBvZmZpY2lhbCBqb3VybmFsIG9mIHRo

ZSBKYXBhbmVzZSBTb2NpZXR5IG9mIE5ldXJvcGF0aG9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+

PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmV1cm9wYXRob2xvZ3k8L2Z1bGwtdGl0bGU+PGFiYnIt

MT5OZXVyb3BhdGhvbG9neSA6IG9mZmljaWFsIGpvdXJuYWwgb2YgdGhlIEphcGFuZXNlIFNvY2ll

dHkgb2YgTmV1cm9wYXRob2xvZ3k8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPk5ldXJvcGF0aG9sb2d5PC9mdWxsLXRpdGxlPjxhYmJyLTE+TmV1cm9wYXRo

b2xvZ3kgOiBvZmZpY2lhbCBqb3VybmFsIG9mIHRoZSBKYXBhbmVzZSBTb2NpZXR5IG9mIE5ldXJv

cGF0aG9sb2d5PC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MjI4LTMyPC9wYWdlcz48

dm9sdW1lPjI3PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFs

emhlaW1lciBEaXNlYXNlLypnZW5ldGljcy9wYXRob2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxr

ZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

QnJhaW4vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkROQSBNdXRhdGlvbmFsIEFuYWx5c2lz

PC9rZXl3b3JkPjxrZXl3b3JkPkRpYWJldGVzIE1lbGxpdHVzLCBUeXBlIDIvcGF0aG9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SHlwZXJ0ZW5zaW9uL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5JbW11bm9o

aXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk11

dGF0aW9uLCBNaXNzZW5zZTwva2V5d29yZD48a2V5d29yZD5QYXJhcGFyZXNpcywgU3Bhc3RpYy8q

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBlZGlncmVlPC9rZXl3b3JkPjxrZXl3b3JkPlBs

YXF1ZSwgQW15bG9pZC8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBvaW50IE11dGF0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPlByZXNlbmlsaW4tMS9jaGVtaXN0cnkvKmdlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPlNlaXp1cmVzLypldGlvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl

cz48eWVhcj4yMDA3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGlzYm4+MDkxOS02NTQ0IChQcmludCkmI3hEOzA5MTktNjU0NCAoTGlua2luZyk8

L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTc2NDUyMzY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0

ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTc2NDUyMzY8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA (Shrimpton, et al., 2007). The idea that PSEN1 mutations located before codon 200 may be associated with a more aggressive disease course was also suggested by Mann et al., who reported younger ages at onset and shorter disease durations in these cases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PihNYW5uLCBldCBhbC4sIDIwMDEpPC9EaXNwbGF5

VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjU5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYW5uLEQuTS48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZy1Ccm93bixTLk0uPC9h

dXRob3I+PGF1dGhvcj5UYWtldWNoaSxBLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sVC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBOZXVy

b3NjaWVuY2UgUmVzZWFyY2ggR3JvdXAsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgTWFuY2hlc3RlciwgTWFuY2hlc3RlciwgVW5pdGVkIEtpbmdkb20uIGRhdmlkLm1hbm5A

bWFuLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBhbmdpb3BhdGh5

IGFuZCB2YXJpYWJpbGl0eSBpbiBhbXlsb2lkIGJldGEgZGVwb3NpdGlvbiBpcyBkZXRlcm1pbmVk

IGJ5IG11dGF0aW9uIHBvc2l0aW9uIGluIHByZXNlbmlsaW4tMS1saW5rZWQgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGF0aG9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjUtMjE3NTwvcGFnZXM+PHZvbHVtZT4x

NTg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29yZD48a2V5d29yZD5ibG9v

ZDwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYmVsbHVtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5Db2Rvbjwva2V5d29yZD48a2V5d29yZD5Db3MgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250YWwgTG9iZTwva2V5d29yZD48a2V5d29yZD5H

ZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQcm90ZWluczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5QZXB0aWRlIEZyYWdtZW50czwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdv

cmQ+PGtleXdvcmQ+dWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD45NjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTEzOTUzOTQ8L3VybD48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTg5MTk5My9wZGYvMjY4NS5wZGY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PihNYW5uLCBldCBhbC4sIDIwMDEpPC9EaXNwbGF5

VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjU5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYW5uLEQuTS48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZy1Ccm93bixTLk0uPC9h

dXRob3I+PGF1dGhvcj5UYWtldWNoaSxBLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sVC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBOZXVy

b3NjaWVuY2UgUmVzZWFyY2ggR3JvdXAsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgTWFuY2hlc3RlciwgTWFuY2hlc3RlciwgVW5pdGVkIEtpbmdkb20uIGRhdmlkLm1hbm5A

bWFuLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBhbmdpb3BhdGh5

IGFuZCB2YXJpYWJpbGl0eSBpbiBhbXlsb2lkIGJldGEgZGVwb3NpdGlvbiBpcyBkZXRlcm1pbmVk

IGJ5IG11dGF0aW9uIHBvc2l0aW9uIGluIHByZXNlbmlsaW4tMS1saW5rZWQgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGF0aG9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjUtMjE3NTwvcGFnZXM+PHZvbHVtZT4x

NTg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29yZD48a2V5d29yZD5ibG9v

ZDwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYmVsbHVtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5Db2Rvbjwva2V5d29yZD48a2V5d29yZD5Db3MgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250YWwgTG9iZTwva2V5d29yZD48a2V5d29yZD5H

ZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQcm90ZWluczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5QZXB0aWRlIEZyYWdtZW50czwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdv

cmQ+PGtleXdvcmQ+dWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD45NjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTEzOTUzOTQ8L3VybD48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTg5MTk5My9wZGYvMjY4NS5wZGY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Mann, et al., 2001).Different genetic risk factors may interact to determine the severity and pathological consequences of CAA. In sporadic AD, the APOE4 allele is associated with CAA severity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmVlbmJlcmc8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFy

PjxSZWNOdW0+MjkzPC9SZWNOdW0+PERpc3BsYXlUZXh0PihDaGFsbWVycywgZXQgYWwuLCAyMDAz

LEdyZWVuYmVyZywgZXQgYWwuLCAxOTk1LEthbGFyaWEsIGV0IGFsLiwgMTk5NixQcmVta3VtYXIs

IGV0IGFsLiwgMTk5Nik8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjkzPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVl

ZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1lc3RhbXA9IjE0MTQ2NzMzMDMiPjI5Mzwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R3JlZW5iZXJnLCBTLiBNLjwvYXV0aG9y

PjxhdXRob3I+UmViZWNrLCBHLiBXLjwvYXV0aG9yPjxhdXRob3I+Vm9uc2F0dGVsLCBKLiBQLjwv

YXV0aG9yPjxhdXRob3I+R29tZXotSXNsYSwgVC48L2F1dGhvcj48YXV0aG9yPkh5bWFuLCBCLiBU

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIEhhcnZhcmQg

TWVkaWNhbCBTY2hvb2wsIEJvc3RvbiAwMjExNCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+

PHRpdGxlPkFwb2xpcG9wcm90ZWluIEUgZXBzaWxvbiA0IGFuZCBjZXJlYnJhbCBoZW1vcnJoYWdl

IGFzc29jaWF0ZWQgd2l0aCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+QW5uIE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QW5uYWxzIG9mIG5ldXJv

bG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFubiBOZXVy

b2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNTQtOTwvcGFnZXM+PHZvbHVtZT4z

ODwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbGxlbGVzPC9r

ZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xp

cG9wcm90ZWlucyBFLypnZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkJhc2Ug

U2VxdWVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5L2Nv

bXBsaWNhdGlvbnMvKmdlbmV0aWNzL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkNlcmVicmFsIEhlbW9ycmhhZ2UvZXRpb2xvZ3kvKmdlbmV0aWNzL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90

eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdl

ZDwva2V5d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgU2VxdWVuY2UgRGF0YTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4xOTk1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDM2NC01MTM0IChQcmludCkmI3hEOzAzNjQtNTEz

NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+NzY1NDA3NDwvYWNjZXNzaW9uLW51bT48

dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1l

ZC83NjU0MDc0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMDAyL2FuYS40MTAzODAyMTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkthbGFyaWE8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFy

PjxSZWNOdW0+Mjk1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4yOTU8L3JlYy1udW1iZXI+

PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4

ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTQxNDY3MzM0OCI+Mjk1PC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LYWxhcmlhLCBSLiBOLjwvYXV0aG9yPjxhdXRob3I+

Q29oZW4sIEQuIEwuPC9hdXRob3I+PGF1dGhvcj5QcmVta3VtYXIsIEQuIFIuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIENhc2UgV2VzdGVybiBSZXNlcnZlIFVuaXZlcnNpdHksIENsZXZlbGFuZCwgT2hpbyA0NDEw

NiwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFwb2xpcG9wcm90ZWluIEUgYWxs

ZWxlcyBhbmQgYnJhaW4gdmFzY3VsYXIgcGF0aG9sb2d5IGluIEFsemhlaW1lciZhcG9zO3MgZGlz

ZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Bbm4gTiBZIEFjYWQgU2NpPC9zZWNvbmRhcnkt

dGl0bGU+PGFsdC10aXRsZT5Bbm5hbHMgb2YgdGhlIE5ldyBZb3JrIEFjYWRlbXkgb2YgU2NpZW5j

ZXM8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Bbm4gTiBZIEFj

YWQgU2NpPC9mdWxsLXRpdGxlPjxhYmJyLTE+QW5uYWxzIG9mIHRoZSBOZXcgWW9yayBBY2FkZW15

IG9mIFNjaWVuY2VzPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5Bbm4gTiBZIEFjYWQgU2NpPC9mdWxsLXRpdGxlPjxhYmJyLTE+QW5uYWxzIG9mIHRoZSBO

ZXcgWW9yayBBY2FkZW15IG9mIFNjaWVuY2VzPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFn

ZXM+MjY2LTcwPC9wYWdlcz48dm9sdW1lPjc3Nzwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD5B

Z2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3Jk

PipBbGxlbGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2NvbXBsaWNhdGlv

bnMvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFLypnZW5ldGlj

czwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkvZXRpb2xvZ3kv

KmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicm92YXNjdWxhciBEaXNvcmRlcnMvKmdl

bmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9o

aXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuIDE3PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDA3Ny04OTIzIChQcmludCkmI3hEOzAwNzct

ODkyMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+ODYyNDA5NjwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC84NjI0MDk2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48

Q2l0ZT48QXV0aG9yPlByZW1rdW1hcjwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJlY051bT4y

OTg8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI5ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1r

ZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRk

dnYwMiIgdGltZXN0YW1wPSIxNDE0NjczMzgzIj4yOTg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVm

LXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48

YXV0aG9ycz48YXV0aG9yPlByZW1rdW1hciwgRC4gUi48L2F1dGhvcj48YXV0aG9yPkNvaGVuLCBE

LiBMLjwvYXV0aG9yPjxhdXRob3I+SGVkZXJhLCBQLjwvYXV0aG9yPjxhdXRob3I+RnJpZWRsYW5k

LCBSLiBQLjwvYXV0aG9yPjxhdXRob3I+S2FsYXJpYSwgUi4gTi48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQ2Fz

ZSBXZXN0ZXJuIFJlc2VydmUgVW5pdmVyc2l0eSwgQ2xldmVsYW5kLCBPaGlvIDQ0MTA2LTQ5Mzgs

IFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BcG9saXBvcHJvdGVpbiBFLWVwc2ls

b240IGFsbGVsZXMgaW4gY2VyZWJyYWwgYW15bG9pZCBhbmdpb3BhdGh5IGFuZCBjZXJlYnJvdmFz

Y3VsYXIgcGF0aG9sb2d5IGFzc29jaWF0ZWQgd2l0aCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBQYXRob2w8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPlRoZSBBbWVyaWNhbiBqb3VybmFsIG9mIHBhdGhvbG9neTwvYWx0LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sPC9mdWxsLXRpdGxlPjxhYmJy

LTE+VGhlIEFtZXJpY2FuIGpvdXJuYWwgb2YgcGF0aG9sb2d5PC9hYmJyLTE+PC9wZXJpb2RpY2Fs

PjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFBhdGhvbDwvZnVsbC10aXRsZT48YWJi

ci0xPlRoZSBBbWVyaWNhbiBqb3VybmFsIG9mIHBhdGhvbG9neTwvYWJici0xPjwvYWx0LXBlcmlv

ZGljYWw+PHBhZ2VzPjIwODMtOTU8L3BhZ2VzPjx2b2x1bWU+MTQ4PC92b2x1bWU+PG51bWJlcj42

PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwg

ODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+KkFs

bGVsZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0aWNzL3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbiBFNDwva2V5d29yZD48a2V5d29y

ZD5BcG9saXBvcHJvdGVpbnMgRS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QmFzZSBTZXF1

ZW5jZTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkvKmdlbmV0

aWNzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJvdmFzY3VsYXIgRGlzb3JkZXJz

LypnZW5ldGljcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPkdlbmUgRnJlcXVlbmN5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3Jk

PjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwv

a2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1hdGNoZWQtUGFpciBBbmFs

eXNpczwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Nb2xl

Y3VsYXIgU2VxdWVuY2UgRGF0YTwva2V5d29yZD48a2V5d29yZD5QYXJraW5zb24gRGlzZWFzZS9n

ZW5ldGljcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UG9seW1lcmFzZSBDaGFpbiBSZWFj

dGlvbjwva2V5d29yZD48a2V5d29yZD5SZWZlcmVuY2UgVmFsdWVzPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW48L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDAyLTk0NDAgKFByaW50KSYjeEQ7MDAwMi05NDQwIChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT44NjY5NDkyPC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzg2

Njk0OTI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+MTg2MTY1NzwvY3VzdG9t

Mj48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5DaGFsbWVyczwvQXV0aG9yPjxZZWFyPjIw

MDM8L1llYXI+PFJlY051bT4yOTc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI5NzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1

ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxNDE0NjczMzcxIj4yOTc8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNoYWxtZXJzLCBLLjwvYXV0aG9yPjxh

dXRob3I+V2lsY29jaywgRy4gSy48L2F1dGhvcj48YXV0aG9yPkxvdmUsIFMuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBDYXJlIG9m

IHRoZSBFbGRlcmx5LCBJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTmV1cm9zY2llbmNlcywgRnJlbmNo

YXkgSG9zcGl0YWwsIEJyaXN0b2wsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFQ

T0UgZXBzaWxvbiA0IGluZmx1ZW5jZXMgdGhlIHBhdGhvbG9naWNhbCBwaGVub3R5cGUgb2YgQWx6

aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGJ5IGZhdm91cmluZyBjZXJlYnJvdmFzY3VsYXIgb3ZlciBw

YXJlbmNoeW1hbCBhY2N1bXVsYXRpb24gb2YgQSBiZXRhIHByb3RlaW48L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+TmV1cm9wYXRob2wgQXBwbCBOZXVyb2Jpb2w8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPk5ldXJvcGF0aG9sb2d5IGFuZCBhcHBsaWVkIG5ldXJvYmlvbG9neTwvYWx0LXRpdGxl

PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvcGF0aG9sIEFwcGwgTmV1cm9i

aW9sPC9mdWxsLXRpdGxlPjxhYmJyLTE+TmV1cm9wYXRob2xvZ3kgYW5kIGFwcGxpZWQgbmV1cm9i

aW9sb2d5PC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5O

ZXVyb3BhdGhvbCBBcHBsIE5ldXJvYmlvbDwvZnVsbC10aXRsZT48YWJici0xPk5ldXJvcGF0aG9s

b2d5IGFuZCBhcHBsaWVkIG5ldXJvYmlvbG9neTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBh

Z2VzPjIzMS04PC9wYWdlcz48dm9sdW1lPjI5PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtl

eXdvcmRzPjxrZXl3b3JkPkFnZSBvZiBPbnNldDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsbGVsZXM8

L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmNvbXBsaWNhdGlvbnMvZ2VuZXRp

Y3MvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBl

cHRpZGVzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9r

ZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFLypnZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5CbG9vZCBWZXNzZWxzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkvKmNv

bXBsaWNhdGlvbnMvZ2VuZXRpY3MvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5JbWFnZSBQcm9jZXNzaW5nLCBDb21wdXRlci1Bc3Npc3Rl

ZDwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBo

ZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5Qb2x5bWVyYXNlIENoYWluIFJlYWN0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDAzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGlzYm4+MDMwNS0xODQ2IChQcmludCkmI3hEOzAzMDUtMTg0NiAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MTI3ODczMjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTI3ODczMjA8L3VybD48

dXJsPmh0dHA6Ly9vbmxpbmVsaWJyYXJ5LndpbGV5LmNvbS9zdG9yZS8xMC4xMDQ2L2ouMTM2NS0y

OTkwLjIwMDMuMDA0NTcueC9hc3NldC9qLjEzNjUtMjk5MC4yMDAzLjAwNDU3LngucGRmP3Y9MSZh

bXA7dD1pNnJycnNiaCZhbXA7cz00MzM3OWFjYWFlZGU0NDdmMTc5ZmVmMjJlYTdlMzRmZWRiMjA5

MmI1PC91cmw+PHVybD5odHRwOi8vb25saW5lbGlicmFyeS53aWxleS5jb20vc3RvcmUvMTAuMTA0

Ni9qLjEzNjUtMjk5MC4yMDAzLjAwNDU3LngvYXNzZXQvai4xMzY1LTI5OTAuMjAwMy4wMDQ1Ny54

LnBkZj92PTEmYW1wO3Q9aTZycnJ6MmwmYW1wO3M9M2ZhYzc4NGYzNDFlN2YyNDVlNTA0MjBmYjE1

YTUxYjNkZGU2YjlmNTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+

PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmVlbmJlcmc8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFy

PjxSZWNOdW0+MjkzPC9SZWNOdW0+PERpc3BsYXlUZXh0PihDaGFsbWVycywgZXQgYWwuLCAyMDAz

LEdyZWVuYmVyZywgZXQgYWwuLCAxOTk1LEthbGFyaWEsIGV0IGFsLiwgMTk5NixQcmVta3VtYXIs

IGV0IGFsLiwgMTk5Nik8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjkzPC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVl

ZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1lc3RhbXA9IjE0MTQ2NzMzMDMiPjI5Mzwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R3JlZW5iZXJnLCBTLiBNLjwvYXV0aG9y

PjxhdXRob3I+UmViZWNrLCBHLiBXLjwvYXV0aG9yPjxhdXRob3I+Vm9uc2F0dGVsLCBKLiBQLjwv

YXV0aG9yPjxhdXRob3I+R29tZXotSXNsYSwgVC48L2F1dGhvcj48YXV0aG9yPkh5bWFuLCBCLiBU

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1l

bnQgb2YgTmV1cm9sb2d5LCBNYXNzYWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwsIEhhcnZhcmQg

TWVkaWNhbCBTY2hvb2wsIEJvc3RvbiAwMjExNCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+

PHRpdGxlPkFwb2xpcG9wcm90ZWluIEUgZXBzaWxvbiA0IGFuZCBjZXJlYnJhbCBoZW1vcnJoYWdl

IGFzc29jaWF0ZWQgd2l0aCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0

bGU+QW5uIE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QW5uYWxzIG9mIG5ldXJv

bG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFubiBOZXVy

b2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNTQtOTwvcGFnZXM+PHZvbHVtZT4z

ODwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbGxlbGVzPC9r

ZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xp

cG9wcm90ZWlucyBFLypnZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkJhc2Ug

U2VxdWVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQW15bG9pZCBBbmdpb3BhdGh5L2Nv

bXBsaWNhdGlvbnMvKmdlbmV0aWNzL21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3

b3JkPkNlcmVicmFsIEhlbW9ycmhhZ2UvZXRpb2xvZ3kvKmdlbmV0aWNzL21ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90

eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdl

ZDwva2V5d29yZD48a2V5d29yZD5Nb2xlY3VsYXIgU2VxdWVuY2UgRGF0YTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4xOTk1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDM2NC01MTM0IChQcmludCkmI3hEOzAzNjQtNTEz

NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+NzY1NDA3NDwvYWNjZXNzaW9uLW51bT48

dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1l

ZC83NjU0MDc0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl

LW51bT4xMC4xMDAyL2FuYS40MTAzODAyMTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj

b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkthbGFyaWE8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFy

PjxSZWNOdW0+Mjk1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4yOTU8L3JlYy1udW1iZXI+

PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4

ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTQxNDY3MzM0OCI+Mjk1PC9rZXk+PC9mb3JlaWdu

LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250

cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LYWxhcmlhLCBSLiBOLjwvYXV0aG9yPjxhdXRob3I+

Q29oZW4sIEQuIEwuPC9hdXRob3I+PGF1dGhvcj5QcmVta3VtYXIsIEQuIFIuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIENhc2UgV2VzdGVybiBSZXNlcnZlIFVuaXZlcnNpdHksIENsZXZlbGFuZCwgT2hpbyA0NDEw

NiwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFwb2xpcG9wcm90ZWluIEUgYWxs

ZWxlcyBhbmQgYnJhaW4gdmFzY3VsYXIgcGF0aG9sb2d5IGluIEFsemhlaW1lciZhcG9zO3MgZGlz

ZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Bbm4gTiBZIEFjYWQgU2NpPC9zZWNvbmRhcnkt

dGl0bGU+PGFsdC10aXRsZT5Bbm5hbHMgb2YgdGhlIE5ldyBZb3JrIEFjYWRlbXkgb2YgU2NpZW5j

ZXM8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Bbm4gTiBZIEFj

YWQgU2NpPC9mdWxsLXRpdGxlPjxhYmJyLTE+QW5uYWxzIG9mIHRoZSBOZXcgWW9yayBBY2FkZW15

IG9mIFNjaWVuY2VzPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5Bbm4gTiBZIEFjYWQgU2NpPC9mdWxsLXRpdGxlPjxhYmJyLTE+QW5uYWxzIG9mIHRoZSBO

ZXcgWW9yayBBY2FkZW15IG9mIFNjaWVuY2VzPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFn

ZXM+MjY2LTcwPC9wYWdlcz48dm9sdW1lPjc3Nzwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD5B

Z2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3Jk

PipBbGxlbGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlL2NvbXBsaWNhdGlv

bnMvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFLypnZW5ldGlj

czwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkvZXRpb2xvZ3kv

KmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicm92YXNjdWxhciBEaXNvcmRlcnMvKmdl

bmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9o

aXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuIDE3PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDA3Ny04OTIzIChQcmludCkmI3hEOzAwNzct

ODkyMyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+ODYyNDA5NjwvYWNjZXNzaW9uLW51

bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1

Ym1lZC84NjI0MDk2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48

Q2l0ZT48QXV0aG9yPlByZW1rdW1hcjwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJlY051bT4y

OTg8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI5ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1r

ZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRk

dnYwMiIgdGltZXN0YW1wPSIxNDE0NjczMzgzIj4yOTg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVm

LXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48

YXV0aG9ycz48YXV0aG9yPlByZW1rdW1hciwgRC4gUi48L2F1dGhvcj48YXV0aG9yPkNvaGVuLCBE

LiBMLjwvYXV0aG9yPjxhdXRob3I+SGVkZXJhLCBQLjwvYXV0aG9yPjxhdXRob3I+RnJpZWRsYW5k

LCBSLiBQLjwvYXV0aG9yPjxhdXRob3I+S2FsYXJpYSwgUi4gTi48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgQ2Fz

ZSBXZXN0ZXJuIFJlc2VydmUgVW5pdmVyc2l0eSwgQ2xldmVsYW5kLCBPaGlvIDQ0MTA2LTQ5Mzgs

IFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BcG9saXBvcHJvdGVpbiBFLWVwc2ls

b240IGFsbGVsZXMgaW4gY2VyZWJyYWwgYW15bG9pZCBhbmdpb3BhdGh5IGFuZCBjZXJlYnJvdmFz

Y3VsYXIgcGF0aG9sb2d5IGFzc29jaWF0ZWQgd2l0aCBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2U8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBQYXRob2w8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPlRoZSBBbWVyaWNhbiBqb3VybmFsIG9mIHBhdGhvbG9neTwvYWx0LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sPC9mdWxsLXRpdGxlPjxhYmJy

LTE+VGhlIEFtZXJpY2FuIGpvdXJuYWwgb2YgcGF0aG9sb2d5PC9hYmJyLTE+PC9wZXJpb2RpY2Fs

PjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFBhdGhvbDwvZnVsbC10aXRsZT48YWJi

ci0xPlRoZSBBbWVyaWNhbiBqb3VybmFsIG9mIHBhdGhvbG9neTwvYWJici0xPjwvYWx0LXBlcmlv

ZGljYWw+PHBhZ2VzPjIwODMtOTU8L3BhZ2VzPjx2b2x1bWU+MTQ4PC92b2x1bWU+PG51bWJlcj42

PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwg

ODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+KkFs

bGVsZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0aWNzL3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbiBFNDwva2V5d29yZD48a2V5d29y

ZD5BcG9saXBvcHJvdGVpbnMgRS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QmFzZSBTZXF1

ZW5jZTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkvKmdlbmV0

aWNzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJvdmFzY3VsYXIgRGlzb3JkZXJz

LypnZW5ldGljcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPkdlbmUgRnJlcXVlbmN5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3Jk

PjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwv

a2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1hdGNoZWQtUGFpciBBbmFs

eXNpczwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Nb2xl

Y3VsYXIgU2VxdWVuY2UgRGF0YTwva2V5d29yZD48a2V5d29yZD5QYXJraW5zb24gRGlzZWFzZS9n

ZW5ldGljcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UG9seW1lcmFzZSBDaGFpbiBSZWFj

dGlvbjwva2V5d29yZD48a2V5d29yZD5SZWZlcmVuY2UgVmFsdWVzPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW48L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDAyLTk0NDAgKFByaW50KSYjeEQ7MDAwMi05NDQwIChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT44NjY5NDkyPC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzg2

Njk0OTI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+MTg2MTY1NzwvY3VzdG9t

Mj48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5DaGFsbWVyczwvQXV0aG9yPjxZZWFyPjIw

MDM8L1llYXI+PFJlY051bT4yOTc8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI5NzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1

ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxNDE0NjczMzcxIj4yOTc8L2tleT48

L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5

cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNoYWxtZXJzLCBLLjwvYXV0aG9yPjxh

dXRob3I+V2lsY29jaywgRy4gSy48L2F1dGhvcj48YXV0aG9yPkxvdmUsIFMuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBDYXJlIG9m

IHRoZSBFbGRlcmx5LCBJbnN0aXR1dGUgb2YgQ2xpbmljYWwgTmV1cm9zY2llbmNlcywgRnJlbmNo

YXkgSG9zcGl0YWwsIEJyaXN0b2wsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFQ

T0UgZXBzaWxvbiA0IGluZmx1ZW5jZXMgdGhlIHBhdGhvbG9naWNhbCBwaGVub3R5cGUgb2YgQWx6

aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGJ5IGZhdm91cmluZyBjZXJlYnJvdmFzY3VsYXIgb3ZlciBw

YXJlbmNoeW1hbCBhY2N1bXVsYXRpb24gb2YgQSBiZXRhIHByb3RlaW48L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+TmV1cm9wYXRob2wgQXBwbCBOZXVyb2Jpb2w8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPk5ldXJvcGF0aG9sb2d5IGFuZCBhcHBsaWVkIG5ldXJvYmlvbG9neTwvYWx0LXRpdGxl

PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvcGF0aG9sIEFwcGwgTmV1cm9i

aW9sPC9mdWxsLXRpdGxlPjxhYmJyLTE+TmV1cm9wYXRob2xvZ3kgYW5kIGFwcGxpZWQgbmV1cm9i

aW9sb2d5PC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5O

ZXVyb3BhdGhvbCBBcHBsIE5ldXJvYmlvbDwvZnVsbC10aXRsZT48YWJici0xPk5ldXJvcGF0aG9s

b2d5IGFuZCBhcHBsaWVkIG5ldXJvYmlvbG9neTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBh

Z2VzPjIzMS04PC9wYWdlcz48dm9sdW1lPjI5PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtl

eXdvcmRzPjxrZXl3b3JkPkFnZSBvZiBPbnNldDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsbGVsZXM8

L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmNvbXBsaWNhdGlvbnMvZ2VuZXRp

Y3MvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVBl

cHRpZGVzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9r

ZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFLypnZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5CbG9vZCBWZXNzZWxzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CcmFpbi8qbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkvKmNv

bXBsaWNhdGlvbnMvZ2VuZXRpY3MvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1

bWFuczwva2V5d29yZD48a2V5d29yZD5JbWFnZSBQcm9jZXNzaW5nLCBDb21wdXRlci1Bc3Npc3Rl

ZDwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBo

ZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5Qb2x5bWVyYXNlIENoYWluIFJlYWN0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4yMDAzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGlzYm4+MDMwNS0xODQ2IChQcmludCkmI3hEOzAzMDUtMTg0NiAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MTI3ODczMjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTI3ODczMjA8L3VybD48

dXJsPmh0dHA6Ly9vbmxpbmVsaWJyYXJ5LndpbGV5LmNvbS9zdG9yZS8xMC4xMDQ2L2ouMTM2NS0y

OTkwLjIwMDMuMDA0NTcueC9hc3NldC9qLjEzNjUtMjk5MC4yMDAzLjAwNDU3LngucGRmP3Y9MSZh

bXA7dD1pNnJycnNiaCZhbXA7cz00MzM3OWFjYWFlZGU0NDdmMTc5ZmVmMjJlYTdlMzRmZWRiMjA5

MmI1PC91cmw+PHVybD5odHRwOi8vb25saW5lbGlicmFyeS53aWxleS5jb20vc3RvcmUvMTAuMTA0

Ni9qLjEzNjUtMjk5MC4yMDAzLjAwNDU3LngvYXNzZXQvai4xMzY1LTI5OTAuMjAwMy4wMDQ1Ny54

LnBkZj92PTEmYW1wO3Q9aTZycnJ6MmwmYW1wO3M9M2ZhYzc4NGYzNDFlN2YyNDVlNTA0MjBmYjE1

YTUxYjNkZGU2YjlmNTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+

PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA (Chalmers, et al., 2003,Greenberg, et al., 1995,Kalaria, et al., 1996,Premkumar, et al., 1996). We found that, even in FAD, APOE4 carriers have a greater proportion of leptomeningeal and, in particular, cortical blood vessels severely affected by CAA. APOE4 is also a risk factor for CAA-ri PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fbmc8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO

dW0+MTU2PC9SZWNOdW0+PERpc3BsYXlUZXh0PihFbmcsIGV0IGFsLiwgMjAwNCxLaW5uZWNvbSwg

ZXQgYWwuLCAyMDA3KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNTY8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVm

ZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTU2PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5FbmcsSi5BLjwvYXV0aG9yPjxhdXRob3I+

RnJvc2NoLE0uUC48L2F1dGhvcj48YXV0aG9yPkNob2ksSy48L2F1dGhvcj48YXV0aG9yPlJlYmVj

ayxHLlcuPC9hdXRob3I+PGF1dGhvcj5HcmVlbmJlcmcsUy5NLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBNYXNz

YWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwgYW5kIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIEJv

c3RvbiwgTUEgMDIxMTQsIFVTQTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNsaW5pY2Fs

IG1hbmlmZXN0YXRpb25zIG9mIGNlcmVicmFsIGFteWxvaWQgYW5naW9wYXRoeS1yZWxhdGVkIGlu

ZmxhbW1hdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Bbm4gTmV1cm9sPC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uIE5ldXJvbDwvZnVsbC10

aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI1MC0yNTY8L3BhZ2VzPjx2b2x1bWU+NTU8L3ZvbHVt

ZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50

LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkcmVuYWwgQ29ydGV4IEhvcm1vbmVzPC9rZXl3

b3JkPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXM8

L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5zIEU8L2tleXdvcmQ+PGtleXdvcmQ+Ymxv

b2Qgc3VwcGx5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVi

cmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBIZW1vcnJo

YWdlPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRlcnM8L2tleXdvcmQ+PGtleXdv

cmQ+Y29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5DeWNsb3Bob3NwaGFtaWRlPC9rZXl3

b3JkPjxrZXl3b3JkPmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5

d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+

PGtleXdvcmQ+R2Vub3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub3N1cHByZXNz

aXZlIEFnZW50czwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdv

cmQ+TWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5

d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9r

ZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFj

dG9yczwva2V5d29yZD48a2V5d29yZD5TZWl6dXJlczwva2V5d29yZD48a2V5d29yZD50aGVyYXBl

dXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IE91dGNvbWU8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIvMjAwNDwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xOTE8L2xhYmVsPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE0NzU1NzI5PC91

cmw+PHVybD5odHRwOi8vb25saW5lbGlicmFyeS53aWxleS5jb20vc3RvcmUvMTAuMTAwMi9hbmEu

MTA4MTAvYXNzZXQvMTA4MTBfZnRwLnBkZj92PTEmYW1wO3Q9aHM3Z3I2OGkmYW1wO3M9ZTVmM2Jl

OGRkZDMxNmE5MjQwM2IyOWE2OTFjMGMyYzEwOTA3NjA4NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LaW5uZWNvbTwvQXV0aG9yPjxZZWFy

PjIwMDc8L1llYXI+PFJlY051bT4xNzE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjE3MTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5

cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNzE8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktpbm5lY29tLEMuPC9hdXRob3I+

PGF1dGhvcj5MZXYsTS5ILjwvYXV0aG9yPjxhdXRob3I+V2VuZGVsbCxMLjwvYXV0aG9yPjxhdXRo

b3I+U21pdGgsRS5FLjwvYXV0aG9yPjxhdXRob3I+Um9zYW5kLEouPC9hdXRob3I+PGF1dGhvcj5G

cm9zY2gsTS5QLjwvYXV0aG9yPjxhdXRob3I+R3JlZW5iZXJnLFMuTS48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5IZW1vcnJoYWdpYyBTdHJva2UgUmVzZWFy

Y2ggUHJvZ3JhbSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE1hc3NhY2h1c2V0dHMgR2VuZXJh

bCBIb3NwaXRhbCwgQm9zdG9uLCBNQSwgVVNBPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

Q291cnNlIG9mIGNlcmVicmFsIGFteWxvaWQgYW5naW9wYXRoeS1yZWxhdGVkIGluZmxhbW1hdGlv

bjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz4xNDExLTE0MTY8L3BhZ2VzPjx2b2x1bWU+Njg8L3ZvbHVtZT48bnVtYmVy

PjE3PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9u

PjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1JbmZs

YW1tYXRvcnkgQWdlbnRzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9rZXl3

b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29y

ZD5Db2duaXRpb24gRGlzb3JkZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkNvaG9ydCBTdHVkaWVzPC9r

ZXl3b3JkPjxrZXl3b3JkPmNvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEs

VmFzY3VsYXI8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48

a2V5d29yZD5kcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3

b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3Jk

PjxrZXl3b3JkPkhlYWRhY2hlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbjwva2V5d29yZD48

a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxl

PC9rZXl3b3JkPjxrZXl3b3JkPm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5yYWRpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3Rv

cnM8L2tleXdvcmQ+PGtleXdvcmQ+U2VpenVyZXM8L2tleXdvcmQ+PGtleXdvcmQ+U3Ryb2tlPC9r

ZXl3b3JkPjxrZXl3b3JkPnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD50aGVyYXB5

PC9rZXl3b3JkPjxrZXl3b3JkPlZhc2N1bGl0aXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjQvMjQvMjAwNzwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD4yMDY8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE3NDUyNTg2PC91cmw+PHVybD5odHRw

Oi8vd3d3Lm5ldXJvbG9neS5vcmcvY29udGVudC82OC8xNy8xNDExLmZ1bGwucGRmPC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fbmc8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO

dW0+MTU2PC9SZWNOdW0+PERpc3BsYXlUZXh0PihFbmcsIGV0IGFsLiwgMjAwNCxLaW5uZWNvbSwg

ZXQgYWwuLCAyMDA3KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNTY8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVm

ZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTU2PC9rZXk+PC9m

b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl

Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5FbmcsSi5BLjwvYXV0aG9yPjxhdXRob3I+

RnJvc2NoLE0uUC48L2F1dGhvcj48YXV0aG9yPkNob2ksSy48L2F1dGhvcj48YXV0aG9yPlJlYmVj

ayxHLlcuPC9hdXRob3I+PGF1dGhvcj5HcmVlbmJlcmcsUy5NLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBNYXNz

YWNodXNldHRzIEdlbmVyYWwgSG9zcGl0YWwgYW5kIEhhcnZhcmQgTWVkaWNhbCBTY2hvb2wsIEJv

c3RvbiwgTUEgMDIxMTQsIFVTQTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNsaW5pY2Fs

IG1hbmlmZXN0YXRpb25zIG9mIGNlcmVicmFsIGFteWxvaWQgYW5naW9wYXRoeS1yZWxhdGVkIGlu

ZmxhbW1hdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Bbm4gTmV1cm9sPC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uIE5ldXJvbDwvZnVsbC10

aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI1MC0yNTY8L3BhZ2VzPjx2b2x1bWU+NTU8L3ZvbHVt

ZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50

LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkcmVuYWwgQ29ydGV4IEhvcm1vbmVzPC9rZXl3

b3JkPjxrZXl3b3JkPkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXM8

L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5zIEU8L2tleXdvcmQ+PGtleXdvcmQ+Ymxv

b2Qgc3VwcGx5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVi

cmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBIZW1vcnJo

YWdlPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRlcnM8L2tleXdvcmQ+PGtleXdv

cmQ+Y29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5DeWNsb3Bob3NwaGFtaWRlPC9rZXl3

b3JkPjxrZXl3b3JkPmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5

d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+

PGtleXdvcmQ+R2Vub3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3

b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub3N1cHByZXNz

aXZlIEFnZW50czwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdv

cmQ+TWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5

d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9r

ZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFj

dG9yczwva2V5d29yZD48a2V5d29yZD5TZWl6dXJlczwva2V5d29yZD48a2V5d29yZD50aGVyYXBl

dXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IE91dGNvbWU8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIvMjAwNDwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xOTE8L2xhYmVsPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE0NzU1NzI5PC91

cmw+PHVybD5odHRwOi8vb25saW5lbGlicmFyeS53aWxleS5jb20vc3RvcmUvMTAuMTAwMi9hbmEu

MTA4MTAvYXNzZXQvMTA4MTBfZnRwLnBkZj92PTEmYW1wO3Q9aHM3Z3I2OGkmYW1wO3M9ZTVmM2Jl

OGRkZDMxNmE5MjQwM2IyOWE2OTFjMGMyYzEwOTA3NjA4NzwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LaW5uZWNvbTwvQXV0aG9yPjxZZWFy

PjIwMDc8L1llYXI+PFJlY051bT4xNzE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjE3MTwv

cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5

cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xNzE8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktpbm5lY29tLEMuPC9hdXRob3I+

PGF1dGhvcj5MZXYsTS5ILjwvYXV0aG9yPjxhdXRob3I+V2VuZGVsbCxMLjwvYXV0aG9yPjxhdXRo

b3I+U21pdGgsRS5FLjwvYXV0aG9yPjxhdXRob3I+Um9zYW5kLEouPC9hdXRob3I+PGF1dGhvcj5G

cm9zY2gsTS5QLjwvYXV0aG9yPjxhdXRob3I+R3JlZW5iZXJnLFMuTS48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5IZW1vcnJoYWdpYyBTdHJva2UgUmVzZWFy

Y2ggUHJvZ3JhbSwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIE1hc3NhY2h1c2V0dHMgR2VuZXJh

bCBIb3NwaXRhbCwgQm9zdG9uLCBNQSwgVVNBPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

Q291cnNlIG9mIGNlcmVicmFsIGFteWxvaWQgYW5naW9wYXRoeS1yZWxhdGVkIGluZmxhbW1hdGlv

bjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz4xNDExLTE0MTY8L3BhZ2VzPjx2b2x1bWU+Njg8L3ZvbHVtZT48bnVtYmVy

PjE3PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9u

PjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aS1JbmZs

YW1tYXRvcnkgQWdlbnRzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9rZXl3

b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29y

ZD5Db2duaXRpb24gRGlzb3JkZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkNvaG9ydCBTdHVkaWVzPC9r

ZXl3b3JkPjxrZXl3b3JkPmNvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWEs

VmFzY3VsYXI8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48

a2V5d29yZD5kcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3

b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3Jk

PjxrZXl3b3JkPkhlYWRhY2hlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbjwva2V5d29yZD48

a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxl

PC9rZXl3b3JkPjxrZXl3b3JkPm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8

L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwv

a2V5d29yZD48a2V5d29yZD5yYWRpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3Rv

cnM8L2tleXdvcmQ+PGtleXdvcmQ+U2VpenVyZXM8L2tleXdvcmQ+PGtleXdvcmQ+U3Ryb2tlPC9r

ZXl3b3JkPjxrZXl3b3JkPnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD50aGVyYXB5

PC9rZXl3b3JkPjxrZXl3b3JkPlZhc2N1bGl0aXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjQvMjQvMjAwNzwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD4yMDY8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5o

dHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE3NDUyNTg2PC91cmw+PHVybD5odHRw

Oi8vd3d3Lm5ldXJvbG9neS5vcmcvY29udGVudC82OC8xNy8xNDExLmZ1bGwucGRmPC91cmw+PC9y

ZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA (Eng, et al., 2004,Kinnecom, et al., 2007) and for the amyloid-related imaging abnormalities, thought to relate to vascular amyloid, observed in amyloid immunotherapy trials PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TcGVybGluZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT4xODQ8L1JlY051bT48RGlzcGxheVRleHQ+KEJhcmFrb3MsIGV0IGFsLiwgMjAxMyxT

cGVybGluZywgZXQgYWwuLCAyMDExKTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4x

ODQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVy

ZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTg0

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TcGVybGluZyxSLkEuPC9h

dXRob3I+PGF1dGhvcj5KYWNrLEMuUi4sSnIuPC9hdXRob3I+PGF1dGhvcj5CbGFjayxTLkUuPC9h

dXRob3I+PGF1dGhvcj5Gcm9zY2gsTS5QLjwvYXV0aG9yPjxhdXRob3I+R3JlZW5iZXJnLFMuTS48

L2F1dGhvcj48YXV0aG9yPkh5bWFuLEIuVC48L2F1dGhvcj48YXV0aG9yPlNjaGVsdGVucyxQLjwv

YXV0aG9yPjxhdXRob3I+Q2FycmlsbG8sTS5DLjwvYXV0aG9yPjxhdXRob3I+VGhpZXMsVy48L2F1

dGhvcj48YXV0aG9yPkJlZG5hcixNLk0uPC9hdXRob3I+PGF1dGhvcj5CbGFjayxSLlMuPC9hdXRo

b3I+PGF1dGhvcj5CcmFzaGVhcixILlIuPC9hdXRob3I+PGF1dGhvcj5HcnVuZG1hbixNLjwvYXV0

aG9yPjxhdXRob3I+U2llbWVycyxFLlIuPC9hdXRob3I+PGF1dGhvcj5GZWxkbWFuLEguSC48L2F1

dGhvcj48YXV0aG9yPlNjaGluZGxlcixSLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2ggYW5kIFRyZWF0

bWVudCwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEJyaWdoYW0gYW5kIFdvbWVuJmFwb3M7cyBI

b3NwaXRhbCwgQm9zdG9uLCBNQSwgVVNBOyBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWFzc2Fj

aHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCBIYXJ2YXJkIE1lZGljYWwgU2Nob29sLCBCb3N0b24s

IE1BLCBVU0E8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbXlsb2lkLXJlbGF0ZWQgaW1h

Z2luZyBhYm5vcm1hbGl0aWVzIGluIGFteWxvaWQtbW9kaWZ5aW5nIHRoZXJhcGV1dGljIHRyaWFs

czogUmVjb21tZW5kYXRpb25zIGZyb20gdGhlIEFsemhlaW1lciZhcG9zO3MgQXNzb2NpYXRpb24g

UmVzZWFyY2ggUm91bmR0YWJsZSBXb3JrZ3JvdXA8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6

aGVpbWVycy5EZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs

bC10aXRsZT5BbHpoZWltZXJzLkRlbWVudDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2Vz

PjM2Ny0zODU8L3BhZ2VzPjx2b2x1bWU+Nzwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxyZXBy

aW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5O

ZXVyb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT43LzIwMTE8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MjE4PC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTc4NDM0ODwvdXJsPjx1cmw+

aHR0cDovL2FjLmVscy1jZG4uY29tL1MxNTUyNTI2MDExMDI1MDY0LzEtczIuMC1TMTU1MjUyNjAx

MTAyNTA2NC1tYWluLnBkZj9fdGlkPTJkMzZkZDM4LWEwNzktMTFlMy05ZWU0LTAwMDAwYWFjYjM2

MiZhbXA7YWNkbmF0PTEzOTM1OTI5ODZfZDVkMDZjOTQ3M2MwN2VlNjM0YTMzNDlmMjZhZjc4Zjk8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

QmFyYWtvczwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT40Mjg8L1JlY051bT48cmVj

b3JkPjxyZWMtbnVtYmVyPjQyODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1w

PSIxNDI1MjkyNzA0Ij40Mjg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkJhcmFrb3MsIEouPC9hdXRob3I+PGF1dGhvcj5TcGVybGluZywgUi48L2F1dGhvcj48YXV0aG9y

PlNhbGxvd2F5LCBTLjwvYXV0aG9yPjxhdXRob3I+SmFjaywgQy48L2F1dGhvcj48YXV0aG9yPkdh

c3MsIEEuPC9hdXRob3I+PGF1dGhvcj5GaWViYWNoLCBKLiBCLjwvYXV0aG9yPjxhdXRob3I+VGFt

cGllcmksIEQuPC9hdXRob3I+PGF1dGhvcj5NZWxhbmNvbiwgRC48L2F1dGhvcj48YXV0aG9yPk1p

YXV4LCBZLjwvYXV0aG9yPjxhdXRob3I+UmlwcG9uLCBHLjwvYXV0aG9yPjxhdXRob3I+QmxhY2ss

IFIuPC9hdXRob3I+PGF1dGhvcj5MdSwgWS48L2F1dGhvcj48YXV0aG9yPkJyYXNoZWFyLCBILiBS

LjwvYXV0aG9yPjxhdXRob3I+QXJyaWdoaSwgSC4gTS48L2F1dGhvcj48YXV0aG9yPk1vcnJpcywg

Sy4gQS48L2F1dGhvcj48YXV0aG9yPkdydW5kbWFuLCBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNhbGlmb3JuaWEgUGFjaWZpYyBNZWRpY2FsIENlbnRl

ciwgU2FuIEZyYW5jaXNjbywgQ2FsaWZvcm5pYS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5NUiBpbWFnaW5nIGZlYXR1cmVzIG9mIGFteWxvaWQtcmVsYXRlZCBpbWFnaW5nIGFibm9ybWFs

aXRpZXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QUpOUiBBbSBKIE5ldXJvcmFkaW9sPC9zZWNv

bmRhcnktdGl0bGU+PGFsdC10aXRsZT5BSk5SLiBBbWVyaWNhbiBqb3VybmFsIG9mIG5ldXJvcmFk

aW9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QUpOUiBB

bSBKIE5ldXJvcmFkaW9sPC9mdWxsLXRpdGxlPjxhYmJyLTE+QUpOUi4gQW1lcmljYW4gam91cm5h

bCBvZiBuZXVyb3JhZGlvbG9neTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+QUpOUiBBbSBKIE5ldXJvcmFkaW9sPC9mdWxsLXRpdGxlPjxhYmJyLTE+QUpO

Ui4gQW1lcmljYW4gam91cm5hbCBvZiBuZXVyb3JhZGlvbG9neTwvYWJici0xPjwvYWx0LXBlcmlv

ZGljYWw+PHBhZ2VzPjE5NTgtNjU8L3BhZ2VzPjx2b2x1bWU+MzQ8L3ZvbHVtZT48bnVtYmVyPjEw

PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypkcnVnIHRoZXJh

cHkvZXBpZGVtaW9sb2d5LypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZG9zaXMvKmNoZW1p

Y2FsbHkgaW5kdWNlZC9lcGlkZW1pb2xvZ3kvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5B

bnRpYm9kaWVzLCBNb25vY2xvbmFsLCBIdW1hbml6ZWQvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9z

YWdlLyphZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vbWV0YWJvbGlzbS9w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4gRWRlbWEvZXBpZGVtaW9sb2d5L3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBIZW1vcnJoYWdlL2VwaWRlbWlvbG9neS9w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwgVHJpYWxzLCBQaGFzZSBJSSBhcyBU

b3BpYzwva2V5d29yZD48a2V5d29yZD5HYWRvbGluaXVtL2RpYWdub3N0aWMgdXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPkhlbW9zaWRlcmluL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z

PC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD4qTWFnbmV0aWMg

UmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+UmFuZG9taXplZCBDb250cm9sbGVk

IFRyaWFscyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0PC9kYXRlPjwvcHViLWRh

dGVzPjwvZGF0ZXM+PGlzYm4+MTkzNi05NTlYIChFbGVjdHJvbmljKSYjeEQ7MDE5NS02MTA4IChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzU3ODY3NDwvYWNjZXNzaW9uLW51bT48dXJs

cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

MzU3ODY3NDwvdXJsPjx1cmw+aHR0cDovL3d3dy5ham5yLm9yZy9jb250ZW50LzM0LzEwLzE5NTgu

ZnVsbC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjMxNzQvYWpuci5BMzUwMDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TcGVybGluZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

PFJlY051bT4xODQ8L1JlY051bT48RGlzcGxheVRleHQ+KEJhcmFrb3MsIGV0IGFsLiwgMjAxMyxT

cGVybGluZywgZXQgYWwuLCAyMDExKTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4x

ODQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVy

ZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTg0

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TcGVybGluZyxSLkEuPC9h

dXRob3I+PGF1dGhvcj5KYWNrLEMuUi4sSnIuPC9hdXRob3I+PGF1dGhvcj5CbGFjayxTLkUuPC9h

dXRob3I+PGF1dGhvcj5Gcm9zY2gsTS5QLjwvYXV0aG9yPjxhdXRob3I+R3JlZW5iZXJnLFMuTS48

L2F1dGhvcj48YXV0aG9yPkh5bWFuLEIuVC48L2F1dGhvcj48YXV0aG9yPlNjaGVsdGVucyxQLjwv

YXV0aG9yPjxhdXRob3I+Q2FycmlsbG8sTS5DLjwvYXV0aG9yPjxhdXRob3I+VGhpZXMsVy48L2F1

dGhvcj48YXV0aG9yPkJlZG5hcixNLk0uPC9hdXRob3I+PGF1dGhvcj5CbGFjayxSLlMuPC9hdXRo

b3I+PGF1dGhvcj5CcmFzaGVhcixILlIuPC9hdXRob3I+PGF1dGhvcj5HcnVuZG1hbixNLjwvYXV0

aG9yPjxhdXRob3I+U2llbWVycyxFLlIuPC9hdXRob3I+PGF1dGhvcj5GZWxkbWFuLEguSC48L2F1

dGhvcj48YXV0aG9yPlNjaGluZGxlcixSLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+Q2VudGVyIGZvciBBbHpoZWltZXIgUmVzZWFyY2ggYW5kIFRyZWF0

bWVudCwgRGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEJyaWdoYW0gYW5kIFdvbWVuJmFwb3M7cyBI

b3NwaXRhbCwgQm9zdG9uLCBNQSwgVVNBOyBEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWFzc2Fj

aHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCBIYXJ2YXJkIE1lZGljYWwgU2Nob29sLCBCb3N0b24s

IE1BLCBVU0E8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5BbXlsb2lkLXJlbGF0ZWQgaW1h

Z2luZyBhYm5vcm1hbGl0aWVzIGluIGFteWxvaWQtbW9kaWZ5aW5nIHRoZXJhcGV1dGljIHRyaWFs

czogUmVjb21tZW5kYXRpb25zIGZyb20gdGhlIEFsemhlaW1lciZhcG9zO3MgQXNzb2NpYXRpb24g

UmVzZWFyY2ggUm91bmR0YWJsZSBXb3JrZ3JvdXA8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QWx6

aGVpbWVycy5EZW1lbnQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs

bC10aXRsZT5BbHpoZWltZXJzLkRlbWVudDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2Vz

PjM2Ny0zODU8L3BhZ2VzPjx2b2x1bWU+Nzwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxyZXBy

aW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5O

ZXVyb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT43LzIwMTE8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MjE4PC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1

cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTc4NDM0ODwvdXJsPjx1cmw+

aHR0cDovL2FjLmVscy1jZG4uY29tL1MxNTUyNTI2MDExMDI1MDY0LzEtczIuMC1TMTU1MjUyNjAx

MTAyNTA2NC1tYWluLnBkZj9fdGlkPTJkMzZkZDM4LWEwNzktMTFlMy05ZWU0LTAwMDAwYWFjYjM2

MiZhbXA7YWNkbmF0PTEzOTM1OTI5ODZfZDVkMDZjOTQ3M2MwN2VlNjM0YTMzNDlmMjZhZjc4Zjk8

L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+

QmFyYWtvczwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051bT40Mjg8L1JlY051bT48cmVj

b3JkPjxyZWMtbnVtYmVyPjQyODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1w

PSIxNDI1MjkyNzA0Ij40Mjg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkJhcmFrb3MsIEouPC9hdXRob3I+PGF1dGhvcj5TcGVybGluZywgUi48L2F1dGhvcj48YXV0aG9y

PlNhbGxvd2F5LCBTLjwvYXV0aG9yPjxhdXRob3I+SmFjaywgQy48L2F1dGhvcj48YXV0aG9yPkdh

c3MsIEEuPC9hdXRob3I+PGF1dGhvcj5GaWViYWNoLCBKLiBCLjwvYXV0aG9yPjxhdXRob3I+VGFt

cGllcmksIEQuPC9hdXRob3I+PGF1dGhvcj5NZWxhbmNvbiwgRC48L2F1dGhvcj48YXV0aG9yPk1p

YXV4LCBZLjwvYXV0aG9yPjxhdXRob3I+UmlwcG9uLCBHLjwvYXV0aG9yPjxhdXRob3I+QmxhY2ss

IFIuPC9hdXRob3I+PGF1dGhvcj5MdSwgWS48L2F1dGhvcj48YXV0aG9yPkJyYXNoZWFyLCBILiBS

LjwvYXV0aG9yPjxhdXRob3I+QXJyaWdoaSwgSC4gTS48L2F1dGhvcj48YXV0aG9yPk1vcnJpcywg

Sy4gQS48L2F1dGhvcj48YXV0aG9yPkdydW5kbWFuLCBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNhbGlmb3JuaWEgUGFjaWZpYyBNZWRpY2FsIENlbnRl

ciwgU2FuIEZyYW5jaXNjbywgQ2FsaWZvcm5pYS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5NUiBpbWFnaW5nIGZlYXR1cmVzIG9mIGFteWxvaWQtcmVsYXRlZCBpbWFnaW5nIGFibm9ybWFs

aXRpZXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QUpOUiBBbSBKIE5ldXJvcmFkaW9sPC9zZWNv

bmRhcnktdGl0bGU+PGFsdC10aXRsZT5BSk5SLiBBbWVyaWNhbiBqb3VybmFsIG9mIG5ldXJvcmFk

aW9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QUpOUiBB

bSBKIE5ldXJvcmFkaW9sPC9mdWxsLXRpdGxlPjxhYmJyLTE+QUpOUi4gQW1lcmljYW4gam91cm5h

bCBvZiBuZXVyb3JhZGlvbG9neTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+QUpOUiBBbSBKIE5ldXJvcmFkaW9sPC9mdWxsLXRpdGxlPjxhYmJyLTE+QUpO

Ui4gQW1lcmljYW4gam91cm5hbCBvZiBuZXVyb3JhZGlvbG9neTwvYWJici0xPjwvYWx0LXBlcmlv

ZGljYWw+PHBhZ2VzPjE5NTgtNjU8L3BhZ2VzPjx2b2x1bWU+MzQ8L3ZvbHVtZT48bnVtYmVyPjEw

PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsemhlaW1lciBEaXNlYXNlLypkcnVnIHRoZXJh

cHkvZXBpZGVtaW9sb2d5LypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZG9zaXMvKmNoZW1p

Y2FsbHkgaW5kdWNlZC9lcGlkZW1pb2xvZ3kvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5B

bnRpYm9kaWVzLCBNb25vY2xvbmFsLCBIdW1hbml6ZWQvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9z

YWdlLyphZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vbWV0YWJvbGlzbS9w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4gRWRlbWEvZXBpZGVtaW9sb2d5L3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBIZW1vcnJoYWdlL2VwaWRlbWlvbG9neS9w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2xpbmljYWwgVHJpYWxzLCBQaGFzZSBJSSBhcyBU

b3BpYzwva2V5d29yZD48a2V5d29yZD5HYWRvbGluaXVtL2RpYWdub3N0aWMgdXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPkhlbW9zaWRlcmluL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z

PC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD4qTWFnbmV0aWMg

UmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+UmFuZG9taXplZCBDb250cm9sbGVk

IFRyaWFscyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0PC9kYXRlPjwvcHViLWRh

dGVzPjwvZGF0ZXM+PGlzYm4+MTkzNi05NTlYIChFbGVjdHJvbmljKSYjeEQ7MDE5NS02MTA4IChM

aW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzU3ODY3NDwvYWNjZXNzaW9uLW51bT48dXJs

cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y

MzU3ODY3NDwvdXJsPjx1cmw+aHR0cDovL3d3dy5ham5yLm9yZy9jb250ZW50LzM0LzEwLzE5NTgu

ZnVsbC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2Ut

bnVtPjEwLjMxNzQvYWpuci5BMzUwMDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Barakos, et al., 2013,Sperling, et al., 2011). It is therefore noteworthy that the only APOE4 homozygote with a PSEN1 post-codon 200 mutation in this study went on to develop clinical, radiological and pathological features of CAA-ri ADDIN EN.CITE <EndNote><Cite><Author>Ryan</Author><Year>2014</Year><RecNum>316</RecNum><DisplayText>(Ryan, et al., 2014)</DisplayText><record><rec-number>316</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1417445854">316</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ryan, N. S.</author><author>Lashley, T.</author><author>Revesz, T.</author><author>Dantu, K.</author><author>Fox, N. C.</author><author>Morris, H. R.</author></authors></contributors><auth-address>Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square, London, UK.&#xD;Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.&#xD;Department of Old Age Psychiatry, Ysbyty Ystrad Fawr Hospital, Hengoed, UK.&#xD;Department of Clinical Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.</auth-address><titles><title>Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer&apos;s Disease</title><secondary-title>J Alzheimers Dis</secondary-title><alt-title>Journal of Alzheimer&apos;s disease : JAD</alt-title></titles><periodical><full-title>J Alzheimers Dis</full-title><abbr-1>Journal of Alzheimer&apos;s disease : JAD</abbr-1></periodical><alt-periodical><full-title>J Alzheimers Dis</full-title><abbr-1>Journal of Alzheimer&apos;s disease : JAD</abbr-1></alt-periodical><dates><year>2014</year><pub-dates><date>Nov 18</date></pub-dates></dates><isbn>1875-8908 (Electronic)&#xD;1387-2877 (Linking)</isbn><accession-num>25408217</accession-num><urls><related-urls><url>;(Ryan, et al., 2014). In the autopsy cohort, APOE4 carriers showed a higher T lymphocytic response in parietal U-fibres, however there was also some evidence for a greater microglial response in non-carriers so the relationship between APOE status and inflammation was not clear-cut. We found no association between APOE4 status and WMH in our cohort. Previous studies of sporadic AD have also found a lack of association between the APOE4 allele and severity of WMH PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXdhZGE8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS

ZWNOdW0+NDg3PC9SZWNOdW0+PERpc3BsYXlUZXh0PihEb29keSwgZXQgYWwuLCAyMDAwLEhpcm9u

bywgZXQgYWwuLCAyMDAwLFNhd2FkYSwgZXQgYWwuLCAyMDAwKTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj40ODc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0i

MTQzMDgzNTIwNiI+NDg3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5T

YXdhZGEsIEguPC9hdXRob3I+PGF1dGhvcj5VZGFrYSwgRi48L2F1dGhvcj48YXV0aG9yPkl6dW1p

LCBZLjwvYXV0aG9yPjxhdXRob3I+TmlzaGluYWthLCBLLjwvYXV0aG9yPjxhdXRob3I+S2F3YWth

bWksIEguPC9hdXRob3I+PGF1dGhvcj5OYWthbXVyYSwgUy48L2F1dGhvcj48YXV0aG9yPkthbWV5

YW1hLCBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRl

cGFydG1lbnQgb2YgTmV1cm9sb2d5LCBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmUsIEt5b3Rv

IFVuaXZlcnNpdHksIDU0IFNob2dvaW4tS2F3YWhhcmFjaG8sIFNha3lva3UsIEt5b3RvLCA2MDYt

ODUwNywgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2VyZWJyYWwgd2hpdGUg

bWF0dGVyIGxlc2lvbnMgYXJlIG5vdCBhc3NvY2lhdGVkIHdpdGggYXBvRSBnZW5vdHlwZSBidXQg

d2l0aCBhZ2UgYW5kIGZlbWFsZSBzZXggaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPkogTmV1cm9sIE5ldXJvc3VyZyBQc3ljaGlhdHJ5PC9zZWNvbmRh

cnktdGl0bGU+PGFsdC10aXRsZT5Kb3VybmFsIG9mIG5ldXJvbG9neSwgbmV1cm9zdXJnZXJ5LCBh

bmQgcHN5Y2hpYXRyeTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl

PkogTmV1cm9sIE5ldXJvc3VyZyBQc3ljaGlhdHJ5PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+NjUzLTY8L3BhZ2VzPjx2b2x1bWU+Njg8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48

a2V5d29yZHM+PGtleXdvcmQ+QWdlIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5

d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbHpoZWlt

ZXIgRGlzZWFzZS8qZ2VuZXRpY3MvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9w

cm90ZWlucyBFLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5CcmFpbiBEaXNlYXNlcy8qZ2Vu

ZXRpY3MvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC8qcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkROQSBQcmltZXJzL2NoZW1pc3RyeTwva2V5d29yZD48a2V5

d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBGcmVxdWVuY3k8L2tleXdvcmQ+PGtl

eXdvcmQ+R2Vub3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlNl

eCBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDA8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT5NYXk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDIyLTMw

NTAgKFByaW50KSYjeEQ7MDAyMi0zMDUwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4x

MDc2NjkwMTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMDc2NjkwMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48Y3VzdG9tMj4xNzM2OTIwPC9jdXN0b20yPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkRvb2R5PC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVjTnVtPjQ4ODwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+NDg4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1lc3Rh

bXA9IjE0MzA4MzUyMzciPjQ4ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+RG9vZHksIFIuIFMuPC9hdXRob3I+PGF1dGhvcj5BemhlciwgUy4gTi48L2F1dGhvcj48YXV0

aG9yPkhheWthbCwgSC4gQS48L2F1dGhvcj48YXV0aG9yPkR1bm4sIEouIEsuPC9hdXRob3I+PGF1

dGhvcj5MaWFvLCBULjwvYXV0aG9yPjxhdXRob3I+U2NobmVpZGVyLCBMLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5

IGFuZCBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggQ2VudGVyLCBCYXlsb3IgQ29s

bGVnZSBvZiBNZWRpY2luZSwgNjU1MCBGYW5uaW4gU3VpdGUsIDE4MDEgSG91c3RvbiwgVFggNzcw

MzAsIFVTQS4gcmRvb2R5QGJjbS50bWMuZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

RG9lcyBBUE8gZXBzaWxvbjQgY29ycmVsYXRlIHdpdGggTVJJIGNoYW5nZXMgaW4gQWx6aGVpbWVy

JmFwb3M7cyBkaXNlYXNlPzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvbCBOZXVyb3N1

cmcgUHN5Y2hpYXRyeTwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+Sm91cm5hbCBvZiBuZXVy

b2xvZ3ksIG5ldXJvc3VyZ2VyeSwgYW5kIHBzeWNoaWF0cnk8L2FsdC10aXRsZT48L3RpdGxlcz48

cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIE5ldXJvbCBOZXVyb3N1cmcgUHN5Y2hpYXRyeTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjY2OC03MTwvcGFnZXM+PHZvbHVtZT42OTwvdm9s

dW1lPjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxr

ZXl3b3JkPkFsbGVsZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0

aWNzLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW4gRTQ8L2tleXdv

cmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5zIEUvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3Jk

PkJyYWluLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5N

YWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5Ob3Y8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDIyLTMwNTAgKFByaW50KSYjeEQ7MDAy

Mi0zMDUwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xMTAzMjYyNjwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC8xMTAzMjYyNjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj4xNzYz

MzkxPC9jdXN0b20yPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhpcm9ubzwvQXV0aG9y

PjxZZWFyPjIwMDA8L1llYXI+PFJlY051bT40OTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjQ5MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUw

ZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxNDMwODM1Mjg0Ij40

OTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhpcm9ubywgTi48L2F1

dGhvcj48YXV0aG9yPllhc3VkYSwgTS48L2F1dGhvcj48YXV0aG9yPlRhbmltdWthaSwgUy48L2F1

dGhvcj48YXV0aG9yPktpdGFnYWtpLCBILjwvYXV0aG9yPjxhdXRob3I+TW9yaSwgRS48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbnMgb2YgQ2xp

bmljYWwgTmV1cm9zY2llbmNlcywgSHlvZ28gSW5zdGl0dXRlIGZvciBBZ2luZyBCcmFpbiBhbmQg

Q29nbml0aXZlIERpc29yZGVycywgSGltZWppLCBKYXBhbi4gaGlyb25vQGhpYWJjZC5nby5qcDwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkVmZmVjdCBvZiB0aGUgYXBvbGlwb3Byb3RlaW4g

RSBlcHNpbG9uNCBhbGxlbGUgb24gd2hpdGUgbWF0dGVyIGh5cGVyaW50ZW5zaXRpZXMgaW4gZGVt

ZW50aWE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U3Ryb2tlPC9zZWNvbmRhcnktdGl0bGU+PGFs

dC10aXRsZT5TdHJva2U7IGEgam91cm5hbCBvZiBjZXJlYnJhbCBjaXJjdWxhdGlvbjwvYWx0LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlN0cm9rZTwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjEyNjMtODwvcGFnZXM+PHZvbHVtZT4zMTwvdm9sdW1lPjxudW1i

ZXI+NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsY29ob2wgRHJpbmtpbmcvZXBpZGVt

aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPipBbGxlbGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhl

aW1lciBEaXNlYXNlL2VwaWRlbWlvbG9neS9nZW5ldGljcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+QXBvbGlwb3Byb3RlaW4gRTQ8L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5z

IEUvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkF4b25zLypwYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CcmFpbiBJc2NoZW1p

YS9lcGlkZW1pb2xvZ3kvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBJbmZh

cmN0aW9uL2VwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5EZW1lbnRpYS9lcGlkZW1pb2xv

Z3kvZ2VuZXRpY3MvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5EZW1lbnRpYSwgVmFzY3Vs

YXIvZXBpZGVtaW9sb2d5L2dlbmV0aWNzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5EaWFi

ZXRlcyBNZWxsaXR1cy9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3

b3JkPjxrZXl3b3JkPkdlbmUgRnJlcXVlbmN5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJl

ZGlzcG9zaXRpb24gdG8gRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SHlwZXJsaXBpZGVtaWFzL2VwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5I

eXBlcnRlbnNpb24vZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkphcGFuL2VwaWRlbWlv

bG9neTwva2V5d29yZD48a2V5d29yZD4qTWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdv

cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+U21va2luZy9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjAwMzktMjQ5OSAoUHJpbnQpJiN4RDswMDM5LTI0OTkgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjEwODM1NDQyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEwODM1NDQyPC91

cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXdhZGE8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS

ZWNOdW0+NDg3PC9SZWNOdW0+PERpc3BsYXlUZXh0PihEb29keSwgZXQgYWwuLCAyMDAwLEhpcm9u

bywgZXQgYWwuLCAyMDAwLFNhd2FkYSwgZXQgYWwuLCAyMDAwKTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj40ODc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0i

MTQzMDgzNTIwNiI+NDg3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5T

YXdhZGEsIEguPC9hdXRob3I+PGF1dGhvcj5VZGFrYSwgRi48L2F1dGhvcj48YXV0aG9yPkl6dW1p

LCBZLjwvYXV0aG9yPjxhdXRob3I+TmlzaGluYWthLCBLLjwvYXV0aG9yPjxhdXRob3I+S2F3YWth

bWksIEguPC9hdXRob3I+PGF1dGhvcj5OYWthbXVyYSwgUy48L2F1dGhvcj48YXV0aG9yPkthbWV5

YW1hLCBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRl

cGFydG1lbnQgb2YgTmV1cm9sb2d5LCBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmUsIEt5b3Rv

IFVuaXZlcnNpdHksIDU0IFNob2dvaW4tS2F3YWhhcmFjaG8sIFNha3lva3UsIEt5b3RvLCA2MDYt

ODUwNywgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2VyZWJyYWwgd2hpdGUg

bWF0dGVyIGxlc2lvbnMgYXJlIG5vdCBhc3NvY2lhdGVkIHdpdGggYXBvRSBnZW5vdHlwZSBidXQg

d2l0aCBhZ2UgYW5kIGZlbWFsZSBzZXggaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlPC90aXRs

ZT48c2Vjb25kYXJ5LXRpdGxlPkogTmV1cm9sIE5ldXJvc3VyZyBQc3ljaGlhdHJ5PC9zZWNvbmRh

cnktdGl0bGU+PGFsdC10aXRsZT5Kb3VybmFsIG9mIG5ldXJvbG9neSwgbmV1cm9zdXJnZXJ5LCBh

bmQgcHN5Y2hpYXRyeTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl

PkogTmV1cm9sIE5ldXJvc3VyZyBQc3ljaGlhdHJ5PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+NjUzLTY8L3BhZ2VzPjx2b2x1bWU+Njg8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48

a2V5d29yZHM+PGtleXdvcmQ+QWdlIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5

d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbHpoZWlt

ZXIgRGlzZWFzZS8qZ2VuZXRpY3MvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9w

cm90ZWlucyBFLypnZW5ldGljczwva2V5d29yZD48a2V5d29yZD5CcmFpbiBEaXNlYXNlcy8qZ2Vu

ZXRpY3MvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC8qcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkROQSBQcmltZXJzL2NoZW1pc3RyeTwva2V5d29yZD48a2V5

d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBGcmVxdWVuY3k8L2tleXdvcmQ+PGtl

eXdvcmQ+R2Vub3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlNl

eCBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDA8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT5NYXk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDIyLTMw

NTAgKFByaW50KSYjeEQ7MDAyMi0zMDUwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4x

MDc2NjkwMTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3

dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMDc2NjkwMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwv

dXJscz48Y3VzdG9tMj4xNzM2OTIwPC9jdXN0b20yPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkRvb2R5PC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVjTnVtPjQ4ODwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+NDg4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0aW1lc3Rh

bXA9IjE0MzA4MzUyMzciPjQ4ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+RG9vZHksIFIuIFMuPC9hdXRob3I+PGF1dGhvcj5BemhlciwgUy4gTi48L2F1dGhvcj48YXV0

aG9yPkhheWthbCwgSC4gQS48L2F1dGhvcj48YXV0aG9yPkR1bm4sIEouIEsuPC9hdXRob3I+PGF1

dGhvcj5MaWFvLCBULjwvYXV0aG9yPjxhdXRob3I+U2NobmVpZGVyLCBMLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5

IGFuZCBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgUmVzZWFyY2ggQ2VudGVyLCBCYXlsb3IgQ29s

bGVnZSBvZiBNZWRpY2luZSwgNjU1MCBGYW5uaW4gU3VpdGUsIDE4MDEgSG91c3RvbiwgVFggNzcw

MzAsIFVTQS4gcmRvb2R5QGJjbS50bWMuZWR1PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+

RG9lcyBBUE8gZXBzaWxvbjQgY29ycmVsYXRlIHdpdGggTVJJIGNoYW5nZXMgaW4gQWx6aGVpbWVy

JmFwb3M7cyBkaXNlYXNlPzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIE5ldXJvbCBOZXVyb3N1

cmcgUHN5Y2hpYXRyeTwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+Sm91cm5hbCBvZiBuZXVy

b2xvZ3ksIG5ldXJvc3VyZ2VyeSwgYW5kIHBzeWNoaWF0cnk8L2FsdC10aXRsZT48L3RpdGxlcz48

cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIE5ldXJvbCBOZXVyb3N1cmcgUHN5Y2hpYXRyeTwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjY2OC03MTwvcGFnZXM+PHZvbHVtZT42OTwvdm9s

dW1lPjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxr

ZXl3b3JkPkFsbGVsZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0

aWNzLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW4gRTQ8L2tleXdv

cmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5zIEUvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3Jk

PkJyYWluLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3

b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5N

YWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5Ob3Y8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDIyLTMwNTAgKFByaW50KSYjeEQ7MDAy

Mi0zMDUwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xMTAzMjYyNjwvYWNjZXNzaW9u

LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292

L3B1Ym1lZC8xMTAzMjYyNjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj4xNzYz

MzkxPC9jdXN0b20yPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhpcm9ubzwvQXV0aG9y

PjxZZWFyPjIwMDA8L1llYXI+PFJlY051bT40OTA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy

PjQ5MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUw

ZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxNDMwODM1Mjg0Ij40

OTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x

NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhpcm9ubywgTi48L2F1

dGhvcj48YXV0aG9yPllhc3VkYSwgTS48L2F1dGhvcj48YXV0aG9yPlRhbmltdWthaSwgUy48L2F1

dGhvcj48YXV0aG9yPktpdGFnYWtpLCBILjwvYXV0aG9yPjxhdXRob3I+TW9yaSwgRS48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbnMgb2YgQ2xp

bmljYWwgTmV1cm9zY2llbmNlcywgSHlvZ28gSW5zdGl0dXRlIGZvciBBZ2luZyBCcmFpbiBhbmQg

Q29nbml0aXZlIERpc29yZGVycywgSGltZWppLCBKYXBhbi4gaGlyb25vQGhpYWJjZC5nby5qcDwv

YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkVmZmVjdCBvZiB0aGUgYXBvbGlwb3Byb3RlaW4g

RSBlcHNpbG9uNCBhbGxlbGUgb24gd2hpdGUgbWF0dGVyIGh5cGVyaW50ZW5zaXRpZXMgaW4gZGVt

ZW50aWE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U3Ryb2tlPC9zZWNvbmRhcnktdGl0bGU+PGFs

dC10aXRsZT5TdHJva2U7IGEgam91cm5hbCBvZiBjZXJlYnJhbCBjaXJjdWxhdGlvbjwvYWx0LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlN0cm9rZTwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjEyNjMtODwvcGFnZXM+PHZvbHVtZT4zMTwvdm9sdW1lPjxudW1i

ZXI+NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFsY29ob2wgRHJpbmtpbmcvZXBpZGVt

aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPipBbGxlbGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhl

aW1lciBEaXNlYXNlL2VwaWRlbWlvbG9neS9nZW5ldGljcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+QXBvbGlwb3Byb3RlaW4gRTQ8L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5z

IEUvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkF4b25zLypwYXRob2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+QnJhaW4vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CcmFpbiBJc2NoZW1p

YS9lcGlkZW1pb2xvZ3kvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBJbmZh

cmN0aW9uL2VwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5EZW1lbnRpYS9lcGlkZW1pb2xv

Z3kvZ2VuZXRpY3MvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5EZW1lbnRpYSwgVmFzY3Vs

YXIvZXBpZGVtaW9sb2d5L2dlbmV0aWNzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5EaWFi

ZXRlcyBNZWxsaXR1cy9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3

b3JkPjxrZXl3b3JkPkdlbmUgRnJlcXVlbmN5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgUHJl

ZGlzcG9zaXRpb24gdG8gRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+SHlwZXJsaXBpZGVtaWFzL2VwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5I

eXBlcnRlbnNpb24vZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkphcGFuL2VwaWRlbWlv

bG9neTwva2V5d29yZD48a2V5d29yZD4qTWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdv

cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+U21va2luZy9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjAwMzktMjQ5OSAoUHJpbnQpJiN4RDswMDM5LTI0OTkgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjEwODM1NDQyPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEwODM1NDQyPC91

cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA (Doody, et al., 2000,Hirono, et al., 2000,Sawada, et al., 2000), although APOE4 homozygosity has been shown to be associated with multiple microbleeds PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb29zPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

TnVtPjE1ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oR29vcywgZXQgYWwuLCAyMDA5KTwvRGlzcGxh

eVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNTg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIi

IHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTU4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5Hb29zLEouRC48L2F1dGhvcj48YXV0aG9yPktlc3RlcixNLkkuPC9hdXRob3I+

PGF1dGhvcj5CYXJraG9mLEYuPC9hdXRob3I+PGF1dGhvcj5LbGVpbixNLjwvYXV0aG9yPjxhdXRo

b3I+QmxhbmtlbnN0ZWluLE0uQS48L2F1dGhvcj48YXV0aG9yPlNjaGVsdGVucyxQLjwvYXV0aG9y

PjxhdXRob3I+dmFuIGRlciBGbGllcixXLk0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3kgYW5kIEFsemhlaW1lciBD

ZW50ZXIsIFZVIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIsIEFtc3RlcmRhbSwgVGhlIE5ldGhl

cmxhbmRzLiBqLmdvb3NAdnVtYy5ubDwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlBhdGll

bnRzIHdpdGggQWx6aGVpbWVyIGRpc2Vhc2Ugd2l0aCBtdWx0aXBsZSBtaWNyb2JsZWVkczogcmVs

YXRpb24gd2l0aCBjZXJlYnJvc3BpbmFsIGZsdWlkIGJpb21hcmtlcnMgYW5kIGNvZ25pdGlvbjwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5TdHJva2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TdHJva2U8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz4zNDU1LTM0NjA8L3BhZ2VzPjx2b2x1bWU+NDA8L3ZvbHVtZT48bnVtYmVyPjExPC9udW1i

ZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jk

cz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsODAgYW5kIG92ZXI8L2tleXdv

cmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwv

a2V5d29yZD48a2V5d29yZD5BdHJvcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkJpb2xvZ2ljYWwgTWFy

a2Vyczwva2V5d29yZD48a2V5d29yZD5DYXNlLUNvbnRyb2wgU3R1ZGllczwva2V5d29yZD48a2V5

d29yZD5DZXJlYnJhbCBIZW1vcnJoYWdlPC9rZXl3b3JkPjxrZXl3b3JkPmNlcmVicm9zcGluYWwg

Zmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25p

dGlvbiBEaXNvcmRlcnM8L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0aW9uczwva2V5d29yZD48

a2V5d29yZD5EZW1lbnRpYTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdv

cmQ+R2Vub3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1h

bGU8L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NaWNyb2NpcmN1

bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5ldGhlcmxhbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk5l

dXJvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwgVGVzdHM8L2tleXdv

cmQ+PGtleXdvcmQ+cHN5Y2hvbG9neTwva2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0

dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+VGVtcG9yYWwgTG9iZTwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDA5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMjAwOTwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xOTM8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE5NzYyNzA1PC91cmw+PHVy

bD5odHRwOi8vc3Ryb2tlLmFoYWpvdXJuYWxzLm9yZy9jb250ZW50LzQwLzExLzM0NTUuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb29zPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

TnVtPjE1ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oR29vcywgZXQgYWwuLCAyMDA5KTwvRGlzcGxh

eVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNTg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIi

IHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTU4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5Hb29zLEouRC48L2F1dGhvcj48YXV0aG9yPktlc3RlcixNLkkuPC9hdXRob3I+

PGF1dGhvcj5CYXJraG9mLEYuPC9hdXRob3I+PGF1dGhvcj5LbGVpbixNLjwvYXV0aG9yPjxhdXRo

b3I+QmxhbmtlbnN0ZWluLE0uQS48L2F1dGhvcj48YXV0aG9yPlNjaGVsdGVucyxQLjwvYXV0aG9y

PjxhdXRob3I+dmFuIGRlciBGbGllcixXLk0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3kgYW5kIEFsemhlaW1lciBD

ZW50ZXIsIFZVIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIsIEFtc3RlcmRhbSwgVGhlIE5ldGhl

cmxhbmRzLiBqLmdvb3NAdnVtYy5ubDwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlBhdGll

bnRzIHdpdGggQWx6aGVpbWVyIGRpc2Vhc2Ugd2l0aCBtdWx0aXBsZSBtaWNyb2JsZWVkczogcmVs

YXRpb24gd2l0aCBjZXJlYnJvc3BpbmFsIGZsdWlkIGJpb21hcmtlcnMgYW5kIGNvZ25pdGlvbjwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5TdHJva2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TdHJva2U8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw

YWdlcz4zNDU1LTM0NjA8L3BhZ2VzPjx2b2x1bWU+NDA8L3ZvbHVtZT48bnVtYmVyPjExPC9udW1i

ZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jk

cz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsODAgYW5kIG92ZXI8L2tleXdv

cmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwv

a2V5d29yZD48a2V5d29yZD5BdHJvcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkJpb2xvZ2ljYWwgTWFy

a2Vyczwva2V5d29yZD48a2V5d29yZD5DYXNlLUNvbnRyb2wgU3R1ZGllczwva2V5d29yZD48a2V5

d29yZD5DZXJlYnJhbCBIZW1vcnJoYWdlPC9rZXl3b3JkPjxrZXl3b3JkPmNlcmVicm9zcGluYWwg

Zmx1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q29nbml0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25p

dGlvbiBEaXNvcmRlcnM8L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0aW9uczwva2V5d29yZD48

a2V5d29yZD5EZW1lbnRpYTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdv

cmQ+R2Vub3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1h

bGU8L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NaWNyb2NpcmN1

bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk5ldGhlcmxhbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk5l

dXJvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwgVGVzdHM8L2tleXdv

cmQ+PGtleXdvcmQ+cHN5Y2hvbG9neTwva2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0

dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+VGVtcG9yYWwgTG9iZTwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDA5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMjAwOTwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xOTM8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE5NzYyNzA1PC91cmw+PHVy

bD5odHRwOi8vc3Ryb2tlLmFoYWpvdXJuYWxzLm9yZy9jb250ZW50LzQwLzExLzM0NTUuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Goos, et al., 2009). The authors of this study found particularly low ARWMC scores in APOE4 homozygous AD patients with multiple microbleeds, prompting them to suggest that separate pathophysiological mechanisms may underpin microbleeds presenting with and without WMH. As we have previously reported, T2*-weighted imaging sensitive to microbleeds was only available in 12 of the FAD patients in this study and the prevalence of one or more microbleeds in this small cohort was 25%,and has been reported elsewhere ADDIN EN.CITE <EndNote><Cite><Author>Ryan</Author><Year>2011</Year><RecNum>166</RecNum><DisplayText>(Ryan, et al., 2011)</DisplayText><record><rec-number>166</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">166</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ryan,N.S.</author><author>Bastos-Leite,A.J.</author><author>Rohrer,J.D.</author><author>Werring,D.J.</author><author>Fox,N.C.</author><author>Rossor,M.N.</author><author>Schott,J.M.</author></authors></contributors><auth-address>1 Dementia Research Centre, Department of Neurodegeneration, University College London (UCL) Institute of Neurology, Queen Square, London WC1N 3BG, UK</auth-address><titles><title>Cerebral microbleeds in familial Alzheimer&apos;s disease</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>e201</pages><volume>135</volume><number>Pt 1</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Dementia</keyword><keyword>Neurology</keyword></keywords><dates><year>2011</year><pub-dates><date>6/17/2011</date></pub-dates></dates><label>201</label><urls><related-urls><url>;(Ryan, et al., 2011) . The prevalence of one or more microbleeds in this subset of FAD patients was 25%, which is comparable to the proportion of microbleeds found in patients with sporadic AD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3Jkb25uaWVyPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh

cj48UmVjTnVtPjE3MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oQ29yZG9ubmllciBhbmQgdmFuIGRl

ciBGbGllciwgMjAxMSxXaGl0d2VsbCwgZXQgYWwuLCAyMDE1KTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xNzA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0i

MTM5MjM3MjcxNSI+MTcwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5D

b3Jkb25uaWVyLEMuPC9hdXRob3I+PGF1dGhvcj52YW4gZGVyIEZsaWVyLFcuTS48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Vbml2IExpbGxlIE5vcmQgZGUg

RnJhbmNlLCBDSFUgTGlsbGUsIEVBIDEwNDYuIFBvbGUgZGUgbmV1cm9sb2dpZSBGLTU5MDAwIExp

bGxlLCBGcmFuY2UuIGNoYXJsb3R0ZS5jb3Jkb25uaWVyQGNocnUtbGlsbGUuZnI8L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5CcmFpbiBtaWNyb2JsZWVkcyBhbmQgQWx6aGVpbWVyJmFwb3M7

cyBkaXNlYXNlOiBpbm5vY2VudCBvYnNlcnZhdGlvbiBvciBrZXkgcGxheWVyPzwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5CcmFpbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPkJyYWluPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzM1LTM0

NDwvcGFnZXM+PHZvbHVtZT4xMzQ8L3ZvbHVtZT48bnVtYmVyPlB0IDI8L251bWJlcj48cmVwcmlu

dC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PmFkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5

d29yZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kIHN1cHBseTwva2V5

d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBIZW1vcnJoYWdl

PC9rZXl3b3JkPjxrZXl3b3JkPmNoZW1pY2FsbHkgaW5kdWNlZDwva2V5d29yZD48a2V5d29yZD5D

bGluaWNhbCBUcmlhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+ZXBpZGVtaW9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFu

Y2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPnBh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QbGF0ZWxldCBBZ2dyZWdhdGlvbiBJbmhpYml0b3Jz

PC9rZXl3b3JkPjxrZXl3b3JkPlBvc2l0cm9uLUVtaXNzaW9uIFRvbW9ncmFwaHk8L2tleXdvcmQ+

PGtleXdvcmQ+UHJldmFsZW5jZTwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIv

MjAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMDU8L2xhYmVsPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxMjU3

NjUxPC91cmw+PHVybD5odHRwOi8vYnJhaW4ub3hmb3Jkam91cm5hbHMub3JnL2NvbnRlbnQvMTM0

LzIvMzM1LmZ1bGwucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPldoaXR3ZWxsPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjQzMjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDMyPC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBw

ZGR2djAyIiB0aW1lc3RhbXA9IjE0MjUyOTUzOTAiPjQzMjwva2V5PjwvZm9yZWlnbi1rZXlzPjxy

ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz

PjxhdXRob3JzPjxhdXRob3I+V2hpdHdlbGwsIEouIEwuPC9hdXRob3I+PGF1dGhvcj5LYW50YXJj

aSwgSy48L2F1dGhvcj48YXV0aG9yPldlaWdhbmQsIFMuIEQuPC9hdXRob3I+PGF1dGhvcj5MdW5k

dCwgRS4gUy48L2F1dGhvcj48YXV0aG9yPkd1bnRlciwgSi4gTC48L2F1dGhvcj48YXV0aG9yPkR1

ZmZ5LCBKLiBSLjwvYXV0aG9yPjxhdXRob3I+U3RyYW5kLCBFLiBBLjwvYXV0aG9yPjxhdXRob3I+

TWFjaHVsZGEsIE0uIE0uPC9hdXRob3I+PGF1dGhvcj5TcHljaGFsbGEsIEEuIEouPC9hdXRob3I+

PGF1dGhvcj5EcnViYWNoLCBELiBBLjwvYXV0aG9yPjxhdXRob3I+UGV0ZXJzZW4sIFIuIEMuPC9h

dXRob3I+PGF1dGhvcj5Mb3dlLCBWLiBKLjwvYXV0aG9yPjxhdXRob3I+SmFjayBKciwgQy4gUi48

L2F1dGhvcj48YXV0aG9yPkpvc2VwaHMsIEsuIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIE1heW8gQ2xpbmlj

LCBSb2NoZXN0ZXIsIE1OLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIEhlYWx0aCBTY2llbmNlcyBS

ZXNlYXJjaCAoQmlvc3RhdGlzdGljcyksIE1heW8gQ2xpbmljLCBSb2NoZXN0ZXIsIE1OLCBVU0Eu

JiN4RDtEZXBhcnRtZW50IG9mIEluZm9ybWF0aW9uIFRlY2hub2xvZ3ksIE1heW8gQ2xpbmljLCBS

b2NoZXN0ZXIsIE1OLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWF5byBDbGlu

aWMsIFJvY2hlc3RlciwgTU4sIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSBhbmQg

UHN5Y2hvbG9neSAoRGl2aXNpb24gb2YgTmV1cm9wc3ljaG9sb2d5KSwgTWF5byBDbGluaWMsIFJv

Y2hlc3RlciwgTU4sIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NaWNyb2JsZWVk

cyBpbiBBdHlwaWNhbCBQcmVzZW50YXRpb25zIG9mIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZTog

QSBDb21wYXJpc29uIHRvIERlbWVudGlhIG9mIHRoZSBBbHpoZWltZXImYXBvcztzIFR5cGU8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+SiBBbHpoZWltZXJzIERpczwvc2Vjb25kYXJ5LXRpdGxlPjxh

bHQtdGl0bGU+Sm91cm5hbCBvZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgOiBKQUQ8L2FsdC10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFsemhlaW1lcnMgRGlzPC9m

dWxsLXRpdGxlPjxhYmJyLTE+Sm91cm5hbCBvZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgOiBK

QUQ8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQWx6

aGVpbWVycyBEaXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5Kb3VybmFsIG9mIEFsemhlaW1lciZhcG9z

O3MgZGlzZWFzZSA6IEpBRDwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PGRhdGVzPjx5ZWFyPjIw

MTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWIgMzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjE4NzUtODkwOCAoRWxlY3Ryb25pYykmI3hEOzEzODctMjg3NyAoTGlua2luZyk8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MjU2NDk2NTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU2NDk2NTU8L3Vy

bD48dXJsPmh0dHA6Ly9pb3NwcmVzcy5tZXRhcHJlc3MuY29tL2NvbnRlbnQvNzYxeDMwMTMyNTEz

NDU3Ny9mdWxsdGV4dC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjMyMzMvSkFELTE0MjYyODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3Jkb25uaWVyPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh

cj48UmVjTnVtPjE3MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oQ29yZG9ubmllciBhbmQgdmFuIGRl

ciBGbGllciwgMjAxMSxXaGl0d2VsbCwgZXQgYWwuLCAyMDE1KTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xNzA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0i

MTM5MjM3MjcxNSI+MTcwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5D

b3Jkb25uaWVyLEMuPC9hdXRob3I+PGF1dGhvcj52YW4gZGVyIEZsaWVyLFcuTS48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Vbml2IExpbGxlIE5vcmQgZGUg

RnJhbmNlLCBDSFUgTGlsbGUsIEVBIDEwNDYuIFBvbGUgZGUgbmV1cm9sb2dpZSBGLTU5MDAwIExp

bGxlLCBGcmFuY2UuIGNoYXJsb3R0ZS5jb3Jkb25uaWVyQGNocnUtbGlsbGUuZnI8L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5CcmFpbiBtaWNyb2JsZWVkcyBhbmQgQWx6aGVpbWVyJmFwb3M7

cyBkaXNlYXNlOiBpbm5vY2VudCBvYnNlcnZhdGlvbiBvciBrZXkgcGxheWVyPzwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5CcmFpbjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPkJyYWluPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzM1LTM0

NDwvcGFnZXM+PHZvbHVtZT4xMzQ8L3ZvbHVtZT48bnVtYmVyPlB0IDI8L251bWJlcj48cmVwcmlu

dC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PmFkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5

d29yZD48a2V5d29yZD5BbXlsb2lkPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kIHN1cHBseTwva2V5

d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBIZW1vcnJoYWdl

PC9rZXl3b3JkPjxrZXl3b3JkPmNoZW1pY2FsbHkgaW5kdWNlZDwva2V5d29yZD48a2V5d29yZD5D

bGluaWNhbCBUcmlhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+ZXBpZGVtaW9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFu

Y2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPnBh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QbGF0ZWxldCBBZ2dyZWdhdGlvbiBJbmhpYml0b3Jz

PC9rZXl3b3JkPjxrZXl3b3JkPlBvc2l0cm9uLUVtaXNzaW9uIFRvbW9ncmFwaHk8L2tleXdvcmQ+

PGtleXdvcmQ+UHJldmFsZW5jZTwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdv

cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIv

MjAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMDU8L2xhYmVsPjx1cmxzPjxy

ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIxMjU3

NjUxPC91cmw+PHVybD5odHRwOi8vYnJhaW4ub3hmb3Jkam91cm5hbHMub3JnL2NvbnRlbnQvMTM0

LzIvMzM1LmZ1bGwucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPldoaXR3ZWxsPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

PjQzMjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NDMyPC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBw

ZGR2djAyIiB0aW1lc3RhbXA9IjE0MjUyOTUzOTAiPjQzMjwva2V5PjwvZm9yZWlnbi1rZXlzPjxy

ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz

PjxhdXRob3JzPjxhdXRob3I+V2hpdHdlbGwsIEouIEwuPC9hdXRob3I+PGF1dGhvcj5LYW50YXJj

aSwgSy48L2F1dGhvcj48YXV0aG9yPldlaWdhbmQsIFMuIEQuPC9hdXRob3I+PGF1dGhvcj5MdW5k

dCwgRS4gUy48L2F1dGhvcj48YXV0aG9yPkd1bnRlciwgSi4gTC48L2F1dGhvcj48YXV0aG9yPkR1

ZmZ5LCBKLiBSLjwvYXV0aG9yPjxhdXRob3I+U3RyYW5kLCBFLiBBLjwvYXV0aG9yPjxhdXRob3I+

TWFjaHVsZGEsIE0uIE0uPC9hdXRob3I+PGF1dGhvcj5TcHljaGFsbGEsIEEuIEouPC9hdXRob3I+

PGF1dGhvcj5EcnViYWNoLCBELiBBLjwvYXV0aG9yPjxhdXRob3I+UGV0ZXJzZW4sIFIuIEMuPC9h

dXRob3I+PGF1dGhvcj5Mb3dlLCBWLiBKLjwvYXV0aG9yPjxhdXRob3I+SmFjayBKciwgQy4gUi48

L2F1dGhvcj48YXV0aG9yPkpvc2VwaHMsIEsuIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp

YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBSYWRpb2xvZ3ksIE1heW8gQ2xpbmlj

LCBSb2NoZXN0ZXIsIE1OLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIEhlYWx0aCBTY2llbmNlcyBS

ZXNlYXJjaCAoQmlvc3RhdGlzdGljcyksIE1heW8gQ2xpbmljLCBSb2NoZXN0ZXIsIE1OLCBVU0Eu

JiN4RDtEZXBhcnRtZW50IG9mIEluZm9ybWF0aW9uIFRlY2hub2xvZ3ksIE1heW8gQ2xpbmljLCBS

b2NoZXN0ZXIsIE1OLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgTWF5byBDbGlu

aWMsIFJvY2hlc3RlciwgTU4sIFVTQS4mI3hEO0RlcGFydG1lbnQgb2YgUHN5Y2hpYXRyeSBhbmQg

UHN5Y2hvbG9neSAoRGl2aXNpb24gb2YgTmV1cm9wc3ljaG9sb2d5KSwgTWF5byBDbGluaWMsIFJv

Y2hlc3RlciwgTU4sIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NaWNyb2JsZWVk

cyBpbiBBdHlwaWNhbCBQcmVzZW50YXRpb25zIG9mIEFsemhlaW1lciZhcG9zO3MgRGlzZWFzZTog

QSBDb21wYXJpc29uIHRvIERlbWVudGlhIG9mIHRoZSBBbHpoZWltZXImYXBvcztzIFR5cGU8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+SiBBbHpoZWltZXJzIERpczwvc2Vjb25kYXJ5LXRpdGxlPjxh

bHQtdGl0bGU+Sm91cm5hbCBvZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgOiBKQUQ8L2FsdC10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFsemhlaW1lcnMgRGlzPC9m

dWxsLXRpdGxlPjxhYmJyLTE+Sm91cm5hbCBvZiBBbHpoZWltZXImYXBvcztzIGRpc2Vhc2UgOiBK

QUQ8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQWx6

aGVpbWVycyBEaXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5Kb3VybmFsIG9mIEFsemhlaW1lciZhcG9z

O3MgZGlzZWFzZSA6IEpBRDwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PGRhdGVzPjx5ZWFyPjIw

MTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5GZWIgMzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjE4NzUtODkwOCAoRWxlY3Ryb25pYykmI3hEOzEzODctMjg3NyAoTGlua2luZyk8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MjU2NDk2NTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQt

dXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjU2NDk2NTU8L3Vy

bD48dXJsPmh0dHA6Ly9pb3NwcmVzcy5tZXRhcHJlc3MuY29tL2NvbnRlbnQvNzYxeDMwMTMyNTEz

NDU3Ny9mdWxsdGV4dC5wZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMt

cmVzb3VyY2UtbnVtPjEwLjMyMzMvSkFELTE0MjYyODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Cordonnier and van der Flier, 2011,Whitwell, et al., 2015). Interestingly, the only patient with multiple microbleeds had both a post-codon 200 PSEN1 mutation (p.Arg269His) and the APOE genotype 3/4. CAA typically affects cortical and leptomeningeal small and medium-sized arteries and arterioles, with veins and capillaries involved less frequently ADDIN EN.CITE <EndNote><Cite><Author>Revesz</Author><Year>2003</Year><RecNum>181</RecNum><DisplayText>(Revesz, et al., 2003)</DisplayText><record><rec-number>181</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">181</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Revesz,T.</author><author>Ghiso,J.</author><author>Lashley,T.</author><author>Plant,G.</author><author>Rostagno,A.</author><author>Frangione,B.</author><author>Holton,J.L.</author></authors></contributors><auth-address>Queen Square Brain Bank, Department of Molecular Neuroscience and Division of Neuropathology, Institute of Neurology, University College London, London, United Kingdom. t.revesz@ion.ucl.ac.uk</auth-address><titles><title>Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view</title><secondary-title>J Neuropathol Exp.Neurol</secondary-title></titles><periodical><full-title>J Neuropathol Exp.Neurol</full-title></periodical><pages>885-898</pages><volume>62</volume><number>9</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Alzheimer Disease</keyword><keyword>Amino Acid Sequence</keyword><keyword>Amyloid</keyword><keyword>Amyloidosis</keyword><keyword>Animals</keyword><keyword>Brain</keyword><keyword>Capillaries</keyword><keyword>Central Nervous System</keyword><keyword>Cerebral Amyloid Angiopathy</keyword><keyword>Cerebral Hemorrhage</keyword><keyword>Dementia</keyword><keyword>Genes</keyword><keyword>genetics</keyword><keyword>Humans</keyword><keyword>metabolism</keyword><keyword>Molecular Sequence Data</keyword><keyword>Mutation</keyword><keyword>Neurology</keyword><keyword>pathology</keyword><keyword>Presenilin-1</keyword><keyword>Proteins</keyword></keywords><dates><year>2003</year><pub-dates><date>9/2003</date></pub-dates></dates><label>215</label><urls><related-urls><url>;(Revesz, et al., 2003). When the cortical capillaries are involved there are sometimes associated dyshoric changes, where amyloid deposits spread beyond the vessel wall into the surrounding neuropil PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWNoYXJkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48

UmVjTnVtPjE4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oUmljaGFyZCwgZXQgYWwuLCAyMDEwKTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xODA8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTgwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5SaWNoYXJkLEUuPC9hdXRob3I+PGF1dGhvcj5DYXJyYW5vLEEuPC9h

dXRob3I+PGF1dGhvcj5Ib296ZW1hbnMsSi5KLjwvYXV0aG9yPjxhdXRob3I+dmFuIEhvcnNzZW4s

Si48L2F1dGhvcj48YXV0aG9yPnZhbiBIYWFzdGVydCxFLlMuPC9hdXRob3I+PGF1dGhvcj5FdXJl

bGluZ3MsTC5TLjwvYXV0aG9yPjxhdXRob3I+ZGUgVnJpZXMsSC5FLjwvYXV0aG9yPjxhdXRob3I+

VGhhbCxELlIuPC9hdXRob3I+PGF1dGhvcj5FaWtlbGVuYm9vbSxQLjwvYXV0aG9yPjxhdXRob3I+

dmFuIEdvb2wsVy5BLjwvYXV0aG9yPjxhdXRob3I+Um96ZW11bGxlcixBLkouPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIEFjYWRlbWljIE1lZGljYWwgQ2VudGVyLCBVbml2ZXJzaXR5IG9mIEFtc3RlcmRhbSwgQW1z

dGVyZGFtLCBUaGUgTmV0aGVybGFuZHMuIGUucmljaGFyZEBhbWMudXZhLm5sPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+Q2hhcmFjdGVyaXN0aWNzIG9mIGR5c2hvcmljIGNhcGlsbGFyeSBj

ZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBOZXVy

b3BhdGhvbCBFeHAuTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+SiBOZXVyb3BhdGhvbCBFeHAuTmV1cm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTE1OC0xMTY3PC9wYWdlcz48dm9sdW1lPjY5PC92b2x1bWU+PG51bWJlcj4x

MTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLDgwIGFuZCBvdmVy

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9rZXl3b3JkPjxr

ZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNhcGlsbGFyaWVzPC9rZXl3b3JkPjxrZXl3

b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub3R5cGU8L2tl

eXdvcmQ+PGtleXdvcmQ+R2xpYWwgRmlicmlsbGFyeSBBY2lkaWMgUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5ITEEtRFIgQW50aWdlbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1h

dGlvbjwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VhbCBB

cnRlcmllczwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5l

dGhlcmxhbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1

IFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlViaXF1aXRpbjwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMjAxMDwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMTQ8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwOTQwNjI1PC91cmw+PHVy

bD5odHRwOi8vZ3JhcGhpY3MudHgub3ZpZC5jb20vb3ZmdHBkZnMvRlBERE5DR0NKQklLQUcwMC9m

czA0Ni9vdmZ0L2xpdmUvZ3YwMjMvMDAwMDUwNzIvMDAwMDUwNzItMjAxMDExMDAwLTAwMDA3LnBk

ZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWNoYXJkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48

UmVjTnVtPjE4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oUmljaGFyZCwgZXQgYWwuLCAyMDEwKTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xODA8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTgwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5SaWNoYXJkLEUuPC9hdXRob3I+PGF1dGhvcj5DYXJyYW5vLEEuPC9h

dXRob3I+PGF1dGhvcj5Ib296ZW1hbnMsSi5KLjwvYXV0aG9yPjxhdXRob3I+dmFuIEhvcnNzZW4s

Si48L2F1dGhvcj48YXV0aG9yPnZhbiBIYWFzdGVydCxFLlMuPC9hdXRob3I+PGF1dGhvcj5FdXJl

bGluZ3MsTC5TLjwvYXV0aG9yPjxhdXRob3I+ZGUgVnJpZXMsSC5FLjwvYXV0aG9yPjxhdXRob3I+

VGhhbCxELlIuPC9hdXRob3I+PGF1dGhvcj5FaWtlbGVuYm9vbSxQLjwvYXV0aG9yPjxhdXRob3I+

dmFuIEdvb2wsVy5BLjwvYXV0aG9yPjxhdXRob3I+Um96ZW11bGxlcixBLkouPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIEFjYWRlbWljIE1lZGljYWwgQ2VudGVyLCBVbml2ZXJzaXR5IG9mIEFtc3RlcmRhbSwgQW1z

dGVyZGFtLCBUaGUgTmV0aGVybGFuZHMuIGUucmljaGFyZEBhbWMudXZhLm5sPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+Q2hhcmFjdGVyaXN0aWNzIG9mIGR5c2hvcmljIGNhcGlsbGFyeSBj

ZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBOZXVy

b3BhdGhvbCBFeHAuTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+SiBOZXVyb3BhdGhvbCBFeHAuTmV1cm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTE1OC0xMTY3PC9wYWdlcz48dm9sdW1lPjY5PC92b2x1bWU+PG51bWJlcj4x

MTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLDgwIGFuZCBvdmVy

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9rZXl3b3JkPjxr

ZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNhcGlsbGFyaWVzPC9rZXl3b3JkPjxrZXl3

b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub3R5cGU8L2tl

eXdvcmQ+PGtleXdvcmQ+R2xpYWwgRmlicmlsbGFyeSBBY2lkaWMgUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5ITEEtRFIgQW50aWdlbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1h

dGlvbjwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VhbCBB

cnRlcmllczwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5l

dGhlcmxhbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1

IFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlViaXF1aXRpbjwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMjAxMDwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMTQ8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwOTQwNjI1PC91cmw+PHVy

bD5odHRwOi8vZ3JhcGhpY3MudHgub3ZpZC5jb20vb3ZmdHBkZnMvRlBERE5DR0NKQklLQUcwMC9m

czA0Ni9vdmZ0L2xpdmUvZ3YwMjMvMDAwMDUwNzIvMDAwMDUwNzItMjAxMDExMDAwLTAwMDA3LnBk

ZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA (Richard, et al., 2010). An association has been observed between APOE4 and capillary CAA, particularly with associated dyshoric changes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGFsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj

TnVtPjE3NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oVGhhbCwgZXQgYWwuLCAyMDAyKTwvRGlzcGxh

eVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNzc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIi

IHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTc3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5UaGFsLEQuUi48L2F1dGhvcj48YXV0aG9yPkdoZWJyZW1lZGhpbixFLjwvYXV0

aG9yPjxhdXRob3I+UnViLFUuPC9hdXRob3I+PGF1dGhvcj5ZYW1hZ3VjaGksSC48L2F1dGhvcj48

YXV0aG9yPkRlbCBUcmVkaWNpLEsuPC9hdXRob3I+PGF1dGhvcj5CcmFhayxILjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2xpbmlj

YWwgTmV1cm9hbmF0b215LCBKLlcuIEdvZXRoZSBVbml2ZXJzaXR5LCBGcmFua2Z1cnQgYW0gTWFp

biwgR2VybWFueTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlR3byB0eXBlcyBvZiBzcG9y

YWRpYyBjZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

SiBOZXVyb3BhdGhvbCBFeHAuTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlv

ZGljYWw+PGZ1bGwtdGl0bGU+SiBOZXVyb3BhdGhvbCBFeHAuTmV1cm9sPC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+MjgyLTI5MzwvcGFnZXM+PHZvbHVtZT42MTwvdm9sdW1lPjxudW1i

ZXI+MzwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlv

bj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29y

ZD48a2V5d29yZD5BZ2VkLDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFnaW5nPC9rZXl3

b3JkPjxrZXl3b3JkPkFsbGVsZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2U8

L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEt

UGVwdGlkZXM8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5zIEU8

L2tleXdvcmQ+PGtleXdvcmQ+Qmxvb2QgVmVzc2Vsczwva2V5d29yZD48a2V5d29yZD5CcmFpbiBE

aXNlYXNlczwva2V5d29yZD48a2V5d29yZD5DYXBpbGxhcmllczwva2V5d29yZD48a2V5d29yZD5D

ZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHk8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgSW5m

YXJjdGlvbjwva2V5d29yZD48a2V5d29yZD5DZXJlYnJvdmFzY3VsYXIgQ2lyY3VsYXRpb248L2tl

eXdvcmQ+PGtleXdvcmQ+Y2xhc3NpZmljYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0

aW9uczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBGcmVx

dWVuY3k8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3NpdGlvbiB0byBEaXNlYXNl

PC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9r

ZXl3b3JkPjxrZXl3b3JkPkdlcm1hbnk8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+bWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5waHlzaW9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5SZWZlcmVuY2UgVmFsdWVz

PC9rZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5TZXZlcml0

eSBvZiBJbGxuZXNzIEluZGV4PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDI8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4zLzIwMDI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

bGFiZWw+MjExPC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8xMTg5NTA0MzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGFsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj

TnVtPjE3NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oVGhhbCwgZXQgYWwuLCAyMDAyKTwvRGlzcGxh

eVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNzc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48

a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIi

IHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTc3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5UaGFsLEQuUi48L2F1dGhvcj48YXV0aG9yPkdoZWJyZW1lZGhpbixFLjwvYXV0

aG9yPjxhdXRob3I+UnViLFUuPC9hdXRob3I+PGF1dGhvcj5ZYW1hZ3VjaGksSC48L2F1dGhvcj48

YXV0aG9yPkRlbCBUcmVkaWNpLEsuPC9hdXRob3I+PGF1dGhvcj5CcmFhayxILjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgQ2xpbmlj

YWwgTmV1cm9hbmF0b215LCBKLlcuIEdvZXRoZSBVbml2ZXJzaXR5LCBGcmFua2Z1cnQgYW0gTWFp

biwgR2VybWFueTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlR3byB0eXBlcyBvZiBzcG9y

YWRpYyBjZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

SiBOZXVyb3BhdGhvbCBFeHAuTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlv

ZGljYWw+PGZ1bGwtdGl0bGU+SiBOZXVyb3BhdGhvbCBFeHAuTmV1cm9sPC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+MjgyLTI5MzwvcGFnZXM+PHZvbHVtZT42MTwvdm9sdW1lPjxudW1i

ZXI+MzwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlv

bj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29y

ZD48a2V5d29yZD5BZ2VkLDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFnaW5nPC9rZXl3

b3JkPjxrZXl3b3JkPkFsbGVsZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWx6aGVpbWVyIERpc2Vhc2U8

L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEt

UGVwdGlkZXM8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW5zIEU8

L2tleXdvcmQ+PGtleXdvcmQ+Qmxvb2QgVmVzc2Vsczwva2V5d29yZD48a2V5d29yZD5CcmFpbiBE

aXNlYXNlczwva2V5d29yZD48a2V5d29yZD5DYXBpbGxhcmllczwva2V5d29yZD48a2V5d29yZD5D

ZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHk8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgSW5m

YXJjdGlvbjwva2V5d29yZD48a2V5d29yZD5DZXJlYnJvdmFzY3VsYXIgQ2lyY3VsYXRpb248L2tl

eXdvcmQ+PGtleXdvcmQ+Y2xhc3NpZmljYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0

aW9uczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBGcmVx

dWVuY3k8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3NpdGlvbiB0byBEaXNlYXNl

PC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9r

ZXl3b3JkPjxrZXl3b3JkPkdlcm1hbnk8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+bWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5waHlzaW9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5SZWZlcmVuY2UgVmFsdWVz

PC9rZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5TZXZlcml0

eSBvZiBJbGxuZXNzIEluZGV4PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDI8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4zLzIwMDI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

bGFiZWw+MjExPC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp

Lm5sbS5uaWguZ292L3B1Ym1lZC8xMTg5NTA0MzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48

L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA (Thal, et al., 2002). Furthermore, capillary CAA has been found to provoke a strong inflammatory response, which does not usually occur in large vessel CAA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWNoYXJkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48

UmVjTnVtPjE4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oUmljaGFyZCwgZXQgYWwuLCAyMDEwKTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xODA8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTgwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5SaWNoYXJkLEUuPC9hdXRob3I+PGF1dGhvcj5DYXJyYW5vLEEuPC9h

dXRob3I+PGF1dGhvcj5Ib296ZW1hbnMsSi5KLjwvYXV0aG9yPjxhdXRob3I+dmFuIEhvcnNzZW4s

Si48L2F1dGhvcj48YXV0aG9yPnZhbiBIYWFzdGVydCxFLlMuPC9hdXRob3I+PGF1dGhvcj5FdXJl

bGluZ3MsTC5TLjwvYXV0aG9yPjxhdXRob3I+ZGUgVnJpZXMsSC5FLjwvYXV0aG9yPjxhdXRob3I+

VGhhbCxELlIuPC9hdXRob3I+PGF1dGhvcj5FaWtlbGVuYm9vbSxQLjwvYXV0aG9yPjxhdXRob3I+

dmFuIEdvb2wsVy5BLjwvYXV0aG9yPjxhdXRob3I+Um96ZW11bGxlcixBLkouPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIEFjYWRlbWljIE1lZGljYWwgQ2VudGVyLCBVbml2ZXJzaXR5IG9mIEFtc3RlcmRhbSwgQW1z

dGVyZGFtLCBUaGUgTmV0aGVybGFuZHMuIGUucmljaGFyZEBhbWMudXZhLm5sPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+Q2hhcmFjdGVyaXN0aWNzIG9mIGR5c2hvcmljIGNhcGlsbGFyeSBj

ZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBOZXVy

b3BhdGhvbCBFeHAuTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+SiBOZXVyb3BhdGhvbCBFeHAuTmV1cm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTE1OC0xMTY3PC9wYWdlcz48dm9sdW1lPjY5PC92b2x1bWU+PG51bWJlcj4x

MTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLDgwIGFuZCBvdmVy

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9rZXl3b3JkPjxr

ZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNhcGlsbGFyaWVzPC9rZXl3b3JkPjxrZXl3

b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub3R5cGU8L2tl

eXdvcmQ+PGtleXdvcmQ+R2xpYWwgRmlicmlsbGFyeSBBY2lkaWMgUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5ITEEtRFIgQW50aWdlbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1h

dGlvbjwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VhbCBB

cnRlcmllczwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5l

dGhlcmxhbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1

IFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlViaXF1aXRpbjwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMjAxMDwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMTQ8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwOTQwNjI1PC91cmw+PHVy

bD5odHRwOi8vZ3JhcGhpY3MudHgub3ZpZC5jb20vb3ZmdHBkZnMvRlBERE5DR0NKQklLQUcwMC9m

czA0Ni9vdmZ0L2xpdmUvZ3YwMjMvMDAwMDUwNzIvMDAwMDUwNzItMjAxMDExMDAwLTAwMDA3LnBk

ZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWNoYXJkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48

UmVjTnVtPjE4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oUmljaGFyZCwgZXQgYWwuLCAyMDEwKTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xODA8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTgwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5SaWNoYXJkLEUuPC9hdXRob3I+PGF1dGhvcj5DYXJyYW5vLEEuPC9h

dXRob3I+PGF1dGhvcj5Ib296ZW1hbnMsSi5KLjwvYXV0aG9yPjxhdXRob3I+dmFuIEhvcnNzZW4s

Si48L2F1dGhvcj48YXV0aG9yPnZhbiBIYWFzdGVydCxFLlMuPC9hdXRob3I+PGF1dGhvcj5FdXJl

bGluZ3MsTC5TLjwvYXV0aG9yPjxhdXRob3I+ZGUgVnJpZXMsSC5FLjwvYXV0aG9yPjxhdXRob3I+

VGhhbCxELlIuPC9hdXRob3I+PGF1dGhvcj5FaWtlbGVuYm9vbSxQLjwvYXV0aG9yPjxhdXRob3I+

dmFuIEdvb2wsVy5BLjwvYXV0aG9yPjxhdXRob3I+Um96ZW11bGxlcixBLkouPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIEFjYWRlbWljIE1lZGljYWwgQ2VudGVyLCBVbml2ZXJzaXR5IG9mIEFtc3RlcmRhbSwgQW1z

dGVyZGFtLCBUaGUgTmV0aGVybGFuZHMuIGUucmljaGFyZEBhbWMudXZhLm5sPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+Q2hhcmFjdGVyaXN0aWNzIG9mIGR5c2hvcmljIGNhcGlsbGFyeSBj

ZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBOZXVy

b3BhdGhvbCBFeHAuTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+SiBOZXVyb3BhdGhvbCBFeHAuTmV1cm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTE1OC0xMTY3PC9wYWdlcz48dm9sdW1lPjY5PC92b2x1bWU+PG51bWJlcj4x

MTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLDgwIGFuZCBvdmVy

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9rZXl3b3JkPjxr

ZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNhcGlsbGFyaWVzPC9rZXl3b3JkPjxrZXl3

b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub3R5cGU8L2tl

eXdvcmQ+PGtleXdvcmQ+R2xpYWwgRmlicmlsbGFyeSBBY2lkaWMgUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5ITEEtRFIgQW50aWdlbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1h

dGlvbjwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VhbCBB

cnRlcmllczwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5l

dGhlcmxhbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1

IFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlViaXF1aXRpbjwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMjAxMDwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMTQ8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwOTQwNjI1PC91cmw+PHVy

bD5odHRwOi8vZ3JhcGhpY3MudHgub3ZpZC5jb20vb3ZmdHBkZnMvRlBERE5DR0NKQklLQUcwMC9m

czA0Ni9vdmZ0L2xpdmUvZ3YwMjMvMDAwMDUwNzIvMDAwMDUwNzItMjAxMDExMDAwLTAwMDA3LnBk

ZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA (Richard, et al., 2010). This could perhaps provide a unifying explanation for how APOE4 status appears to increase the risk of developing both microbleeds and inflammation as a consequence of CAA. Although we did not find associations between capillary CAA and APOE status or ARWMC score in our pathology cohort, subject numbers were small and this would be an interesting issue to explore in larger studies. It is possible that other vascular risk factors also play a role in the manifestation of CAA in FAD. Our results suggested that increased age and the presence (albeit very minor) of conventional vascular risk factors may contribute to some of the difference in ARWMC observed between the PSEN1 pre- and post-codon 200 groups. However, these factors could not account for the differences between the PSEN1 post-codon 200 group and controls. It is noteworthy that the vascular risk scores in subjects with increased vascular risk were still very low - 1 or 2 at most- signifying the presence of only mild hypertension and/or hypercholesterolaemia in most cases. It seems highly unlikely that this minor increased vascular risk could wholly explain the severity of WMH seen in many of the PSEN1 post-codon 200 patients’ scans. Furthermore, the occurrence of increased vascular risk scores in the PSEN1 post-codon 200 group could have been biased by the imaging findings themselves. Patients with FAD and WMH may be more thoroughly investigated for vascular risk factors than patients lacking such imaging features. Nevertheless, it may be that post-codon 200 mutations cause particularly enhanced white matter injury in the presence of vascular risk factors, similar to the way in which cognitively normal APOE4 carriers have been found to have a markedly increased risk of WMH if they have hypertension or cerebrovascular disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBMZWV1dzwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+

PFJlY051bT40OTU8L1JlY051bT48RGlzcGxheVRleHQ+KGRlIExlZXV3LCBldCBhbC4sIDIwMDQs

RGVDYXJsaSwgZXQgYWwuLCAxOTk5KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40

OTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVy

ZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTQzMDgzNjc0NiI+NDk1

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5kZSBMZWV1dywgRi4gRS48

L2F1dGhvcj48YXV0aG9yPlJpY2hhcmQsIEYuPC9hdXRob3I+PGF1dGhvcj5kZSBHcm9vdCwgSi4g

Qy48L2F1dGhvcj48YXV0aG9yPnZhbiBEdWlqbiwgQy4gTS48L2F1dGhvcj48YXV0aG9yPkhvZm1h

biwgQS48L2F1dGhvcj48YXV0aG9yPlZhbiBHaWpuLCBKLjwvYXV0aG9yPjxhdXRob3I+QnJldGVs

ZXIsIE0uIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

RGVwYXJ0bWVudCBvZiBFcGlkZW1pb2xvZ3kgYW5kIEJpb3N0YXRpc3RpY3MsIEVyYXNtdXMgTWVk

aWNhbCBDZW50ZXIsIFJvdHRlcmRhbSwgVGhlIE5ldGhlcmxhbmRzLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkludGVyYWN0aW9uIGJldHdlZW4gaHlwZXJ0ZW5zaW9uLCBhcG9FLCBhbmQg

Y2VyZWJyYWwgd2hpdGUgbWF0dGVyIGxlc2lvbnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U3Ry

b2tlPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5TdHJva2U7IGEgam91cm5hbCBvZiBjZXJl

YnJhbCBjaXJjdWxhdGlvbjwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPlN0cm9rZTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEwNTctNjA8L3BhZ2Vz

Pjx2b2x1bWU+MzU8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+

QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y

ZD5BcG9saXBvcHJvdGVpbnMgRS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKnBh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CcmFpbiBEaXNlYXNlcy9kaWFnbm9zaXMvKmVwaWRl

bWlvbG9neS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyb3Zhc2N1bGFyIERpc29y

ZGVycy9lcGlkZW1pb2xvZ3kvZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29tb3JiaWRpdHk8

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVk

aWVzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkhldGVyb3p5

Z290ZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJ0ZW5z

aW9uLyplcGlkZW1pb2xvZ3kvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJl

c29uYW5jZSBJbWFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+

TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV0aGVybGFuZHMvZXBpZGVtaW9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPlBvbHltb3JwaGlzbSwgR2VuZXRpYy9nZW5ldGljczwva2V5d29yZD48

a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAw

NDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjE1MjQtNDYyOCAoRWxlY3Ryb25pYykmI3hEOzAwMzktMjQ5OSAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MTUwNjAzMTY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTUwNjAzMTY8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExNjEvMDEu

U1RSLjAwMDAxMjU4NTkuNzEwNTEuODM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRlQ2FybGk8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS

ZWNOdW0+NDkyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40OTI8L3JlYy1udW1iZXI+PGZv

cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4Zjdz

cDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTQzMDgzNjY5NCI+NDkyPC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5EZUNhcmxpLCBDLjwvYXV0aG9yPjxhdXRob3I+UmVlZCwg

VC48L2F1dGhvcj48YXV0aG9yPk1pbGxlciwgQi4gTC48L2F1dGhvcj48YXV0aG9yPldvbGYsIFAu

IEEuPC9hdXRob3I+PGF1dGhvcj5Td2FuLCBHLiBFLjwvYXV0aG9yPjxhdXRob3I+Q2FybWVsbGks

IEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgb2YgS2Fuc2FzLCBLYW5zYXMgQ2l0eSwgTU8g

NjYxNjAsIFVTQS4gY2RlY2FybGlAa3VtYy5lZHU8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5JbXBhY3Qgb2YgYXBvbGlwb3Byb3RlaW4gRSBlcHNpbG9uNCBhbmQgdmFzY3VsYXIgZGlzZWFz

ZSBvbiBicmFpbiBtb3JwaG9sb2d5IGluIG1lbiBmcm9tIHRoZSBOSExCSSB0d2luIHN0dWR5PC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlN0cm9rZTwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+

U3Ryb2tlOyBhIGpvdXJuYWwgb2YgY2VyZWJyYWwgY2lyY3VsYXRpb248L2FsdC10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TdHJva2U8L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp

Y2FsPjxwYWdlcz4xNTQ4LTUzPC9wYWdlcz48dm9sdW1lPjMwPC92b2x1bWU+PG51bWJlcj44PC9u

dW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFsbGVsZXM8

L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW4gRTQ8L2tleXdvcmQ+PGtleXdvcmQ+QXBv

bGlwb3Byb3RlaW5zIEUvKmdlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QnJh

aW4vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJvdmFzY3VsYXIgRGlzb3JkZXJz

L2RpYWdub3Npcy9lcGlkZW1pb2xvZ3kvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5Db3JvbmFyeSBEaXNlYXNlL2RpYWdub3Npcy9lcGlkZW1pb2xvZ3kvZ2VuZXRpY3MvbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD4qRGlzZWFzZXMgaW4gVHdpbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+Rm9sbG93LVVwIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBNYXJrZXJz

PC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5

d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk9i

c2VydmVyIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5QZXJpcGhlcmFsIFZhc2N1bGFyIERp

c2Vhc2VzL2RpYWdub3Npcy9lcGlkZW1pb2xvZ3kvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5Qb2x5bWVyYXNlIENoYWluIFJlYWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBy

ZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+UmV0cm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3Jk

PjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5Vbml0ZWQgU3RhdGVzL2Vw

aWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5WYXNjdWxhciBEaXNlYXNlcy9kaWFnbm9zaXMv

KmVwaWRlbWlvbG9neS9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjE5OTk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0

ZXM+PC9kYXRlcz48aXNibj4wMDM5LTI0OTkgKFByaW50KSYjeEQ7MDAzOS0yNDk5IChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4xMDQzNjA5OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMDQzNjA5

OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBMZWV1dzwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+

PFJlY051bT40OTU8L1JlY051bT48RGlzcGxheVRleHQ+KGRlIExlZXV3LCBldCBhbC4sIDIwMDQs

RGVDYXJsaSwgZXQgYWwuLCAxOTk5KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40

OTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVy

ZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTQzMDgzNjc0NiI+NDk1

PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8

L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5kZSBMZWV1dywgRi4gRS48

L2F1dGhvcj48YXV0aG9yPlJpY2hhcmQsIEYuPC9hdXRob3I+PGF1dGhvcj5kZSBHcm9vdCwgSi4g

Qy48L2F1dGhvcj48YXV0aG9yPnZhbiBEdWlqbiwgQy4gTS48L2F1dGhvcj48YXV0aG9yPkhvZm1h

biwgQS48L2F1dGhvcj48YXV0aG9yPlZhbiBHaWpuLCBKLjwvYXV0aG9yPjxhdXRob3I+QnJldGVs

ZXIsIE0uIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

RGVwYXJ0bWVudCBvZiBFcGlkZW1pb2xvZ3kgYW5kIEJpb3N0YXRpc3RpY3MsIEVyYXNtdXMgTWVk

aWNhbCBDZW50ZXIsIFJvdHRlcmRhbSwgVGhlIE5ldGhlcmxhbmRzLjwvYXV0aC1hZGRyZXNzPjx0

aXRsZXM+PHRpdGxlPkludGVyYWN0aW9uIGJldHdlZW4gaHlwZXJ0ZW5zaW9uLCBhcG9FLCBhbmQg

Y2VyZWJyYWwgd2hpdGUgbWF0dGVyIGxlc2lvbnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U3Ry

b2tlPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5TdHJva2U7IGEgam91cm5hbCBvZiBjZXJl

YnJhbCBjaXJjdWxhdGlvbjwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPlN0cm9rZTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEwNTctNjA8L3BhZ2Vz

Pjx2b2x1bWU+MzU8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+

QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y

ZD5BcG9saXBvcHJvdGVpbnMgRS8qZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKnBh

dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CcmFpbiBEaXNlYXNlcy9kaWFnbm9zaXMvKmVwaWRl

bWlvbG9neS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyb3Zhc2N1bGFyIERpc29y

ZGVycy9lcGlkZW1pb2xvZ3kvZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29tb3JiaWRpdHk8

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVk

aWVzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkhldGVyb3p5

Z290ZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHlwZXJ0ZW5z

aW9uLyplcGlkZW1pb2xvZ3kvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJl

c29uYW5jZSBJbWFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+

TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmV0aGVybGFuZHMvZXBpZGVtaW9sb2d5PC9r

ZXl3b3JkPjxrZXl3b3JkPlBvbHltb3JwaGlzbSwgR2VuZXRpYy9nZW5ldGljczwva2V5d29yZD48

a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAw

NDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjE1MjQtNDYyOCAoRWxlY3Ryb25pYykmI3hEOzAwMzktMjQ5OSAoTGlua2luZyk8L2lzYm4+

PGFjY2Vzc2lvbi1udW0+MTUwNjAzMTY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTUwNjAzMTY8L3VybD48

L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExNjEvMDEu

U1RSLjAwMDAxMjU4NTkuNzEwNTEuODM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRlQ2FybGk8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS

ZWNOdW0+NDkyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40OTI8L3JlYy1udW1iZXI+PGZv

cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4Zjdz

cDUycHBkZHZ2MDIiIHRpbWVzdGFtcD0iMTQzMDgzNjY5NCI+NDkyPC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5EZUNhcmxpLCBDLjwvYXV0aG9yPjxhdXRob3I+UmVlZCwg

VC48L2F1dGhvcj48YXV0aG9yPk1pbGxlciwgQi4gTC48L2F1dGhvcj48YXV0aG9yPldvbGYsIFAu

IEEuPC9hdXRob3I+PGF1dGhvcj5Td2FuLCBHLiBFLjwvYXV0aG9yPjxhdXRob3I+Q2FybWVsbGks

IEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0

bWVudCBvZiBOZXVyb2xvZ3ksIFVuaXZlcnNpdHkgb2YgS2Fuc2FzLCBLYW5zYXMgQ2l0eSwgTU8g

NjYxNjAsIFVTQS4gY2RlY2FybGlAa3VtYy5lZHU8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs

ZT5JbXBhY3Qgb2YgYXBvbGlwb3Byb3RlaW4gRSBlcHNpbG9uNCBhbmQgdmFzY3VsYXIgZGlzZWFz

ZSBvbiBicmFpbiBtb3JwaG9sb2d5IGluIG1lbiBmcm9tIHRoZSBOSExCSSB0d2luIHN0dWR5PC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlN0cm9rZTwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+

U3Ryb2tlOyBhIGpvdXJuYWwgb2YgY2VyZWJyYWwgY2lyY3VsYXRpb248L2FsdC10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TdHJva2U8L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp

Y2FsPjxwYWdlcz4xNTQ4LTUzPC9wYWdlcz48dm9sdW1lPjMwPC92b2x1bWU+PG51bWJlcj44PC9u

dW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFsbGVsZXM8

L2tleXdvcmQ+PGtleXdvcmQ+QXBvbGlwb3Byb3RlaW4gRTQ8L2tleXdvcmQ+PGtleXdvcmQ+QXBv

bGlwb3Byb3RlaW5zIEUvKmdlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QnJh

aW4vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJvdmFzY3VsYXIgRGlzb3JkZXJz

L2RpYWdub3Npcy9lcGlkZW1pb2xvZ3kvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5

d29yZD5Db3JvbmFyeSBEaXNlYXNlL2RpYWdub3Npcy9lcGlkZW1pb2xvZ3kvZ2VuZXRpY3MvbWV0

YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD4qRGlzZWFzZXMgaW4gVHdpbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+Rm9sbG93LVVwIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZXRpYyBNYXJrZXJz

PC9rZXl3b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5

d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29y

ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk9i

c2VydmVyIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5QZXJpcGhlcmFsIFZhc2N1bGFyIERp

c2Vhc2VzL2RpYWdub3Npcy9lcGlkZW1pb2xvZ3kvZ2VuZXRpY3MvbWV0YWJvbGlzbTwva2V5d29y

ZD48a2V5d29yZD5Qb2x5bWVyYXNlIENoYWluIFJlYWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBy

ZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+UmV0cm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3Jk

PjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5Vbml0ZWQgU3RhdGVzL2Vw

aWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5WYXNjdWxhciBEaXNlYXNlcy9kaWFnbm9zaXMv

KmVwaWRlbWlvbG9neS9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjE5OTk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0

ZXM+PC9kYXRlcz48aXNibj4wMDM5LTI0OTkgKFByaW50KSYjeEQ7MDAzOS0yNDk5IChMaW5raW5n

KTwvaXNibj48YWNjZXNzaW9uLW51bT4xMDQzNjA5OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVs

YXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMDQzNjA5

OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA (de Leeuw, et al., 2004,DeCarli, et al., 1999). Smoking history was not known for all of the subjects in this study. Although smoking status is not included in the system for scoring vascular risk that we used PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZUNhcmxpPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48

UmVjTnVtPjE2NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oRGVDYXJsaSwgZXQgYWwuLCAyMDA0KTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTY0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5EZUNhcmxpLEMuPC9hdXRob3I+PGF1dGhvcj5NdW5nYXMsRC48L2F1

dGhvcj48YXV0aG9yPkhhcnZleSxELjwvYXV0aG9yPjxhdXRob3I+UmVlZCxCLjwvYXV0aG9yPjxh

dXRob3I+V2VpbmVyLE0uPC9hdXRob3I+PGF1dGhvcj5DaHVpLEguPC9hdXRob3I+PGF1dGhvcj5K

YWd1c3QsVy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5E

ZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhIGF0IFNhbiBG

cmFuY2lzY28sIFVTQS4gY2RlY2FybGlAdWNkYXZpcy5lZHU8L2F1dGgtYWRkcmVzcz48dGl0bGVz

Pjx0aXRsZT5NZW1vcnkgaW1wYWlybWVudCwgYnV0IG5vdCBjZXJlYnJvdmFzY3VsYXIgZGlzZWFz

ZSwgcHJlZGljdHMgcHJvZ3Jlc3Npb24gb2YgTUNJIHRvIGRlbWVudGlhPC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIy

MC0yMjc8L3BhZ2VzPjx2b2x1bWU+NjM8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmlu

dC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y

ZD5BZ2luZzwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5d29yZD48a2V5

d29yZD5hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29y

ZD48a2V5d29yZD5DYXJkaW92YXNjdWxhciBEaXNlYXNlczwva2V5d29yZD48a2V5d29yZD5DZXJl

YnJvdmFzY3VsYXIgRGlzb3JkZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRl

cnM8L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWE8L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMg

TWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48

a2V5d29yZD5lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48

a2V5d29yZD5IeXBlcmxpcGlkZW1pYXM8L2tleXdvcmQ+PGtleXdvcmQ+TGlmZSBUYWJsZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+TG9uZ2l0dWRpbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+TWFn

bmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48

a2V5d29yZD5NZW1vcnk8L2tleXdvcmQ+PGtleXdvcmQ+TWVtb3J5IERpc29yZGVyczwva2V5d29y

ZD48a2V5d29yZD5tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3Jk

PjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwg

VGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByb3Nw

ZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+cHN5Y2hvbG9neTwva2V5d29yZD48a2V5

d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+U3Ryb2tlPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT43LzI3LzIwMDQ8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MTk5PC9sYWJlbD48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNTI3NzYxMjwv

dXJsPjx1cmw+aHR0cDovL3d3dy5uZXVyb2xvZ3kub3JnL2NvbnRlbnQvNjMvMi8yMjAuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZUNhcmxpPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48

UmVjTnVtPjE2NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oRGVDYXJsaSwgZXQgYWwuLCAyMDA0KTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTY0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5EZUNhcmxpLEMuPC9hdXRob3I+PGF1dGhvcj5NdW5nYXMsRC48L2F1

dGhvcj48YXV0aG9yPkhhcnZleSxELjwvYXV0aG9yPjxhdXRob3I+UmVlZCxCLjwvYXV0aG9yPjxh

dXRob3I+V2VpbmVyLE0uPC9hdXRob3I+PGF1dGhvcj5DaHVpLEguPC9hdXRob3I+PGF1dGhvcj5K

YWd1c3QsVy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5E

ZXBhcnRtZW50IG9mIE5ldXJvbG9neSwgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhIGF0IFNhbiBG

cmFuY2lzY28sIFVTQS4gY2RlY2FybGlAdWNkYXZpcy5lZHU8L2F1dGgtYWRkcmVzcz48dGl0bGVz

Pjx0aXRsZT5NZW1vcnkgaW1wYWlybWVudCwgYnV0IG5vdCBjZXJlYnJvdmFzY3VsYXIgZGlzZWFz

ZSwgcHJlZGljdHMgcHJvZ3Jlc3Npb24gb2YgTUNJIHRvIGRlbWVudGlhPC90aXRsZT48c2Vjb25k

YXJ5LXRpdGxlPk5ldXJvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIy

MC0yMjc8L3BhZ2VzPjx2b2x1bWU+NjM8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmlu

dC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y

ZD5BZ2luZzwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZTwva2V5d29yZD48a2V5

d29yZD5hbmFseXNpczwva2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29y

ZD48a2V5d29yZD5DYXJkaW92YXNjdWxhciBEaXNlYXNlczwva2V5d29yZD48a2V5d29yZD5DZXJl

YnJvdmFzY3VsYXIgRGlzb3JkZXJzPC9rZXl3b3JkPjxrZXl3b3JkPkNvZ25pdGlvbiBEaXNvcmRl

cnM8L2tleXdvcmQ+PGtleXdvcmQ+RGVtZW50aWE8L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMg

TWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBQcm9ncmVzc2lvbjwva2V5d29yZD48

a2V5d29yZD5lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr

ZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPmdlbmV0aWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48

a2V5d29yZD5IeXBlcmxpcGlkZW1pYXM8L2tleXdvcmQ+PGtleXdvcmQ+TGlmZSBUYWJsZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+TG9uZ2l0dWRpbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+TWFn

bmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48

a2V5d29yZD5NZW1vcnk8L2tleXdvcmQ+PGtleXdvcmQ+TWVtb3J5IERpc29yZGVyczwva2V5d29y

ZD48a2V5d29yZD5tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3Jk

PjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwg

VGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByb3Nw

ZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+cHN5Y2hvbG9neTwva2V5d29yZD48a2V5

d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+U3Ryb2tlPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT43LzI3LzIwMDQ8

L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MTk5PC9sYWJlbD48dXJscz48cmVsYXRl

ZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNTI3NzYxMjwv

dXJsPjx1cmw+aHR0cDovL3d3dy5uZXVyb2xvZ3kub3JnL2NvbnRlbnQvNjMvMi8yMjAuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (DeCarli, et al., 2004), the absence of this information should be considered a limitation. The lack of T2* imaging in all subjects is an important but inevitable limitation of this retrospective study, which is due to the fact that scans were collected over a twenty year period, with the majority having been acquired before the introduction of gradient echo imaging to our protocol. Investigation of associations between microbleeds and different FAD mutations will be an important direction for future research in large cohorts of mutation carriers with gradient echo imaging, such as the multi-centre collaborative dominantly inherited Alzheimer network (DIAN). A further limitation of the current study is that, although it is one of the largest pre-morbid imaging investigations of FAD with post-mortem neuropathological correlation, the number of autopsy cases is small.?Due to the limited sample size, we did not include correction for multiple comparisons in our analysis of the data, which should be considered exploratory and requires corroboration in larger datasets.Investigation of why PSEN1 mutations located after codon 200 should be associated with increased CAA and/or a different inflammatory response is an important area for future research, with the potential to reveal how other functions of PSEN1 may be affected by mutations at different sites. For example, certain post-codon 200 PSEN1 mutations may interfere with the role of PSEN1 in Notch processing, resulting in vulnerability of the vascular wall PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PihNYW5uLCBldCBhbC4sIDIwMDEpPC9EaXNwbGF5

VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjU5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYW5uLEQuTS48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZy1Ccm93bixTLk0uPC9h

dXRob3I+PGF1dGhvcj5UYWtldWNoaSxBLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sVC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBOZXVy

b3NjaWVuY2UgUmVzZWFyY2ggR3JvdXAsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgTWFuY2hlc3RlciwgTWFuY2hlc3RlciwgVW5pdGVkIEtpbmdkb20uIGRhdmlkLm1hbm5A

bWFuLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBhbmdpb3BhdGh5

IGFuZCB2YXJpYWJpbGl0eSBpbiBhbXlsb2lkIGJldGEgZGVwb3NpdGlvbiBpcyBkZXRlcm1pbmVk

IGJ5IG11dGF0aW9uIHBvc2l0aW9uIGluIHByZXNlbmlsaW4tMS1saW5rZWQgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGF0aG9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjUtMjE3NTwvcGFnZXM+PHZvbHVtZT4x

NTg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29yZD48a2V5d29yZD5ibG9v

ZDwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYmVsbHVtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5Db2Rvbjwva2V5d29yZD48a2V5d29yZD5Db3MgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250YWwgTG9iZTwva2V5d29yZD48a2V5d29yZD5H

ZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQcm90ZWluczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5QZXB0aWRlIEZyYWdtZW50czwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdv

cmQ+PGtleXdvcmQ+dWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD45NjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTEzOTUzOTQ8L3VybD48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTg5MTk5My9wZGYvMjY4NS5wZGY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PihNYW5uLCBldCBhbC4sIDIwMDEpPC9EaXNwbGF5

VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjU5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYW5uLEQuTS48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZy1Ccm93bixTLk0uPC9h

dXRob3I+PGF1dGhvcj5UYWtldWNoaSxBLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sVC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBOZXVy

b3NjaWVuY2UgUmVzZWFyY2ggR3JvdXAsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgTWFuY2hlc3RlciwgTWFuY2hlc3RlciwgVW5pdGVkIEtpbmdkb20uIGRhdmlkLm1hbm5A

bWFuLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBhbmdpb3BhdGh5

IGFuZCB2YXJpYWJpbGl0eSBpbiBhbXlsb2lkIGJldGEgZGVwb3NpdGlvbiBpcyBkZXRlcm1pbmVk

IGJ5IG11dGF0aW9uIHBvc2l0aW9uIGluIHByZXNlbmlsaW4tMS1saW5rZWQgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGF0aG9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjUtMjE3NTwvcGFnZXM+PHZvbHVtZT4x

NTg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29yZD48a2V5d29yZD5ibG9v

ZDwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYmVsbHVtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5Db2Rvbjwva2V5d29yZD48a2V5d29yZD5Db3MgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250YWwgTG9iZTwva2V5d29yZD48a2V5d29yZD5H

ZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQcm90ZWluczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5QZXB0aWRlIEZyYWdtZW50czwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdv

cmQ+PGtleXdvcmQ+dWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD45NjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTEzOTUzOTQ8L3VybD48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTg5MTk5My9wZGYvMjY4NS5wZGY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Mann, et al., 2001). Indeed, the functionally important residues of the PSEN1 endoproteolytic cleavage site lie at or around amino acid 298. By contrast, recent work on -secretase modulators has highlighted the importance of an N-terminal, predominantly pre-codon 200 region of PSEN1, in the carboxypeptidase-like activity that alters A profiles PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaGtpPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj

TnVtPjMyODwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oT2hraSwgZXQgYWwuLCAyMDExLFRha2VvLCBl

dCBhbC4sIDIwMTQpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMyODwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZk

MDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxNDIxMzI5OTM3Ij4zMjg8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk9oa2ksIFkuPC9hdXRob3I+PGF1dGhvcj5I

aWdvLCBULjwvYXV0aG9yPjxhdXRob3I+VWVtdXJhLCBLLjwvYXV0aG9yPjxhdXRob3I+U2hpbWFk

YSwgTi48L2F1dGhvcj48YXV0aG9yPk9zYXdhLCBTLjwvYXV0aG9yPjxhdXRob3I+QmVyZXpvdnNr

YSwgTy48L2F1dGhvcj48YXV0aG9yPllva29zaGltYSwgUy48L2F1dGhvcj48YXV0aG9yPkZ1a3V5

YW1hLCBULjwvYXV0aG9yPjxhdXRob3I+VG9taXRhLCBULjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1

Ym8sIFQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVw

YXJ0bWVudCBvZiBOZXVyb3BhdGhvbG9neSBhbmQgTmV1cm9zY2llbmNlLCBHcmFkdWF0ZSBTY2hv

b2wgb2YgUGhhcm1hY2V1dGljYWwgU2NpZW5jZXMsIFRoZSBVbml2ZXJzaXR5IG9mIFRva3lvLCBU

b2t5bywgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UGhlbnlscGlwZXJpZGlu

ZS10eXBlIGdhbW1hLXNlY3JldGFzZSBtb2R1bGF0b3JzIHRhcmdldCB0aGUgdHJhbnNtZW1icmFu

ZSBkb21haW4gMSBvZiBwcmVzZW5pbGluIDE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RU1CTyBK

PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5UaGUgRU1CTyBqb3VybmFsPC9hbHQtdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+RU1CTyBKPC9mdWxsLXRpdGxlPjxhYmJy

LTE+VGhlIEVNQk8gam91cm5hbDwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+RU1CTyBKPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIEVNQk8gam91cm5hbDwv

YWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjQ4MTUtMjQ8L3BhZ2VzPjx2b2x1bWU+MzA8

L3ZvbHVtZT48bnVtYmVyPjIzPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsbG9zdGVyaWMg

UmVndWxhdGlvbi8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlL3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD4qQW15bG9pZCBQcmVjdXJzb3Ig

UHJvdGVpbiBTZWNyZXRhc2VzL2FudGFnb25pc3RzICZhbXA7IGluaGliaXRvcnMvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvYW5hbHlzaXMvKm1ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CaW5kaW5n

IFNpdGVzL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5DSE8gQ2VsbHM8L2tleXdvcmQ+

PGtleXdvcmQ+Q3JpY2V0aW5hZTwva2V5d29yZD48a2V5d29yZD5DcmljZXR1bHVzPC9rZXl3b3Jk

PjxrZXl3b3JkPkhFSzI5MyBDZWxsczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdv

cmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvYW5hbHlzaXMvKm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+UGlwZXJpZGluZXMvY2hlbWljYWwgc3ludGhlc2lzLypwaGFybWFjb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+KlByZXNlbmlsaW4tMS9jaGVtaXN0cnkvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5Qcm90ZWluIEJpbmRpbmcvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3

b3JkPlByb3RlaW4gQ29uZm9ybWF0aW9uLypkcnVnIGVmZmVjdHM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdiAzMDwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NjAtMjA3NSAoRWxlY3Ryb25pYykmI3hEOzAyNjEt

NDE4OSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjIwMDI1Mzk8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjIwMDI1Mzk8L3VybD48dXJsPmh0dHA6Ly9lbWJvai5lbWJvcHJlc3Mub3JnL2NvbnRl

bnQvZW1ib2pubC8zMC8yMy80ODE1LmZ1bGwucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxjdXN0b20yPjMyNDM2MTY8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEw

MzgvZW1ib2ouMjAxMS4zNzI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPlRha2VvPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjMy

OTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzI5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtl

eXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2

djAyIiB0aW1lc3RhbXA9IjE0MjEzMjk5NzAiPjMyOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+VGFrZW8sIEsuPC9hdXRob3I+PGF1dGhvcj5UYW5pbXVyYSwgUy48L2F1

dGhvcj48YXV0aG9yPlNoaW5vZGEsIFQuPC9hdXRob3I+PGF1dGhvcj5Pc2F3YSwgUy48L2F1dGhv

cj48YXV0aG9yPlphaGFyaWV2LCBJLiBLLjwvYXV0aG9yPjxhdXRob3I+VGFrZWdhbWksIE4uPC9h

dXRob3I+PGF1dGhvcj5Jc2hpenVrYS1LYXRzdXJhLCBZLjwvYXV0aG9yPjxhdXRob3I+U2hpbnlh

LCBOLjwvYXV0aG9yPjxhdXRob3I+VGFrYWdpLU5paWRvbWUsIFMuPC9hdXRob3I+PGF1dGhvcj5U

b21pbmFnYSwgQS48L2F1dGhvcj48YXV0aG9yPk9oc2F3YSwgTi48L2F1dGhvcj48YXV0aG9yPktp

bXVyYS1Tb21leWEsIFQuPC9hdXRob3I+PGF1dGhvcj5TaGlyb3V6dSwgTS48L2F1dGhvcj48YXV0

aG9yPllva29zaGltYSwgUy48L2F1dGhvcj48YXV0aG9yPllva295YW1hLCBTLjwvYXV0aG9yPjxh

dXRob3I+RnVrdXlhbWEsIFQuPC9hdXRob3I+PGF1dGhvcj5Ub21pdGEsIFQuPC9hdXRob3I+PGF1

dGhvcj5Jd2F0c3VibywgVC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5EZXBhcnRtZW50cyBvZiBOZXVyb3BhdGhvbG9neSBhbmQgTmV1cm9zY2llbmNlIGFu

ZC4mI3hEO1N5bnRoZXRpYyBOYXR1cmFsIFByb2R1Y3RzIENoZW1pc3RyeSwgR3JhZHVhdGUgU2No

b29sIG9mIFBoYXJtYWNldXRpY2FsIFNjaWVuY2VzLCBhbmQuJiN4RDtSSUtFTiBTeXN0ZW1zIGFu

ZCBTdHJ1Y3R1cmFsIEJpb2xvZ3kgQ2VudGVyIGFuZERpdmlzaW9uIG9mIFN0cnVjdHVyYWwgYW5k

IFN5bnRoZXRpYyBCaW9sb2d5LCBSSUtFTiBDZW50ZXIgZm9yIExpZmUgU2NpZW5jZSBUZWNobm9s

b2dpZXMsIDEtNy0yMiBTdWVoaXJvLWNobywgVHN1cnVtaSwgWW9rb2hhbWEsIEthbmFnYXdhIDIz

MC0wMDQ1LCBKYXBhbjsmI3hEO0RlcGFydG1lbnRzIG9mIE5ldXJvcGF0aG9sb2d5IGFuZCBOZXVy

b3NjaWVuY2UgYW5kRmFjdWx0eSBvZiBNZWRpY2luZSwgVGhlIFVuaXZlcnNpdHkgb2YgVG9reW8s

IDctMy0xIEhvbmdvLCBCdW5reW8ta3UsIFRva3lvIDExMy0wMDMzLCBKYXBhbjtEZXBhcnRtZW50

IG9mIE5ldXJvcGF0aG9sb2d5LCBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmUsIFRoZSBVbml2

ZXJzaXR5IG9mIFRva3lvLCA3LTMtMSBIb25nbywgQnVua3lvLWt1LCBUb2t5byAxMTMtMDAzMywg

SmFwYW47JiN4RDtSSUtFTiBTeXN0ZW1zIGFuZCBTdHJ1Y3R1cmFsIEJpb2xvZ3kgQ2VudGVyIGFu

ZFJJS0VOIFN0cnVjdHVyYWwgQmlvbG9neSBMYWJvcmF0b3J5LCAxLTctMjIgU3VlaGlyby1jaG8s

IFRzdXJ1bWksIFlva29oYW1hLCBLYW5hZ2F3YSAyMzAtMDA0NSwgSmFwYW47IGFuZC4mI3hEO0Rl

cGFydG1lbnRzIG9mIE5ldXJvcGF0aG9sb2d5IGFuZCBOZXVyb3NjaWVuY2UgYW5kQ29yZSBSZXNl

YXJjaCBmb3IgRXZvbHV0aW9uYWwgU2NpZW5jZSBhbmQgVGVjaG5vbG9neSwgSmFwYW4gU2NpZW5j

ZSBhbmQgVGVjaG5vbG9neSBBZ2VuY3ksIDctMy0xIEhvbmdvLCBCdW5reW8ta3UsIFRva3lvIDEx

My0wMDMzLCBKYXBhbiB0YWlzdWtlQG1vbC5mLnUtdG9reW8uYWMuanAuJiN4RDtEZXBhcnRtZW50

cyBvZiBOZXVyb3BhdGhvbG9neSBhbmQgTmV1cm9zY2llbmNlIGFuZEZhY3VsdHkgb2YgTWVkaWNp

bmUsIFRoZSBVbml2ZXJzaXR5IG9mIFRva3lvLCA3LTMtMSBIb25nbywgQnVua3lvLWt1LCBUb2t5

byAxMTMtMDAzMywgSmFwYW47Q29yZSBSZXNlYXJjaCBmb3IgRXZvbHV0aW9uYWwgU2NpZW5jZSBh

bmQgVGVjaG5vbG9neSwgSmFwYW4gU2NpZW5jZSBhbmQgVGVjaG5vbG9neSBBZ2VuY3ksIDctMy0x

IEhvbmdvLCBCdW5reW8ta3UsIFRva3lvIDExMy0wMDMzLCBKYXBhbi48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5BbGxvc3RlcmljIHJlZ3VsYXRpb24gb2YgZ2FtbWEtc2VjcmV0YXNlIGFj

dGl2aXR5IGJ5IGEgcGhlbnlsaW1pZGF6b2xlLXR5cGUgZ2FtbWEtc2VjcmV0YXNlIG1vZHVsYXRv

cjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBTIEE8L3NlY29u

ZGFyeS10aXRsZT48YWx0LXRpdGxlPlByb2NlZWRpbmdzIG9mIHRoZSBOYXRpb25hbCBBY2FkZW15

IG9mIFNjaWVuY2VzIG9mIHRoZSBVbml0ZWQgU3RhdGVzIG9mIEFtZXJpY2E8L2FsdC10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBTIEE8

L2Z1bGwtdGl0bGU+PGFiYnItMT5Qcm9jZWVkaW5ncyBvZiB0aGUgTmF0aW9uYWwgQWNhZGVteSBv

ZiBTY2llbmNlcyBvZiB0aGUgVW5pdGVkIFN0YXRlcyBvZiBBbWVyaWNhPC9hYmJyLTE+PC9wZXJp

b2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBT

IEE8L2Z1bGwtdGl0bGU+PGFiYnItMT5Qcm9jZWVkaW5ncyBvZiB0aGUgTmF0aW9uYWwgQWNhZGVt

eSBvZiBTY2llbmNlcyBvZiB0aGUgVW5pdGVkIFN0YXRlcyBvZiBBbWVyaWNhPC9hYmJyLTE+PC9h

bHQtcGVyaW9kaWNhbD48cGFnZXM+MTA1NDQtOTwvcGFnZXM+PHZvbHVtZT4xMTE8L3ZvbHVtZT48

bnVtYmVyPjI5PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsbG9zdGVyaWMgUmVndWxhdGlv

bi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QW1pbm8gQWNpZHMvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5BbXlsb2lkIFByZWN1cnNvciBQcm90ZWluIFNlY3JldGFzZXMvZ2Vu

ZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2F0YWx5dGljIERvbWFpbjwva2V5

d29yZD48a2V5d29yZD5Fbnp5bWUgQWN0aXZhdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+Rmx1b3Jlc2NlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5JbWlkYXpvbGVzL2NoZW1pc3RyeS8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk1vZGVscywgTW9sZWN1bGFyPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uL2dlbmV0aWNzPC9r

ZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U3Ry

dWN0dXJhbCBIb21vbG9neSwgUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5TdWJzdHJhdGUgU3Bl

Y2lmaWNpdHkvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWwgMjI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xMDkxLTY0OTAgKEVsZWN0cm9uaWMpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI1MDA5MTgwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1MDA5MTgwPC91

cmw+PHVybD5odHRwOi8vd3d3LnBuYXMub3JnL2NvbnRlbnQvMTExLzI5LzEwNTQ0LmZ1bGwucGRm

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPjQxMTU1NjQ8L2N1c3RvbTI+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNzMvcG5hcy4xNDAyMTcxMTExPC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaGtpPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj

TnVtPjMyODwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oT2hraSwgZXQgYWwuLCAyMDExLFRha2VvLCBl

dCBhbC4sIDIwMTQpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMyODwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZk

MDVwZXhmN3NwNTJwcGRkdnYwMiIgdGltZXN0YW1wPSIxNDIxMzI5OTM3Ij4zMjg8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk9oa2ksIFkuPC9hdXRob3I+PGF1dGhvcj5I

aWdvLCBULjwvYXV0aG9yPjxhdXRob3I+VWVtdXJhLCBLLjwvYXV0aG9yPjxhdXRob3I+U2hpbWFk

YSwgTi48L2F1dGhvcj48YXV0aG9yPk9zYXdhLCBTLjwvYXV0aG9yPjxhdXRob3I+QmVyZXpvdnNr

YSwgTy48L2F1dGhvcj48YXV0aG9yPllva29zaGltYSwgUy48L2F1dGhvcj48YXV0aG9yPkZ1a3V5

YW1hLCBULjwvYXV0aG9yPjxhdXRob3I+VG9taXRhLCBULjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1

Ym8sIFQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVw

YXJ0bWVudCBvZiBOZXVyb3BhdGhvbG9neSBhbmQgTmV1cm9zY2llbmNlLCBHcmFkdWF0ZSBTY2hv

b2wgb2YgUGhhcm1hY2V1dGljYWwgU2NpZW5jZXMsIFRoZSBVbml2ZXJzaXR5IG9mIFRva3lvLCBU

b2t5bywgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UGhlbnlscGlwZXJpZGlu

ZS10eXBlIGdhbW1hLXNlY3JldGFzZSBtb2R1bGF0b3JzIHRhcmdldCB0aGUgdHJhbnNtZW1icmFu

ZSBkb21haW4gMSBvZiBwcmVzZW5pbGluIDE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RU1CTyBK

PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5UaGUgRU1CTyBqb3VybmFsPC9hbHQtdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+RU1CTyBKPC9mdWxsLXRpdGxlPjxhYmJy

LTE+VGhlIEVNQk8gam91cm5hbDwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+RU1CTyBKPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIEVNQk8gam91cm5hbDwv

YWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjQ4MTUtMjQ8L3BhZ2VzPjx2b2x1bWU+MzA8

L3ZvbHVtZT48bnVtYmVyPjIzPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsbG9zdGVyaWMg

UmVndWxhdGlvbi8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkFsemhlaW1lciBEaXNl

YXNlL3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD4qQW15bG9pZCBQcmVjdXJzb3Ig

UHJvdGVpbiBTZWNyZXRhc2VzL2FudGFnb25pc3RzICZhbXA7IGluaGliaXRvcnMvbWV0YWJvbGlz

bTwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUGVwdGlkZXMvYW5hbHlzaXMvKm1ldGFi

b2xpc208L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5CaW5kaW5n

IFNpdGVzL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5DSE8gQ2VsbHM8L2tleXdvcmQ+

PGtleXdvcmQ+Q3JpY2V0aW5hZTwva2V5d29yZD48a2V5d29yZD5DcmljZXR1bHVzPC9rZXl3b3Jk

PjxrZXl3b3JkPkhFSzI5MyBDZWxsczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+

PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdv

cmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHMvYW5hbHlzaXMvKm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+UGlwZXJpZGluZXMvY2hlbWljYWwgc3ludGhlc2lzLypwaGFybWFjb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+KlByZXNlbmlsaW4tMS9jaGVtaXN0cnkvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5Qcm90ZWluIEJpbmRpbmcvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3

b3JkPlByb3RlaW4gQ29uZm9ybWF0aW9uLypkcnVnIGVmZmVjdHM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdiAzMDwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NjAtMjA3NSAoRWxlY3Ryb25pYykmI3hEOzAyNjEt

NDE4OSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjIwMDI1Mzk8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w

dWJtZWQvMjIwMDI1Mzk8L3VybD48dXJsPmh0dHA6Ly9lbWJvai5lbWJvcHJlc3Mub3JnL2NvbnRl

bnQvZW1ib2pubC8zMC8yMy80ODE1LmZ1bGwucGRmPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz

PjxjdXN0b20yPjMyNDM2MTY8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEw

MzgvZW1ib2ouMjAxMS4zNzI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0

ZT48Q2l0ZT48QXV0aG9yPlRha2VvPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjMy

OTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzI5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtl

eXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2

djAyIiB0aW1lc3RhbXA9IjE0MjEzMjk5NzAiPjMyOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+VGFrZW8sIEsuPC9hdXRob3I+PGF1dGhvcj5UYW5pbXVyYSwgUy48L2F1

dGhvcj48YXV0aG9yPlNoaW5vZGEsIFQuPC9hdXRob3I+PGF1dGhvcj5Pc2F3YSwgUy48L2F1dGhv

cj48YXV0aG9yPlphaGFyaWV2LCBJLiBLLjwvYXV0aG9yPjxhdXRob3I+VGFrZWdhbWksIE4uPC9h

dXRob3I+PGF1dGhvcj5Jc2hpenVrYS1LYXRzdXJhLCBZLjwvYXV0aG9yPjxhdXRob3I+U2hpbnlh

LCBOLjwvYXV0aG9yPjxhdXRob3I+VGFrYWdpLU5paWRvbWUsIFMuPC9hdXRob3I+PGF1dGhvcj5U

b21pbmFnYSwgQS48L2F1dGhvcj48YXV0aG9yPk9oc2F3YSwgTi48L2F1dGhvcj48YXV0aG9yPktp

bXVyYS1Tb21leWEsIFQuPC9hdXRob3I+PGF1dGhvcj5TaGlyb3V6dSwgTS48L2F1dGhvcj48YXV0

aG9yPllva29zaGltYSwgUy48L2F1dGhvcj48YXV0aG9yPllva295YW1hLCBTLjwvYXV0aG9yPjxh

dXRob3I+RnVrdXlhbWEsIFQuPC9hdXRob3I+PGF1dGhvcj5Ub21pdGEsIFQuPC9hdXRob3I+PGF1

dGhvcj5Jd2F0c3VibywgVC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5EZXBhcnRtZW50cyBvZiBOZXVyb3BhdGhvbG9neSBhbmQgTmV1cm9zY2llbmNlIGFu

ZC4mI3hEO1N5bnRoZXRpYyBOYXR1cmFsIFByb2R1Y3RzIENoZW1pc3RyeSwgR3JhZHVhdGUgU2No

b29sIG9mIFBoYXJtYWNldXRpY2FsIFNjaWVuY2VzLCBhbmQuJiN4RDtSSUtFTiBTeXN0ZW1zIGFu

ZCBTdHJ1Y3R1cmFsIEJpb2xvZ3kgQ2VudGVyIGFuZERpdmlzaW9uIG9mIFN0cnVjdHVyYWwgYW5k

IFN5bnRoZXRpYyBCaW9sb2d5LCBSSUtFTiBDZW50ZXIgZm9yIExpZmUgU2NpZW5jZSBUZWNobm9s

b2dpZXMsIDEtNy0yMiBTdWVoaXJvLWNobywgVHN1cnVtaSwgWW9rb2hhbWEsIEthbmFnYXdhIDIz

MC0wMDQ1LCBKYXBhbjsmI3hEO0RlcGFydG1lbnRzIG9mIE5ldXJvcGF0aG9sb2d5IGFuZCBOZXVy

b3NjaWVuY2UgYW5kRmFjdWx0eSBvZiBNZWRpY2luZSwgVGhlIFVuaXZlcnNpdHkgb2YgVG9reW8s

IDctMy0xIEhvbmdvLCBCdW5reW8ta3UsIFRva3lvIDExMy0wMDMzLCBKYXBhbjtEZXBhcnRtZW50

IG9mIE5ldXJvcGF0aG9sb2d5LCBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmUsIFRoZSBVbml2

ZXJzaXR5IG9mIFRva3lvLCA3LTMtMSBIb25nbywgQnVua3lvLWt1LCBUb2t5byAxMTMtMDAzMywg

SmFwYW47JiN4RDtSSUtFTiBTeXN0ZW1zIGFuZCBTdHJ1Y3R1cmFsIEJpb2xvZ3kgQ2VudGVyIGFu

ZFJJS0VOIFN0cnVjdHVyYWwgQmlvbG9neSBMYWJvcmF0b3J5LCAxLTctMjIgU3VlaGlyby1jaG8s

IFRzdXJ1bWksIFlva29oYW1hLCBLYW5hZ2F3YSAyMzAtMDA0NSwgSmFwYW47IGFuZC4mI3hEO0Rl

cGFydG1lbnRzIG9mIE5ldXJvcGF0aG9sb2d5IGFuZCBOZXVyb3NjaWVuY2UgYW5kQ29yZSBSZXNl

YXJjaCBmb3IgRXZvbHV0aW9uYWwgU2NpZW5jZSBhbmQgVGVjaG5vbG9neSwgSmFwYW4gU2NpZW5j

ZSBhbmQgVGVjaG5vbG9neSBBZ2VuY3ksIDctMy0xIEhvbmdvLCBCdW5reW8ta3UsIFRva3lvIDEx

My0wMDMzLCBKYXBhbiB0YWlzdWtlQG1vbC5mLnUtdG9reW8uYWMuanAuJiN4RDtEZXBhcnRtZW50

cyBvZiBOZXVyb3BhdGhvbG9neSBhbmQgTmV1cm9zY2llbmNlIGFuZEZhY3VsdHkgb2YgTWVkaWNp

bmUsIFRoZSBVbml2ZXJzaXR5IG9mIFRva3lvLCA3LTMtMSBIb25nbywgQnVua3lvLWt1LCBUb2t5

byAxMTMtMDAzMywgSmFwYW47Q29yZSBSZXNlYXJjaCBmb3IgRXZvbHV0aW9uYWwgU2NpZW5jZSBh

bmQgVGVjaG5vbG9neSwgSmFwYW4gU2NpZW5jZSBhbmQgVGVjaG5vbG9neSBBZ2VuY3ksIDctMy0x

IEhvbmdvLCBCdW5reW8ta3UsIFRva3lvIDExMy0wMDMzLCBKYXBhbi48L2F1dGgtYWRkcmVzcz48

dGl0bGVzPjx0aXRsZT5BbGxvc3RlcmljIHJlZ3VsYXRpb24gb2YgZ2FtbWEtc2VjcmV0YXNlIGFj

dGl2aXR5IGJ5IGEgcGhlbnlsaW1pZGF6b2xlLXR5cGUgZ2FtbWEtc2VjcmV0YXNlIG1vZHVsYXRv

cjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBTIEE8L3NlY29u

ZGFyeS10aXRsZT48YWx0LXRpdGxlPlByb2NlZWRpbmdzIG9mIHRoZSBOYXRpb25hbCBBY2FkZW15

IG9mIFNjaWVuY2VzIG9mIHRoZSBVbml0ZWQgU3RhdGVzIG9mIEFtZXJpY2E8L2FsdC10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBTIEE8

L2Z1bGwtdGl0bGU+PGFiYnItMT5Qcm9jZWVkaW5ncyBvZiB0aGUgTmF0aW9uYWwgQWNhZGVteSBv

ZiBTY2llbmNlcyBvZiB0aGUgVW5pdGVkIFN0YXRlcyBvZiBBbWVyaWNhPC9hYmJyLTE+PC9wZXJp

b2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9jIE5hdGwgQWNhZCBTY2kgVSBT

IEE8L2Z1bGwtdGl0bGU+PGFiYnItMT5Qcm9jZWVkaW5ncyBvZiB0aGUgTmF0aW9uYWwgQWNhZGVt

eSBvZiBTY2llbmNlcyBvZiB0aGUgVW5pdGVkIFN0YXRlcyBvZiBBbWVyaWNhPC9hYmJyLTE+PC9h

bHQtcGVyaW9kaWNhbD48cGFnZXM+MTA1NDQtOTwvcGFnZXM+PHZvbHVtZT4xMTE8L3ZvbHVtZT48

bnVtYmVyPjI5PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFsbG9zdGVyaWMgUmVndWxhdGlv

bi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QW1pbm8gQWNpZHMvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5BbXlsb2lkIFByZWN1cnNvciBQcm90ZWluIFNlY3JldGFzZXMvZ2Vu

ZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q2F0YWx5dGljIERvbWFpbjwva2V5

d29yZD48a2V5d29yZD5Fbnp5bWUgQWN0aXZhdGlvbi9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtl

eXdvcmQ+Rmx1b3Jlc2NlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5JbWlkYXpvbGVzL2NoZW1pc3RyeS8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk1vZGVscywgTW9sZWN1bGFyPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uL2dlbmV0aWNzPC9r

ZXl3b3JkPjxrZXl3b3JkPlBlcHRpZGVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+U3Ry

dWN0dXJhbCBIb21vbG9neSwgUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5TdWJzdHJhdGUgU3Bl

Y2lmaWNpdHkvZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIw

MTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWwgMjI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRl

cz48aXNibj4xMDkxLTY0OTAgKEVsZWN0cm9uaWMpJiN4RDswMDI3LTg0MjQgKExpbmtpbmcpPC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI1MDA5MTgwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk

LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI1MDA5MTgwPC91

cmw+PHVybD5odHRwOi8vd3d3LnBuYXMub3JnL2NvbnRlbnQvMTExLzI5LzEwNTQ0LmZ1bGwucGRm

PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPjQxMTU1NjQ8L2N1c3RvbTI+PGVs

ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNzMvcG5hcy4xNDAyMTcxMTExPC9lbGVjdHJvbmlj

LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA (Ohki, et al., 2011,Takeo, et al., 2014). One could speculate that mutations involving this allosteric core may alter more dramatically the A profiles and cause a more aggressive phenotype. Another potential source of variability in the pathological consequences of different PSEN1 mutations is their role in calcium homeostasis, which could have implications for vascular, immune and neuronal function. The function of presenilins as calcium leak channels in the endoplasmic reticulum appears to be impaired by most PSEN1 mutations ADDIN EN.CITE <EndNote><Cite><Author>Nelson</Author><Year>2011</Year><RecNum>183</RecNum><DisplayText>(Nelson, et al., 2011)</DisplayText><record><rec-number>183</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">183</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nelson,O.</author><author>Supnet,C.</author><author>Tolia,A.</author><author>Horre,K.</author><author>De Strooper,B.</author><author>Bezprozvanny,I.</author></authors></contributors><auth-address>From the Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9040</auth-address><titles><title>Mutagenesis mapping of the presenilin 1 calcium leak conductance pore</title><secondary-title>J Biol.Chem.</secondary-title></titles><periodical><full-title>J Biol.Chem.</full-title></periodical><pages>22339-22347</pages><volume>286</volume><number>25</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Alzheimer Disease</keyword><keyword>Amyloid</keyword><keyword>Calcium</keyword><keyword>Endoplasmic Reticulum</keyword><keyword>Mutagenesis</keyword><keyword>Mutation</keyword><keyword>physiology</keyword><keyword>Presenilin-1</keyword><keyword>Presenilin-2</keyword><keyword>Presenilins</keyword><keyword>Proteins</keyword></keywords><dates><year>2011</year><pub-dates><date>6/24/2011</date></pub-dates></dates><label>217</label><urls><related-urls><url>;(Nelson, et al., 2011). However, calcium leak function is preserved with certain mutations, particularly those in a cluster located beyond codon 200 in exons 8-9 ADDIN EN.CITE <EndNote><Cite><Author>Nelson</Author><Year>2010</Year><RecNum>182</RecNum><DisplayText>(Nelson, et al., 2010)</DisplayText><record><rec-number>182</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1392372715">182</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nelson,O.</author><author>Supnet,C.</author><author>Liu,H.</author><author>Bezprozvanny,I.</author></authors></contributors><auth-address>Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, Texas 75390-9040, USA</auth-address><titles><title>Familial Alzheimer&apos;s disease mutations in presenilins: effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes</title><secondary-title>J Alzheimers.Dis</secondary-title></titles><periodical><full-title>J Alzheimers.Dis</full-title></periodical><pages>781-793</pages><volume>21</volume><number>3</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Alzheimer Disease</keyword><keyword>Amyloid</keyword><keyword>Amyloid Precursor Protein Secretases</keyword><keyword>Analysis of Variance</keyword><keyword>Animals</keyword><keyword>Calcium</keyword><keyword>Cell Line</keyword><keyword>Cells,Cultured</keyword><keyword>Endoplasmic Reticulum</keyword><keyword>Fibroblasts</keyword><keyword>genetics</keyword><keyword>Humans</keyword><keyword>metabolism</keyword><keyword>Mice</keyword><keyword>Mice,Knockout</keyword><keyword>Mutation</keyword><keyword>Phenotype</keyword><keyword>physiology</keyword><keyword>Presenilins</keyword></keywords><dates><year>2010</year><pub-dates><date>2010</date></pub-dates></dates><label>216</label><urls><related-urls><url>;(Nelson, et al., 2010), which tend to be associated with cotton wool plaque pathology. Further work investigating functionally relevant differences between mutations at different sites will be important to refine our understanding of how mutation position influences pathology and phenotype, beyond the simple dichotomy of pre or post-codon 200 location. In conclusion, we observed increased posterior WMH and later ages at onset in the PSEN1 post-codon 200 group. WMH correlated with severity of CAA and cotton wool plaque pathology at post-mortem. In contrast, the PSEN1 pre-codon 200 group had younger ages at onset and greater axonal loss, gliosis and T-lymphocytic response in the deep white matter. A significantly later age at onset in cases with PSEN1 mutations beyond codon 200 cases was also reported in Mann’s study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PihNYW5uLCBldCBhbC4sIDIwMDEpPC9EaXNwbGF5

VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjU5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYW5uLEQuTS48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZy1Ccm93bixTLk0uPC9h

dXRob3I+PGF1dGhvcj5UYWtldWNoaSxBLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sVC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBOZXVy

b3NjaWVuY2UgUmVzZWFyY2ggR3JvdXAsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgTWFuY2hlc3RlciwgTWFuY2hlc3RlciwgVW5pdGVkIEtpbmdkb20uIGRhdmlkLm1hbm5A

bWFuLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBhbmdpb3BhdGh5

IGFuZCB2YXJpYWJpbGl0eSBpbiBhbXlsb2lkIGJldGEgZGVwb3NpdGlvbiBpcyBkZXRlcm1pbmVk

IGJ5IG11dGF0aW9uIHBvc2l0aW9uIGluIHByZXNlbmlsaW4tMS1saW5rZWQgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGF0aG9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjUtMjE3NTwvcGFnZXM+PHZvbHVtZT4x

NTg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29yZD48a2V5d29yZD5ibG9v

ZDwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYmVsbHVtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5Db2Rvbjwva2V5d29yZD48a2V5d29yZD5Db3MgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250YWwgTG9iZTwva2V5d29yZD48a2V5d29yZD5H

ZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQcm90ZWluczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5QZXB0aWRlIEZyYWdtZW50czwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdv

cmQ+PGtleXdvcmQ+dWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD45NjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTEzOTUzOTQ8L3VybD48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTg5MTk5My9wZGYvMjY4NS5wZGY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjU5PC9SZWNOdW0+PERpc3BsYXlUZXh0PihNYW5uLCBldCBhbC4sIDIwMDEpPC9EaXNwbGF5

VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0iMnhyZTBlcmY0MjlwZXVlZmQwNXBleGY3c3A1MnBwZGR2djAyIiB0

aW1lc3RhbXA9IjEzOTIzNzI3MTUiPjU5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5NYW5uLEQuTS48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZy1Ccm93bixTLk0uPC9h

dXRob3I+PGF1dGhvcj5UYWtldWNoaSxBLjwvYXV0aG9yPjxhdXRob3I+SXdhdHN1Ym8sVC48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBOZXVy

b3NjaWVuY2UgUmVzZWFyY2ggR3JvdXAsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNp

dHkgb2YgTWFuY2hlc3RlciwgTWFuY2hlc3RlciwgVW5pdGVkIEtpbmdkb20uIGRhdmlkLm1hbm5A

bWFuLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW15bG9pZCBhbmdpb3BhdGh5

IGFuZCB2YXJpYWJpbGl0eSBpbiBhbXlsb2lkIGJldGEgZGVwb3NpdGlvbiBpcyBkZXRlcm1pbmVk

IGJ5IG11dGF0aW9uIHBvc2l0aW9uIGluIHByZXNlbmlsaW4tMS1saW5rZWQgQWx6aGVpbWVyJmFw

b3M7cyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGF0aG9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGF0aG9sLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjUtMjE3NTwvcGFnZXM+PHZvbHVtZT4x

NTg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3

b3JkPkFsemhlaW1lciBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW15bG9pZCBiZXRhLVByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwv

a2V5d29yZD48a2V5d29yZD5BcG9saXBvcHJvdGVpbnMgRTwva2V5d29yZD48a2V5d29yZD5ibG9v

ZDwva2V5d29yZD48a2V5d29yZD5CcmFpbjwva2V5d29yZD48a2V5d29yZD5DZXJlYmVsbHVtPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5

d29yZD5Db2Rvbjwva2V5d29yZD48a2V5d29yZD5Db3MgQ2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZyb250YWwgTG9iZTwva2V5d29yZD48a2V5d29yZD5H

ZW5ldGljIFZhcmlhdGlvbjwva2V5d29yZD48a2V5d29yZD5nZW5ldGljczwva2V5d29yZD48a2V5

d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBQcm90ZWluczwva2V5d29yZD48a2V5d29y

ZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPk11dGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5QZXB0aWRlIEZyYWdtZW50czwva2V5d29yZD48a2V5d29yZD5QcmVzZW5pbGluLTE8L2tleXdv

cmQ+PGtleXdvcmQ+dWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD45NjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93

d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTEzOTUzOTQ8L3VybD48dXJsPmh0dHA6Ly93d3cu

bmNiaS5ubG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTg5MTk5My9wZGYvMjY4NS5wZGY8L3Vy

bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Mann, et al., 2001). It may suggest that some degree of protection is conferred by the source of the WMH in the post-codon 200 group, whether this is preferential deposition of amyloid in the vasculature, differing inflammatory responses, plaque species or a combination. Pathological studies have found an inverse relationship between the severity of capillary CAA and the density of amyloid plaques surrounding these capillaries, which has been interpreted as providing support for the idea that Aβ may be transported between the neuropil and circulation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWNoYXJkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48

UmVjTnVtPjE4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oUmljaGFyZCwgZXQgYWwuLCAyMDEwKTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xODA8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTgwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5SaWNoYXJkLEUuPC9hdXRob3I+PGF1dGhvcj5DYXJyYW5vLEEuPC9h

dXRob3I+PGF1dGhvcj5Ib296ZW1hbnMsSi5KLjwvYXV0aG9yPjxhdXRob3I+dmFuIEhvcnNzZW4s

Si48L2F1dGhvcj48YXV0aG9yPnZhbiBIYWFzdGVydCxFLlMuPC9hdXRob3I+PGF1dGhvcj5FdXJl

bGluZ3MsTC5TLjwvYXV0aG9yPjxhdXRob3I+ZGUgVnJpZXMsSC5FLjwvYXV0aG9yPjxhdXRob3I+

VGhhbCxELlIuPC9hdXRob3I+PGF1dGhvcj5FaWtlbGVuYm9vbSxQLjwvYXV0aG9yPjxhdXRob3I+

dmFuIEdvb2wsVy5BLjwvYXV0aG9yPjxhdXRob3I+Um96ZW11bGxlcixBLkouPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIEFjYWRlbWljIE1lZGljYWwgQ2VudGVyLCBVbml2ZXJzaXR5IG9mIEFtc3RlcmRhbSwgQW1z

dGVyZGFtLCBUaGUgTmV0aGVybGFuZHMuIGUucmljaGFyZEBhbWMudXZhLm5sPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+Q2hhcmFjdGVyaXN0aWNzIG9mIGR5c2hvcmljIGNhcGlsbGFyeSBj

ZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBOZXVy

b3BhdGhvbCBFeHAuTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+SiBOZXVyb3BhdGhvbCBFeHAuTmV1cm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTE1OC0xMTY3PC9wYWdlcz48dm9sdW1lPjY5PC92b2x1bWU+PG51bWJlcj4x

MTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLDgwIGFuZCBvdmVy

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9rZXl3b3JkPjxr

ZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNhcGlsbGFyaWVzPC9rZXl3b3JkPjxrZXl3

b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub3R5cGU8L2tl

eXdvcmQ+PGtleXdvcmQ+R2xpYWwgRmlicmlsbGFyeSBBY2lkaWMgUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5ITEEtRFIgQW50aWdlbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1h

dGlvbjwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VhbCBB

cnRlcmllczwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5l

dGhlcmxhbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1

IFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlViaXF1aXRpbjwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMjAxMDwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMTQ8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwOTQwNjI1PC91cmw+PHVy

bD5odHRwOi8vZ3JhcGhpY3MudHgub3ZpZC5jb20vb3ZmdHBkZnMvRlBERE5DR0NKQklLQUcwMC9m

czA0Ni9vdmZ0L2xpdmUvZ3YwMjMvMDAwMDUwNzIvMDAwMDUwNzItMjAxMDExMDAwLTAwMDA3LnBk

ZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWNoYXJkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48

UmVjTnVtPjE4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oUmljaGFyZCwgZXQgYWwuLCAyMDEwKTwv

RGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xODA8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyeHJlMGVyZjQyOXBldWVmZDA1cGV4ZjdzcDUycHBk

ZHZ2MDIiIHRpbWVzdGFtcD0iMTM5MjM3MjcxNSI+MTgwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5SaWNoYXJkLEUuPC9hdXRob3I+PGF1dGhvcj5DYXJyYW5vLEEuPC9h

dXRob3I+PGF1dGhvcj5Ib296ZW1hbnMsSi5KLjwvYXV0aG9yPjxhdXRob3I+dmFuIEhvcnNzZW4s

Si48L2F1dGhvcj48YXV0aG9yPnZhbiBIYWFzdGVydCxFLlMuPC9hdXRob3I+PGF1dGhvcj5FdXJl

bGluZ3MsTC5TLjwvYXV0aG9yPjxhdXRob3I+ZGUgVnJpZXMsSC5FLjwvYXV0aG9yPjxhdXRob3I+

VGhhbCxELlIuPC9hdXRob3I+PGF1dGhvcj5FaWtlbGVuYm9vbSxQLjwvYXV0aG9yPjxhdXRob3I+

dmFuIEdvb2wsVy5BLjwvYXV0aG9yPjxhdXRob3I+Um96ZW11bGxlcixBLkouPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIEFjYWRlbWljIE1lZGljYWwgQ2VudGVyLCBVbml2ZXJzaXR5IG9mIEFtc3RlcmRhbSwgQW1z

dGVyZGFtLCBUaGUgTmV0aGVybGFuZHMuIGUucmljaGFyZEBhbWMudXZhLm5sPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+Q2hhcmFjdGVyaXN0aWNzIG9mIGR5c2hvcmljIGNhcGlsbGFyeSBj

ZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBOZXVy

b3BhdGhvbCBFeHAuTmV1cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+SiBOZXVyb3BhdGhvbCBFeHAuTmV1cm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MTE1OC0xMTY3PC9wYWdlcz48dm9sdW1lPjY5PC92b2x1bWU+PG51bWJlcj4x

MTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLDgwIGFuZCBvdmVy

PC9rZXl3b3JkPjxrZXl3b3JkPkFteWxvaWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW15bG9pZCBiZXRh

LVBlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWluIEU0PC9rZXl3b3JkPjxr

ZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNhcGlsbGFyaWVzPC9rZXl3b3JkPjxrZXl3

b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9wYXRoeTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub3R5cGU8L2tl

eXdvcmQ+PGtleXdvcmQ+R2xpYWwgRmlicmlsbGFyeSBBY2lkaWMgUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5ITEEtRFIgQW50aWdlbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1h

dGlvbjwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VhbCBB

cnRlcmllczwva2V5d29yZD48a2V5d29yZD5tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5l

dGhlcmxhbmRzPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXJvbG9neTwva2V5d29yZD48a2V5d29yZD5w

YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+dGF1

IFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPlViaXF1aXRpbjwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMjAxMDwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4yMTQ8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+

PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwOTQwNjI1PC91cmw+PHVy

bD5odHRwOi8vZ3JhcGhpY3MudHgub3ZpZC5jb20vb3ZmdHBkZnMvRlBERE5DR0NKQklLQUcwMC9m

czA0Ni9vdmZ0L2xpdmUvZ3YwMjMvMDAwMDUwNzIvMDAwMDUwNzItMjAxMDExMDAwLTAwMDA3LnBk

ZjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA (Richard, et al., 2010). A similar observation, of increased CAA in areas of decreased amyloid plaque burden, was also made at post-mortem in brains of some of the AD patients who received Aβ immunisation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NoZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4xMzE8L1JlY051bT48RGlzcGxheVRleHQ+KEJvY2hlLCBldCBhbC4sIDIwMDgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEzMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xMzE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkJvY2hlLEQuPC9hdXRob3I+PGF1dGhvcj5ab3RvdmEsRS48L2F1dGhvcj48

YXV0aG9yPldlbGxlcixSLk8uPC9hdXRob3I+PGF1dGhvcj5Mb3ZlLFMuPC9hdXRob3I+PGF1dGhv

cj5OZWFsLEouVy48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZyxSLk0uPC9hdXRob3I+PGF1dGhv

cj5XaWxraW5zb24sRC48L2F1dGhvcj48YXV0aG9yPkhvbG1lcyxDLjwvYXV0aG9yPjxhdXRob3I+

Tmljb2xsLEouQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EaXZpc2lvbiBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFNvdXRo

YW1wdG9uLCBTb3V0aGFtcHRvbiBHZW5lcmFsIEhvc3BpdGFsLCBTb3V0aGFtcHRvbiwgVUsuIEQu

Qm9jaGVAc290b24uYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Db25zZXF1ZW5j

ZSBvZiBBYmV0YSBpbW11bml6YXRpb24gb24gdGhlIHZhc2N1bGF0dXJlIG9mIGh1bWFuIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZSBicmFpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFpbjwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWluPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzI5OS0zMzEwPC9wYWdlcz48dm9sdW1lPjEz

MTwvdm9sdW1lPjxudW1iZXI+UHQgMTI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgVmFjY2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5BbnRpYm9kaWVzPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kPC9rZXl3b3JkPjxrZXl3

b3JkPmJsb29kIHN1cHBseTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBWZXNzZWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9w

YXRoeTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXg8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VyZWJyYWwgSGVtb3JyaGFnZTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rm9sbG93LVVwIFN0dWRpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPmltbXVub2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5LEFj

dGl2ZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VzPC9r

ZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5

d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+U29sdWJp

bGl0eTwva2V5d29yZD48a2V5d29yZD50aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5WYWNjaW5lczwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTIvMjAwODwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xNjY8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE4OTUzMDU2PC91cmw+PHVybD5o

dHRwOi8vYnJhaW4ub3hmb3Jkam91cm5hbHMub3JnL2NvbnRlbnQvMTMxLzEyLzMyOTkuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NoZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4xMzE8L1JlY051bT48RGlzcGxheVRleHQ+KEJvY2hlLCBldCBhbC4sIDIwMDgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEzMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xMzE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkJvY2hlLEQuPC9hdXRob3I+PGF1dGhvcj5ab3RvdmEsRS48L2F1dGhvcj48

YXV0aG9yPldlbGxlcixSLk8uPC9hdXRob3I+PGF1dGhvcj5Mb3ZlLFMuPC9hdXRob3I+PGF1dGhv

cj5OZWFsLEouVy48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZyxSLk0uPC9hdXRob3I+PGF1dGhv

cj5XaWxraW5zb24sRC48L2F1dGhvcj48YXV0aG9yPkhvbG1lcyxDLjwvYXV0aG9yPjxhdXRob3I+

Tmljb2xsLEouQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EaXZpc2lvbiBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFNvdXRo

YW1wdG9uLCBTb3V0aGFtcHRvbiBHZW5lcmFsIEhvc3BpdGFsLCBTb3V0aGFtcHRvbiwgVUsuIEQu

Qm9jaGVAc290b24uYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Db25zZXF1ZW5j

ZSBvZiBBYmV0YSBpbW11bml6YXRpb24gb24gdGhlIHZhc2N1bGF0dXJlIG9mIGh1bWFuIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZSBicmFpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFpbjwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWluPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzI5OS0zMzEwPC9wYWdlcz48dm9sdW1lPjEz

MTwvdm9sdW1lPjxudW1iZXI+UHQgMTI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgVmFjY2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5BbnRpYm9kaWVzPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kPC9rZXl3b3JkPjxrZXl3

b3JkPmJsb29kIHN1cHBseTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBWZXNzZWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9w

YXRoeTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXg8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VyZWJyYWwgSGVtb3JyaGFnZTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rm9sbG93LVVwIFN0dWRpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPmltbXVub2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5LEFj

dGl2ZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VzPC9r

ZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5

d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+U29sdWJp

bGl0eTwva2V5d29yZD48a2V5d29yZD50aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5WYWNjaW5lczwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTIvMjAwODwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xNjY8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE4OTUzMDU2PC91cmw+PHVybD5o

dHRwOi8vYnJhaW4ub3hmb3Jkam91cm5hbHMub3JnL2NvbnRlbnQvMTMxLzEyLzMyOTkuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Boche, et al., 2008). The findings of a decrease in both CAA and plaques in immunised patients who survived longer led to the suggestion that this vascular amyloid may be cleared over time PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NoZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4xMzE8L1JlY051bT48RGlzcGxheVRleHQ+KEJvY2hlLCBldCBhbC4sIDIwMDgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEzMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xMzE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkJvY2hlLEQuPC9hdXRob3I+PGF1dGhvcj5ab3RvdmEsRS48L2F1dGhvcj48

YXV0aG9yPldlbGxlcixSLk8uPC9hdXRob3I+PGF1dGhvcj5Mb3ZlLFMuPC9hdXRob3I+PGF1dGhv

cj5OZWFsLEouVy48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZyxSLk0uPC9hdXRob3I+PGF1dGhv

cj5XaWxraW5zb24sRC48L2F1dGhvcj48YXV0aG9yPkhvbG1lcyxDLjwvYXV0aG9yPjxhdXRob3I+

Tmljb2xsLEouQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EaXZpc2lvbiBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFNvdXRo

YW1wdG9uLCBTb3V0aGFtcHRvbiBHZW5lcmFsIEhvc3BpdGFsLCBTb3V0aGFtcHRvbiwgVUsuIEQu

Qm9jaGVAc290b24uYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Db25zZXF1ZW5j

ZSBvZiBBYmV0YSBpbW11bml6YXRpb24gb24gdGhlIHZhc2N1bGF0dXJlIG9mIGh1bWFuIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZSBicmFpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFpbjwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWluPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzI5OS0zMzEwPC9wYWdlcz48dm9sdW1lPjEz

MTwvdm9sdW1lPjxudW1iZXI+UHQgMTI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgVmFjY2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5BbnRpYm9kaWVzPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kPC9rZXl3b3JkPjxrZXl3

b3JkPmJsb29kIHN1cHBseTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBWZXNzZWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9w

YXRoeTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXg8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VyZWJyYWwgSGVtb3JyaGFnZTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rm9sbG93LVVwIFN0dWRpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPmltbXVub2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5LEFj

dGl2ZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VzPC9r

ZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5

d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+U29sdWJp

bGl0eTwva2V5d29yZD48a2V5d29yZD50aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5WYWNjaW5lczwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTIvMjAwODwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xNjY8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE4OTUzMDU2PC91cmw+PHVybD5o

dHRwOi8vYnJhaW4ub3hmb3Jkam91cm5hbHMub3JnL2NvbnRlbnQvMTMxLzEyLzMyOTkuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NoZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4xMzE8L1JlY051bT48RGlzcGxheVRleHQ+KEJvY2hlLCBldCBhbC4sIDIwMDgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEzMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz

PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJwcGRkdnYw

MiIgdGltZXN0YW1wPSIxMzkyMzcyNzE1Ij4xMzE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5

cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0

aG9ycz48YXV0aG9yPkJvY2hlLEQuPC9hdXRob3I+PGF1dGhvcj5ab3RvdmEsRS48L2F1dGhvcj48

YXV0aG9yPldlbGxlcixSLk8uPC9hdXRob3I+PGF1dGhvcj5Mb3ZlLFMuPC9hdXRob3I+PGF1dGhv

cj5OZWFsLEouVy48L2F1dGhvcj48YXV0aG9yPlBpY2tlcmluZyxSLk0uPC9hdXRob3I+PGF1dGhv

cj5XaWxraW5zb24sRC48L2F1dGhvcj48YXV0aG9yPkhvbG1lcyxDLjwvYXV0aG9yPjxhdXRob3I+

Tmljb2xsLEouQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5EaXZpc2lvbiBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFNvdXRo

YW1wdG9uLCBTb3V0aGFtcHRvbiBHZW5lcmFsIEhvc3BpdGFsLCBTb3V0aGFtcHRvbiwgVUsuIEQu

Qm9jaGVAc290b24uYWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Db25zZXF1ZW5j

ZSBvZiBBYmV0YSBpbW11bml6YXRpb24gb24gdGhlIHZhc2N1bGF0dXJlIG9mIGh1bWFuIEFsemhl

aW1lciZhcG9zO3MgZGlzZWFzZSBicmFpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFpbjwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWluPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzI5OS0zMzEwPC9wYWdlcz48dm9sdW1lPjEz

MTwvdm9sdW1lPjxudW1iZXI+UHQgMTI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgVmFjY2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+

QW15bG9pZDwva2V5d29yZD48a2V5d29yZD5BbXlsb2lkIGJldGEtUHJvdGVpbjwva2V5d29yZD48

a2V5d29yZD5BbnRpYm9kaWVzPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kPC9rZXl3b3JkPjxrZXl3

b3JkPmJsb29kIHN1cHBseTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBWZXNzZWxzPC9rZXl3b3Jk

PjxrZXl3b3JkPkJyYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIEFteWxvaWQgQW5naW9w

YXRoeTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBDb3J0ZXg8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VyZWJyYWwgSGVtb3JyaGFnZTwva2V5d29yZD48a2V5d29yZD5ldGlvbG9neTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rm9sbG93LVVwIFN0dWRpZXM8L2tleXdv

cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPmltbXVub2xvZ3k8L2tleXdvcmQ+

PGtleXdvcmQ+SW1tdW5vdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5JbW11bm90aGVyYXB5LEFj

dGl2ZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lbmluZ2VzPC9r

ZXl3b3JkPjxrZXl3b3JkPm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5

d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+UGVwdGlkZSBGcmFnbWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+U29sdWJp

bGl0eTwva2V5d29yZD48a2V5d29yZD50aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5WYWNjaW5lczwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTIvMjAwODwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xNjY8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy

bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE4OTUzMDU2PC91cmw+PHVybD5o

dHRwOi8vYnJhaW4ub3hmb3Jkam91cm5hbHMub3JnL2NvbnRlbnQvMTMxLzEyLzMyOTkuZnVsbC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Boche, et al., 2008). What remains an unknown and critical issue for clinical trials in FAD, is how an individual’s baseline propensity for developing CAA may influence the processes by which amyloid may be cleared after immunotherapy or other amyloid depleting strategies. AcknowledgementsThe study was undertaken at UCL/UCLH, which received a proportion of funding from the Department of Health’s NIHR Queen Square Dementia Biomedical Research Unit funding scheme. NSR is supported by a Brain Exit Fellowship and has held a Medical Research Council (MRC) Clinical Research Training Fellowship. TL is supported by an Alzheimer’s Research UK (ARUK) research fellowship. JMS acknowledges the support of the UCL/UCLH Biomedical Research Centre. NCF and MNR are NIHR senior investigators. The Dementia Research Centre is an ARUK Co-ordinating Centre and is grateful for support from the Leonard Wolfson Experimental Neurology Centre. We thank the participants and their families for their generous support of this study; our clinical colleagues across the UK for referring patients; and present and past staff at the Dementia Research Centre for their contribution to our ongoing longitudinal study of FAD. In particular, we thank Giovanna Mallucci, Catherine Mummery, Jason Warren, Adam Zeman, Will Knight, Alison Godbolt, John Janssen and Angus Kennedy. Genetic analysis was undertaken by the MRC Prion Unit at UCL Institute of Neurology and we are grateful to Tracy Campbell, James Uphill and Jessica Lowe for their assistance with this. Supplementary InformationImmunohistochemical methods in the pathology cohortParaffin sections were dewaxed in xylene. Endogenous peroxidase activity was blocked with 0.3% H2O2 in methanol and non-specific binding with 10% dried milk solution. Immunohistochemistry required pressure cooker pretreatment in citrate buffer (pH 6.0) for all antibodies unless otherwise stated. Tissue sections were incubated with the primary antibodies for one hour at room temperature, followed by biotinylated anti-rabbit IgG (1:200, 30 min; Dako) or biotinylated anti-mouse IgG (1:200, 30 min; Dako) and Avidin–biotin complex (30 min; Dako). Colour was developed with di-aminobenzidine/H2O2. Antibodies to the following proteins were used: amyloid-β (Aβ) (Dako, 1:100), requiring formic acid pretreatment before pressure cooking; tau (AT8 clone; Autogen Bioclear, 1:600); Iba1 (Wako, 1:1000); glial fibrillary acidic protein (Dako, 1:1000); Myelin Basic Protein (MBP, Covance, 1:500) and RT-97 (Vector, 1:20), CD3 (Dako, 1:100); CD20 (Dako, 1:200) and CD68 (Dako, 1:150). Sections were also stained with routine haematoxylin and eosin (HE) stains to evaluate any structural or cellular abnormalities in the cases being examined.Grading system used to assess severity of cerebral amyloid angiopathy Score 0 was given to vessels devoid of amyloid deposition, while score 1 reflected trace to scattered distribution of amyloid in leptomeningeal or cortical blood vessels. A score of 2 indicated that at least some vessels demonstrated circumferential amyloid deposition. A score of 3 corresponded to widespread, circumferential staining of many leptomeningeal and superficial cortical vessels. A score of 4 indicated severe amyloid deposition accompanied by projection of amyloid into the adjacent parenchyma or the presence of amyloid deposition in capillaries PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PbGljaG5leTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+

PFJlY051bT4yMDc8L1JlY051bT48RGlzcGxheVRleHQ+KE9saWNobmV5LCBldCBhbC4sIDE5OTYp

PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIwNzwvcmVjLW51bWJlcj48Zm9yZWln

bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJw

cGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzc3Nzk4Ij4yMDc8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPk9saWNobmV5LCBKLiBNLjwvYXV0aG9yPjxhdXRob3I+SGFuc2Vu

LCBMLiBBLjwvYXV0aG9yPjxhdXRob3I+R2FsYXNrbywgRC48L2F1dGhvcj48YXV0aG9yPlNhaXRv

aCwgVC48L2F1dGhvcj48YXV0aG9yPkhvZnN0ZXR0ZXIsIEMuIFIuPC9hdXRob3I+PGF1dGhvcj5L

YXR6bWFuLCBSLjwvYXV0aG9yPjxhdXRob3I+VGhhbCwgTC4gSi48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvc2NpZW5jZXMs

IFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSwgU2FuIERpZWdvLCBMYSBKb2xsYSwgVVNBLjwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBhcG9saXBvcHJvdGVpbiBFIGVwc2lsb24gNCBh

bGxlbGUgaXMgYXNzb2NpYXRlZCB3aXRoIGluY3JlYXNlZCBuZXVyaXRpYyBwbGFxdWVzIGFuZCBj

ZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHkgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGFu

ZCBMZXd5IGJvZHkgdmFyaWFudDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2xvZ3k8L3Nl

Y29uZGFyeS10aXRsZT48YWx0LXRpdGxlPk5ldXJvbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L2FsdC1w

ZXJpb2RpY2FsPjxwYWdlcz4xOTAtNjwvcGFnZXM+PHZvbHVtZT40Nzwvdm9sdW1lPjxudW1iZXI+

MTwvbnVtYmVyPjxlZGl0aW9uPjE5OTYvMDcvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFuYWx5c2lz

IG9mIFZhcmlhbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFLypnZW5ldGlj

czwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkvKmdlbmV0aWNz

PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HZW5vdHlwZTwva2V5

d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TGV3eSBCb2RpZXMvKmdlbmV0

aWNzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MTk5NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjAwMjgtMzg3OCAoUHJpbnQpJiN4RDswMDI4LTM4NzggKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjg3MTAwNzY8L2FjY2Vzc2lvbi1udW0+PHdvcmstdHlwZT5SZXNlYXJj

aCBTdXBwb3J0LCBVLlMuIEdvdiZhcG9zO3QsIE5vbi1QLkguUy4mI3hEO1Jlc2VhcmNoIFN1cHBv

cnQsIFUuUy4gR292JmFwb3M7dCwgUC5ILlMuPC93b3JrLXR5cGU+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODcxMDA3NjwvdXJsPjx1

cmw+aHR0cDovL2dyYXBoaWNzLnR4Lm92aWQuY29tL292ZnRwZGZzL0ZQREROQ0dDSkJJS0FHMDAv

ZnMwNDcvb3ZmdC9saXZlL2d2MDMxLzAwMDA2MTE0LzAwMDA2MTE0LTE5OTYwNzAwMC0wMDAzNC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PbGljaG5leTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+

PFJlY051bT4yMDc8L1JlY051bT48RGlzcGxheVRleHQ+KE9saWNobmV5LCBldCBhbC4sIDE5OTYp

PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIwNzwvcmVjLW51bWJlcj48Zm9yZWln

bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJ4cmUwZXJmNDI5cGV1ZWZkMDVwZXhmN3NwNTJw

cGRkdnYwMiIgdGltZXN0YW1wPSIxMzkyMzc3Nzk4Ij4yMDc8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPk9saWNobmV5LCBKLiBNLjwvYXV0aG9yPjxhdXRob3I+SGFuc2Vu

LCBMLiBBLjwvYXV0aG9yPjxhdXRob3I+R2FsYXNrbywgRC48L2F1dGhvcj48YXV0aG9yPlNhaXRv

aCwgVC48L2F1dGhvcj48YXV0aG9yPkhvZnN0ZXR0ZXIsIEMuIFIuPC9hdXRob3I+PGF1dGhvcj5L

YXR6bWFuLCBSLjwvYXV0aG9yPjxhdXRob3I+VGhhbCwgTC4gSi48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE5ldXJvc2NpZW5jZXMs

IFVuaXZlcnNpdHkgb2YgQ2FsaWZvcm5pYSwgU2FuIERpZWdvLCBMYSBKb2xsYSwgVVNBLjwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBhcG9saXBvcHJvdGVpbiBFIGVwc2lsb24gNCBh

bGxlbGUgaXMgYXNzb2NpYXRlZCB3aXRoIGluY3JlYXNlZCBuZXVyaXRpYyBwbGFxdWVzIGFuZCBj

ZXJlYnJhbCBhbXlsb2lkIGFuZ2lvcGF0aHkgaW4gQWx6aGVpbWVyJmFwb3M7cyBkaXNlYXNlIGFu

ZCBMZXd5IGJvZHkgdmFyaWFudDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2xvZ3k8L3Nl

Y29uZGFyeS10aXRsZT48YWx0LXRpdGxlPk5ldXJvbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvbG9neTwvZnVsbC10aXRsZT48L2FsdC1w

ZXJpb2RpY2FsPjxwYWdlcz4xOTAtNjwvcGFnZXM+PHZvbHVtZT40Nzwvdm9sdW1lPjxudW1iZXI+

MTwvbnVtYmVyPjxlZGl0aW9uPjE5OTYvMDcvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdv

cmQ+QWx6aGVpbWVyIERpc2Vhc2UvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFuYWx5c2lz

IG9mIFZhcmlhbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFLypnZW5ldGlj

czwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBBbXlsb2lkIEFuZ2lvcGF0aHkvKmdlbmV0aWNz

PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HZW5vdHlwZTwva2V5

d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TGV3eSBCb2RpZXMvKmdlbmV0

aWNzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MTk5NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjAwMjgtMzg3OCAoUHJpbnQpJiN4RDswMDI4LTM4NzggKExpbmtpbmcpPC9pc2Ju

PjxhY2Nlc3Npb24tbnVtPjg3MTAwNzY8L2FjY2Vzc2lvbi1udW0+PHdvcmstdHlwZT5SZXNlYXJj

aCBTdXBwb3J0LCBVLlMuIEdvdiZhcG9zO3QsIE5vbi1QLkguUy4mI3hEO1Jlc2VhcmNoIFN1cHBv

cnQsIFUuUy4gR292JmFwb3M7dCwgUC5ILlMuPC93b3JrLXR5cGU+PHVybHM+PHJlbGF0ZWQtdXJs

cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODcxMDA3NjwvdXJsPjx1

cmw+aHR0cDovL2dyYXBoaWNzLnR4Lm92aWQuY29tL292ZnRwZGZzL0ZQREROQ0dDSkJJS0FHMDAv

ZnMwNDcvb3ZmdC9saXZlL2d2MDMxLzAwMDA2MTE0LzAwMDA2MTE0LTE5OTYwNzAwMC0wMDAzNC5w

ZGY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA (Olichney, et al., 1996). The severity of CAA was graded in frontal, temporal, parietal and occipital cortex and cerebellum. Semi-quantitative assessment of myelin loss, gliosis and microglial expression.The deep white matter in the occipital and parietal lobes were semi-quantitatively assessed for white matter pallor, gliosis and microglial expression, through examination by eye down the microscope. This was based on a four-tier grading system where ‘0’ represented no change in the white matter, no gliosis or microglial activation; ‘+’ represented mild pallor of the white matter, mild gliosis and the minimal presence of activated microglia (figure 3,K); ‘++’ represented a moderate degree of white matter pallor, gliosis and microglial activation (figure 3, L); ‘+++’ represents severe pallor of the white matter, severe gliosis and severe microglial activation; ‘++++’ represents very severe microglial activation where the majority of the microglial cells are highlighted using immunohistochemical methods (figure 3, M). ADDIN EN.REFLIST Reference ListAlafuzoff, I., Thal, D.R., Arzberger, T., Bogdanovic, N., Al Sarraj, S., Bodi, I., Boluda, S., Bugiani, O., Duyckaerts, C., Gelpi, E., Gentleman, S., Giaccone, G., Graeber, M., Hortobagyi, T., Hoftberger, R., Ince, P., Ironside, J.W., Kavantzas, N., King, A., Korkolopoulou, P., Kovacs, G.G., Meyronet, D., Monoranu, C., Nilsson, T., Parchi, P., Patsouris, E., Pikkarainen, M., Revesz, T., Rozemuller, A., Seilhean, D., Schulz-Schaeffer, W., Streichenberger, N., Wharton, S.B., Kretzschmar, H. 2009. Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol 117(3), 309-20.Barakos, J., Sperling, R., Salloway, S., Jack, C., Gass, A., Fiebach, J.B., Tampieri, D., Melancon, D., Miaux, Y., Rippon, G., Black, R., Lu, Y., Brashear, H.R., Arrighi, H.M., Morris, K.A., Grundman, M. 2013. MR imaging features of amyloid-related imaging abnormalities. AJNR American journal of neuroradiology 34(10), 1958-65. doi:10.3174/ajnr.A3500.Bateman, R.J., Aisen, P.S., De Strooper, B., Fox, N.C., Lemere, C.A., Ringman, J.M., Salloway, S., Sperling, R.A., Windisch, M., Xiong, C. 2011. Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease. AlzheimersResTher 3(1), 1.Bergeron, C., Ranalli, P.J., Miceli, P.N. 1987. Amyloid angiopathy in Alzheimer's disease. CanJ Neurol Sci 14(4), 564-9.Boche, D., Zotova, E., Weller, R.O., Love, S., Neal, J.W., Pickering, R.M., Wilkinson, D., Holmes, C., Nicoll, J.A. 2008. Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain. Brain 131(Pt 12), 3299-310.Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H., Del Tredici, K. 2006. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112(4), 389-404. doi:10.1007/s00401-006-0127-z.Chalmers, K., Wilcock, G.K., Love, S. 2003. APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein. Neuropathology and applied neurobiology 29(3), 231-8.Chao, C.P., Kotsenas, A.L., Broderick, D.F. 2006. Cerebral amyloid angiopathy: CT and MR imaging findings. Radiographics 26(5), 1517-31.Chavez-Gutierrez, L., Bammens, L., Benilova, I., Vandersteen, A., Benurwar, M., Borgers, M., Lismont, S., Zhou, L., Van Cleynenbreugel, S., Esselmann, H., Wiltfang, J., Serneels, L., Karran, E., Gijsen, H., Schymkowitz, J., Rousseau, F., Broersen, K., De Strooper, B. 2012. The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. The EMBO journal 31(10), 2261-74. doi:10.1038/emboj.2012.79.Chung, K.K., Anderson, N.E., Hutchinson, D., Synek, B., Barber, P.A. 2011. Cerebral amyloid angiopathy related inflammation: three case reports and a review. J Neurol Neurosurg Psychiatry 82(1), 20-6.Church, A., Prescott, J., Lillis, S., Rees, J., Chance, P., Williamson, K., Morris, H.R. 2011. A novel presenilin 1 mutation, I202F occurring at a previously predicted pathogenic site causing autosomal dominant Alzheimer's disease. Neurobiol Aging 32(3), 556-2.Cordonnier, C., van der Flier, W.M. 2011. Brain microbleeds and Alzheimer's disease: innocent observation or key player? Brain 134(Pt 2), 335-44.Crook, R., Verkkoniemi, A., Perez-Tur, J., Mehta, N., Baker, M., Houlden, H., Farrer, M., Hutton, M., Lincoln, S., Hardy, J., Gwinn, K., Somer, M., Paetau, A., Kalimo, H., Ylikoski, R., Poyhonen, M., Kucera, S., Haltia, M. 1998. A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nature medicine 4(4), 452-5.Cruts, M., van Duijn, C.M., Backhovens, H., Van den, B.M., Wehnert, A., Serneels, S., Sherrington, R., Hutton, M., Hardy, J., George-Hyslop, P.H., Hofman, A., Van Broeckhoven, C. 1998. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. HumMolGenet 7(1), 43-51.de Leeuw, F.E., Richard, F., de Groot, J.C., van Duijn, C.M., Hofman, A., Van Gijn, J., Breteler, M.M. 2004. Interaction between hypertension, apoE, and cerebral white matter lesions. Stroke 35(5), 1057-60. doi:10.1161/01.STR.0000125859.71051.83.DeCarli, C., Mungas, D., Harvey, D., Reed, B., Weiner, M., Chui, H., Jagust, W. 2004. Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia. Neurology 63(2), 220-7.DeCarli, C., Reed, T., Miller, B.L., Wolf, P.A., Swan, G.E., Carmelli, D. 1999. Impact of apolipoprotein E epsilon4 and vascular disease on brain morphology in men from the NHLBI twin study. Stroke 30(8), 1548-53.Dillen, K., Annaert, W. 2006. A two decade contribution of molecular cell biology to the centennial of Alzheimer's disease: are we progressing toward therapy? International review of cytology 254, 215-300. doi:10.1016/S0074-7696(06)54005-7.Doody, R.S., Azher, S.N., Haykal, H.A., Dunn, J.K., Liao, T., Schneider, L. 2000. Does APO epsilon4 correlate with MRI changes in Alzheimer's disease? J Neurol Neurosurg Psychiatry 69(5), 668-71.Ellis, R.J., Olichney, J.M., Thal, L.J., Mirra, S.S., Morris, J.C., Beekly, D., Heyman, A. 1996. Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, Part XV. Neurology 46(6), 1592-6.Eng, J.A., Frosch, M.P., Choi, K., Rebeck, G.W., Greenberg, S.M. 2004. Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol 55(2), 250-6.Fox, N.C., Petersen, R.C. 2013. The G8 Dementia Research Summit--a starter for eight? Lancet 382(9909), 1968-9. doi:10.1016/S0140-6736(13)62426-5.Gomez-Isla, T., Growdon, W.B., McNamara, M.J., Nochlin, D., Bird, T.D., Arango, J.C., Lopera, F., Kosik, K.S., Lantos, P.L., Cairns, N.J., Hyman, B.T. 1999. The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. Brain 122 ( Pt 9), 1709-19.Goos, J.D., Kester, M.I., Barkhof, F., Klein, M., Blankenstein, M.A., Scheltens, P., van der Flier, W.M. 2009. Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke 40(11), 3455-60.Greenberg, S.M., Rebeck, G.W., Vonsattel, J.P., Gomez-Isla, T., Hyman, B.T. 1995. Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol 38(2), 254-9. doi:10.1002/ana.410380219.Guerreiro, R.J., Baquero, M., Blesa, R., Boada, M., Bras, J.M., Bullido, M.J., Calado, A., Crook, R., Ferreira, C., Frank, A., Gomez-Isla, T., Hernandez, I., Lleo, A., Machado, A., Martinez-Lage, P., Masdeu, J., Molina-Porcel, L., Molinuevo, J.L., Pastor, P., Perez-Tur, J., Relvas, R., Oliveira, C.R., Ribeiro, M.H., Rogaeva, E., Sa, A., Samaranch, L., Sanchez-Valle, R., Santana, I., Tarraga, L., Valdivieso, F., Singleton, A., Hardy, J., Clarimon, J. 2010. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging 31(5), 725-31.Harkness, K.A., Coles, A., Pohl, U., Xuereb, J.H., Baron, J.C., Lennox, G.G. 2004. Rapidly reversible dementia in cerebral amyloid inflammatory vasculopathy. Eur J Neurol 11(1), 59-62.Hirono, N., Yasuda, M., Tanimukai, S., Kitagaki, H., Mori, E. 2000. Effect of the apolipoprotein E epsilon4 allele on white matter hyperintensities in dementia. Stroke 31(6), 1263-8.Hopkins, R.O., Beck, C.J., Burnett, D.L., Weaver, L.K., Victoroff, J., Bigler, E.D. 2006. Prevalence of white matter hyperintensities in a young healthy population. Journal of neuroimaging : official journal of the American Society of Neuroimaging 16(3), 243-51. doi:10.1111/j.1552-6569.2006.00047.x.Houlden, H., Baker, M., McGowan, E., Lewis, P., Hutton, M., Crook, R., Wood, N.W., Kumar-Singh, S., Geddes, J., Swash, M., Scaravilli, F., Holton, J.L., Lashley, T., Tomita, T., Hashimoto, T., Verkkoniemi, A., Kalimo, H., Somer, M., Paetau, A., Martin, J.J., Van Broeckhoven, C., Golde, T., Hardy, J., Haltia, M., Revesz, T. 2000. Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol 48(5), 806-8.Jiao, B., Tang, B., Liu, X., Xu, J., Wang, Y., Zhou, L., Zhang, F., Yan, X., Zhou, Y., Shen, L. 2014. Mutational analysis in early-onset familial Alzheimer's disease in Mainland China. Neurobiol Aging 35(8), 1957 e1-6. doi:10.1016/j.neurobiolaging.2014.02.014.Kalaria, R.N., Cohen, D.L., Premkumar, D.R. 1996. Apolipoprotein E alleles and brain vascular pathology in Alzheimer's disease. Annals of the New York Academy of Sciences 777, 266-70.Kinnecom, C., Lev, M.H., Wendell, L., Smith, E.E., Rosand, J., Frosch, M.P., Greenberg, S.M. 2007. Course of cerebral amyloid angiopathy-related inflammation. Neurology 68(17), 1411-6.Lashley, T., Holton, J.L., Gray, E., Kirkham, K., O'Sullivan, S.S., Hilbig, A., Wood, N.W., Lees, A.J., Revesz, T. 2008. Cortical alpha-synuclein load is associated with amyloid-beta plaque burden in a subset of Parkinson's disease patients. Acta Neuropathol 115(4), 417-25. doi:10.1007/s00401-007-0336-0.Maarouf, C.L., Daugs, I.D., Spina, S., Vidal, R., Kokjohn, T.A., Patton, R.L., Kalback, W.M., Luehrs, D.C., Walker, D.G., Castano, E.M., Beach, T.G., Ghetti, B., Roher, A.E. 2008. Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. MolNeurodegener 3, 20.Mann, D.M., Pickering-Brown, S.M., Takeuchi, A., Iwatsubo, T. 2001. Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease. Am J Pathol 158(6), 2165-75.Miao, J., Xu, F., Davis, J., Otte-Holler, I., Verbeek, M.M., Van Nostrand, W.E. 2005. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol 167(2), 505-15.Mirra, S.S., Heyman, A., McKeel, D., Sumi, S.M., Crain, B.J., Brownlee, L.M., Vogel, F.S., Hughes, J.P., van Belle, G., Berg, L. 1991. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41(4), 479-86.Nelson, O., Supnet, C., Liu, H., Bezprozvanny, I. 2010. Familial Alzheimer's disease mutations in presenilins: effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes. J AlzheimersDis 21(3), 781-93.Nelson, O., Supnet, C., Tolia, A., Horre, K., De Strooper, B., Bezprozvanny, I. 2011. Mutagenesis mapping of the presenilin 1 calcium leak conductance pore. J BiolChem 286(25), 22339-47.Nilsberth, C., Westlind-Danielsson, A., Eckman, C.B., Condron, M.M., Axelman, K., Forsell, C., Stenh, C., Luthman, J., Teplow, D.B., Younkin, S.G., Naslund, J., Lannfelt, L. 2001. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. NatNeurosci 4(9), 887-93.Ohki, Y., Higo, T., Uemura, K., Shimada, N., Osawa, S., Berezovska, O., Yokoshima, S., Fukuyama, T., Tomita, T., Iwatsubo, T. 2011. Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1. The EMBO journal 30(23), 4815-24. doi:10.1038/emboj.2011.372.Olichney, J.M., Hansen, L.A., Galasko, D., Saitoh, T., Hofstetter, C.R., Katzman, R., Thal, L.J. 1996. The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant. Neurology 47(1), 190-6.Plant, G.T., Revesz, T., Barnard, R.O., Harding, A.E., Gautier-Smith, P.C. 1990. Familial cerebral amyloid angiopathy with nonneuritic amyloid plaque formation. Brain 113 ( Pt 3), 721-47.Premkumar, D.R., Cohen, D.L., Hedera, P., Friedland, R.P., Kalaria, R.N. 1996. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. The American journal of pathology 148(6), 2083-95.Prince, M., Bryce, R., Albanese, E., Wimo, A., Ribeiro, W., Ferri, C.P. 2013. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimer's & dementia : the journal of the Alzheimer's Association 9(1), 63-75 e2. doi:10.1016/j.jalz.2012.11.007.Prins, N.D., Scheltens, P. 2015. White matter hyperintensities, cognitive impairment and dementia: an update. Nature reviews Neurology. doi:10.1038/nrneurol.2015.10.Reiman, E.M., Langbaum, J.B., Tariot, P.N. 2010. Alzheimer's prevention initiative: a proposal to evaluate presymptomatic treatments as quickly as possible. BiomarkMed 4(1), 3-14.Revesz, T., Ghiso, J., Lashley, T., Plant, G., Rostagno, A., Frangione, B., Holton, J.L. 2003. Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol ExpNeurol 62(9), 885-98.Revesz, T., Hawkins, C.P., du Boulay, E.P., Barnard, R.O., McDonald, W.I. 1989. Pathological findings correlated with magnetic resonance imaging in subcortical arteriosclerotic encephalopathy (Binswanger's disease). J Neurol Neurosurg Psychiatry 52(12), 1337-44.Revesz, T., Holton, J.L., Lashley, T., Plant, G., Frangione, B., Rostagno, A., Ghiso, J. 2009. Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol 118(1), 115-30. doi:10.1007/s00401-009-0501-8.Richard, E., Carrano, A., Hoozemans, J.J., van Horssen, J., van Haastert, E.S., Eurelings, L.S., de Vries, H.E., Thal, D.R., Eikelenboom, P., van Gool, W.A., Rozemuller, A.J. 2010. Characteristics of dyshoric capillary cerebral amyloid angiopathy. J Neuropathol ExpNeurol 69(11), 1158-67.Ryan, N.S., Bastos-Leite, A.J., Rohrer, J.D., Werring, D.J., Fox, N.C., Rossor, M.N., Schott, J.M. 2011. Cerebral microbleeds in familial Alzheimer's disease. Brain 135(Pt 1), e201.Ryan, N.S., Lashley, T., Revesz, T., Dantu, K., Fox, N.C., Morris, H.R. 2014. Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer's Disease. Journal of Alzheimer's disease : JAD. doi:10.3233/JAD-142325.Ryan, N.S., Rossor, M.N. 2010. Correlating familial Alzheimer's disease gene mutations with clinical phenotype. BiomarkMed 4(1), 99-112.Saito, T., Suemoto, T., Brouwers, N., Sleegers, K., Funamoto, S., Mihira, N., Matsuba, Y., Yamada, K., Nilsson, P., Takano, J., Nishimura, M., Iwata, N., Van Broeckhoven, C., Ihara, Y., Saido, T.C. 2011. Potent amyloidogenicity and pathogenicity of Abeta43. NatNeurosci 14(8), 1023-32.Sakai, K., Boche, D., Carare, R., Johnston, D., Holmes, C., Love, S., Nicoll, J.A. 2014. Abeta immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy. Acta Neuropathol 128(6), 777-89. doi:10.1007/s00401-014-1340-9.Sawada, H., Udaka, F., Izumi, Y., Nishinaka, K., Kawakami, H., Nakamura, S., Kameyama, M. 2000. Cerebral white matter lesions are not associated with apoE genotype but with age and female sex in Alzheimer's disease. J Neurol Neurosurg Psychiatry 68(5), 653-6.Scolding, N.J., Joseph, F., Kirby, P.A., Mazanti, I., Gray, F., Mikol, J., Ellison, D., Hilton, D.A., Williams, T.L., MacKenzie, J.M., Xuereb, J.H., Love, S. 2005. Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 128(Pt 3), 500-15.Shepherd, C., McCann, H., Halliday, G.M. 2009. Variations in the neuropathology of familial Alzheimer's disease. Acta Neuropathol 118(1), 37-52.Shrimpton, A.E., Schelper, R.L., Linke, R.P., Hardy, J., Crook, R., Dickson, D.W., Ishizawa, T., Davis, R.L. 2007. A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease, seizures and cotton wool plaques, but not spastic paraparesis. Neuropathology : official journal of the Japanese Society of Neuropathology 27(3), 228-32.Sperling, R.A., Jack, C.R., Jr., Black, S.E., Frosch, M.P., Greenberg, S.M., Hyman, B.T., Scheltens, P., Carrillo, M.C., Thies, W., Bednar, M.M., Black, R.S., Brashear, H.R., Grundman, M., Siemers, E.R., Feldman, H.H., Schindler, R.J. 2011. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup. AlzheimersDement 7(4), 367-85.Tabira, T., Chui, D.H., Nakayama, H., Kuroda, S., Shibuya, M. 2002. Alzheimer's disease with spastic paresis and cotton wool type plaques. J Neurosci Res 70(3), 367-72.Takeo, K., Tanimura, S., Shinoda, T., Osawa, S., Zahariev, I.K., Takegami, N., Ishizuka-Katsura, Y., Shinya, N., Takagi-Niidome, S., Tominaga, A., Ohsawa, N., Kimura-Someya, T., Shirouzu, M., Yokoshima, S., Yokoyama, S., Fukuyama, T., Tomita, T., Iwatsubo, T. 2014. Allosteric regulation of gamma-secretase activity by a phenylimidazole-type gamma-secretase modulator. Proceedings of the National Academy of Sciences of the United States of America 111(29), 10544-9. doi:10.1073/pnas.1402171111.Thal, D.R., Ghebremedhin, E., Rub, U., Yamaguchi, H., Del Tredici, K., Braak, H. 2002. Two types of sporadic cerebral amyloid angiopathy. J Neuropathol ExpNeurol 61(3), 282-93.Thanprasertsuk, S., Martinez-Ramirez, S., Pontes-Neto, O.M., Ni, J., Ayres, A., Reed, A., Swords, K., Gurol, M.E., Greenberg, S.M., Viswanathan, A. 2014. Posterior white matter disease distribution as a predictor of amyloid angiopathy. Neurology. doi:10.1212/WNL.0000000000000732.Wahlund, L.O., Barkhof, F., Fazekas, F., Bronge, L., Augustin, M., Sjogren, M., Wallin, A., Ader, H., Leys, D., Pantoni, L., Pasquier, F., Erkinjuntti, T., Scheltens, P. 2001. A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 32(6), 1318-22.Whitwell, J.L., Kantarci, K., Weigand, S.D., Lundt, E.S., Gunter, J.L., Duffy, J.R., Strand, E.A., Machulda, M.M., Spychalla, A.J., Drubach, D.A., Petersen, R.C., Lowe, V.J., Jack Jr, C.R., Josephs, K.A. 2015. Microbleeds in Atypical Presentations of Alzheimer's Disease: A Comparison to Dementia of the Alzheimer's Type. Journal of Alzheimer's disease : JAD. doi:10.3233/JAD-142628.Figures and tableTable 1: Subjects’ characteristics and total ARWMC scoresSubject groupControlsAPPPSEN1 pre-codon 200PSEN1post-codon 200p-value for PSEN1pre-codon 200 vs post-codon 200p-value for control vs PSEN1post-codon 200No. of subjects25131821GenderM/F13/126/79/910/11Age (y) at scanMean (sd)53.5 (10.6)53.8 (3.5)43.5(7.0)51.1(5.9)0.0007*0.4*Disease duration in yearsMean (sd)N/A5.9 (5.6)4.3(1.8)4.4(2.5)0.9*N/AAge at onsetMean (sd)N/A47.9 (5.3)39.2(6.2)46.8(6.1)0.0005*N/AMRI scan Teslaa1.5T/3T16/912/112/616/50.5**0.8**Proportion carrying APOE4 alleleN/A38%22%38%0.3+N/ANo. of subjects with vascular risk known19101621Proportion with increased vascular risk score21%30%0%24%0.06+1.0+Total ARWMC scoreMedianMean(interquartile range)00.9(0-1)01.8(0-2)01.1(0-1)33.6(0-7)<0.01§<0.005§*T-test **Pearson chi-squared test+Fisher’s exact test §Bootstrapped regressiona) One subject only (in the PSEN1 post-codon 200 group) had a 1.0T MRI scan, so was included in the 1.5T group.Table 2. Mean total white matter hyperintensity score for each PSEN1 mutation in the cohortPSEN1 mutationNo of subjectsMean total ARWMC scoreIntron 4 (g.23024delG)60p.Tyr115His11p.Glu120Lys10p.Met139Val61p.Ile143Phe10p.Leu166del12p.Leu166Arg18p.Glu184Asp11p.Ile202Phe18p.Gln222Pro10p.Leu235Val25p.Phe237Leu10p.Leu250Ser10p.Pro264Leu23p.Arg269His14p.Arg278Ile38p.Glu280Gly52p.Phe283Leup.Arg377Met1140p.Gly394Val11p.Thr291Ala & p.Ala434Thr17Figure 1: Example MR images from subjects with (A) pGlu120Lys (B) Intron 4 (g.23024delG) (C) p.Met139Val (D) p.Ile202Phe (E) p.Leu235Val (F) p.Glu280Gly (G) and (H) p.Arg278Ile and (I) p.Pro264Leu mutations, whose location within the PSEN1 gene is indicated. In some cases, particularly those with the p.Arg278Ile mutation (G and H), some of the white matter hyperintensities have an atypical appearance with extension into the U-fibres. Green stars indicate mutation positions where the mean age-related white matter change score was four or more. Figure adapted from ADDIN EN.CITE <EndNote><Cite><Author>Dillen</Author><Year>2006</Year><RecNum>445</RecNum><DisplayText>(Dillen and Annaert, 2006)</DisplayText><record><rec-number>445</rec-number><foreign-keys><key app="EN" db-id="2xre0erf429peuefd05pexf7sp52ppddvv02" timestamp="1426175131">445</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dillen, K.</author><author>Annaert, W.</author></authors></contributors><auth-address>Laboratory for Membrane Trafficking, Center for Human Genetics/VIB1104 &amp; KULeuven, Gasthuisberg O&amp;N1, B-3000 Leuven, Belgium.</auth-address><titles><title>A two decade contribution of molecular cell biology to the centennial of Alzheimer&apos;s disease: are we progressing toward therapy?</title><secondary-title>Int Rev Cytol</secondary-title><alt-title>International review of cytology</alt-title></titles><periodical><full-title>Int Rev Cytol</full-title><abbr-1>International review of cytology</abbr-1></periodical><alt-periodical><full-title>Int Rev Cytol</full-title><abbr-1>International review of cytology</abbr-1></alt-periodical><pages>215-300</pages><volume>254</volume><keywords><keyword>Alzheimer Disease/history/*therapy</keyword><keyword>Amino Acid Sequence</keyword><keyword>Amyloid Precursor Protein Secretases</keyword><keyword>Amyloid beta-Protein Precursor/chemistry</keyword><keyword>History, 20th Century</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword><keyword>*Molecular Biology</keyword><keyword>Molecular Sequence Data</keyword></keywords><dates><year>2006</year></dates><isbn>0074-7696 (Print)&#xD;0074-7696 (Linking)</isbn><accession-num>17148000</accession-num><urls><related-urls><url>(06)54005-7</electronic-resource-num></record></Cite></EndNote>(Dillen and Annaert, 2006). FAD-linked mutations are indicated in red, while non-pathogenic mutations are marked in orange. Interaction domains with APP/TLN or NCT/APH-1/PEN-2 are marked in blue, as well as the conserved residues D257 and D385 forming the putative catalytic site. Interactions of the C-terminal domain and the hydrophilic loop domain with proteins such as the brain G-protein Go, calsenilin, the PSEN1-associated protein, b- and d-catenin, p0071 and PLD1, are shown in dark green. The endoproteolytic cleavage site separating PSEN1-NTF and -CTF in the seventh hydrophobic region, the SPP cleavage site in the ninth TMD and the caspase cleavage site in the hydrophilic loop domain are indicated by yellow arrows. APH: Anterior pharynx-defective; CTF: C-terminal fragment; NTF: N-terminal fragment; PEN: Presenilin enhancer; PLD: Phospholipase D; NCT: Nicastrin; SPP: Signal peptide peptidase; TLN: Telencephalin; TMD: Transmembrane domain.Table 3. Autopsy cohort subject demographics and results of CAA grading and blood vessel analysisAll PSEN1 cases (N=10)PSEN1pre-codon 200 (N=5)PSEN1post-codon 200 (N=5)p value for PSEN1 pre-codon 200 vs post-codon 200Disease durationMean (sd)10.6(4.6)9.4(4.4)11.7(5.1)0.4*Age at onsetMean (sd)40(5.1)36.6(4.2)43.6(3.8)0.02*Years from MRI to post-mortemMean (sd)5.0(3.8)4.2(3.2)5.8(4.5)0.6APOE statusTwo 44,one 34, seven 33One 44, four 33One 44, one 34,three 331.00**CAA gradeMedian (range)FrontalTemporalParietalOccipitalCerebellar2.5 (0-3)2 (0-3)2.5 (0-3)3 (3)3 (2-3)2 (1-3)2 (0-2)2 (1-3)3 (3)2 (2-3)3 (0-3)3 (0-3)3 (0-3)3 (3)3 (3)1.0+0.4+1.0+.0.05+Proportion of blood vessels affected by amyloid depositionMean (SD) percentageCorticalCortical ‘severely affected’LeptomeningealLeptomeningeal ‘severely affected’Vessel diameterCortical vessel diameterLeptomeningeal vessel diameter38.1 (37.3)27.2 (36.5)75.2 (32.3)44.6 (28.5)19.0 (4.2)17.1 (3.4)28.6 (41.3)21 (36.7)72.2 (36.4)38.6 (29.6)18.1 (2.9)17.7 (2.9)47.6 (34.5)33.4 (39.4)78.2 (31.5)50.6 (29.3)19.8 (5.5)16.5 (4.1)0.5*0.6*0.8*0.5*0.6*0.6**T-test ** Fisher’s exact test +Wilcoxon rank sum testTable 4: Semi-quantitative assessment of myelin loss, gliosis and microglial expression in parietal and occipital deep white matterMutationLocationOnset age Duration (years)BlockHEMBPRT97GFAP Iba1Intron 4 Pre 2003516.9Parietal++++++++(g.23024delG)Occipital+++++Intron 4 Pre 200398.1Parietal+++++++(g.23024delG)Occipital000++++Intron 4 Pre 200365.6Parietal++++++(g.23024delG)Occipital+++++Intron 4 Pre 200429.7Parietal000+++++++(g.23024delG)Occipital+00++++p.Glu120LysPre 200316.9Parietal+0++++++++Occipital000+++++p.Ile202PhePost 2004812.3Parietal0+++++Occipital000+++p.Leu235ValPost 200449.3Parietal000+++Occipital0+0+++p.Arg278IlePost 2004619.6Parietal000++++Occipital000++++p.Arg377MetPost 2003811.6Parietal000+++++p.Thr291Ala Post 200425.9Parietal000++++& p.Ala434ThrOccipital000+++++Figure 2: Mean density of immunohistochemical staining in parietal and occipital white matter. Error bars indicate standard errors. Figure 3: Pathological analysis of FAD with PSEN1 mutations. Aβ immunohistochemistry demonstrates prominent mature amyloid plaques (A) and mild CAA (B) in a case with a PSEN1 mutation located before codon 200 and no white matter hyperintensities on MRI. In PSEN1 cases with mutations beyond codon 200 and white matter hyperintensites on MRI, there was severe CAA both in the parenchyma (C), showing double barrelling, and the leptomeninges (D). Some of these post codon 200 cases also contained ‘cotton wool like’ Aβ plaques (E) with severe CAA involvement in the occipital cortex where Aβ deposition severely affected the capillaries (F). CD68 (G) and Iba1 (H) were used to assess any alterations in microglia response between the deep white matter and ‘U’ fibres. In the PSEN1 pre-codon 200 group, lower axonal density was observed in the deep white matter (I,) compared to the ‘U’ fibres (J). The semiquantitative assessment suggested a trend for cases with white matter pallor to show only a minimal (K) or moderate (L) degree of microglial activation, whilst cases with normal-appearing white matter showed moderate to very severe (M) microglial activation. ................
................