Update on small vessel diseases
Update on cerebral small vessel disease – a dynamic, whole-brain diseaseYulu Shi, MBBS, MNeurol; Joanna M Wardlaw, MDAffiliations and address:Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (Y.S., J.M.W.); Department of Neurology, Zhongnan Hospital, Wuhan University, Wuhan, China (Y.S.).Correspondence to: Prof Joanna M Wardlaw, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom. Joanna.Wardlaw@ed.ac.uk. Phone: +44-(0)131-465-958Word counts: 4810 words Figs: 4Key words: Cerebral Small Vessel Disease; Lacunar Infarct; White Matter Hyperintensities; Blood Brain Barrier; Microvascular dysfunctionList of abbreviationsAbbreviationDefinitionASCOAtherosclerosis - Small-vessel disease - Cardiac pathology - Other causesBBBBlood brain barrierCADASIL Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and LeukoencephalopathycAMPProstacyclin/cyclic adenosine monophosphateCBFCerebral blood flowcGMPNitric oxide/cyclic guanylate monophosphateCMBCerebral microbleedCSFCerebrospinal fluidCSVDCerebral small vessel diseaseDTIDiffusion-tensor imagingDWIDiffusion-weighted imagingFLAIRFluid-attenuated inversion recoveryISFInterstitial fluidMRIMagnetic resonance imagingNAWMNormal appearing white matterOCSPthe Oxfordshire Community Stroke ProjectPVSPerivascular spacesSPS3the Secondary Prevention of Small Subcortical Stokes TrialSWISusceptibility-weighted imagingTOASTthe Trial of Org 10172 in Acute Stroke TreatmentVITATOPSThe VITAmins TO Prevent Stroke studyWASIDthe Warfarin Aspirin Symptomatic Intracranial Disease studyWMHWhite matter hyperintensitiesABTRACTCerebral small vessel disease (CSVD) is a very common neurological disease in older people. It causes stroke and dementia, mood disturbance and gait problems. Since it is difficult to visualise CSVD pathologies in vivo, the diagnosis of CSVD has relied on imaging findings including white matter hyperintensities, lacunar ischaemic stroke, lacunes, microbleeds, visible perivascular spaces, and many haemorrhagic strokes. However, variations in the use of definition and terms of these features has probably caused confusion and difficulties in interpreting results of previous studies. A standardised use of terms should be encouraged in CSVD research. These CSVD features have long been regarded as different lesions, but emerging evidence has indicated that they might share some common intrinsic microvascular pathologies and therefore, because of its diffuse nature, CSVD should be regarded as a ‘whole-brain disease’. Single antiplatelet (for acute lacunar ischaemic stroke) and management of traditional risk factors still remain the most important therapeutic and preventive approach, due to limited understanding of pathophysiology in CSVD. Increasing evidence suggests that new studies should consider drugs that target endothelium and blood brain barrier to prevent and treat CSVD. Epidemiology of CSVD might differ in Asian compared to Western populations (where most results and guidelines about CSVD and stroke originate), but more community-based data and clear stratification of stroke types are required to address this. INTRODUCTIONThe term “cerebral small vessel disease (CSVD)” refers to a syndrome of clinical and imaging findings that are thought to result from pathologies in perforating cerebral arterioles, capillaries, and venules. CSVD causes up to 45% of dementia, and accounts for about 20% of all stroke worldwide, 25% of ischaemic (or lacunar strokes), of whom about 20% are left disabled. ADDIN EN.CITE <EndNote><Cite><Author>Pantoni</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463785719">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pantoni, L.</author></authors></contributors><auth-address>Department of Neurological and Psychiatric Sciences, University of Florence, Italy. pantoni@unifi.it</auth-address><titles><title>Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>689-701</pages><volume>9</volume><number>7</number><keywords><keyword>Age Factors</keyword><keyword>Anticoagulants/therapeutic use</keyword><keyword>Blood Vessels/*pathology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cerebrovascular Disorders/classification/*etiology/*pathology/*therapy</keyword><keyword>Cognition Disorders/physiopathology</keyword><keyword>Diagnostic Imaging/methods</keyword><keyword>Endarterectomy, Carotid/methods</keyword><keyword>Humans</keyword><keyword>Thrombolytic Therapy/methods</keyword></keywords><dates><year>2010</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1474-4465 (Electronic)
1474-4422 (Linking)</isbn><accession-num>20610345</accession-num><urls><related-urls><url>(10)70104-6</electronic-resource-num></record></Cite></EndNote>[1] Cognitive impairment, depression and gait problems are also frequently seen in patients with CSVD. The prevalence of lacunar stroke may be higher in patients in China where recent studies have suggested that lacunar infarction accounts for 38-46% of ischaemic stroke.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Uc2FpPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Uc2FpPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE.DATA [2, 3] Generally, including in this review, CSVD is used to describe a series of imaging changes in white matter and subcortical grey matter, including recent small subcortical infarct, lacunes, white matter hyperintensities (WMH), prominent perivascular spaces (PVS), cerebral microbleeds (CMB), and atrophy.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA [4] Usually, recent small subcortical infarcts cause acute stroke symptoms, whereas other CSVD lesions are clinically more insidious and thus referred to as ‘silent’ lesions. However, the definitions and terms of these lesions have varied greatly among studies. For example, a recent review identified 159 different names for recent small subcortical infarcts, but these names like “lacunar infarct” were also frequently used to describe lacunes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXJtZWVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXJtZWVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE.DATA [4, 5] that were not necessarily related to symptoms and might have been due to haemorrhage. The substantial variation in the use of these terms have probably contributed to confusion and difficulties in interpreting previous research. Therefore in 2013 an expert workgroup on CSVD proposed a list of standard terms to help avoid confusion and suggests that CSVD researchers should be encouraged to apply these terms in future studies.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA [4] We will also use these terms in this review.The different features of CSVD have long been regarded as different types of tissue changes. However, recent studies show that these features are correlated, are more likely to share common diffuse intrinsic small vessel pathologies, and are probably also more ‘dynamic’ than previously thought. Advances in imaging techniques have brought new insights into mechanisms of CSVD. In this review, we will summarise findings in recent clinical studies on CSVD, discuss CSVD mechanisms, and explore emerging prevention and treatment options. Clinical lacunar stroke A lacunar clinical syndrome could be due to either ischaemia or a small haemorrhage. ADDIN EN.CITE <EndNote><Cite><Author>Mori</Author><Year>1985</Year><RecNum>97</RecNum><DisplayText>[6]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468589276">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mori, E.</author><author>Tabuchi, M.</author><author>Yamadori, A.</author></authors></contributors><titles><title>Lacunar syndrome due to intracerebral hemorrhage</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>454-9</pages><volume>16</volume><number>3</number><keywords><keyword>Ataxia/*etiology/radiography</keyword><keyword>Cerebral Hemorrhage/*complications/radiography</keyword><keyword>Hemiplegia/*etiology/radiography</keyword><keyword>Humans</keyword><keyword>Pons/blood supply</keyword><keyword>Putamen/blood supply</keyword><keyword>Syndrome</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>1985</year><pub-dates><date>May-Jun</date></pub-dates></dates><isbn>0039-2499 (Print)
0039-2499 (Linking)</isbn><accession-num>4002260</accession-num><urls><related-urls><url>;[6] Many haemorrhagic strokes in older people are also due to CSVD pathology. ADDIN EN.CITE <EndNote><Cite><Author>Pantoni</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463785719">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pantoni, L.</author></authors></contributors><auth-address>Department of Neurological and Psychiatric Sciences, University of Florence, Italy. pantoni@unifi.it</auth-address><titles><title>Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>689-701</pages><volume>9</volume><number>7</number><keywords><keyword>Age Factors</keyword><keyword>Anticoagulants/therapeutic use</keyword><keyword>Blood Vessels/*pathology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cerebrovascular Disorders/classification/*etiology/*pathology/*therapy</keyword><keyword>Cognition Disorders/physiopathology</keyword><keyword>Diagnostic Imaging/methods</keyword><keyword>Endarterectomy, Carotid/methods</keyword><keyword>Humans</keyword><keyword>Thrombolytic Therapy/methods</keyword></keywords><dates><year>2010</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1474-4465 (Electronic)
1474-4422 (Linking)</isbn><accession-num>20610345</accession-num><urls><related-urls><url>(10)70104-6</electronic-resource-num></record></Cite></EndNote>[1] In this review, we will focus mainly on ischaemic CSVD. Lacunar ischaemic stroke is defined as a stroke that is attributable to a recent small infarct less than 1.5 (or some say 2) cm diameter in white matter, basal ganglia, pons or brainstem, and is consistent with a lacunar clinical syndrome. ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2013</Year><RecNum>7</RecNum><DisplayText>[7]</DisplayText><record><rec-number>7</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463787133">7</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw, J. M.</author><author>Smith, C.</author><author>Dichgans, M.</author></authors></contributors><auth-address>Neuroimaging Sciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. joanna.wardlaw@ed.ac.uk</auth-address><titles><title>Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>483-97</pages><volume>12</volume><number>5</number><keywords><keyword>Brain/*blood supply/pathology</keyword><keyword>Cerebral Small Vessel Diseases/*pathology</keyword><keyword>Dementia, Vascular/*pathology</keyword><keyword>Humans</keyword><keyword>Neuroimaging</keyword></keywords><dates><year>2013</year><pub-dates><date>May</date></pub-dates></dates><isbn>1474-4465 (Electronic)
1474-4422 (Linking)</isbn><accession-num>23602162</accession-num><urls><related-urls><url>(13)70060-7</electronic-resource-num></record></Cite></EndNote>[7] It is commonly attributed to an abnormality in a single small deep perforating (or lenticulostriate) artery. On magnetic resonance imaging (MRI), an acute lacunar infarct is shown as hyperintense on diffusion-weighted imaging (DWI), hypointense on apparent diffusion coefficient map, hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR), hypointense on T1, and hypoattenuated on CT. (Figure 1) It can be rounded, ovoid, or tubular.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA [4] Generally, the Oxfordshire Community Stroke Project (OCSP) classification, which uses only clinical features to diagnose the stroke subtype, can predict correctly the size and location of a recent brain infarct on imaging in 75-80% of stroke patients. ADDIN EN.CITE <EndNote><Cite><Author>Mead</Author><Year>2000</Year><RecNum>10</RecNum><DisplayText>[8]</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463787630">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mead, G. E.</author><author>Lewis, S. C.</author><author>Wardlaw, J. M.</author><author>Dennis, M. S.</author><author>Warlow, C. P.</author></authors></contributors><auth-address>Neurosciences Trials Unit, Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK.</auth-address><titles><title>How well does the Oxfordshire community stroke project classification predict the site and size of the infarct on brain imaging?</title><secondary-title>J Neurol Neurosurg Psychiatry</secondary-title></titles><periodical><full-title>J Neurol Neurosurg Psychiatry</full-title></periodical><pages>558-62</pages><volume>68</volume><number>5</number><keywords><keyword>Aged</keyword><keyword>Brain/*pathology</keyword><keyword>Cerebral Infarction/*classification/diagnosis</keyword><keyword>Cohort Studies</keyword><keyword>*Diagnostic Imaging</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prognosis</keyword><keyword>Stroke/*classification/diagnosis</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>2000</year><pub-dates><date>May</date></pub-dates></dates><isbn>0022-3050 (Print)
0022-3050 (Linking)</isbn><accession-num>10766882</accession-num><urls><related-urls><url>;[8] However, up to 20% of acute lacunar infarcts can present with cortical symptoms and vice versa cortical infarcts can present with lacunar syndromes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3R0ZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS
ZWNOdW0+ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bOV08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJl
Yy1udW1iZXI+ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9
InAyMjUwZDl4NHcwd3hyZXR4czNwejB4NnJ6dnd2d2F4emRkeCIgdGltZXN0YW1wPSIxNDYzNzg3
Mjg5Ij44PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs
ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Qb3R0ZXIsIEcu
PC9hdXRob3I+PGF1dGhvcj5Eb3ViYWwsIEYuPC9hdXRob3I+PGF1dGhvcj5KYWNrc29uLCBDLjwv
YXV0aG9yPjxhdXRob3I+U3VkbG93LCBDLjwvYXV0aG9yPjxhdXRob3I+RGVubmlzLCBNLjwvYXV0
aG9yPjxhdXRob3I+V2FyZGxhdywgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+
PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENsaW5pY2FsIE5ldXJvc2NpZW5jZXMsIFVuaXZl
cnNpdHkgb2YgRWRpbmJ1cmdoLCBXZXN0ZXJuIEdlbmVyYWwgSG9zcGl0YWwsIEVkaW5idXJnaCwg
VUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QXNzb2NpYXRpb25zIG9mIGNsaW5pY2Fs
IHN0cm9rZSBtaXNjbGFzc2lmaWNhdGlvbiAoJmFwb3M7Y2xpbmljYWwtaW1hZ2luZyBkaXNzb2Np
YXRpb24mYXBvczspIGluIGFjdXRlIGlzY2hlbWljIHN0cm9rZTwvdGl0bGU+PHNlY29uZGFyeS10
aXRsZT5DZXJlYnJvdmFzYyBEaXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh
bD48ZnVsbC10aXRsZT5DZXJlYnJvdmFzYyBEaXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw
YWdlcz4zOTUtNDAyPC9wYWdlcz48dm9sdW1lPjI5PC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+
PGtleXdvcmRzPjxrZXl3b3JkPkFjdXRlIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwv
a2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5CYXNh
bCBHYW5nbGlhL2Jsb29kIHN1cHBseS9yYWRpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5CcmFp
biBJbmZhcmN0aW9uLypjbGFzc2lmaWNhdGlvbi9jb21wbGljYXRpb25zL2RpYWdub3Npcy9yYWRp
b2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5CcmFpbiBJc2NoZW1pYS8qZGlhZ25vc2lzL3JhZGlv
Z3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluIFN0ZW0vYmxvb2Qgc3VwcGx5L3JhZGlvZ3Jh
cGh5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFsIENvcnRleC9ibG9vZCBzdXBwbHkvcmFkaW9n
cmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgSW5mYXJjdGlvbi9kaWFnbm9zaXMvcmFk
aW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgQ29tcGxpY2F0aW9ucy9kaWFnbm9z
aXMvcmFkaW9ncmFwaHk8L2tleXdvcmQ+PGtleXdvcmQ+RGlhZ25vc2lzLCBEaWZmZXJlbnRpYWw8
L2tleXdvcmQ+PGtleXdvcmQ+KkRpYWdub3N0aWMgRXJyb3JzPC9rZXl3b3JkPjxrZXl3b3JkPipE
aWZmdXNpb24gTWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+RmVt
YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmZhcmN0aW9u
LCBBbnRlcmlvciBDZXJlYnJhbCBBcnRlcnkvZGlhZ25vc2lzL3JhZGlvZ3JhcGh5PC9rZXl3b3Jk
PjxrZXl3b3JkPkluZmFyY3Rpb24sIFBvc3RlcmlvciBDZXJlYnJhbCBBcnRlcnkvZGlhZ25vc2lz
L3JhZGlvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlk
ZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TW92ZW1lbnQgRGlzb3JkZXJzL2V0aW9sb2d5PC9r
ZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+U2Vu
c2F0aW9uIERpc29yZGVycy9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5TZW5zaXRpdml0eSBh
bmQgU3BlY2lmaWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+U2luZ2xlLUJsaW5kIE1ldGhvZDwva2V5
d29yZD48a2V5d29yZD5Ub21vZ3JhcGh5LCBYLVJheSBDb21wdXRlZDwva2V5d29yZD48L2tleXdv
cmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjwvZGF0ZXM+PGlzYm4+MTQyMS05Nzg2IChFbGVj
dHJvbmljKSYjeEQ7MTAxNS05NzcwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMDE3
MzMyMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5u
Y2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDE3MzMyMzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs
cz48Y3VzdG9tMj5QTUM0MDY3NzIwPC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4x
MC4xMTU5LzAwMDI4NjM0MjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRl
PjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3R0ZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS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ADDIN EN.CITE.DATA [9] One explanation is that lacunar infarcts closer to the cortex are more likely to cause cortical symptoms.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3R0ZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3R0ZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS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ADDIN EN.CITE.DATA [9] Therefore, in studies where stroke diagnosis relied mainly on the clinical presentations, this ‘mismatch’ may have added ‘noise’. Thus in epidemiology, mechanistic studies or clinical trials, it is important to verify stroke lesions using sensitive imaging wherever possible. However, even with sensitive imaging like DWI, about 30% of patients with clinically definite stroke did not show any recent ischaemic change on MRI;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl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ADDIN EN.CITE.DATA [10] when followed-up for a year, the DWI-negative patients had just as much recurrent stroke, dependency and cognitive impairment as the DWI-positive patients. Therefore, negative DWI/MRI cannot exclude stroke diagnosis. Rapid access to scanning after stroke onset can increase the chance of positive findings. ADDIN EN.CITE <EndNote><Cite><Author>Doubal</Author><Year>2011</Year><RecNum>9</RecNum><DisplayText>[11]</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463787396">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Doubal, F. N.</author><author>Dennis, M. S.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Bramwell Dott Building, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. fergus.doubal@ed.ac.uk</auth-address><titles><title>Characteristics of patients with minor ischaemic strokes and negative MRI: a cross-sectional study</title><secondary-title>J Neurol Neurosurg Psychiatry</secondary-title></titles><periodical><full-title>J Neurol Neurosurg Psychiatry</full-title></periodical><pages>540-2</pages><volume>82</volume><number>5</number><keywords><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Brain/*pathology</keyword><keyword>Brain Infarction/diagnosis/pathology</keyword><keyword>Cross-Sectional Studies</keyword><keyword>False Negative Reactions</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Multivariate Analysis</keyword><keyword>Sex Factors</keyword><keyword>Stroke/diagnosis/*pathology</keyword><keyword>Time Factors</keyword></keywords><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1468-330X (Electronic)
0022-3050 (Linking)</isbn><accession-num>20584742</accession-num><urls><related-urls><url>;[11] It is also noteworthy that DWI positive lesions can be clinically ‘silent’, e.g. a) as a second silent acute infarct in patients presenting with stroke due to another acute symptomatic infarct, or b) in patients with acute haemorrhagic stroke, and c) in patients with severe WMHs who did not have any overt stroke symptoms.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW1iZXJseTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW1iZXJseTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+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ADDIN EN.CITE.DATA [12] In some clinical stroke classifications such as the Trial of Org 10172 in Acute Stroke Treatment (TOAST) or the ASCO (A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other causes), another term “small vessel/artery disease” rather than “lacunar stroke” is used to represent a stroke that is supposed to be due to a small artery occlusion. However, these classifications use risk factors to decide the stroke subtype not just the clinical presentation, so as to distinguish “small vessel/artery disease” from strokes caused by large artery atherosclerosis, cardiac emboli or other unknown reasons. However, a small embolus, or atheroma in the middle cerebral artery (MCA) or perforating arterioles can all block the perforating arteriole, and any of these can cause a lacunar ischaemic stroke (see Figure 2). Therefore it might be better to focus on the clinical presentation to assign the stroke syndrome and separately focus on the risk factors for patient management. Risk factors and causes of lacunar infarctsFour possible main aetiologies for lacunar ischaemic stroke have been proposed (Figure 2): atheroma of parent arteries (usually MCA) or perforating arterioles, embolism from heart or carotid arteries, and intrinsic small vessel disease (lipohyalinosis or fibrinoid necrosis). Atheroma in MCA appears to cause less than 20% of lacunar ischaemic stroke. In the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial, only 11% (38/347) of all stroke patients were lacunar type,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGFuPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGFuPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj
TnVtPjIwPC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxM108L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJl
Yy1udW1iZXI+MjA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk
PSJwMjI1MGQ5eDR3MHd4cmV0eHMzcHoweDZyenZ3dndheHpkZHgiIHRpbWVzdGFtcD0iMTQ2Mzc4
OTU0NSI+MjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRp
Y2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktoYW4sIEEu
PC9hdXRob3I+PGF1dGhvcj5LYXNuZXIsIFMuIEUuPC9hdXRob3I+PGF1dGhvcj5MeW5uLCBNLiBK
LjwvYXV0aG9yPjxhdXRob3I+Q2hpbW93aXR6LCBNLiBJLjwvYXV0aG9yPjxhdXRob3I+V2FyZmFy
aW4gQXNwaXJpbiBTeW1wdG9tYXRpYyBJbnRyYWNyYW5pYWwgRGlzZWFzZSBUcmlhbCwgSW52ZXN0
aWdhdG9yczwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRl
cGFydG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IG9mIFBlbm5zeWx2YW5pYSwgUGhpbGFk
ZWxwaGlhLCBQQSAxOTEwNCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlJpc2sg
ZmFjdG9ycyBhbmQgb3V0Y29tZSBvZiBwYXRpZW50cyB3aXRoIHN5bXB0b21hdGljIGludHJhY3Jh
bmlhbCBzdGVub3NpcyBwcmVzZW50aW5nIHdpdGggbGFjdW5hciBzdHJva2U8L3RpdGxlPjxzZWNv
bmRhcnktdGl0bGU+U3Ryb2tlPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+
PGZ1bGwtdGl0bGU+U3Ryb2tlPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTIzMC0z
PC9wYWdlcz48dm9sdW1lPjQzPC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PGtleXdvcmRzPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4gSXNjaGVtaWEvKmNvbXBsaWNhdGlv
bnMvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DYW5hZGE8L2tleXdvcmQ+PGtl
eXdvcmQ+Q29uc3RyaWN0aW9uLCBQYXRob2xvZ2ljL2NvbXBsaWNhdGlvbnMvcGh5c2lvcGF0aG9s
b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tl
eXdvcmQ+PGtleXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkludHJhY3JhbmlhbCBB
cnRlcmlhbCBEaXNlYXNlcy8qY29tcGxpY2F0aW9ucy8qcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3Jk
PjxrZXl3b3JkPkxvbmdpdHVkaW5hbCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tl
eXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJvZ25vc2lzPC9r
ZXl3b3JkPjxrZXl3b3JkPlByb3BvcnRpb25hbCBIYXphcmRzIE1vZGVsczwva2V5d29yZD48a2V5
d29yZD5SZWN1cnJlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwv
a2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+U3Ryb2tlLCBM
YWN1bmFyLypkaWFnbm9zaXMvKmVwaWRlbWlvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+
PGtleXdvcmQ+VW5pdGVkIFN0YXRlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y
MDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+
PGlzYm4+MTUyNC00NjI4IChFbGVjdHJvbmljKSYjeEQ7MDAzOS0yNDk5IChMaW5raW5nKTwvaXNi
bj48YWNjZXNzaW9uLW51bT4yMjM2MzA1NDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11
cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMjM2MzA1NDwvdXJs
PjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMzMzM2MDQxPC9jdXN0b20yPjxlbGVj
dHJvbmljLXJlc291cmNlLW51bT4xMC4xMTYxL1NUUk9LRUFIQS4xMTEuNjQxNjk2PC9lbGVjdHJv
bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA [13] which is surprising if MCA stenosis is supposed to be a common cause of lacunar stroke. A recent study also did not find any association between lacunar stroke and MCA stenosis.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48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=
ADDIN EN.CITE.DATA [14] A systematic review of Asian studies showed that parent artery atherosclerosis accounted for 20% of single lacunar infarcts in anterior circulation territory, however these hospital-based studies were rather small (n=71-118) and some were even retrospective. ADDIN EN.CITE <EndNote><Cite><Author>Kim</Author><Year>2013</Year><RecNum>21</RecNum><DisplayText>[15]</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463789611">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim, J. S.</author><author>Yoon, Y.</author></authors></contributors><auth-address>Stroke Center and Department of Neurology, University of Ulsan, Asan Medical Center, Seoul, South Korea. jongskim@amc.seoul.kr</auth-address><titles><title>Single subcortical infarction associated with parental arterial disease: important yet neglected sub-type of atherothrombotic stroke</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>197-203</pages><volume>8</volume><number>3</number><keywords><keyword>Cerebral Arteries/pathology</keyword><keyword>Cerebral Infarction/*etiology/pathology</keyword><keyword>Diagnosis, Differential</keyword><keyword>Humans</keyword><keyword>Intracranial Arteriosclerosis/*complications/pathology</keyword><keyword>Magnetic Resonance Angiography</keyword><keyword>Stroke/classification/*etiology/pathology</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1747-4949 (Electronic)
1747-4930 (Linking)</isbn><accession-num>22568537</accession-num><urls><related-urls><url>;[15] Larger and tubular lacunar infarcts might be more likely to be caused by proximal artery diseases. ADDIN EN.CITE <EndNote><Cite><Author>de Jong</Author><Year>2002</Year><RecNum>98</RecNum><DisplayText>[16]</DisplayText><record><rec-number>98</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468597089">98</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Jong, G.</author><author>Kessels, F.</author><author>Lodder, J.</author></authors></contributors><auth-address>Department of Neurology, Isala Clinics Location Weezenlanden, Zwolle, The Netherlands.</auth-address><titles><title>Two types of lacunar infarcts: further arguments from a study on prognosis</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>2072-6</pages><volume>33</volume><number>8</number><keywords><keyword>Arteriosclerosis/diagnosis/pathology</keyword><keyword>Brain/blood supply/pathology</keyword><keyword>Brain Infarction/*classification/*diagnosis/mortality/pathology</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Diagnosis, Differential</keyword><keyword>Disease-Free Survival</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Hypertension/complications</keyword><keyword>Logistic Models</keyword><keyword>Microcirculation/pathology</keyword><keyword>Odds Ratio</keyword><keyword>Prognosis</keyword><keyword>Prospective Studies</keyword><keyword>Recurrence</keyword><keyword>Risk Factors</keyword><keyword>Survival Rate</keyword><keyword>Tomography, X-Ray Computed</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2002</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>12154265</accession-num><urls><related-urls><url>;[16] However results of both our study and the Secondary Prevention of Small Subcortical Stokes Trial (SPS3) suggest that it is not possible to identify the cause of a particular recent lacunar ischaemic stroke based on its size, shape or location.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc2RhZ2hpPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc2RhZ2hpPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48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ADDIN EN.CITE.DATA [17, 18] Evidence for embolism as a common cause for lacunar ischaemic stroke is limited. Presence of cardioembolic sources was found significantly less often in lacunar than in non-lacunar ischaemic stroke.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWNrc29uPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWNrc29uPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48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ADDIN EN.CITE.DATA [19, 20] Few if any associations were found between ipsilateral carotid stenosis and lacunar ischaemic stroke or other features of CSVD.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3R0ZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3R0ZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
ZWNOdW0+MjY8L1JlY051bT48RGlzcGxheVRleHQ+WzIxLCAyMl08L0Rpc3BsYXlUZXh0PjxyZWNv
cmQ+PHJlYy1udW1iZXI+MjY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i
IGRiLWlkPSJwMjI1MGQ5eDR3MHd4cmV0eHMzcHoweDZyenZ3dndheHpkZHgiIHRpbWVzdGFtcD0i
MTQ2Mzc5MDAxNyI+MjY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h
bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlBv
dHRlciwgRy4gTS48L2F1dGhvcj48YXV0aG9yPkRvdWJhbCwgRi4gTi48L2F1dGhvcj48YXV0aG9y
PkphY2tzb24sIEMuIEEuPC9hdXRob3I+PGF1dGhvcj5TdWRsb3csIEMuIEwuPC9hdXRob3I+PGF1
dGhvcj5EZW5uaXMsIE0uIFMuPC9hdXRob3I+PGF1dGhvcj5XYXJkbGF3LCBKLiBNLjwvYXV0aG9y
PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIENsaW5p
Y2FsIE5ldXJvc2NpZW5jZXMsIEJyYWluIFJlc2VhcmNoIEltYWdpbmcgQ2VudHJlLCBVbml2ZXJz
aXR5IG9mIEVkaW5idXJnaCwgV2VzdGVybiBHZW5lcmFsIEhvc3BpdGFsLCBFZGluYnVyZ2gsIFVL
LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkxhY2sgb2YgYXNzb2NpYXRpb24gb2Ygd2hp
dGUgbWF0dGVyIGxlc2lvbnMgd2l0aCBpcHNpbGF0ZXJhbCBjYXJvdGlkIGFydGVyeSBzdGVub3Np
czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DZXJlYnJvdmFzYyBEaXM8L3NlY29uZGFyeS10aXRs
ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DZXJlYnJvdmFzYyBEaXM8L2Z1bGwt
dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4zNzgtODQ8L3BhZ2VzPjx2b2x1bWU+MzM8L3ZvbHVt
ZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5
d29yZD5CcmFpbi8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluIElzY2hlbWlhL3Bh
dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DYXJvdGlkIFN0ZW5vc2lzLypwYXRob2xvZ3kvdWx0
cmFzb25vZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5G
dW5jdGlvbmFsIExhdGVyYWxpdHkvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8
L2tleXdvcmQ+PGtleXdvcmQ+SW1hZ2UgUHJvY2Vzc2luZywgQ29tcHV0ZXItQXNzaXN0ZWQ8L2tl
eXdvcmQ+PGtleXdvcmQ+SXNjaGVtaWMgQXR0YWNrLCBUcmFuc2llbnQvcGF0aG9sb2d5PC9rZXl3
b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJlc29uYW5jZSBJbWFnaW5nPC9rZXl3b3JkPjxrZXl3b3Jk
Pk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJv
c3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+
PGtleXdvcmQ+U3Ryb2tlL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5UaHJvbWJvZW1ib2xp
c20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlZhc2N1bGFyIERpc2Vhc2VzL2VwaWRlbWlv
bG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjwvZGF0ZXM+
PGlzYm4+MTQyMS05Nzg2IChFbGVjdHJvbmljKSYjeEQ7MTAxNS05NzcwIChMaW5raW5nKTwvaXNi
bj48YWNjZXNzaW9uLW51bT4yMjQzMzI4NTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11
cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMjQzMzI4NTwvdXJs
PjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0MDY3NzExPC9jdXN0b20yPjxlbGVj
dHJvbmljLXJlc291cmNlLW51bT4xMC4xMTU5LzAwMDMzNjc2MjwvZWxlY3Ryb25pYy1yZXNvdXJj
ZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+S3dvbjwvQXV0aG9yPjxZZWFyPjIw
MTY8L1llYXI+PFJlY051bT4yNzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+Mjc8L3JlYy1u
dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJwMjI1MGQ5eDR3MHd4cmV0
eHMzcHoweDZyenZ3dndheHpkZHgiIHRpbWVzdGFtcD0iMTQ2Mzc5MDA3NCI+Mjc8L2tleT48L2Zv
cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+
PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkt3b24sIEguIE0uPC9hdXRob3I+PGF1dGhv
cj5MeW5uLCBNLiBKLjwvYXV0aG9yPjxhdXRob3I+VHVyYW4sIFQuIE4uPC9hdXRob3I+PGF1dGhv
cj5EZXJkZXluLCBDLiBQLjwvYXV0aG9yPjxhdXRob3I+RmlvcmVsbGEsIEQuPC9hdXRob3I+PGF1
dGhvcj5MYW5lLCBCLiBGLjwvYXV0aG9yPjxhdXRob3I+TW9udGdvbWVyeSwgSi48L2F1dGhvcj48
YXV0aG9yPkphbmlzLCBMLiBTLjwvYXV0aG9yPjxhdXRob3I+UnVtYm9sZHQsIFouPC9hdXRob3I+
PGF1dGhvcj5DaGltb3dpdHosIE0uIEkuPC9hdXRob3I+PGF1dGhvcj5TYW1tcHJpcyBJbnZlc3Rp
Z2F0b3JzPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVw
YXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFNlb3VsIE1ldHJvcG9saXRhbiBHb3Zlcm5tZW50LVNlb3Vs
IE5hdGlvbmFsIFVuaXZlcnNpdHkgQm9yYW1hZSBNZWRpY2FsIENlbnRlciwgU2VvdWwsIEtvcmVh
LiYjeEQ7RGVwYXJ0bWVudCBvZiBCaW9zdGF0aXN0aWNzIGFuZCBCaW9pbmZvbWF0aWNzLCBSb2xs
aW5zIFNjaG9vbCBvZiBQdWJsaWMgSGVhbHRoLCBFbW9yeSBVbml2ZXJzaXR5LCBBdGxhbnRhLCBH
ZW9yZ2lhLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBNZWRpY2FsIFVuaXZlcnNp
dHkgb2YgU291dGggQ2Fyb2xpbmEgU3Ryb2tlIFByb2dyYW0sIENoYXJsZXN0b24uJiN4RDtEZXBh
cnRtZW50IG9mIE5ldXJvbG9neSBhbmQgTmV1cm9zdXJnZXJ5LCBTY2hvb2wgb2YgTWVkaWNpbmUs
IFdhc2hpbmd0b24gVW5pdmVyc2l0eSwgU3QgTG91aXMsIE1pc3NvdXJpLiYjeEQ7RGVwYXJ0bWVu
dCBvZiBOZXVyb3N1cmdlcnksIFN0YXRlIFVuaXZlcnNpdHkgb2YgTmV3IFlvcmssIFN0b255IEJy
b29rLiYjeEQ7Q2xpbmljYWwgUmVzZWFyY2ggQ2VudGVyLCBNb3JlaG91c2UgU2Nob29sIG9mIE1l
ZGljaW5lLCBBdGxhbnRhLCBHZW9yZ2lhLiYjeEQ7TmF0aW9uYWwgSW5zdGl0dXRlIG9mIE5ldXJv
bG9naWNhbCBEaXNvcmRlcnMgYW5kIFN0cm9rZSwgTmF0aW9uYWwgSW5zdGl0dXRlcyBvZiBIZWFs
dGgsIEJldGhlc2RhLCBNYXJ5bGFuZC4mI3hEO0RlcGFydG1lbnQgb2YgUmFkaW9sb2d5LCBNZWRp
Y2FsIFVuaXZlcnNpdHkgb2YgU291dGggQ2Fyb2xpbmEgU3Ryb2tlIFByb2dyYW0sIENoYXJsZXN0
b24uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RnJlcXVlbmN5LCBSaXNrIEZhY3RvcnMs
IGFuZCBPdXRjb21lIG9mIENvZXhpc3RlbnQgU21hbGwgVmVzc2VsIERpc2Vhc2UgYW5kIEludHJh
Y3JhbmlhbCBBcnRlcmlhbCBTdGVub3NpczogUmVzdWx0cyBGcm9tIHRoZSBTdGVudGluZyBhbmQg
QWdncmVzc2l2ZSBNZWRpY2FsIE1hbmFnZW1lbnQgZm9yIFByZXZlbnRpbmcgUmVjdXJyZW50IFN0
cm9rZSBpbiBJbnRyYWNyYW5pYWwgU3Rlbm9zaXMgKFNBTU1QUklTKSBUcmlhbDwvdGl0bGU+PHNl
Y29uZGFyeS10aXRsZT5KQU1BIE5ldXJvbDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp
b2RpY2FsPjxmdWxsLXRpdGxlPkpBTUEgTmV1cm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48
cGFnZXM+MzYtNDI8L3BhZ2VzPjx2b2x1bWU+NzM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48
a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBTbWFsbCBW
ZXNzZWwgRGlzZWFzZXMvZGlhZ25vc2lzLyplcGlkZW1pb2xvZ3kvdGhlcmFweTwva2V5d29yZD48
a2V5d29yZD5Db21vcmJpZGl0eTwva2V5d29yZD48a2V5d29yZD4qRGlzZWFzZSBNYW5hZ2VtZW50
PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5Gb2xsb3ctVXAgU3R1
ZGllczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW50cmFjcmFu
aWFsIEFydGVyaW9zY2xlcm9zaXMvZGlhZ25vc2lzLyplcGlkZW1pb2xvZ3kvdGhlcmFweTwva2V5
d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3Jk
PjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmVjdXJyZW5j
ZTwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+KlN0ZW50
czwva2V5d29yZD48a2V5d29yZD5TdHJva2UvZGlhZ25vc2lzLyplcGlkZW1pb2xvZ3kvcHJldmVu
dGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9r
ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0
ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4yMTY4LTYxNTcgKEVsZWN0cm9u
aWMpJiN4RDsyMTY4LTYxNDkgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NjE4NTM0
PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmku
bmxtLm5paC5nb3YvcHVibWVkLzI2NjE4NTM0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxl
bGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDAxL2phbWFuZXVyb2wuMjAxNS4zMTQ1PC9lbGVj
dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE.DATA [21, 22] In primate models, less than 6% of emboli injected into carotid arteries entered the lenticulostriate arteries, while the majority entered cortical arteries. ADDIN EN.CITE <EndNote><Cite><Author>Macdonald</Author><Year>1995</Year><RecNum>28</RecNum><DisplayText>[23]</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463790171">28</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Macdonald, R. L.</author><author>Kowalczuk, A.</author><author>Johns, L.</author></authors></contributors><auth-address>Department of Surgery, University of Chicago Medical Center, IL 60637, USA.</auth-address><titles><title>Emboli enter penetrating arteries of monkey brain in relation to their size</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>1247-50; discussion 1250-1</pages><volume>26</volume><number>7</number><keywords><keyword>Acrylic Resins</keyword><keyword>Animals</keyword><keyword>Basilar Artery/pathology</keyword><keyword>Brain/pathology</keyword><keyword>Carotid Artery, Internal/pathology</keyword><keyword>Cerebral Arteries/*pathology</keyword><keyword>Cerebral Infarction/pathology</keyword><keyword>Cerebrovascular Circulation</keyword><keyword>Image Processing, Computer-Assisted</keyword><keyword>Injections, Intra-Arterial</keyword><keyword>Intracranial Embolism and Thrombosis/*pathology</keyword><keyword>Macaca fascicularis</keyword><keyword>Microspheres</keyword><keyword>Particle Size</keyword><keyword>Polymers</keyword><keyword>Sepharose</keyword><keyword>Triazines</keyword></keywords><dates><year>1995</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0039-2499 (Print)
0039-2499 (Linking)</isbn><accession-num>7604423</accession-num><urls><related-urls><url>;[23] Lacunar ischaemic stroke in the basal ganglia were marginally more often associated with embolism than those in the centrum semiovale (11% vs 3% respectively), but the overall rate of known embolic sources in symptomatic lacunar ischaemic stroke was very low (11%).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZWwgQmVuZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZWwgQmVuZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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ADDIN EN.CITE.DATA [18] Intrinsic small vessel pathologies remain the most common cause of lacunar ischaemic stroke, although the underlying mechanism is unclear. Fisher attributed the lipohyalinosis in small arteries to hypertension. However, the diagnosis and treatment of hypertension were less good when Fisher was working in the 1950s and 1960s and he may have seen some particularly severe cases of hypertension. Now, epidemiology data show that hypertension is equally common in non-lacunar as in lacunar ischaemic stroke; ADDIN EN.CITE <EndNote><Cite><Author>Jackson</Author><Year>2010</Year><RecNum>24</RecNum><DisplayText>[19]</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463789910">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jackson, C. A.</author><author>Hutchison, A.</author><author>Dennis, M. S.</author><author>Wardlaw, J. M.</author><author>Lindgren, A.</author><author>Norrving, B.</author><author>Anderson, C. S.</author><author>Hankey, G. J.</author><author>Jamrozik, K.</author><author>Appelros, P.</author><author>Sudlow, C. L.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, University of Edinburgh, United Kingdom.</auth-address><titles><title>Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy?</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>624-9</pages><volume>41</volume><number>4</number><keywords><keyword>Aged</keyword><keyword>*Brain/anatomy & histology/pathology</keyword><keyword>*Brain Infarction/classification/epidemiology/pathology</keyword><keyword>*Brain Ischemia/classification/epidemiology/pathology</keyword><keyword>Cerebral Arteries/*pathology</keyword><keyword>Cerebrovascular Circulation</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Registries</keyword><keyword>Risk Factors</keyword><keyword>*Stroke/classification/epidemiology/pathology</keyword></keywords><dates><year>2010</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>20150553</accession-num><urls><related-urls><url>;[19] and many lacunar stroke patients are normotensive. Similarly, other traditional risk factors like diabetes mellitus, hypercholesterolaemia and smoking were as frequent in lacunar stroke as in other ischaemic strokes. ADDIN EN.CITE <EndNote><Cite><Author>Jackson</Author><Year>2005</Year><RecNum>99</RecNum><DisplayText>[24]</DisplayText><record><rec-number>99</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468597991">99</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jackson, C.</author><author>Sudlow, C.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, University of Edinburgh, United Kingdom.</auth-address><titles><title>Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and nonlacunar infarcts</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>891-901</pages><volume>36</volume><number>4</number><keywords><keyword>Aged</keyword><keyword>Atrial Fibrillation/complications</keyword><keyword>Blood Pressure</keyword><keyword>Brain Infarction/*diagnosis/pathology</keyword><keyword>Carotid Stenosis/complications</keyword><keyword>Diabetes Complications/diagnosis</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hypertension/complications</keyword><keyword>Ischemia</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Risk</keyword><keyword>Risk Factors</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Stroke/*diagnosis/pathology</keyword></keywords><dates><year>2005</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>15761206</accession-num><urls><related-urls><url>;[24] Risk factor profiles of lacunar stroke seemed different in China, but it might be too early to say so. The Beijing stroke registry (n=1184) showed a higher proportion of hypertension in lacunar (acute stroke symptoms + subcortical lesion <2 cm diameter on acute CT/MRI) than in non-lacunar stroke after adjusting for age and gender. ADDIN EN.CITE <EndNote><Cite><Author>Fang</Author><Year>2012</Year><RecNum>30</RecNum><DisplayText>[3]</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463790458">30</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fang, X. H.</author><author>Wang, W. H.</author><author>Zhang, X. Q.</author><author>Liu, H. J.</author><author>Zhang, H. M.</author><author>Qin, X. M.</author><author>Wang, Z. C.</author><author>Ji, X. M.</author><author>Li, L. M.</author></authors></contributors><auth-address>Department of Evidence-based Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.</auth-address><titles><title>Incidence and survival of symptomatic lacunar infarction in a Beijing population: a 6-year prospective study</title><secondary-title>Eur J Neurol</secondary-title></titles><periodical><full-title>Eur J Neurol</full-title></periodical><pages>1114-20</pages><volume>19</volume><number>8</number><keywords><keyword>Adult</keyword><keyword>Age Distribution</keyword><keyword>Aged</keyword><keyword>China/epidemiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Sex Distribution</keyword><keyword>Stroke, Lacunar/*epidemiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1468-1331 (Electronic)
1351-5101 (Linking)</isbn><accession-num>22494183</accession-num><urls><related-urls><url>;[3] Some other studies had similar findings, but the stroke diagnosis varied: in some studies the differentiation between lacunar stroke and “large artery atherosclerosis” stroke relied only on lesion size, and clinical classification included risk factors.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl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ADDIN EN.CITE.DATA [25, 26] Additionally, most studies were hospital-based. Hence population-scale data on lacunar stroke are lacking. It is important to distinguish lacunar stroke from other subtypes because the mechanism, hence prevention and treatment might differ. More data and careful separation of lacunar stroke from other subtypes are required in future studies. Clinically ‘Silent CSVD’White matter hyperintensitiesWMH of presumed vascular origin are very common in older individuals and regarded as typical signs of CSVD. Symptoms of WMH develop insidiously, such as cognitive impairment, dementia and depression; ADDIN EN.CITE <EndNote><Cite><Author>Pantoni</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463785719">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pantoni, L.</author></authors></contributors><auth-address>Department of Neurological and Psychiatric Sciences, University of Florence, Italy. pantoni@unifi.it</auth-address><titles><title>Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>689-701</pages><volume>9</volume><number>7</number><keywords><keyword>Age Factors</keyword><keyword>Anticoagulants/therapeutic use</keyword><keyword>Blood Vessels/*pathology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cerebrovascular Disorders/classification/*etiology/*pathology/*therapy</keyword><keyword>Cognition Disorders/physiopathology</keyword><keyword>Diagnostic Imaging/methods</keyword><keyword>Endarterectomy, Carotid/methods</keyword><keyword>Humans</keyword><keyword>Thrombolytic Therapy/methods</keyword></keywords><dates><year>2010</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1474-4465 (Electronic)
1474-4422 (Linking)</isbn><accession-num>20610345</accession-num><urls><related-urls><url>(10)70104-6</electronic-resource-num></record></Cite></EndNote>[1] but it almost triples the risk of stroke, doubles the risk of dementia and increases the risk of death. ADDIN EN.CITE <EndNote><Cite><Author>Debette</Author><Year>2010</Year><RecNum>32</RecNum><DisplayText>[27]</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463791069">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Debette, S.</author><author>Markus, H. S.</author></authors></contributors><auth-address>Clinical Neuroscience, St George's University of London, London. sdebette@bu.edu</auth-address><titles><title>The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis</title><secondary-title>BMJ</secondary-title></titles><periodical><full-title>BMJ</full-title></periodical><pages>c3666</pages><volume>341</volume><keywords><keyword>Cerebrovascular Disorders/*pathology</keyword><keyword>Cognition Disorders/*pathology/prevention & control</keyword><keyword>Dementia, Vascular/pathology/prevention & control</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Longitudinal Studies</keyword><keyword>Magnetic Resonance Angiography</keyword><keyword>Microcirculation</keyword><keyword>Prognosis</keyword><keyword>Risk Factors</keyword><keyword>Stroke/pathology/prevention & control</keyword></keywords><dates><year>2010</year></dates><isbn>1756-1833 (Electronic)
0959-535X (Linking)</isbn><accession-num>20660506</accession-num><urls><related-urls><url>;[27] WMH are usually symmetrically and bilaterally distributed in white matter including pons and brain stem, and also occur in deep grey matter. They appear hyperintense to normal brain on T2 or FLAIR MRI,(Figure 1) and can be patchy or confluent depending on their stage in development and severity. Due to limited pathology studies the underlying pathology of WMH remains imprecise. Demyelination, loss of oligodendrocytes and axonal damage were often reported. Diffusion tensor imaging (DTI) studies provided indirect evidence for axonal damage and impaired white matter integrity in WMH. ADDIN EN.CITE <EndNote><Cite><Author>Madden</Author><Year>2012</Year><RecNum>35</RecNum><DisplayText>[28]</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463791493">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Madden, D. J.</author><author>Bennett, I. J.</author><author>Burzynska, A.</author><author>Potter, G. G.</author><author>Chen, N. K.</author><author>Song, A. W.</author></authors></contributors><auth-address>Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC 27710, USA. madden@biac.duke.edu</auth-address><titles><title>Diffusion tensor imaging of cerebral white matter integrity in cognitive aging</title><secondary-title>Biochim Biophys Acta</secondary-title></titles><periodical><full-title>Biochim Biophys Acta</full-title></periodical><pages>386-400</pages><volume>1822</volume><number>3</number><keywords><keyword>Age Factors</keyword><keyword>Cerebrum/pathology/*physiology</keyword><keyword>Cognition/*physiology</keyword><keyword>Cognition Disorders/*pathology</keyword><keyword>Diffusion Tensor Imaging/methods</keyword><keyword>Humans</keyword><keyword>Nerve Fibers, Myelinated/*pathology</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0006-3002 (Print)
0006-3002 (Linking)</isbn><accession-num>21871957</accession-num><urls><related-urls><url>;[28] Indeed, recent evidence indicates that WMH are rather heterogeneous, perhaps reflecting different disease stages. Reduced density of glia and vacuolation were observed in severe WMH suggesting end stage disease. ADDIN EN.CITE <EndNote><Cite><Author>Munoz</Author><Year>1993</Year><RecNum>34</RecNum><DisplayText>[29]</DisplayText><record><rec-number>34</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463791281">34</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Munoz, D. G.</author><author>Hastak, S. M.</author><author>Harper, B.</author><author>Lee, D.</author><author>Hachinski, V. C.</author></authors></contributors><auth-address>Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada.</auth-address><titles><title>Pathologic correlates of increased signals of the centrum ovale on magnetic resonance imaging</title><secondary-title>Arch Neurol</secondary-title></titles><periodical><full-title>Arch Neurol</full-title></periodical><pages>492-7</pages><volume>50</volume><number>5</number><keywords><keyword>Aged</keyword><keyword>Cerebral Cortex/blood supply/*pathology</keyword><keyword>Cerebral Hemorrhage/pathology</keyword><keyword>Cerebral Infarction/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Vacuoles/pathology</keyword></keywords><dates><year>1993</year><pub-dates><date>May</date></pub-dates></dates><isbn>0003-9942 (Print)
0003-9942 (Linking)</isbn><accession-num>8489405</accession-num><urls><related-urls><url>;[29] Autopsy MRI studies also found oedema that suggests leakage of fluid from impaired blood brain barrier (BBB) in and around WMH.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZWlnaW48L0F1dGhvcj48WWVhcj4xOTYzPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZWlnaW48L0F1dGhvcj48WWVhcj4xOTYzPC9ZZWFyPjxS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ADDIN EN.CITE.DATA [30, 31] Although these ‘white’ lesions have until now been treated as if they were all the same, different degrees of ‘whiteness’ might indicate different ‘stages of formation’ - some very white WMH are probably at the end stage of disease and irreversible once demyelination or axonal damage have happened; some perhaps less white lesions might be reversible if they are mainly interstitial fluid imbalances before permanent tissue damage has occurred. These observations remain to be confirmed in larger studies. These microstructural changes not only happen in WMH, but are also present in normal appearing white matter (NAWM).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5pZWdhPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5pZWdhPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48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ADDIN EN.CITE.DATA [32, 33] The white matter integrity in NAWM declines with increasing closeness to the edge of WMHPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5pZWdhPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5pZWdhPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48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ADDIN EN.CITE.DATA [32] and with more severe WMHPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWlsbGFyZDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWlsbGFyZDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA [34]. Multiple mechanisms underlying WMH such as incomplete infarct, chronic hypoperfusion and venous collagenous have been proposed but evidence for each is limited. In a pathology study (n=15), no incomplete infarct was found in WMH. ADDIN EN.CITE <EndNote><Cite><Author>Munoz</Author><Year>1993</Year><RecNum>34</RecNum><DisplayText>[29]</DisplayText><record><rec-number>34</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463791281">34</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Munoz, D. G.</author><author>Hastak, S. M.</author><author>Harper, B.</author><author>Lee, D.</author><author>Hachinski, V. C.</author></authors></contributors><auth-address>Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada.</auth-address><titles><title>Pathologic correlates of increased signals of the centrum ovale on magnetic resonance imaging</title><secondary-title>Arch Neurol</secondary-title></titles><periodical><full-title>Arch Neurol</full-title></periodical><pages>492-7</pages><volume>50</volume><number>5</number><keywords><keyword>Aged</keyword><keyword>Cerebral Cortex/blood supply/*pathology</keyword><keyword>Cerebral Hemorrhage/pathology</keyword><keyword>Cerebral Infarction/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Vacuoles/pathology</keyword></keywords><dates><year>1993</year><pub-dates><date>May</date></pub-dates></dates><isbn>0003-9942 (Print)
0003-9942 (Linking)</isbn><accession-num>8489405</accession-num><urls><related-urls><url>;[29] Though many cross-sectional studies have found low cerebral blood flow (CBF) associated with higher WMH burden, the causality between low CBF and WMH is unclear. ADDIN EN.CITE <EndNote><Cite><Author>Shi</Author><Year>Published online first: 5 August 2016 </Year><RecNum>96</RecNum><DisplayText>[35]</DisplayText><record><rec-number>96</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468574466">96</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shi, Y.</author><author>Thrippleton, M. J.</author><author>Makin, S. D.</author><author>Marshall, I.</author><author>Geerlings, M. J.</author><author>de Craen, A. J. M.</author><author>van Buchem, M. A.</author><author>Wardlaw, J. M.</author></authors></contributors><titles><title>Cerebral blood flow in small vessel disease: a systematic review and meta-analysis</title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><volume>DOI: 10.1177/0271678X16662891.</volume><dates><year>Published online first: 5 August 2016 </year></dates><urls></urls></record></Cite></EndNote>[35] A longitudinal study (n=575) showed that more severe baseline WMH predated CBF decline over time rather than falling CBF predating WMH progression.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZlZW48L0F1dGhvcj48WWVhcj4yMDE1PC9Z
ZWFyPjxSZWNOdW0+NDI8L1JlY051bT48RGlzcGxheVRleHQ+WzM2XTwvRGlzcGxheVRleHQ+PHJl
Y29yZD48cmVjLW51bWJlcj40MjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF
TiIgZGItaWQ9InAyMjUwZDl4NHcwd3hyZXR4czNwejB4NnJ6dnd2d2F4emRkeCIgdGltZXN0YW1w
PSIxNDYzNzkyOTY0Ij40Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy
bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+
dmFuIGRlciBWZWVuLCBQLiBILjwvYXV0aG9yPjxhdXRob3I+TXVsbGVyLCBNLjwvYXV0aG9yPjxh
dXRob3I+VmluY2tlbiwgSy4gTC48L2F1dGhvcj48YXV0aG9yPkhlbmRyaWtzZSwgSi48L2F1dGhv
cj48YXV0aG9yPk1hbGksIFcuIFAuPC9hdXRob3I+PGF1dGhvcj52YW4gZGVyIEdyYWFmLCBZLjwv
YXV0aG9yPjxhdXRob3I+R2VlcmxpbmdzLCBNLiBJLjwvYXV0aG9yPjxhdXRob3I+U21hcnQgU3R1
ZHkgR3JvdXA8L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5G
cm9tIHRoZSBEZXBhcnRtZW50IG9mIFJhZGlvbG9neSAoUC5ILnYuZC5WLiwgSi5ILiwgVy5QLlQu
TS5NLiksIEp1bGl1cyBDZW50ZXIgZm9yIEhlYWx0aCBTY2llbmNlcyBhbmQgUHJpbWFyeSBDYXJl
IChQLkgudi5kLlYuLCBNLk0uLCBZLnYuZC5HLiwgTS5JLkcuKSwgYW5kIEltYWdlIFNjaWVuY2Vz
IEluc3RpdHV0ZSAoSy5MLlYuKSwgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciBVdHJlY2h0LCBV
dHJlY2h0LCBUaGUgTmV0aGVybGFuZHM7IGFuZCBEZXBhcnRtZW50IG9mIEdlcm9udG9sb2d5IGFu
ZCBHZXJpYXRyaWNzLCBMZWlkZW4gVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRlciwgTGVpZGVuLCBU
aGUgTmV0aGVybGFuZHMgKE0uTS4pLiYjeEQ7RnJvbSB0aGUgRGVwYXJ0bWVudCBvZiBSYWRpb2xv
Z3kgKFAuSC52LmQuVi4sIEouSC4sIFcuUC5ULk0uTS4pLCBKdWxpdXMgQ2VudGVyIGZvciBIZWFs
dGggU2NpZW5jZXMgYW5kIFByaW1hcnkgQ2FyZSAoUC5ILnYuZC5WLiwgTS5NLiwgWS52LmQuRy4s
IE0uSS5HLiksIGFuZCBJbWFnZSBTY2llbmNlcyBJbnN0aXR1dGUgKEsuTC5WLiksIFVuaXZlcnNp
dHkgTWVkaWNhbCBDZW50ZXIgVXRyZWNodCwgVXRyZWNodCwgVGhlIE5ldGhlcmxhbmRzOyBhbmQg
RGVwYXJ0bWVudCBvZiBHZXJvbnRvbG9neSBhbmQgR2VyaWF0cmljcywgTGVpZGVuIFVuaXZlcnNp
dHkgTWVkaWNhbCBDZW50ZXIsIExlaWRlbiwgVGhlIE5ldGhlcmxhbmRzIChNLk0uKS4gbS5nZWVy
bGluZ3NAdW1jdXRyZWNodC5ubC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Mb25naXR1
ZGluYWwgcmVsYXRpb25zaGlwIGJldHdlZW4gY2VyZWJyYWwgc21hbGwtdmVzc2VsIGRpc2Vhc2Ug
YW5kIGNlcmVicmFsIGJsb29kIGZsb3c6IHRoZSBzZWNvbmQgbWFuaWZlc3RhdGlvbnMgb2YgYXJ0
ZXJpYWwgZGlzZWFzZS1tYWduZXRpYyByZXNvbmFuY2Ugc3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnkt
dGl0bGU+U3Ryb2tlPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt
dGl0bGU+U3Ryb2tlPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTIzMy04PC9wYWdl
cz48dm9sdW1lPjQ2PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3Jk
PkFnZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2Vy
ZWJyYWwgQXJ0ZXJpYWwgRGlzZWFzZXMvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y
ZD5DZXJlYnJhbCBTbWFsbCBWZXNzZWwgRGlzZWFzZXMvKnBoeXNpb3BhdGhvbG9neTwva2V5d29y
ZD48a2V5d29yZD4qQ2VyZWJyb3Zhc2N1bGFyIENpcmN1bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk
PkNvaG9ydCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29y
ZD5Gb2xsb3ctVXAgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl
eXdvcmQ+TG9uZ2l0dWRpbmFsIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVz
b25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5N
aWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Qcm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3Jk
PjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5TZXggRmFjdG9yczwva2V5
d29yZD48a2V5d29yZD5TdHJva2UsIExhY3VuYXIvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk
PldoaXRlIE1hdHRlci9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+YXRoZXJvc2NsZXJvc2lz
PC9rZXl3b3JkPjxrZXl3b3JkPmNlcmVicmFsIHNtYWxsIHZlc3NlbCBkaXNlYXNlPC9rZXl3b3Jk
Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXk8
L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI0LTQ2MjggKEVsZWN0cm9uaWMpJiN4
RDswMDM5LTI0OTkgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1ODA0OTI0PC9hY2Nl
c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5p
aC5nb3YvcHVibWVkLzI1ODA0OTI0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv
bmljLXJlc291cmNlLW51bT4xMC4xMTYxL1NUUk9LRUFIQS4xMTQuMDA4MDMwPC9lbGVjdHJvbmlj
LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZlZW48L0F1dGhvcj48WWVhcj4yMDE1PC9Z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ADDIN EN.CITE.DATA [36] In post-mortem study, some non-inflammatory, periventricular venulopathy were observed in periventricular WMH, suggesting that venous collagenosis might cause tissue damage by vasogenic oedema and impede interstitial fluid circulation. ADDIN EN.CITE <EndNote><Cite><Author>Black</Author><Year>2009</Year><RecNum>43</RecNum><DisplayText>[31]</DisplayText><record><rec-number>43</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463793058">43</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Black, S.</author><author>Gao, F.</author><author>Bilbao, J.</author></authors></contributors><auth-address>FRCP(C), Brill Professor of Neurology, Cognitive Neurology, A421, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5. sandra.black@sunnybrook.ca</auth-address><titles><title>Understanding white matter disease: imaging-pathological correlations in vascular cognitive impairment</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>S48-52</pages><volume>40</volume><number>3 Suppl</number><keywords><keyword>Aging/*pathology</keyword><keyword>Alzheimer Disease/pathology</keyword><keyword>Cognition Disorders/*pathology</keyword><keyword>Dementia, Vascular/*pathology</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Magnetic Resonance Spectroscopy</keyword><keyword>Positron-Emission Tomography</keyword></keywords><dates><year>2009</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>19064767</accession-num><urls><related-urls><url>;[31] However this theory remains to be confirmed in in vivo studies. Impaired BBB was noted in WMH areas in autopsies,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdW5vejwvQXV0aG9yPjxZZWFyPjE5OTM8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdW5vejwvQXV0aG9yPjxZZWFyPjE5OTM8L1llYXI+PFJl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ADDIN EN.CITE.DATA [29, 30] which was corroborated by studies using cerebrospinal fluid (CSF)/plasma albumin ratio ADDIN EN.CITE <EndNote><Cite><Author>Farrall</Author><Year>2009</Year><RecNum>103</RecNum><DisplayText>[37]</DisplayText><record><rec-number>103</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468790051">103</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Farrall, A. J.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK. Andrew.Farrall@ed.ac.uk</auth-address><titles><title>Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis</title><secondary-title>Neurobiol Aging</secondary-title></titles><periodical><full-title>Neurobiol Aging</full-title></periodical><pages>337-52</pages><volume>30</volume><number>3</number><keywords><keyword>*Aging/physiology</keyword><keyword>Alzheimer Disease/metabolism/physiopathology</keyword><keyword>Animals</keyword><keyword>Blood-Brain Barrier/*metabolism/*physiopathology</keyword><keyword>Capillary Permeability/physiology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cerebrovascular Disorders/metabolism/physiopathology</keyword><keyword>Dementia, Vascular/metabolism/physiopathology</keyword><keyword>Humans</keyword><keyword>Microvessels/*metabolism/*physiopathology</keyword></keywords><dates><year>2009</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1558-1497 (Electronic)
0197-4580 (Linking)</isbn><accession-num>17869382</accession-num><urls><related-urls><url>;[37] and MRIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA [38-41]. It is hypothesized that the disrupted BBB would result in leakage of fluid, plasma components and cells and eventually lead to perivascular inflammation, demyelination and gliosis. Indeed, the formation of WMH is likely to be multi-factorial. Hypoperfusion, venous pathologies and BBB impairment might all play critical roles in WMH initiation or progression and interact with each other, but which one is the key initial factor remains unknown. LacunesThe term “lacune” was used by Fisher to describe a small fluid cavity in the brain which he thought was a healed lacunar infarct. Therefore in CSVD research, it is very common that terms like “lacunar infarction”, “lacunar stroke”, “silent brain infarct” were used to refer to the CSF-filled cavities on brain MRI or autopsy. ADDIN EN.CITE <EndNote><Cite><Author>Potter</Author><Year>2011</Year><RecNum>11</RecNum><DisplayText>[42]</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463787790">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Potter, G. M.</author><author>Marlborough, F. J.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK.</auth-address><titles><title>Wide variation in definition, detection, and description of lacunar lesions on imaging</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>359-66</pages><volume>42</volume><number>2</number><keywords><keyword>Brain Infarction/*classification/*diagnosis</keyword><keyword>Diagnostic Imaging/*methods/*standards</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/methods/standards</keyword><keyword>Random Allocation</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>21193752</accession-num><urls><related-urls><url>;[42] In fact, lacunes are not always “ischaemic”. They can also be the residual lesion of a small haemorrhage. ADDIN EN.CITE <EndNote><Cite><Author>Franke</Author><Year>1991</Year><RecNum>14</RecNum><DisplayText>[43]</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463788062">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Franke, C. L.</author><author>van Swieten, J. C.</author><author>van Gijn, J.</author></authors></contributors><auth-address>Department of Neurology, De Wever-Ziekenhuis, Heerlen, The Netherlands.</auth-address><titles><title>Residual lesions on computed tomography after intracerebral hemorrhage</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>1530-3</pages><volume>22</volume><number>12</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Basal Ganglia/radiography</keyword><keyword>Caudate Nucleus/radiography</keyword><keyword>Cerebral Hemorrhage/*radiography</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Putamen/radiography</keyword><keyword>Rupture, Spontaneous</keyword><keyword>Thalamus/radiography</keyword><keyword>*Tomography, X-Ray Computed</keyword></keywords><dates><year>1991</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0039-2499 (Print)
0039-2499 (Linking)</isbn><accession-num>1962328</accession-num><urls><related-urls><url>;[43] (Figure 3) Also it is common that many non-cavitated lacunar ischaemic strokes were not counted as ‘lacunar infarcts’. Therefore, in order to avoid more confusion, the term “lacune of presumed vascular origin” was proposed to replace “lacune” and the term ‘lacunar infarct’ should NOT be used to describe ‘lacunes’ any more. Lacunes of presumed vascular origin are round or ovoid, subcortical, fluid-filled cavities, with a diameter of 3-15 mm. These can occur without any prior symptoms, but can also result from a previous acute small subcortical infarct or haemorrhage.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA [4] (Figure 1) PVS could also mimic lacunes when they are more than 3 mm in diameter.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXJuYW5kZXogTWRlbDwvQXV0aG9yPjxZZWFyPjIwMTM8
L1llYXI+PFJlY051bT44ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNDRdPC9EaXNwbGF5VGV4dD48
cmVjb3JkPjxyZWMtbnVtYmVyPjg4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9
IkVOIiBkYi1pZD0icDIyNTBkOXg0dzB3eHJldHhzM3B6MHg2cnp2d3Z3YXh6ZGR4IiB0aW1lc3Rh
bXA9IjE0NjgzOTk2MjEiPjg4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv
dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv
cj5IZXJuYW5kZXogTWRlbCwgQy48L2F1dGhvcj48YXV0aG9yPlBpcGVyLCBSLiBKLjwvYXV0aG9y
PjxhdXRob3I+V2FuZywgWC48L2F1dGhvcj48YXV0aG9yPkRlYXJ5LCBJLiBKLjwvYXV0aG9yPjxh
dXRob3I+V2FyZGxhdywgSi4gTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1
dGgtYWRkcmVzcz5CcmFpbiBSZXNlYXJjaCBJbWFnaW5nIENlbnRyZSwgRGVwYXJ0bWVudCBvZiBO
ZXVyb2ltYWdpbmcgU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2YgRWRpbmJ1cmdoLCBFZGluYnVyZ2gs
IFVuaXRlZCBLaW5nZG9tOyBDZW50cmUgZm9yIENvZ25pdGl2ZSBBZ2VpbmcgYW5kIENvZ25pdGl2
ZSBFcGlkZW1pb2xvZ3kgKENDQUNFKSwgVW5pdmVyc2l0eSBvZiBFZGluYnVyZ2gsIEVkaW5idXJn
aCwgVW5pdGVkIEtpbmdkb207IFNJTkFQU0UgKFNjb3R0aXNoIEltYWdpbmcgTmV0d29yaywgQSBQ
bGF0Zm9ybSBmb3IgU2NpZW50aWZpYyBFeGNlbGxlbmNlKSBjb2xsYWJvcmF0aW9uLCBTY290bGFu
ZCwgVW5pdGVkIEtpbmdkb20uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VG93YXJkcyB0
aGUgYXV0b21hdGljIGNvbXB1dGF0aW9uYWwgYXNzZXNzbWVudCBvZiBlbmxhcmdlZCBwZXJpdmFz
Y3VsYXIgc3BhY2VzIG9uIGJyYWluIG1hZ25ldGljIHJlc29uYW5jZSBpbWFnZXM6IGEgc3lzdGVt
YXRpYyByZXZpZXc8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBNYWduIFJlc29uIEltYWdpbmc8
L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIE1hZ24g
UmVzb24gSW1hZ2luZzwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjc3NC04NTwvcGFn
ZXM+PHZvbHVtZT4zODwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29y
ZD5BdXRvbWF0aWMgRGF0YSBQcm9jZXNzaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkF1dG9tYXRpb248
L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CcmFp
biBJbmZhcmN0aW9uL2RpYWdub3Npcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJy
YWwgQXJ0ZXJpZXMvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPipEaWFnbm9zaXMsIENvbXB1
dGVyLUFzc2lzdGVkPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5J
bWFnZSBFbmhhbmNlbWVudDwva2V5d29yZD48a2V5d29yZD5JbWFnZSBJbnRlcnByZXRhdGlvbiwg
Q29tcHV0ZXItQXNzaXN0ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+KkltYWdlIFByb2Nlc3NpbmcsIENv
bXB1dGVyLUFzc2lzdGVkPC9rZXl3b3JkPjxrZXl3b3JkPipNYWduZXRpYyBSZXNvbmFuY2UgSW1h
Z2luZzwva2V5d29yZD48a2V5d29yZD5SYWRpb2xvZ3kgSW5mb3JtYXRpb24gU3lzdGVtczwva2V5
d29yZD48a2V5d29yZD5SZXByb2R1Y2liaWxpdHkgb2YgUmVzdWx0czwva2V5d29yZD48a2V5d29y
ZD5Tb2Z0d2FyZTwva2V5d29yZD48a2V5d29yZD5TdWJhcmFjaG5vaWQgU3BhY2UvcGF0aG9sb2d5
PC9rZXl3b3JkPjxrZXl3b3JkPk1yaTwva2V5d29yZD48a2V5d29yZD5WaXJjaG93LVJvYmluIHNw
YWNlczwva2V5d29yZD48a2V5d29yZD5icmFpbjwva2V5d29yZD48a2V5d29yZD5jb21wdXRhdGlv
bmFsIGFzc2Vzc21lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+cGVyaXZhc2N1bGFyIHNwYWNlczwva2V5
d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+
T2N0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyMi0yNTg2IChFbGVjdHJvbmlj
KSYjeEQ7MTA1My0xODA3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMzQ0MTAzNjwv
YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5s
bS5uaWguZ292L3B1Ym1lZC8yMzQ0MTAzNjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl
Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwMi9qbXJpLjI0MDQ3PC9lbGVjdHJvbmljLXJlc291
cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXJuYW5kZXogTWRlbDwvQXV0aG9yPjxZZWFyPjIwMTM8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ADDIN EN.CITE.DATA [44] Large PVS might have also been miscounted as lacunes in many studies. ADDIN EN.CITE <EndNote><Cite><Author>Potter</Author><Year>2011</Year><RecNum>11</RecNum><DisplayText>[42]</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463787790">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Potter, G. M.</author><author>Marlborough, F. J.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK.</auth-address><titles><title>Wide variation in definition, detection, and description of lacunar lesions on imaging</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>359-66</pages><volume>42</volume><number>2</number><keywords><keyword>Brain Infarction/*classification/*diagnosis</keyword><keyword>Diagnostic Imaging/*methods/*standards</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/methods/standards</keyword><keyword>Random Allocation</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>21193752</accession-num><urls><related-urls><url>;[42] Lacunes usually present as a hypointense ‘hole’ on FLAIR surrounded by a hyperintense rim which can help its differentiation from PVS. However, the rim can be absent in some cases and PVS within extensive WMH areas may appear as if surrounded by hyperintentisities, so the insistence on a rim to differentiate lacunes from PVS is not helpful in practice. Nonetheless, it is important to distinguish between lacunes and PVS if possible, on size at least, because they not only represent different pathologies but also differ in clinical associations and implications. Although many lacunes might have lacked acute symptoms, when present in larger numbers they are associated with dementia, cognitive impairment, gait disturbance and an increased risk of stroke.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXJtZWVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
UmVjTnVtPjE2PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls1LCA0NSwgNDZdPC9EaXNwbGF5VGV4dD48
cmVjb3JkPjxyZWMtbnVtYmVyPjE2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9
IkVOIiBkYi1pZD0icDIyNTBkOXg0dzB3eHJldHhzM3B6MHg2cnp2d3Z3YXh6ZGR4IiB0aW1lc3Rh
bXA9IjE0NjM3ODgzNDIiPjE2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv
dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv
cj5WZXJtZWVyLCBTLiBFLjwvYXV0aG9yPjxhdXRob3I+TG9uZ3N0cmV0aCwgVy4gVC4sIEpyLjwv
YXV0aG9yPjxhdXRob3I+S291ZHN0YWFsLCBQLiBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy
aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBFcmFzbXVzIE1l
ZGljYWwgQ2VudGVyLCBSb3R0ZXJkYW0sIFRoZSBOZXRoZXJsYW5kcy4gcy52ZXJtZWVyQGVyYXNt
dXNtYy5ubDwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlNpbGVudCBicmFpbiBpbmZhcmN0
czogYSBzeXN0ZW1hdGljIHJldmlldzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQgTmV1
cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TGFu
Y2V0IE5ldXJvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjYxMS05PC9wYWdlcz48
dm9sdW1lPjY8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWR1
bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwv
a2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5CcmFp
biBJbmZhcmN0aW9uLypldGlvbG9neS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFs
ZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVz
b25hbmNlIEltYWdpbmcvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxr
ZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlJpc2s8L2tleXdvcmQ+PGtleXdv
cmQ+U2V4IEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+U3Ryb2tlLypjb21wbGljYXRpb25zPC9r
ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0
ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0LTQ0MjIgKFByaW50KSYj
eEQ7MTQ3NC00NDIyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNzU4MjM2MTwvYWNj
ZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5u
aWguZ292L3B1Ym1lZC8xNzU4MjM2MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ry
b25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3NC00NDIyKDA3KTcwMTcwLTk8L2VsZWN0cm9u
aWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlNub3dkb248L0F1
dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxSZWNOdW0+NjI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt
YmVyPjYyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0icDIy
NTBkOXg0dzB3eHJldHhzM3B6MHg2cnp2d3Z3YXh6ZGR4IiB0aW1lc3RhbXA9IjE0NjQ5NDU4MTAi
PjYyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+
MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Tbm93ZG9uLCBELiBB
LjwvYXV0aG9yPjxhdXRob3I+R3JlaW5lciwgTC4gSC48L2F1dGhvcj48YXV0aG9yPk1vcnRpbWVy
LCBKLiBBLjwvYXV0aG9yPjxhdXRob3I+UmlsZXksIEsuIFAuPC9hdXRob3I+PGF1dGhvcj5HcmVp
bmVyLCBQLiBBLjwvYXV0aG9yPjxhdXRob3I+TWFya2VzYmVyeSwgVy4gUi48L2F1dGhvcj48L2F1
dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5TYW5kZXJzLUJyb3duIENlbnRlciBv
biBBZ2luZywgVW5pdmVyc2l0eSBvZiBLZW50dWNreSwgTGV4aW5ndG9uIDQwNTM2LTAyMzAsIFVT
QS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5CcmFpbiBpbmZhcmN0aW9uIGFuZCB0aGUg
Y2xpbmljYWwgZXhwcmVzc2lvbiBvZiBBbHpoZWltZXIgZGlzZWFzZS4gVGhlIE51biBTdHVkeTwv
dGl0bGU+PHNlY29uZGFyeS10aXRsZT5KQU1BPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl
cmlvZGljYWw+PGZ1bGwtdGl0bGU+SkFNQTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2Vz
PjgxMy03PC9wYWdlcz48dm9sdW1lPjI3Nzwvdm9sdW1lPjxudW1iZXI+MTA8L251bWJlcj48a2V5
d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwv
a2V5d29yZD48a2V5d29yZD5BbHpoZWltZXIgRGlzZWFzZS8qY29tcGxpY2F0aW9ucy9nZW5ldGlj
cy8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFwb2xpcG9wcm90ZWlucyBFL2dlbmV0aWNz
PC9rZXl3b3JkPjxrZXl3b3JkPkFydGVyaW9zY2xlcm9zaXMvY29tcGxpY2F0aW9ucy9wYXRob2xv
Z3k8L2tleXdvcmQ+PGtleXdvcmQ+QXV0b3BzeTwva2V5d29yZD48a2V5d29yZD5CcmFpbi9ibG9v
ZCBzdXBwbHkvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJhbCBJbmZhcmN0aW9u
Lypjb21wbGljYXRpb25zL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Db2duaXRpb248L2tl
eXdvcmQ+PGtleXdvcmQ+RGVtZW50aWE8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3Jk
PjxrZXl3b3JkPkdlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5
d29yZD5Mb25naXR1ZGluYWwgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5OZXVyb2ZpYnJpbGxh
cnkgVGFuZ2xlcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9wc3ljaG9sb2dpY2Fs
IFRlc3RzPC9rZXl3b3JkPjxrZXl3b3JkPlJlZ3Jlc3Npb24gQW5hbHlzaXM8L2tleXdvcmQ+PC9r
ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5NzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hciAxMjwv
ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwOTgtNzQ4NCAoUHJpbnQpJiN4RDswMDk4
LTc0ODQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjkwNTI3MTE8L2FjY2Vzc2lvbi1u
dW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9w
dWJtZWQvOTA1MjcxMTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+
PENpdGU+PEF1dGhvcj5WZXJtZWVyPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVjTnVtPjYz
PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj42MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz
PjxrZXkgYXBwPSJFTiIgZGItaWQ9InAyMjUwZDl4NHcwd3hyZXR4czNwejB4NnJ6dnd2d2F4emRk
eCIgdGltZXN0YW1wPSIxNDY0OTQ2MTA1Ij42Mzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw
ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo
b3JzPjxhdXRob3I+VmVybWVlciwgUy4gRS48L2F1dGhvcj48YXV0aG9yPlByaW5zLCBOLiBELjwv
YXV0aG9yPjxhdXRob3I+ZGVuIEhlaWplciwgVC48L2F1dGhvcj48YXV0aG9yPkhvZm1hbiwgQS48
L2F1dGhvcj48YXV0aG9yPktvdWRzdGFhbCwgUC4gSi48L2F1dGhvcj48YXV0aG9yPkJyZXRlbGVy
LCBNLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRl
cGFydG1lbnQgb2YgRXBpZGVtaW9sb2d5IGFuZCBCaW9zdGF0aXN0aWNzLCBFcmFzbXVzIE1lZGlj
YWwgQ2VudGVyLCBSb3R0ZXJkYW0sIFRoZSBOZXRoZXJsYW5kcy48L2F1dGgtYWRkcmVzcz48dGl0
bGVzPjx0aXRsZT5TaWxlbnQgYnJhaW4gaW5mYXJjdHMgYW5kIHRoZSByaXNrIG9mIGRlbWVudGlh
IGFuZCBjb2duaXRpdmUgZGVjbGluZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OIEVuZ2wgSiBN
ZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OIEVu
Z2wgSiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjE1LTIyPC9wYWdlcz48
dm9sdW1lPjM0ODwvdm9sdW1lPjxudW1iZXI+MTM8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+
QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29y
ZD5CcmFpbiBJbmZhcmN0aW9uLypjb21wbGljYXRpb25zL3BhdGhvbG9neTwva2V5d29yZD48a2V5
d29yZD5Db2duaXRpb24gRGlzb3JkZXJzL2RpYWdub3Npcy8qZXRpb2xvZ3k8L2tleXdvcmQ+PGtl
eXdvcmQ+RGVtZW50aWEvZGlhZ25vc2lzLypldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5GZW1h
bGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkxpbmVhciBNb2Rl
bHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdvcmQ+
PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5
d29yZD5OZXVyb3BzeWNob2xvZ2ljYWwgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UHJvcG9ydGlv
bmFsIEhhemFyZHMgTW9kZWxzPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8
L2tleXdvcmQ+PGtleXdvcmQ+UHN5Y2hpYXRyaWMgU3RhdHVzIFJhdGluZyBTY2FsZXM8L2tleXdv
cmQ+PGtleXdvcmQ+UmVjdXJyZW5jZTwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tl
eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMzwveWVhcj48cHViLWRhdGVzPjxkYXRl
Pk1hciAyNzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MzMtNDQwNiAoRWxlY3Ry
b25pYykmI3hEOzAwMjgtNDc5MyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTI2NjAz
ODU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi
aS5ubG0ubmloLmdvdi9wdWJtZWQvMTI2NjAzODU8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+
PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNTYvTkVKTW9hMDIyMDY2PC9lbGVjdHJvbmlj
LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXJtZWVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE.DATA [5, 45, 46] In the general elderly population, the prevalence of lacunes ranges from 8% to 28% (mean age = 50 -75 years). ADDIN EN.CITE <EndNote><Cite><Author>Vermeer</Author><Year>2007</Year><RecNum>16</RecNum><DisplayText>[5]</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463788342">16</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vermeer, S. E.</author><author>Longstreth, W. T., Jr.</author><author>Koudstaal, P. J.</author></authors></contributors><auth-address>Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. s.vermeer@erasmusmc.nl</auth-address><titles><title>Silent brain infarcts: a systematic review</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>611-9</pages><volume>6</volume><number>7</number><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain Infarction/*etiology/*pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/methods</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Risk</keyword><keyword>Sex Factors</keyword><keyword>Stroke/*complications</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1474-4422 (Print)
1474-4422 (Linking)</isbn><accession-num>17582361</accession-num><urls><related-urls><url>(07)70170-9</electronic-resource-num></record></Cite></EndNote>[5] A systematic review suggests that silent brain infarcts (another term sometimes used for lacune) are more prevalent in Asian than in non-Asian population. ADDIN EN.CITE <EndNote><Cite><Author>Fanning</Author><Year>2014</Year><RecNum>18</RecNum><DisplayText>[47]</DisplayText><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463788810">18</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fanning, J. P.</author><author>Wong, A. A.</author><author>Fraser, J. F.</author></authors></contributors><titles><title>The epidemiology of silent brain infarction: a systematic review of population-based cohorts</title><secondary-title>BMC Med</secondary-title></titles><periodical><full-title>BMC Med</full-title></periodical><pages>119</pages><volume>12</volume><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain Infarction/*epidemiology/etiology/pathology/prevention & control</keyword><keyword>Cohort Studies</keyword><keyword>Ethnic Groups</keyword><keyword>Female</keyword><keyword>Global Health</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2014</year></dates><isbn>1741-7015 (Electronic)
1741-7015 (Linking)</isbn><accession-num>25012298</accession-num><urls><related-urls><url>;[47] However it is noteworthy that most of these Asian studies were hospital-based whereas all non-Asian studies were community-based, therefore more relevant comparisons are needed to determine if the prevalence of lacunes and other CSVD features does differ between world regions and ethnic groups. PVSPVS are the extension of subarachnoid spaces that surround cerebral microvessels. ADDIN EN.CITE <EndNote><Cite><Author>Braffman</Author><Year>1988</Year><RecNum>64</RecNum><DisplayText>[48]</DisplayText><record><rec-number>64</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1464951360">64</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Braffman, B. H.</author><author>Zimmerman, R. A.</author><author>Trojanowski, J. Q.</author><author>Gonatas, N. K.</author><author>Hickey, W. F.</author><author>Schlaepfer, W. W.</author></authors></contributors><auth-address>Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia 19104.</auth-address><titles><title>Brain MR: pathologic correlation with gross and histopathology. 1. Lacunar infarction and Virchow-Robin spaces</title><secondary-title>AJR Am J Roentgenol</secondary-title></titles><periodical><full-title>AJR Am J Roentgenol</full-title></periodical><pages>551-8</pages><volume>151</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Basal Ganglia/pathology</keyword><keyword>Blood Vessels/pathology</keyword><keyword>Brain/blood supply/*pathology</keyword><keyword>Cerebral Infarction/*diagnosis</keyword><keyword>Cranial Fossa, Posterior</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Thalamus/pathology</keyword></keywords><dates><year>1988</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0361-803X (Print)
0361-803X (Linking)</isbn><accession-num>3261517</accession-num><urls><related-urls><url>;[48] They are fluid-filled spaces that follow the course of a vessel through the brain parenchyma. ADDIN EN.CITE <EndNote><Cite><Author>Braffman</Author><Year>1988</Year><RecNum>65</RecNum><DisplayText>[48]</DisplayText><record><rec-number>65</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465233515">65</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Braffman, B. H.</author><author>Zimmerman, R. A.</author><author>Trojanowski, J. Q.</author><author>Gonatas, N. K.</author><author>Hickey, W. F.</author><author>Schlaepfer, W. W.</author></authors></contributors><auth-address>Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia 19104.</auth-address><titles><title>Brain MR: pathologic correlation with gross and histopathology. 1. Lacunar infarction and Virchow-Robin spaces</title><secondary-title>AJR Am J Roentgenol</secondary-title></titles><periodical><full-title>AJR Am J Roentgenol</full-title></periodical><pages>551-8</pages><volume>151</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Basal Ganglia/pathology</keyword><keyword>Blood Vessels/pathology</keyword><keyword>Brain/blood supply/*pathology</keyword><keyword>Cerebral Infarction/*diagnosis</keyword><keyword>Cranial Fossa, Posterior</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Thalamus/pathology</keyword></keywords><dates><year>1988</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0361-803X (Print)
0361-803X (Linking)</isbn><accession-num>3261517</accession-num><urls><related-urls><url>;[48] PVS are usually microscopic and not detected on CT or conventional MRIs. When enlarged, PVS are commonly seen as hyperintense on T2 MRI , either punctuate with a diameter less than 3 mm if imaged perpendicular to the course of the vessel, or linear if imaged parallel to the course of the vessel. ADDIN EN.CITE <EndNote><Cite><Author>Potter</Author><Year>2015</Year><RecNum>87</RecNum><DisplayText>[49]</DisplayText><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468399521">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Potter, G. M.</author><author>Chappell, F. M.</author><author>Morris, Z.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Brain Imaging Research Centre, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Cerebral perivascular spaces visible on magnetic resonance imaging: development of a qualitative rating scale and its observer reliability</title><secondary-title>Cerebrovasc Dis</secondary-title></titles><periodical><full-title>Cerebrovasc Dis</full-title></periodical><pages>224-31</pages><volume>39</volume><number>3-4</number><keywords><keyword>Age Distribution</keyword><keyword>Blood-Brain Barrier/pathology</keyword><keyword>Brain/*pathology</keyword><keyword>Cerebral Small Vessel Diseases/*pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging/methods</keyword><keyword>Male</keyword><keyword>Reproducibility of Results</keyword></keywords><dates><year>2015</year></dates><isbn>1421-9786 (Electronic)
1015-9770 (Linking)</isbn><accession-num>25823458</accession-num><urls><related-urls><url>;[49](Figure 1) PVS are most frequent in the inferior parts of the basal ganglia and centrum semiovale but can also occur in brainstem. Though 3 mm has generally been considered as the cut-off diameter for distinguishing PVS from lacunes,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXJuYW5kZXogTWRlbDwvQXV0aG9yPjxZZWFyPjIwMTM8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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXJuYW5kZXogTWRlbDwvQXV0aG9yPjxZZWFyPjIwMTM8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ADDIN EN.CITE.DATA [44] occasional PVS could be larger and even cause mass effect.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA [4] PVS usually do not have a hyperintense rim on T2-weighted or FLAIR unless passing through a WMH area, which can help the discrimination between PVS and lacunes. Whether PVS should be regarded as ‘lesions’ is still controversial, as their clinical significance remains unclear. Although a few PVS can be normal, ADDIN EN.CITE <EndNote><Cite><Author>Groeschel</Author><Year>2006</Year><RecNum>66</RecNum><DisplayText>[50]</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465234555">66</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Groeschel, S.</author><author>Chong, W. K.</author><author>Surtees, R.</author><author>Hanefeld, F.</author></authors></contributors><auth-address>Department of Pediatrics and Child Neurology, Georg-August-University, Goettingen, Germany.</auth-address><titles><title>Virchow-Robin spaces on magnetic resonance images: normative data, their dilatation, and a review of the literature</title><secondary-title>Neuroradiology</secondary-title></titles><periodical><full-title>Neuroradiology</full-title></periodical><pages>745-54</pages><volume>48</volume><number>10</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Brain/*blood supply/*pathology/physiopathology</keyword><keyword>Brain Diseases/*pathology/physiopathology</keyword><keyword>Case-Control Studies</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Dilatation, Pathologic/pathology</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Microcirculation/physiology</keyword><keyword>Reference Values</keyword></keywords><dates><year>2006</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0028-3940 (Print)
0028-3940 (Linking)</isbn><accession-num>16896908</accession-num><urls><related-urls><url>;[50] numbers of PVS increased with advancing age and other features of CSVD.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaHU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO
dW0+Njc8L1JlY051bT48RGlzcGxheVRleHQ+WzUxLTU0XTwvRGlzcGxheVRleHQ+PHJlY29yZD48
cmVjLW51bWJlcj42NzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGIt
aWQ9InAyMjUwZDl4NHcwd3hyZXR4czNwejB4NnJ6dnd2d2F4emRkeCIgdGltZXN0YW1wPSIxNDY1
MjkwOTgwIj42Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy
dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Wmh1LCBZ
LiBDLjwvYXV0aG9yPjxhdXRob3I+VHpvdXJpbywgQy48L2F1dGhvcj48YXV0aG9yPlNvdW1hcmUs
IEEuPC9hdXRob3I+PGF1dGhvcj5NYXpveWVyLCBCLjwvYXV0aG9yPjxhdXRob3I+RHVmb3VpbCwg
Qy48L2F1dGhvcj48YXV0aG9yPkNoYWJyaWF0LCBILjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy
aWJ1dG9ycz48YXV0aC1hZGRyZXNzPklOU0VSTSBVbml0IDcwOCwgUGFyaXMgQ2VkZXggMTMsIEZy
YW5jZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5TZXZlcml0eSBvZiBkaWxhdGVkIFZp
cmNob3ctUm9iaW4gc3BhY2VzIGlzIGFzc29jaWF0ZWQgd2l0aCBhZ2UsIGJsb29kIHByZXNzdXJl
LCBhbmQgTVJJIG1hcmtlcnMgb2Ygc21hbGwgdmVzc2VsIGRpc2Vhc2U6IGEgcG9wdWxhdGlvbi1i
YXNlZCBzdHVkeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5TdHJva2U8L3NlY29uZGFyeS10aXRs
ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TdHJva2U8L2Z1bGwtdGl0bGU+PC9w
ZXJpb2RpY2FsPjxwYWdlcz4yNDgzLTkwPC9wYWdlcz48dm9sdW1lPjQxPC92b2x1bWU+PG51bWJl
cj4xMTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFn
aW5nLypwYXRob2xvZ3kvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5CYXNhbCBHYW5nbGlh
IENlcmVicm92YXNjdWxhciBEaXNlYXNlL2RpYWdub3Npcy8qcGF0aG9sb2d5L3BoeXNpb3BhdGhv
bG9neTwva2V5d29yZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZS9waHlzaW9sb2d5PC9rZXl3b3Jk
PjxrZXl3b3JkPkNvaG9ydCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRpbGF0YXRpb24sIFBh
dGhvbG9naWMvZGlhZ25vc2lzL3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl
eXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5I
eXBlcnRlbnNpb24vKnBhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+
TG9naXN0aWMgTW9kZWxzPC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJlc29uYW5jZSBJbWFn
aW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljcm92ZXNzZWxz
LypwYXRob2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByZWRpY3RpdmUg
VmFsdWUgb2YgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UHJvZ25vc2lzPC9rZXl3b3JkPjxrZXl3
b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8
L2tleXdvcmQ+PGtleXdvcmQ+KlNldmVyaXR5IG9mIElsbG5lc3MgSW5kZXg8L2tleXdvcmQ+PC9r
ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0
ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MjQtNDYyOCAoRWxlY3Ryb25pYykmI3hEOzAw
MzktMjQ5OSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjA4NjQ2NjE8L2FjY2Vzc2lv
bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdv
di9wdWJtZWQvMjA4NjQ2NjE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMt
cmVzb3VyY2UtbnVtPjEwLjExNjEvU1RST0tFQUhBLjExMC41OTE1ODY8L2VsZWN0cm9uaWMtcmVz
b3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhlaWVyPC9BdXRob3I+PFll
YXI+MTk4OTwvWWVhcj48UmVjTnVtPjY4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj42ODwv
cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InAyMjUwZDl4NHcw
d3hyZXR4czNwejB4NnJ6dnd2d2F4emRkeCIgdGltZXN0YW1wPSIxNDY1MjkzMTk4Ij42ODwva2V5
PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt
dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGVpZXIsIEwuIEEuPC9hdXRob3I+
PGF1dGhvcj5CYXVlciwgQy4gSi48L2F1dGhvcj48YXV0aG9yPlNjaHdhcnR6LCBMLjwvYXV0aG9y
PjxhdXRob3I+WmltbWVybWFuLCBSLiBELjwvYXV0aG9yPjxhdXRob3I+TW9yZ2VsbG8sIFMuPC9h
dXRob3I+PGF1dGhvcj5EZWNrLCBNLiBELjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y
cz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUmFkaW9sb2d5LCBOZXcgWW9yayBIb3NwaXRh
bC9Db3JuZWxsIE1lZGljYWwgQ2VudGVyLCBOWSAxMDAyMS48L2F1dGgtYWRkcmVzcz48dGl0bGVz
Pjx0aXRsZT5MYXJnZSBWaXJjaG93LVJvYmluIHNwYWNlczogTVItY2xpbmljYWwgY29ycmVsYXRp
b248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QUpOUiBBbSBKIE5ldXJvcmFkaW9sPC9zZWNvbmRh
cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QUpOUiBBbSBKIE5ldXJv
cmFkaW9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+OTI5LTM2PC9wYWdlcz48dm9s
dW1lPjEwPC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xl
c2NlbnQ8L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5
d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BZ2luZy8q
cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJhc2FsIEdhbmdsaWEvcGF0aG9sb2d5PC9rZXl3
b3JkPjxrZXl3b3JkPkJyYWluL2Jsb29kIHN1cHBseS8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3
b3JkPkNlcmVicmFsIEFydGVyaWVzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZXJlYnJv
dmFzY3VsYXIgRGlzb3JkZXJzL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DaGlsZDwva2V5
d29yZD48a2V5d29yZD5DaGlsZCwgUHJlc2Nob29sPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwv
a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mYW50PC9rZXl3b3Jk
PjxrZXl3b3JkPkluZmFudCwgTmV3Ym9ybjwva2V5d29yZD48a2V5d29yZD4qTWFnbmV0aWMgUmVz
b25hbmNlIEltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5N
aWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5SZWdyZXNzaW9uIEFuYWx5c2lzPC9rZXl3b3Jk
PjxrZXl3b3JkPlN1YmFyYWNobm9pZCBTcGFjZS9wYXRob2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jk
cz48ZGF0ZXM+PHllYXI+MTk4OTwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcC1PY3Q8L2RhdGU+
PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMTk1LTYxMDggKFByaW50KSYjeEQ7MDE5NS02MTA4
IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNTA1NTM2PC9hY2Nlc3Npb24tbnVtPjx1
cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk
LzI1MDU1MzY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl
PjxBdXRob3I+UG90dGVyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVtPjY5PC9SZWNO
dW0+PHJlY29yZD48cmVjLW51bWJlcj42OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg
YXBwPSJFTiIgZGItaWQ9InAyMjUwZDl4NHcwd3hyZXR4czNwejB4NnJ6dnd2d2F4emRkeCIgdGlt
ZXN0YW1wPSIxNDY1MjkzOTExIj42OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l
PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh
dXRob3I+UG90dGVyLCBHLiBNLjwvYXV0aG9yPjxhdXRob3I+RG91YmFsLCBGLiBOLjwvYXV0aG9y
PjxhdXRob3I+SmFja3NvbiwgQy4gQS48L2F1dGhvcj48YXV0aG9yPkNoYXBwZWxsLCBGLiBNLjwv
YXV0aG9yPjxhdXRob3I+U3VkbG93LCBDLiBMLjwvYXV0aG9yPjxhdXRob3I+RGVubmlzLCBNLiBT
LjwvYXV0aG9yPjxhdXRob3I+V2FyZGxhdywgSi4gTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250
cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2Vz
IGFuZCBTSU5BUFNFIENvbGxhYm9yYXRpb24sIFVuaXZlcnNpdHkgb2YgRWRpbmJ1cmdoLCBXZXN0
ZXJuIEdlbmVyYWwgSG9zcGl0YWwsIEVkaW5idXJnaCwgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxl
cz48dGl0bGU+RW5sYXJnZWQgcGVyaXZhc2N1bGFyIHNwYWNlcyBhbmQgY2VyZWJyYWwgc21hbGwg
dmVzc2VsIGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SW50IEogU3Ryb2tlPC9zZWNv
bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SW50IEogU3Ryb2tl
PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+Mzc2LTgxPC9wYWdlcz48dm9sdW1lPjEw
PC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdv
cmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwg
SGVtb3JyaGFnZS9kaWFnbm9zaXMvKmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFs
IFNtYWxsIFZlc3NlbCBEaXNlYXNlcy8qY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5D
ZXJlYnJhbCBWZW50cmljbGVzLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9r
ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFu
Y2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRs
ZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk11bHRpdmFyaWF0ZSBBbmFseXNpczwva2V5d29yZD48
a2V5d29yZD5Qcm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3Rp
dmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5Ncmk8L2tleXdvcmQ+PGtleXdvcmQ+YnJhaW48
L2tleXdvcmQ+PGtleXdvcmQ+Y2VyZWJyYWwgaW5mYXJjdGlvbjwva2V5d29yZD48a2V5d29yZD5s
ZXVrb2FyYWlvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPnN0cm9rZTwva2V5d29yZD48a2V5d29yZD5z
dHJva2Ugc3VidHlwZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVh
cj48cHViLWRhdGVzPjxkYXRlPkFwcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3
NDctNDk0OSAoRWxlY3Ryb25pYykmI3hEOzE3NDctNDkzMCAoTGlua2luZyk8L2lzYm4+PGFjY2Vz
c2lvbi1udW0+MjM2OTI2MTA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs
Pmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjM2OTI2MTA8L3VybD48L3JlbGF0
ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDQ2Mzk0NDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1y
ZXNvdXJjZS1udW0+MTAuMTExMS9panMuMTIwNTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv
cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRvdWJhbDwvQXV0aG9yPjxZZWFyPjIwMTA8L1ll
YXI+PFJlY051bT43MjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+NzI8L3JlYy1udW1iZXI+
PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJwMjI1MGQ5eDR3MHd4cmV0eHMzcHow
eDZyenZ3dndheHpkZHgiIHRpbWVzdGFtcD0iMTQ2NTI5NTMyNiI+NzI8L2tleT48L2ZvcmVpZ24t
a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy
aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRvdWJhbCwgRi4gTi48L2F1dGhvcj48YXV0aG9yPk1h
Y0x1bGxpY2gsIEEuIE0uPC9hdXRob3I+PGF1dGhvcj5GZXJndXNvbiwgSy4gSi48L2F1dGhvcj48
YXV0aG9yPkRlbm5pcywgTS4gUy48L2F1dGhvcj48YXV0aG9yPldhcmRsYXcsIEouIE0uPC9hdXRo
b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TVJDUCwgRGl2aXNpb24g
b2YgQ2xpbmljYWwgTmV1cm9zY2llbmNlcywgQnJhbXdlbGwgRG90dCBCdWlsZGluZywgV2VzdGVy
biBHZW5lcmFsIEhvc3BpdGFsLCBDcmV3ZSBSb2FkLCBFZGluYnVyZ2gsIEVINCAyWFUsIFVLLiBm
ZXJndXMuZG91YmFsQGVkLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RW5sYXJn
ZWQgcGVyaXZhc2N1bGFyIHNwYWNlcyBvbiBNUkkgYXJlIGEgZmVhdHVyZSBvZiBjZXJlYnJhbCBz
bWFsbCB2ZXNzZWwgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5TdHJva2U8L3NlY29u
ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TdHJva2U8L2Z1bGwt
dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40NTAtNDwvcGFnZXM+PHZvbHVtZT40MTwvdm9sdW1l
PjxudW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5
d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxr
ZXl3b3JkPkFydGVyaW9sZXMvKnBhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl
eXdvcmQ+QnJhaW4gSW5mYXJjdGlvbi9wYXRob2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3Jk
PjxrZXl3b3JkPkNlcmVicmFsIFZlbnRyaWNsZXMvKmJsb29kIHN1cHBseS8qcGF0aG9sb2d5PC9r
ZXl3b3JkPjxrZXl3b3JkPkNlcmVicm92YXNjdWxhciBEaXNvcmRlcnMvKnBhdGhvbG9neS9waHlz
aW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1
bWFuczwva2V5d29yZD48a2V5d29yZD4qTWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmc8L2tleXdv
cmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48
a2V5d29yZD5Qcm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5
ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0ZXM+PC9k
YXRlcz48aXNibj4xNTI0LTQ2MjggKEVsZWN0cm9uaWMpJiN4RDswMDM5LTI0OTkgKExpbmtpbmcp
PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIwMDU2OTMwPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh
dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwMDU2OTMw
PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x
MTYxL1NUUk9LRUFIQS4xMDkuNTY0OTE0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29y
ZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaHU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA [51-54] In some studies, more PVSs were associated with increased risk of dementia or worse cognitive function or hypertension.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaHU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaHU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA [44, 55, 56] The mechanisms underlying enlarged PVS are not well understood. In normal aging and other neurological diseases like multiple sclerosis, PVS are associated with inflammatory markers.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XdWVyZmVsPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48
UmVjTnVtPjc0PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls1N108L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+
PHJlYy1udW1iZXI+NzQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRi
LWlkPSJwMjI1MGQ5eDR3MHd4cmV0eHMzcHoweDZyenZ3dndheHpkZHgiIHRpbWVzdGFtcD0iMTQ2
NTU1Mzk2NSI+NzQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB
cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPld1ZXJm
ZWwsIEouPC9hdXRob3I+PGF1dGhvcj5IYWVydGxlLCBNLjwvYXV0aG9yPjxhdXRob3I+V2FpY3pp
ZXMsIEguPC9hdXRob3I+PGF1dGhvcj5UeXNpYWssIEUuPC9hdXRob3I+PGF1dGhvcj5CZWNobWFu
biwgSS48L2F1dGhvcj48YXV0aG9yPldlcm5lY2tlLCBLLiBELjwvYXV0aG9yPjxhdXRob3I+Wmlw
cCwgRi48L2F1dGhvcj48YXV0aG9yPlBhdWwsIEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp
YnV0b3JzPjxhdXRoLWFkZHJlc3M+Q2VjaWxpZSBWb2d0IENsaW5pYyBmb3IgTmV1cm9sb2d5IGlu
IHRoZSBIS0JCLCBDaGFyaXRlLVVuaXZlcnNpdGFldHNtZWRpemluIEJlcmxpbiwgQmVybGluLCBH
ZXJtYW55LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlBlcml2YXNjdWxhciBzcGFjZXMt
LU1SSSBtYXJrZXIgb2YgaW5mbGFtbWF0b3J5IGFjdGl2aXR5IGluIHRoZSBicmFpbj88L3RpdGxl
PjxzZWNvbmRhcnktdGl0bGU+QnJhaW48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9k
aWNhbD48ZnVsbC10aXRsZT5CcmFpbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIz
MzItNDA8L3BhZ2VzPjx2b2x1bWU+MTMxPC92b2x1bWU+PG51bWJlcj5QdCA5PC9udW1iZXI+PGtl
eXdvcmRzPjxrZXl3b3JkPkFjdXRlIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8L2tl
eXdvcmQ+PGtleXdvcmQ+QWdpbmcvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJhc2FsIEdh
bmdsaWEvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJsb29kLUJyYWluIEJhcnJpZXIvcGF0
aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluL2Jsb29kIHN1cHBseS8qcGF0aG9sb2d5PC9r
ZXl3b3JkPjxrZXl3b3JkPkV4dHJhY2VsbHVsYXIgU3BhY2U8L2tleXdvcmQ+PGtleXdvcmQ+RmVt
YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBS
ZXNvbmFuY2UgSW1hZ2luZy9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+
PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TXVsdGlwbGUgU2NsZXJvc2lz
LCBSZWxhcHNpbmctUmVtaXR0aW5nLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJvc3Bl
Y3RpdmUgU3R1ZGllczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA4PC95ZWFy
PjxwdWItZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ2
MC0yMTU2IChFbGVjdHJvbmljKSYjeEQ7MDAwNi04OTUwIChMaW5raW5nKTwvaXNibj48YWNjZXNz
aW9uLW51bT4xODY3NjQzOTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+
aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xODY3NjQzOTwvdXJsPjwvcmVsYXRl
ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA5My9icmFpbi9hd24x
NzE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9y
Pld1ZXJmZWw8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNOdW0+NzU8L1JlY051bT48cmVj
b3JkPjxyZWMtbnVtYmVyPjc1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO
IiBkYi1pZD0icDIyNTBkOXg0dzB3eHJldHhzM3B6MHg2cnp2d3Z3YXh6ZGR4IiB0aW1lc3RhbXA9
IjE0NjU1NTQwMzAiPjc1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu
YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5X
dWVyZmVsLCBKLjwvYXV0aG9yPjxhdXRob3I+SGFlcnRsZSwgTS48L2F1dGhvcj48YXV0aG9yPldh
aWN6aWVzLCBILjwvYXV0aG9yPjxhdXRob3I+VHlzaWFrLCBFLjwvYXV0aG9yPjxhdXRob3I+QmVj
aG1hbm4sIEkuPC9hdXRob3I+PGF1dGhvcj5XZXJuZWNrZSwgSy4gRC48L2F1dGhvcj48YXV0aG9y
PlppcHAsIEYuPC9hdXRob3I+PGF1dGhvcj5QYXVsLCBGLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv
bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkNlY2lsaWUgVm9ndCBDbGluaWMgZm9yIE5ldXJvbG9n
eSBpbiB0aGUgSEtCQiwgQ2hhcml0ZS1Vbml2ZXJzaXRhZXRzbWVkaXppbiBCZXJsaW4sIEJlcmxp
biwgR2VybWFueS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5QZXJpdmFzY3VsYXIgc3Bh
Y2VzLS1NUkkgbWFya2VyIG9mIGluZmxhbW1hdG9yeSBhY3Rpdml0eSBpbiB0aGUgYnJhaW4/PC90
aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkJyYWluPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl
cmlvZGljYWw+PGZ1bGwtdGl0bGU+QnJhaW48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl
cz4yMzMyLTQwPC9wYWdlcz48dm9sdW1lPjEzMTwvdm9sdW1lPjxudW1iZXI+UHQgOTwvbnVtYmVy
PjxrZXl3b3Jkcz48a2V5d29yZD5BY3V0ZSBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0
PC9rZXl3b3JkPjxrZXl3b3JkPkFnaW5nL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CYXNh
bCBHYW5nbGlhL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CbG9vZC1CcmFpbiBCYXJyaWVy
L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5CcmFpbi9ibG9vZCBzdXBwbHkvKnBhdGhvbG9n
eTwva2V5d29yZD48a2V5d29yZD5FeHRyYWNlbGx1bGFyIFNwYWNlPC9rZXl3b3JkPjxrZXl3b3Jk
PkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0
aWMgUmVzb25hbmNlIEltYWdpbmcvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3
b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk11bHRpcGxlIFNjbGVy
b3NpcywgUmVsYXBzaW5nLVJlbWl0dGluZy8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBy
b3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwv
eWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju
PjE0NjAtMjE1NiAoRWxlY3Ryb25pYykmI3hEOzAwMDYtODk1MCAoTGlua2luZyk8L2lzYm4+PGFj
Y2Vzc2lvbi1udW0+MTg2NzY0Mzk8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48
dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTg2NzY0Mzk8L3VybD48L3Jl
bGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwOTMvYnJhaW4v
YXduMTcxPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl
Pn==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XdWVyZmVsPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48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ADDIN EN.CITE.DATA [57] In CSVD, it might be a sign of impaired BBB. ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2009</Year><RecNum>73</RecNum><DisplayText>[39]</DisplayText><record><rec-number>73</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465553815">73</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw, J. M.</author><author>Doubal, F.</author><author>Armitage, P.</author><author>Chappell, F.</author><author>Carpenter, T.</author><author>Munoz Maniega, S.</author><author>Farrall, A.</author><author>Sudlow, C.</author><author>Dennis, M.</author><author>Dhillon, B.</author></authors></contributors><auth-address>University of Edinburgh, United Kingdom. joanna.wardlaw@ed.ac.uk</auth-address><titles><title>Lacunar stroke is associated with diffuse blood-brain barrier dysfunction</title><secondary-title>Ann Neurol</secondary-title></titles><periodical><full-title>Ann Neurol</full-title></periodical><pages>194-202</pages><volume>65</volume><number>2</number><keywords><keyword>Aged</keyword><keyword>Blood-Brain Barrier/pathology/*physiopathology</keyword><keyword>Brain Infarction/pathology/*physiopathology</keyword><keyword>Diffusion Magnetic Resonance Imaging/methods</keyword><keyword>Female</keyword><keyword>Gadolinium</keyword><keyword>Humans</keyword><keyword>Image Processing, Computer-Assisted/methods</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Retrospective Studies</keyword><keyword>Stroke/classification/pathology/physiopathology</keyword><keyword>Time Factors</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1531-8249 (Electronic)
0364-5134 (Linking)</isbn><accession-num>19260033</accession-num><urls><related-urls><url>;[39] There is also hypothesis that visible PVSs are associated with blockage of drainage of interstitial fluid (ISF) ADDIN EN.CITE <EndNote><Cite><Author>Weller</Author><Year>2009</Year><RecNum>76</RecNum><DisplayText>[58]</DisplayText><record><rec-number>76</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465555877">76</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weller, R. O.</author><author>Djuanda, E.</author><author>Yow, H. Y.</author><author>Carare, R. O.</author></authors></contributors><auth-address>Clinical Neurosciences, Southampton General Hospital, University of Southampton School of Medicine, LD74, South Lab and Path Block, Southampton, SO16 6YD, UK. row@soton.ac.uk</auth-address><titles><title>Lymphatic drainage of the brain and the pathophysiology of neurological disease</title><secondary-title>Acta Neuropathol</secondary-title></titles><periodical><full-title>Acta Neuropathol</full-title></periodical><pages>1-14</pages><volume>117</volume><number>1</number><keywords><keyword>Animals</keyword><keyword>Brain/metabolism/*physiopathology</keyword><keyword>Cerebral Arteries/metabolism/physiopathology</keyword><keyword>Cerebrospinal Fluid/metabolism</keyword><keyword>Extracellular Fluid/metabolism</keyword><keyword>Humans</keyword><keyword>Lymph/metabolism</keyword><keyword>Lymphatic System/metabolism/*physiopathology</keyword><keyword>Models, Biological</keyword><keyword>Nervous System Diseases/metabolism/*physiopathology</keyword></keywords><dates><year>2009</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1432-0533 (Electronic)
0001-6322 (Linking)</isbn><accession-num>19002474</accession-num><urls><related-urls><url>;[58] which might be attributed to increased vessel stiffness, as arterial pulsatility is thought to be a key driver of ISF drainagePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JbGlmZjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JbGlmZjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl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ADDIN EN.CITE.DATA [59]. They may also be a key conduit for drainage of brain interstitial metabolic products that occurs during sleep.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YaWU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YaWU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO
dW0+ODk8L1JlY051bT48RGlzcGxheVRleHQ+WzYwXTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVj
LW51bWJlcj44OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9
InAyMjUwZDl4NHcwd3hyZXR4czNwejB4NnJ6dnd2d2F4emRkeCIgdGltZXN0YW1wPSIxNDY4NDAw
MjcwIj44OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj
bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+WGllLCBMLjwv
YXV0aG9yPjxhdXRob3I+S2FuZywgSC48L2F1dGhvcj48YXV0aG9yPlh1LCBRLjwvYXV0aG9yPjxh
dXRob3I+Q2hlbiwgTS4gSi48L2F1dGhvcj48YXV0aG9yPkxpYW8sIFkuPC9hdXRob3I+PGF1dGhv
cj5UaGl5YWdhcmFqYW4sIE0uPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7RG9ubmVsbCwgSi48L2F1
dGhvcj48YXV0aG9yPkNocmlzdGVuc2VuLCBELiBKLjwvYXV0aG9yPjxhdXRob3I+TmljaG9sc29u
LCBDLjwvYXV0aG9yPjxhdXRob3I+SWxpZmYsIEouIEouPC9hdXRob3I+PGF1dGhvcj5UYWthbm8s
IFQuPC9hdXRob3I+PGF1dGhvcj5EZWFuZSwgUi48L2F1dGhvcj48YXV0aG9yPk5lZGVyZ2FhcmQs
IE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNp
b24gb2YgR2xpYWwgRGlzZWFzZSBhbmQgVGhlcmFwZXV0aWNzLCBDZW50ZXIgZm9yIFRyYW5zbGF0
aW9uYWwgTmV1cm9tZWRpY2luZSwgRGVwYXJ0bWVudCBvZiBOZXVyb3N1cmdlcnksIFVuaXZlcnNp
dHkgb2YgUm9jaGVzdGVyIE1lZGljYWwgQ2VudGVyLCBSb2NoZXN0ZXIsIE5ZIDE0NjQyLCBVU0Eu
PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2xlZXAgZHJpdmVzIG1ldGFib2xpdGUgY2xl
YXJhbmNlIGZyb20gdGhlIGFkdWx0IGJyYWluPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlNjaWVu
Y2U8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5TY2ll
bmNlPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzczLTc8L3BhZ2VzPjx2b2x1bWU+
MzQyPC92b2x1bWU+PG51bWJlcj42MTU2PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkcmVu
ZXJnaWMgQW50YWdvbmlzdHMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxr
ZXl3b3JkPkFteWxvaWQgYmV0YS1QZXB0aWRlcy8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29y
ZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLyptZXRhYm9saXNtL3BoeXNpb2xvZ3k8
L2tleXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQ29ydGV4L21ldGFib2xpc20vcGh5c2lvbG9neTwv
a2V5d29yZD48a2V5d29yZD5DZXJlYnJvc3BpbmFsIEZsdWlkL21ldGFib2xpc208L2tleXdvcmQ+
PGtleXdvcmQ+RGlmZnVzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkVsZWN0cm9lbmNlcGhhbG9ncmFw
aHk8L2tleXdvcmQ+PGtleXdvcmQ+RXh0cmFjZWxsdWxhciBTcGFjZTwva2V5d29yZD48a2V5d29y
ZD5JbnRyYWNlbGx1bGFyIFNwYWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl
eXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+
PGtleXdvcmQ+TmV1cm9kZWdlbmVyYXRpdmUgRGlzZWFzZXMvKm1ldGFib2xpc208L2tleXdvcmQ+
PGtleXdvcmQ+UXVhdGVybmFyeSBBbW1vbml1bSBDb21wb3VuZHMvY2hlbWlzdHJ5PC9rZXl3b3Jk
PjxrZXl3b3JkPlJlY2VwdG9ycywgQWRyZW5lcmdpYy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3
b3JkPlNsZWVwLypwaHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPldha2VmdWxuZXNzL3BoeXNp
b2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRh
dGVzPjxkYXRlPk9jdCAxODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwOTUtOTIw
MyAoRWxlY3Ryb25pYykmI3hEOzAwMzYtODA3NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1u
dW0+MjQxMzY5NzA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6
Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQxMzY5NzA8L3VybD48L3JlbGF0ZWQtdXJs
cz48L3VybHM+PGN1c3RvbTI+UE1DMzg4MDE5MDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJj
ZS1udW0+MTAuMTEyNi9zY2llbmNlLjEyNDEyMjQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwv
cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA [60]CMBCMBs are regarded as small round and homogeneous foci of hypointensity on T2*-weighted (gradient echo) MRI and susceptibility-weighted imaging (SWI).(Figure 1) In the very few studies of radiological-pathological correlation, perivascular hemosiderin-laden macrophages were found underlying most of the CMBs shown on MRI. Other possible pathologies include old hematomas, intact erythrocytes, and very rarely vascular pseudocalcification, microaneurysm and distended dissected vessels. ADDIN EN.CITE <EndNote><Cite><Author>Shoamanesh</Author><Year>2011</Year><RecNum>80</RecNum><DisplayText>[61]</DisplayText><record><rec-number>80</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465982391">80</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shoamanesh, A.</author><author>Kwok, C. S.</author><author>Benavente, O.</author></authors></contributors><auth-address>Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, B.C., Canada. ashkan.sho@</auth-address><titles><title>Cerebral microbleeds: histopathological correlation of neuroimaging</title><secondary-title>Cerebrovasc Dis</secondary-title></titles><periodical><full-title>Cerebrovasc Dis</full-title></periodical><pages>528-34</pages><volume>32</volume><number>6</number><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain Neoplasms/complications</keyword><keyword>Cerebral Arteries/pathology</keyword><keyword>Cerebral Hemorrhage/etiology/*pathology</keyword><keyword>Cerebral Small Vessel Diseases/pathology</keyword><keyword>Cerebral Veins/pathology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cerebrovascular Disorders/pathology</keyword><keyword>Female</keyword><keyword>Hemosiderin/metabolism</keyword><keyword>Histocytochemistry</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neuroimaging</keyword></keywords><dates><year>2011</year></dates><isbn>1421-9786 (Electronic)
1015-9770 (Linking)</isbn><accession-num>22104448</accession-num><urls><related-urls><url>;[61] Lipofibrohyalinosis and amyloid angiopathy are the most common vascular findings in relation to CMB. These two vasculopathies are thought to have different patterns of CMBs distribution: CMBs in basal ganglia, thalamus, brainstem, and cerebellum are typically attributed to lipofibrohyalinosis; whereas amyloid angiopathy is more associated with lobar CMBs. ADDIN EN.CITE <EndNote><Cite><Author>Greenberg</Author><Year>2009</Year><RecNum>81</RecNum><DisplayText>[62]</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465985480">81</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Greenberg, S. M.</author><author>Vernooij, M. W.</author><author>Cordonnier, C.</author><author>Viswanathan, A.</author><author>Al-Shahi Salman, R.</author><author>Warach, S.</author><author>Launer, L. J.</author><author>Van Buchem, M. A.</author><author>Breteler, M. M.</author><author>Microbleed Study, Group</author></authors></contributors><auth-address>Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. sgreenberg@</auth-address><titles><title>Cerebral microbleeds: a guide to detection and interpretation</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>165-74</pages><volume>8</volume><number>2</number><keywords><keyword>Aged</keyword><keyword>Cerebral Hemorrhage/*diagnosis/epidemiology/pathology</keyword><keyword>Humans</keyword><keyword>Image Processing, Computer-Assisted</keyword><keyword>Magnetic Resonance Imaging</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1474-4422 (Print)
1474-4422 (Linking)</isbn><accession-num>19161908</accession-num><urls><related-urls><url>(09)70013-4</electronic-resource-num></record></Cite></EndNote>[62] However some studies suggest there may be more overlap and larger studies are awaited to confirm the specificity of CMB distribution for particular pathologies. Most CMBs are asymptomatic; they can be found in healthy adults but are more often a marker of vascular risk factor exposure or amyloid deposition. ADDIN EN.CITE <EndNote><Cite><Author>Cordonnier</Author><Year>2007</Year><RecNum>82</RecNum><DisplayText>[63]</DisplayText><record><rec-number>82</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465990156">82</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cordonnier, C.</author><author>Al-Shahi Salman, R.</author><author>Wardlaw, J.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. c-cordonnier@chru-lille.fr</auth-address><titles><title>Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>1988-2003</pages><volume>130</volume><number>Pt 8</number><keywords><keyword>Adult</keyword><keyword>Cerebral Hemorrhage/diagnosis/epidemiology/*etiology</keyword><keyword>Cerebrovascular Disorders/complications</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>Prognosis</keyword><keyword>Research Design/standards</keyword><keyword>Risk Factors</keyword><keyword>Stroke/complications</keyword></keywords><dates><year>2007</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1460-2156 (Electronic)
0006-8950 (Linking)</isbn><accession-num>17322562</accession-num><urls><related-urls><url>;[63] In addition to its potential association with stroke, CMBs also contribute to cognitive impairment and dementia, and to transient neurological deficits. ADDIN EN.CITE <EndNote><Cite><Author>Martinez-Ramirez</Author><Year>2014</Year><RecNum>83</RecNum><DisplayText>[64]</DisplayText><record><rec-number>83</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465998930">83</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martinez-Ramirez, S.</author><author>Greenberg, S. M.</author><author>Viswanathan, A.</author></authors></contributors><auth-address>Philip J. Kistler Stroke Research Center, Massachusetts General Hospital, 175 Cambridge Street Suite 300, Boston, MA 02114, USA.</auth-address><titles><title>Cerebral microbleeds: overview and implications in cognitive impairment</title><secondary-title>Alzheimers Res Ther</secondary-title></titles><periodical><full-title>Alzheimers Res Ther</full-title></periodical><pages>33</pages><volume>6</volume><number>3</number><dates><year>2014</year></dates><isbn>1758-9193 (Electronic)</isbn><accession-num>24987468</accession-num><urls><related-urls><url>;[64] The prevalence of CMBs detected in community-dwelling subjects in the Rotterdam Scan study (n=3979, mean age= 60.3 years) and AGES-Reykjavik study (n=1962, mean age=76 years) was 11.1-15.3%PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdmVpbmJqb3Juc2RvdHRpcjwvQXV0aG9yPjxZZWFyPjIw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdmVpbmJqb3Juc2RvdHRpcjwvQXV0aG9yPjxZZWFyPjIw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ADDIN EN.CITE.DATA [65, 66] and increased with age ADDIN EN.CITE <EndNote><Cite><Author>Poels</Author><Year>2010</Year><RecNum>79</RecNum><DisplayText>[66]</DisplayText><record><rec-number>79</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465982040">79</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Poels, M. M.</author><author>Vernooij, M. W.</author><author>Ikram, M. A.</author><author>Hofman, A.</author><author>Krestin, G. P.</author><author>van der Lugt, A.</author><author>Breteler, M. M.</author></authors></contributors><auth-address>Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.</auth-address><titles><title>Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>S103-6</pages><volume>41</volume><number>10 Suppl</number><keywords><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain/*blood supply/pathology</keyword><keyword>Cerebral Hemorrhage/*epidemiology/pathology</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prevalence</keyword><keyword>Risk</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2010</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>20876479</accession-num><urls><related-urls><url>;[66]. In patients with ischaemic stroke and non-traumatic intracerebral haemorrhage (ICH), the prevalence of CMBs could be as high as 33.5-67.5%. ADDIN EN.CITE <EndNote><Cite><Author>Cordonnier</Author><Year>2007</Year><RecNum>82</RecNum><DisplayText>[63]</DisplayText><record><rec-number>82</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465990156">82</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cordonnier, C.</author><author>Al-Shahi Salman, R.</author><author>Wardlaw, J.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. c-cordonnier@chru-lille.fr</auth-address><titles><title>Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>1988-2003</pages><volume>130</volume><number>Pt 8</number><keywords><keyword>Adult</keyword><keyword>Cerebral Hemorrhage/diagnosis/epidemiology/*etiology</keyword><keyword>Cerebrovascular Disorders/complications</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>Prognosis</keyword><keyword>Research Design/standards</keyword><keyword>Risk Factors</keyword><keyword>Stroke/complications</keyword></keywords><dates><year>2007</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1460-2156 (Electronic)
0006-8950 (Linking)</isbn><accession-num>17322562</accession-num><urls><related-urls><url>;[63] It seems that CMBs may be more common in Asian than in non-Asian population. However, the differences might be due to a higher proportion of hypertensive patients recruited in these Asian studies or more hospital-based than community studies. It is unclear whether CMBs increase the risk of haemorrhage in patients receiving antiplatelet or anticoagulant or thrombolytic therapy and further discussion is outside the ischaemic focus of this review. We refer the reader to recent reviews on this topic. PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3Jkb25uaWVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVh
cj48UmVjTnVtPjgyPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls2MywgNjddPC9EaXNwbGF5VGV4dD48
cmVjb3JkPjxyZWMtbnVtYmVyPjgyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9
IkVOIiBkYi1pZD0icDIyNTBkOXg0dzB3eHJldHhzM3B6MHg2cnp2d3Z3YXh6ZGR4IiB0aW1lc3Rh
bXA9IjE0NjU5OTAxNTYiPjgyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv
dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv
cj5Db3Jkb25uaWVyLCBDLjwvYXV0aG9yPjxhdXRob3I+QWwtU2hhaGkgU2FsbWFuLCBSLjwvYXV0
aG9yPjxhdXRob3I+V2FyZGxhdywgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+
PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBDbGluaWNhbCBOZXVyb3NjaWVuY2VzLCBXZXN0ZXJu
IEdlbmVyYWwgSG9zcGl0YWwsIFVuaXZlcnNpdHkgb2YgRWRpbmJ1cmdoLCBFZGluYnVyZ2ggRUg0
IDJYVSwgVUsuIGMtY29yZG9ubmllckBjaHJ1LWxpbGxlLmZyPC9hdXRoLWFkZHJlc3M+PHRpdGxl
cz48dGl0bGU+U3BvbnRhbmVvdXMgYnJhaW4gbWljcm9ibGVlZHM6IHN5c3RlbWF0aWMgcmV2aWV3
LCBzdWJncm91cCBhbmFseXNlcyBhbmQgc3RhbmRhcmRzIGZvciBzdHVkeSBkZXNpZ24gYW5kIHJl
cG9ydGluZzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CcmFpbjwvc2Vjb25kYXJ5LXRpdGxlPjwv
dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyYWluPC9mdWxsLXRpdGxlPjwvcGVyaW9k
aWNhbD48cGFnZXM+MTk4OC0yMDAzPC9wYWdlcz48dm9sdW1lPjEzMDwvdm9sdW1lPjxudW1iZXI+
UHQgODwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5D
ZXJlYnJhbCBIZW1vcnJoYWdlL2RpYWdub3Npcy9lcGlkZW1pb2xvZ3kvKmV0aW9sb2d5PC9rZXl3
b3JkPjxrZXl3b3JkPkNlcmVicm92YXNjdWxhciBEaXNvcmRlcnMvY29tcGxpY2F0aW9uczwva2V5
d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr
ZXl3b3JkPk1hZ25ldGljIFJlc29uYW5jZSBJbWFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8
L2tleXdvcmQ+PGtleXdvcmQ+UHJldmFsZW5jZTwva2V5d29yZD48a2V5d29yZD5Qcm9nbm9zaXM8
L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2ggRGVzaWduL3N0YW5kYXJkczwva2V5d29yZD48a2V5
d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+U3Ryb2tlL2NvbXBsaWNhdGlvbnM8
L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNzwveWVhcj48cHViLWRhdGVzPjxk
YXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0NjAtMjE1NiAoRWxlY3Ry
b25pYykmI3hEOzAwMDYtODk1MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTczMjI1
NjI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi
aS5ubG0ubmloLmdvdi9wdWJtZWQvMTczMjI1NjI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+
PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwOTMvYnJhaW4vYXdsMzg3PC9lbGVjdHJvbmlj
LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5LYWthcjwvQXV0aG9y
PjxZZWFyPjIwMTI8L1llYXI+PFJlY051bT4xMTE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVy
PjExMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InAyMjUw
ZDl4NHcwd3hyZXR4czNwejB4NnJ6dnd2d2F4emRkeCIgdGltZXN0YW1wPSIxNDcyNDIwNTQwIj4x
MTE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x
NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPktha2FyLCBQLjwvYXV0
aG9yPjxhdXRob3I+Q2hhcmlkaW1vdSwgQS48L2F1dGhvcj48YXV0aG9yPldlcnJpbmcsIEQuIEou
PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVu
dCBvZiBTdHJva2UgTWVkaWNpbmUsIEltcGVyaWFsIENvbGxlZ2UgSGVhbHRoY2FyZSBOSFMgVHJ1
c3QgLCBMb25kb24gVzYgOFJGICwgVUsuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2Vy
ZWJyYWwgbWljcm9ibGVlZHM6IGEgbmV3IGRpbGVtbWEgaW4gc3Ryb2tlIG1lZGljaW5lPC90aXRs
ZT48c2Vjb25kYXJ5LXRpdGxlPkpSU00gQ2FyZGlvdmFzYyBEaXM8L3NlY29uZGFyeS10aXRsZT48
L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KUlNNIENhcmRpb3Zhc2MgRGlzPC9mdWxs
LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjA0ODAwNDAxMjQ3NDc1NDwvcGFnZXM+PHZvbHVt
ZT4xPC92b2x1bWU+PG51bWJlcj44PC9udW1iZXI+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PC9k
YXRlcz48aXNibj4yMDQ4LTAwNDAgKEVsZWN0cm9uaWMpJiN4RDsyMDQ4LTAwNDAgKExpbmtpbmcp
PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0MTc1MDc5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh
dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI0MTc1MDc5
PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzM3MzgzNzE8L2N1c3RvbTI+
PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExNzcvMjA0ODAwNDAxMjQ3NDc1NDwvZWxlY3Ry
b25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3Jkb25uaWVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVh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ADDIN EN.CITE.DATA [63, 67] and note that randomised trials are needed to answer these questions. Risk factors and causes of ‘silent’ CSVDIncreasing age is significantly associated with CSVD features, thus age has to be controlled for while interpreting relevant studies. Modifiable risk factors including hypertension, hypercholesterolaemia, smoking and diabetes mellitus are also thought to be key risk factors in the pathogenesis of CSVD, particularly hypertension. However the relationship between these risk factors and CSVD is complex. Lipohyalinosis, the typical vascular changes of CSVD, has long been thought to result from hypertension. The theory is supported by clinical evidence showing that hypertension is more prevalent in patients with WMH and that higher blood pressure was associated with more severe WMH.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gRGlqazwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gRGlqazwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+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ADDIN EN.CITE.DATA [68] A recent study shows that vascular risk factors and large artery disease explained only 2% of the variance in WMH, leaving 98% of the variance unexplained, providing further evidence that WMH are mostly nonathromatous.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48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 EN.CITE.DATA [69] This finding may give a clue as to why risk factor modifications so far have very limited effects on preventing WMH progression. Other important risk factors for CSVD include other high risk lifestyles: lack of exercise, poor diet, and smoking. High salt intake is associated with more severe WMH, not only through causing high blood pressure but may also have direct effects on the endothelium. ADDIN EN.CITE <EndNote><Cite><Author>Ihara</Author><Year>2016</Year><RecNum>52</RecNum><DisplayText>[70]</DisplayText><record><rec-number>52</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463794644">52</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ihara, M.</author><author>Yamamoto, Y.</author></authors></contributors><auth-address>From the Departments of Stroke and Cerebrovascular Diseases (M.I.) and Regenerative Medicine and Tissue Engineering (M.I., Y.Y.), National Cerebral and Cardiovascular Center, Suita, Japan. ihara@ncvc.go.jp.
From the Departments of Stroke and Cerebrovascular Diseases (M.I.) and Regenerative Medicine and Tissue Engineering (M.I., Y.Y.), National Cerebral and Cardiovascular Center, Suita, Japan.</auth-address><titles><title>Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>554-60</pages><volume>47</volume><number>2</number><keywords><keyword>blood pressure</keyword><keyword>cerebral small vessel diseases</keyword><keyword>endothelium</keyword><keyword>hypertension</keyword><keyword>infection</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>26742799</accession-num><urls><related-urls><url>;[70] Current smoking is also an independent predictor of WMH progression ADDIN EN.CITE <EndNote><Cite><Author>van Dijk</Author><Year>2008</Year><RecNum>53</RecNum><DisplayText>[71]</DisplayText><record><rec-number>53</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463794724">53</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Dijk, E. J.</author><author>Prins, N. D.</author><author>Vrooman, H. A.</author><author>Hofman, A.</author><author>Koudstaal, P. J.</author><author>Breteler, M. M.</author></authors></contributors><auth-address>Department of Epidemiology &Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.</auth-address><titles><title>Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>2712-9</pages><volume>39</volume><number>10</number><keywords><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Blood Pressure/physiology</keyword><keyword>Brain/*blood supply/pathology</keyword><keyword>Brain Infarction/*complications/*pathology</keyword><keyword>Cognition Disorders/*etiology/*pathology/psychology</keyword><keyword>Disease Progression</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neuropsychological Tests</keyword><keyword>Risk Factors</keyword><keyword>Sex Factors</keyword><keyword>Smoking/adverse effects</keyword></keywords><dates><year>2008</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>18635849</accession-num><urls><related-urls><url>;[71] and is associated with a high burden of combined CSVD featuresPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFhbHM8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
ZWNOdW0+NTU8L1JlY051bT48RGlzcGxheVRleHQ+WzcyXTwvRGlzcGxheVRleHQ+PHJlY29yZD48
cmVjLW51bWJlcj41NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGIt
aWQ9InAyMjUwZDl4NHcwd3hyZXR4czNwejB4NnJ6dnd2d2F4emRkeCIgdGltZXN0YW1wPSIxNDYz
Nzk0OTEyIj41NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy
dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U3RhYWxz
LCBKLjwvYXV0aG9yPjxhdXRob3I+TWFraW4sIFMuIEQuPC9hdXRob3I+PGF1dGhvcj5Eb3ViYWws
IEYuIE4uPC9hdXRob3I+PGF1dGhvcj5EZW5uaXMsIE0uIFMuPC9hdXRob3I+PGF1dGhvcj5XYXJk
bGF3LCBKLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz
PkZyb20gdGhlIENlbnRyZSBmb3IgQ2xpbmljYWwgQnJhaW4gU2NpZW5jZXMgKFMuRC5KLk0uLCBG
Lk4uRC4sIE0uUy5ELiwgSi5NLlcuKSwgVW5pdmVyc2l0eSBvZiBFZGluYnVyZ2gsIFVLOyBhbmQg
RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3kgYW5kIENhcmRpb3Zhc2N1bGFyIFJlc2VhcmNoIEluc3Rp
dHV0ZSBNYWFzdHJpY2h0IChKLlMuKSwgTWFhc3RyaWNodCBVbml2ZXJzaXR5IE1lZGljYWwgQ2Vu
dHJlLCB0aGUgTmV0aGVybGFuZHMuJiN4RDtGcm9tIHRoZSBDZW50cmUgZm9yIENsaW5pY2FsIEJy
YWluIFNjaWVuY2VzIChTLkQuSi5NLiwgRi5OLkQuLCBNLlMuRC4sIEouTS5XLiksIFVuaXZlcnNp
dHkgb2YgRWRpbmJ1cmdoLCBVSzsgYW5kIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5IGFuZCBDYXJk
aW92YXNjdWxhciBSZXNlYXJjaCBJbnN0aXR1dGUgTWFhc3RyaWNodCAoSi5TLiksIE1hYXN0cmlj
aHQgVW5pdmVyc2l0eSBNZWRpY2FsIENlbnRyZSwgdGhlIE5ldGhlcmxhbmRzLiBqb2FubmEud2Fy
ZGxhd0BlZC5hYy51ay48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5TdHJva2Ugc3VidHlw
ZSwgdmFzY3VsYXIgcmlzayBmYWN0b3JzLCBhbmQgdG90YWwgTVJJIGJyYWluIHNtYWxsLXZlc3Nl
bCBkaXNlYXNlIGJ1cmRlbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2xvZ3k8L3NlY29u
ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2xvZ3k8L2Z1
bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjI4LTM0PC9wYWdlcz48dm9sdW1lPjgzPC92
b2x1bWU+PG51bWJlcj4xNDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29y
ZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3
b3JkPjxrZXl3b3JkPkF0cm9waHkvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluLypw
YXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4gSXNjaGVtaWEvKnBhdGhvbG9neTwva2V5
d29yZD48a2V5d29yZD5DZXJlYnJhbCBTbWFsbCBWZXNzZWwgRGlzZWFzZXMvKnBhdGhvbG9neTwv
a2V5d29yZD48a2V5d29yZD5Dcm9zcy1TZWN0aW9uYWwgU3R1ZGllczwva2V5d29yZD48a2V5d29y
ZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cGVy
dGVuc2lvbjwva2V5d29yZD48a2V5d29yZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5
d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3Jk
PjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0
b3JzPC9rZXl3b3JkPjxrZXl3b3JkPipTZXZlcml0eSBvZiBJbGxuZXNzIEluZGV4PC9rZXl3b3Jk
PjxrZXl3b3JkPlNleCBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlNtb2tpbmc8L2tleXdvcmQ+
PGtleXdvcmQ+U3Ryb2tlL2NsYXNzaWZpY2F0aW9uLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv
cmQ+U3Ryb2tlLCBMYWN1bmFyLypwYXRob2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+
PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPlNlcCAzMDwvZGF0ZT48L3B1Yi1kYXRl
cz48L2RhdGVzPjxpc2JuPjE1MjYtNjMyWCAoRWxlY3Ryb25pYykmI3hEOzAwMjgtMzg3OCAoTGlu
a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjUxNjUzODg8L2FjY2Vzc2lvbi1udW0+PHVybHM+
PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjUx
NjUzODg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNDE4MDQ4NDwvY3Vz
dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTIxMi9XTkwuMDAwMDAwMDAwMDAwMDgz
NzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFhbHM8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA [72]. And lack of exercise is a risk factor for having more WMH in later life, although it is not clear if active exercise programs reduce WMH risk.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb3c8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb3c8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA [73] CSVD as a ‘whole-brain disease’ Common small vessel pathologies and BBB impairment were found in both clinically evident and covert CSVD features, suggesting that CSVD should be regarded as a whole-brain disease rather than be treated separately as individual conditions. Small penetrating vessels and endothelium which forms the BBB are diffuse in the brain. Various studies also demonstrate that all these CSVD features were associated with each other: patients with small vessel stroke (TOAST classification) or lacunar stroke (OCSP classification) had more WMH than those who had other stroke subtypes;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3N0PC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3N0PC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj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ADDIN EN.CITE.DATA [74, 75] more than 90% of incident lacunes appeared at the edge of WMH or had partial overlap with WMH in 365 Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWVyaW5nPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWVyaW5nPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA [4] visible PVS were frequently seen in patients with lacunar stroke, WMH and lacunes; CMBs were also associated with WMH and lacunar stroke. ADDIN EN.CITE <EndNote><Cite><Author>Cordonnier</Author><Year>2007</Year><RecNum>56</RecNum><DisplayText>[63]</DisplayText><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463795018">56</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cordonnier, C.</author><author>Al-Shahi Salman, R.</author><author>Wardlaw, J.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. c-cordonnier@chru-lille.fr</auth-address><titles><title>Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>1988-2003</pages><volume>130</volume><number>Pt 8</number><keywords><keyword>Adult</keyword><keyword>Cerebral Hemorrhage/diagnosis/epidemiology/*etiology</keyword><keyword>Cerebrovascular Disorders/complications</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>Prognosis</keyword><keyword>Research Design/standards</keyword><keyword>Risk Factors</keyword><keyword>Stroke/complications</keyword></keywords><dates><year>2007</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1460-2156 (Electronic)
0006-8950 (Linking)</isbn><accession-num>17322562</accession-num><urls><related-urls><url>;[63] When counting the presence of any CSVD as total CSVD score, patients with lacunar stroke had significantly higher CSVD burden than those with cortical stroke.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFhbHM8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFhbHM8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA [72] But why do some CSVD lesions cause stroke while others are ‘silent’? One explanation is the locations of lesions. A study using probability mapping shows that lesions presenting with stroke were predominantly located in or near the primary motor and sensory tracts, whereas silent lesions were mostly in basal ganglia and centrum semiovale away from these main tracts.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWxkZXMgSGVybmFuZGV6IE1kZWw8L0F1dGhvcj48WWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWxkZXMgSGVybmFuZGV6IE1kZWw8L0F1dGhvcj48WWVh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ADDIN EN.CITE.DATA [76] Another explanation could be the levels of vessels where the vascular pathologies happened. In general, disrupted BBB would enable plasma fluid components and blood cells enter the vessel wall, leading to disintegration of the vessel wall and fibrin deposition. If this happens at arterioles where there is smooth muscle, the components deposited in the arteriolar wall could result in both dilation and narrowing of the vessel lumen and vessel wall thickening, which would eventually precipitate inflammation, platelet adhesion, luminal occlusion and thus traditional infarct. Whereas at capillary level where there is no smooth muscle between epithelium and brain tissue, the leaky BBB would cause direct damage in the tissue, such as oedema and demyelination in white matter tracts. Further studies to assess changes over time in lesion development and symptoms are required to find out the reasons.CSVD as a ‘dynamic disease’There is increasing evidence showing that CSVD is more dynamic than originally thought. Lesions progress over time and the long-term outcome and impact on brain damage varies. Cavitation is not the only fate of acute lacunar ischaemic stroke.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3R0ZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3R0ZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS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ADDIN EN.CITE.DATA [77] An acute lacunar ischaemic stroke can also disappear or resemble a WMH.(Figure 4) In a prospective study (n=90), definite cavitation (i.e. that looked like a lacune) was only present in 20% of patients, and was marginally associated with increasing time from stroke onset to follow-up scans. A large proportion of lacunar lesions remained looking like WMH. Thus only calculating cavitated lacunes could lead to a large underestimation of lacunar ischaemic stroke burden. Similarly, WMH burden is likely to be overestimated without previous scans of index stroke lesions. The evolution of WMH also varies. The single strongest predictor of WMH progression is high baseline WMH,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2htaWR0PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2htaWR0PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48
UmVjTnVtPjQwPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3OCwgNzldPC9EaXNwbGF5VGV4dD48cmVj
b3JkPjxyZWMtbnVtYmVyPjQwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO
IiBkYi1pZD0icDIyNTBkOXg0dzB3eHJldHhzM3B6MHg2cnp2d3Z3YXh6ZGR4IiB0aW1lc3RhbXA9
IjE0NjM3OTI0MTUiPjQwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu
YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5T
Y2htaWR0LCBSLjwvYXV0aG9yPjxhdXRob3I+RW56aW5nZXIsIEMuPC9hdXRob3I+PGF1dGhvcj5S
b3BlbGUsIFMuPC9hdXRob3I+PGF1dGhvcj5TY2htaWR0LCBILjwvYXV0aG9yPjxhdXRob3I+RmF6
ZWthcywgRi48L2F1dGhvcj48YXV0aG9yPkF1c3RyaWFuIFN0cm9rZSBQcmV2ZW50aW9uLCBTdHVk
eTwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1l
bnQgb2YgTmV1cm9sb2d5LCBLYXJsLUZyYW56ZW5zIFVuaXZlcnNpdHkgR3JheiwgQS04MDM2LCBH
cmF6LCBBdXN0cmlhLiByZWluaG9sZC5zY2htaWR0QGtmdW5pZ3Jhei5hYy5hdDwvYXV0aC1hZGRy
ZXNzPjx0aXRsZXM+PHRpdGxlPlByb2dyZXNzaW9uIG9mIGNlcmVicmFsIHdoaXRlIG1hdHRlciBs
ZXNpb25zOiA2LXllYXIgcmVzdWx0cyBvZiB0aGUgQXVzdHJpYW4gU3Ryb2tlIFByZXZlbnRpb24g
U3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0PC9zZWNvbmRhcnktdGl0bGU+PC90
aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TGFuY2V0PC9mdWxsLXRpdGxlPjwvcGVyaW9k
aWNhbD48cGFnZXM+MjA0Ni04PC9wYWdlcz48dm9sdW1lPjM2MTwvdm9sdW1lPjxudW1iZXI+OTM3
NDwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnaW5n
LypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vKnBhdGhvbG9neTwva2V5d29yZD48
a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rm9sbG93LVVwIFN0dWRpZXM8L2tleXdv
cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJlc29uYW5jZSBJ
bWFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFn
ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh
dGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW4gMTQ8L2RhdGU+PC9wdWIt
ZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0LTU0N1ggKEVsZWN0cm9uaWMpJiN4RDswMTQwLTY3MzYg
KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEyODE0NzE4PC9hY2Nlc3Npb24tbnVtPjx1
cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk
LzEyODE0NzE4PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0
ZT48QXV0aG9yPkdvdXc8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNOdW0+NDE8L1JlY051
bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh
cHA9IkVOIiBkYi1pZD0icDIyNTBkOXg0dzB3eHJldHhzM3B6MHg2cnp2d3Z3YXh6ZGR4IiB0aW1l
c3RhbXA9IjE0NjM3OTI0OTYiPjQxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9
IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1
dGhvcj5Hb3V3LCBBLiBBLjwvYXV0aG9yPjxhdXRob3I+dmFuIGRlciBGbGllciwgVy4gTS48L2F1
dGhvcj48YXV0aG9yPkZhemVrYXMsIEYuPC9hdXRob3I+PGF1dGhvcj52YW4gU3RyYWF0ZW4sIEUu
IEMuPC9hdXRob3I+PGF1dGhvcj5QYW50b25pLCBMLjwvYXV0aG9yPjxhdXRob3I+UG9nZ2VzaSwg
QS48L2F1dGhvcj48YXV0aG9yPklueml0YXJpLCBELjwvYXV0aG9yPjxhdXRob3I+RXJraW5qdW50
dGksIFQuPC9hdXRob3I+PGF1dGhvcj5XYWhsdW5kLCBMLiBPLjwvYXV0aG9yPjxhdXRob3I+V2Fs
ZGVtYXIsIEcuPC9hdXRob3I+PGF1dGhvcj5TY2htaWR0LCBSLjwvYXV0aG9yPjxhdXRob3I+U2No
ZWx0ZW5zLCBQLjwvYXV0aG9yPjxhdXRob3I+QmFya2hvZiwgRi48L2F1dGhvcj48YXV0aG9yPkxh
ZGlzIFN0dWR5IEdyb3VwPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk
ZHJlc3M+RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIEFsemhlaW1lciBDZW50ZXIgYW5kIEltYWdl
IEFuYWx5c2lzIENlbnRlciwgVnJpamUgVW5pdmVyc2l0ZWl0IE1lZGljYWwgQ2VudGVyLCBQTyBC
b3ggNzA1NywgMTAwNyBNQiBBbXN0ZXJkYW0sIFRoZSBOZXRoZXJsYW5kcy4gQUEuR291d0B2dW1j
Lm5sPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UHJvZ3Jlc3Npb24gb2Ygd2hpdGUgbWF0
dGVyIGh5cGVyaW50ZW5zaXRpZXMgYW5kIGluY2lkZW5jZSBvZiBuZXcgbGFjdW5lcyBvdmVyIGEg
My15ZWFyIHBlcmlvZDogdGhlIExldWtvYXJhaW9zaXMgYW5kIERpc2FiaWxpdHkgc3R1ZHk8L3Rp
dGxlPjxzZWNvbmRhcnktdGl0bGU+U3Ryb2tlPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl
cmlvZGljYWw+PGZ1bGwtdGl0bGU+U3Ryb2tlPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn
ZXM+MTQxNC0yMDwvcGFnZXM+PHZvbHVtZT4zOTwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxr
ZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVy
PC9rZXl3b3JkPjxrZXl3b3JkPkJhc2FsIEdhbmdsaWEvYmxvb2Qgc3VwcGx5L3BhdGhvbG9neS9w
aHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QnJhaW4vYmxvb2Qgc3VwcGx5LypwYXRo
b2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluIEluZmFyY3Rpb24v
KmVwaWRlbWlvbG9neS8qcGF0aG9sb2d5L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y
ZD5CcmFpbiBJc2NoZW1pYS9lcGlkZW1pb2xvZ3kvcGF0aG9sb2d5L3BoeXNpb3BhdGhvbG9neTwv
a2V5d29yZD48a2V5d29yZD5DYXJkaW92YXNjdWxhciBEaXNlYXNlcy9lcGlkZW1pb2xvZ3k8L2tl
eXdvcmQ+PGtleXdvcmQ+Q2VyZWJyYWwgQXJ0ZXJpZXMvcGF0aG9sb2d5L3BoeXNpb3BhdGhvbG9n
eTwva2V5d29yZD48a2V5d29yZD5Db21vcmJpZGl0eTwva2V5d29yZD48a2V5d29yZD5EaXNlYXNl
IFByb2dyZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5G
b2xsb3ctVXAgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5Gcm9udGFsIExvYmUvYmxvb2Qgc3Vw
cGx5L3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r
ZXl3b3JkPjxrZXl3b3JkPkh5cGVybGlwaWRlbWlhcy9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtl
eXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkxldWtvYXJhaW9zaXMvKmVwaWRlbWlv
bG9neS8qcGF0aG9sb2d5L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5NYWduZXRp
YyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3
b3JkPk5lcnZlIEZpYmVycywgTXllbGluYXRlZC8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk
PlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3
b3JkPlRpbWUgRmFjdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA4PC95
ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+
MTUyNC00NjI4IChFbGVjdHJvbmljKSYjeEQ7MDAzOS0yNDk5IChMaW5raW5nKTwvaXNibj48YWNj
ZXNzaW9uLW51bT4xODMyMzUwNTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1
cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xODMyMzUwNTwvdXJsPjwvcmVs
YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE2MS9TVFJPS0VB
SEEuMTA3LjQ5ODUzNTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwv
RW5kTm90ZT4A
ADDIN EN.CITE.DATA [78, 79] with little progression in punctuate WMH but rapid progression in confluent WMHs. ADDIN EN.CITE <EndNote><Cite><Author>Schmidt</Author><Year>2016</Year><RecNum>85</RecNum><DisplayText>[80]</DisplayText><record><rec-number>85</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1466520405">85</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schmidt, R.</author><author>Seiler, S.</author><author>Loitfelder, M.</author></authors></contributors><titles><title>Longitudinal change of small-vessel disease-related brain abnormalities</title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><pages>26-39</pages><volume>36</volume><number>1</number><keywords><keyword>Brain/*blood supply/pathology</keyword><keyword>Cerebral Hemorrhage/pathology</keyword><keyword>Cerebral Small Vessel Diseases/*pathology</keyword><keyword>Dementia, Vascular/pathology</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Microvessels/*pathology</keyword><keyword>Stroke, Lacunar/pathology</keyword><keyword>Time Factors</keyword><keyword>White Matter/blood supply/pathology</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1559-7016 (Electronic)
0271-678X (Linking)</isbn><accession-num>25899293</accession-num><urls><related-urls><url>;[80] The Austrian Stroke Prevention Study, a community-based study, reported WMH progression in about 18% of subjects with vascular risk factors. ADDIN EN.CITE <EndNote><Cite><Author>Schmidt</Author><Year>2003</Year><RecNum>40</RecNum><DisplayText>[78]</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463792415">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schmidt, R.</author><author>Enzinger, C.</author><author>Ropele, S.</author><author>Schmidt, H.</author><author>Fazekas, F.</author><author>Austrian Stroke Prevention, Study</author></authors></contributors><auth-address>Department of Neurology, Karl-Franzens University Graz, A-8036, Graz, Austria. reinhold.schmidt@kfunigraz.ac.at</auth-address><titles><title>Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>2046-8</pages><volume>361</volume><number>9374</number><keywords><keyword>Aged</keyword><keyword>Aging/*pathology</keyword><keyword>Brain/*pathology</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2003</year><pub-dates><date>Jun 14</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>12814718</accession-num><urls><related-urls><url>;[78] WMH can also cavitate to take on the appearance of lacunes and they can also disappear – these dynamic features are only now being realised. Though early microstructural impairment could be detected in NAWM contouring WMH, not all NAWM will eventually develop into WMH. ADDIN EN.CITE <EndNote><Cite><Author>Munoz Maniega</Author><Year>Published online first: 1 March 2016 </Year><RecNum>92</RecNum><DisplayText>[81]</DisplayText><record><rec-number>92</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468401740">92</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Munoz Maniega, S.</author><author>Chappell, F. M.</author><author>Valdes Hernandez, M. C.</author><author>Armitage, P. A.</author><author>Makin, S. D.</author><author>Heye, A. K.</author><author>Thrippleton, M. J.</author><author>Sakka, E.</author><author>Shuler, K.</author><author>Dennis, M. S.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK joanna.wardlaw@ed.ac.uk.</auth-address><titles><title>Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease</title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><volume>DOI: 10.1177/0271678X16635657.</volume><keywords><keyword>Magnetic resonance imaging</keyword><keyword>ageing</keyword><keyword>blood-brain barrier</keyword><keyword>cerebrovascular disease</keyword><keyword>diffusion tensor imaging</keyword></keywords><dates><year>Published online first: 1 March 2016 </year><pub-dates><date>Mar 1</date></pub-dates></dates><isbn>1559-7016 (Electronic)
0271-678X (Linking)</isbn><accession-num>26933133</accession-num><urls><related-urls><url>;[81] The level of NAWM deterioration was also strongly associated with WMH severity, regardless of distance from the WMH.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5pZWdhPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5pZWdhPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48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ADDIN EN.CITE.DATA [32] The variance in long-term changes of CSVD lesions might reflect different pathologies underlying the similar appearance on imaging, e.g. reversible lacunar ischaemic stroke lesions versus those that cavitated, or NAWM in patients with mild WMH versus in extensive WMH. Serial imaging studies using advanced techniques like cerebral vascular reactivity, BBB and CBF imaging and use of higher fields e.g. 7 tesla MRI might help differentiate these changes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3V2eTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3V2eTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl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ADDIN EN.CITE.DATA [82] Treatments for CSVDManagement of traditional risk factors is still the main approach for treating or preventing CSVD, despite the fact that most of these treatments have not yet shown ideal effects on long-term outcome. Antihypertensive treatment produced contradicting results: it reduced WMH progression in some observational studies ADDIN EN.CITE <EndNote><Cite><Author>Dufouil</Author><Year>2001</Year><RecNum>46</RecNum><DisplayText>[83]</DisplayText><record><rec-number>46</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463793426">46</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dufouil, C.</author><author>de Kersaint-Gilly, A.</author><author>Besancon, V.</author><author>Levy, C.</author><author>Auffray, E.</author><author>Brunnereau, L.</author><author>Alperovitch, A.</author><author>Tzourio, C.</author></authors></contributors><auth-address>Institut National de la Sante et de la Recherche Medicale U360, Hopital la Salpetriere, Paris, France. carole.dufouil@chups.jussieu.fr</auth-address><titles><title>Longitudinal study of blood pressure and white matter hyperintensities: the EVA MRI Cohort</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>921-6</pages><volume>56</volume><number>7</number><keywords><keyword>Aged</keyword><keyword>Blood Pressure/*physiology</keyword><keyword>Brain/*pathology/physiopathology</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Hypertension/*pathology/*physiopathology</keyword><keyword>Longitudinal Studies</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr 10</date></pub-dates></dates><isbn>0028-3878 (Print)
0028-3878 (Linking)</isbn><accession-num>11294930</accession-num><urls><related-urls><url>;[83] but showed little or no effects in randomized controlled trialsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWZvdWlsPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48
UmVjTnVtPjQ3PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls4NCwgODVdPC9EaXNwbGF5VGV4dD48cmVj
b3JkPjxyZWMtbnVtYmVyPjQ3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO
IiBkYi1pZD0icDIyNTBkOXg0dzB3eHJldHhzM3B6MHg2cnp2d3Z3YXh6ZGR4IiB0aW1lc3RhbXA9
IjE0NjM3OTM3MDkiPjQ3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu
YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5E
dWZvdWlsLCBDLjwvYXV0aG9yPjxhdXRob3I+Q2hhbG1lcnMsIEouPC9hdXRob3I+PGF1dGhvcj5D
b3NrdW4sIE8uPC9hdXRob3I+PGF1dGhvcj5CZXNhbmNvbiwgVi48L2F1dGhvcj48YXV0aG9yPkJv
dXNzZXIsIE0uIEcuPC9hdXRob3I+PGF1dGhvcj5HdWlsbG9uLCBQLjwvYXV0aG9yPjxhdXRob3I+
TWFjTWFob24sIFMuPC9hdXRob3I+PGF1dGhvcj5NYXpveWVyLCBCLjwvYXV0aG9yPjxhdXRob3I+
TmVhbCwgQi48L2F1dGhvcj48YXV0aG9yPldvb2R3YXJkLCBNLjwvYXV0aG9yPjxhdXRob3I+VHpv
dXJpby1NYXpveWVyLCBOLjwvYXV0aG9yPjxhdXRob3I+VHpvdXJpbywgQy48L2F1dGhvcj48YXV0
aG9yPlByb2dyZXNzIE1yaSBTdWJzdHVkeSBJbnZlc3RpZ2F0b3JzPC9hdXRob3I+PC9hdXRob3Jz
PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SU5TRVJNIFU3MDgsIFBhcmlzLCBGcmFuY2Uu
PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RWZmZWN0cyBvZiBibG9vZCBwcmVzc3VyZSBs
b3dlcmluZyBvbiBjZXJlYnJhbCB3aGl0ZSBtYXR0ZXIgaHlwZXJpbnRlbnNpdGllcyBpbiBwYXRp
ZW50cyB3aXRoIHN0cm9rZTogdGhlIFBST0dSRVNTIChQZXJpbmRvcHJpbCBQcm90ZWN0aW9uIEFn
YWluc3QgUmVjdXJyZW50IFN0cm9rZSBTdHVkeSkgTWFnbmV0aWMgUmVzb25hbmNlIEltYWdpbmcg
U3Vic3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2lyY3VsYXRpb248L3NlY29uZGFyeS10
aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaXJjdWxhdGlvbjwvZnVsbC10
aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE2NDQtNTA8L3BhZ2VzPjx2b2x1bWU+MTEyPC92b2x1
bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxr
ZXl3b3JkPkFudGloeXBlcnRlbnNpdmUgQWdlbnRzLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+
PGtleXdvcmQ+Qmxvb2QgUHJlc3N1cmUvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5C
cmFpbi8qZHJ1ZyBlZmZlY3RzLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZSBQ
cm9ncmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVt
YW5zPC9rZXl3b3JkPjxrZXl3b3JkPipNYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29y
ZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxr
ZXl3b3JkPk11bHRpY2VudGVyIFN0dWRpZXMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+UGVy
aW5kb3ByaWwvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5SYW5kb21pemVkIENv
bnRyb2xsZWQgVHJpYWxzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3JkPlNlY29uZGFyeSBQcmV2
ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlN0cm9rZS9kaWFnbm9zaXMvKmRydWcgdGhlcmFweS9w
aHlzaW9wYXRob2xvZ3kvcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3Jk
PlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDU8
L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXAgMTM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48
aXNibj4xNTI0LTQ1MzkgKEVsZWN0cm9uaWMpJiN4RDswMDA5LTczMjIgKExpbmtpbmcpPC9pc2Ju
PjxhY2Nlc3Npb24tbnVtPjE2MTQ1MDA0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy
bHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE2MTQ1MDA0PC91cmw+
PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTYxL0NJ
UkNVTEFUSU9OQUhBLjEwNC41MDExNjM8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3Jk
PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPldlYmVyPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj
TnVtPjQ4PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40ODwvcmVjLW51bWJlcj48Zm9yZWln
bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InAyMjUwZDl4NHcwd3hyZXR4czNwejB4NnJ6dnd2
d2F4emRkeCIgdGltZXN0YW1wPSIxNDYzNzkzODg0Ij40ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxy
ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz
PjxhdXRob3JzPjxhdXRob3I+V2ViZXIsIFIuPC9hdXRob3I+PGF1dGhvcj5XZWltYXIsIEMuPC9h
dXRob3I+PGF1dGhvcj5CbGF0Y2hmb3JkLCBKLjwvYXV0aG9yPjxhdXRob3I+SGVybWFuc3Nvbiwg
Sy48L2F1dGhvcj48YXV0aG9yPldhbmtlLCBJLjwvYXV0aG9yPjxhdXRob3I+TW9sbGVyLUhhcnRt
YW5uLCBDLjwvYXV0aG9yPjxhdXRob3I+R2l6ZXdza2ksIEUuIFIuPC9hdXRob3I+PGF1dGhvcj5G
b3JzdGluZywgTS48L2F1dGhvcj48YXV0aG9yPkRlbWNodWssIEEuIE0uPC9hdXRob3I+PGF1dGhv
cj5TYWNjbywgUi4gTC48L2F1dGhvcj48YXV0aG9yPlNhdmVyLCBKLiBMLjwvYXV0aG9yPjxhdXRo
b3I+V2FyYWNoLCBTLjwvYXV0aG9yPjxhdXRob3I+RGllbmVyLCBILiBDLjwvYXV0aG9yPjxhdXRo
b3I+RGllaGwsIEEuPC9hdXRob3I+PGF1dGhvcj5QLiBSb0ZFU1MgSW1hZ2luZyBTdWJzdHVkeSBH
cm91cDwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFy
dG1lbnQgb2YgTmV1cm9sb2d5LCBVbml2ZXJzaXR5IER1aXNidXJnLUVzc2VuLCBIdWZlbGFuZHN0
ci4gNTUsIDQ1MTIyIEVzc2VuLCBHZXJtYW55LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl
PlRlbG1pc2FydGFuIG9uIHRvcCBvZiBhbnRpaHlwZXJ0ZW5zaXZlIHRyZWF0bWVudCBkb2VzIG5v
dCBwcmV2ZW50IHByb2dyZXNzaW9uIG9mIGNlcmVicmFsIHdoaXRlIG1hdHRlciBsZXNpb25zIGlu
IHRoZSBwcmV2ZW50aW9uIHJlZ2ltZW4gZm9yIGVmZmVjdGl2ZWx5IGF2b2lkaW5nIHNlY29uZCBz
dHJva2VzIChQUm9GRVNTKSBNUkkgc3Vic3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+U3Ry
b2tlPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+U3Ry
b2tlPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjMzNi00MjwvcGFnZXM+PHZvbHVt
ZT40Mzwvdm9sdW1lPjxudW1iZXI+OTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2UgRmFj
dG9yczwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFu
ZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFuZ2lvdGVuc2luIElJIFR5cGUgMSBSZWNlcHRvciBC
bG9ja2Vycy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFudGloeXBlcnRlbnNp
dmUgQWdlbnRzLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QXNwaXJpbi90aGVy
YXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QmVuemltaWRhem9sZXMvKnRoZXJhcGV1dGlj
IHVzZTwva2V5d29yZD48a2V5d29yZD5CZW56b2F0ZXMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29y
ZD48a2V5d29yZD5CbG9vZCBQcmVzc3VyZS9kcnVnIGVmZmVjdHMvcGh5c2lvbG9neTwva2V5d29y
ZD48a2V5d29yZD5CcmFpbi8qcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgUHJv
Z3Jlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxv
dy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5M
b2dpc3RpYyBNb2RlbHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVzb25hbmNlIEltYWdp
bmc8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwv
a2V5d29yZD48a2V5d29yZD5QbGF0ZWxldCBBZ2dyZWdhdGlvbiBJbmhpYml0b3JzL3RoZXJhcGV1
dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+
U2Vjb25kYXJ5IFByZXZlbnRpb248L2tleXdvcmQ+PGtleXdvcmQ+U3Ryb2tlLypkcnVnIHRoZXJh
cHkvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3Jk
Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5TZXA8
L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTI0LTQ2MjggKEVsZWN0cm9uaWMpJiN4
RDswMDM5LTI0OTkgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIyNzM4OTIyPC9hY2Nl
c3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5p
aC5nb3YvcHVibWVkLzIyNzM4OTIyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJv
bmljLXJlc291cmNlLW51bT4xMC4xMTYxL1NUUk9LRUFIQS4xMTEuNjQ4NTc2PC9lbGVjdHJvbmlj
LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWZvdWlsPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48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ADDIN EN.CITE.DATA [84, 85]. Although hypertension has been reported highly associated with CSVD, other factors may be involved, or be influenced by genetic factors,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdXJuZXI8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdXJuZXI8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS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ADDIN EN.CITE.DATA [86] yet more evidences are required. Likewise, most lipid-lowering treatment had neutral results in preventing WMH, like pravastatin.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj50ZW4gRGFtPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj50ZW4gRGFtPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48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ADDIN EN.CITE.DATA [87] Post hoc analysis of a 2-year follow-up study from Hong Kong showed that statins might be able to delay WMH progression in patients with severe baseline WMH.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2s8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxSZWNO
dW0+NDk8L1JlY051bT48RGlzcGxheVRleHQ+Wzg4XTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVj
LW51bWJlcj40OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9
InAyMjUwZDl4NHcwd3hyZXR4czNwejB4NnJ6dnd2d2F4emRkeCIgdGltZXN0YW1wPSIxNDYzNzkz
OTk2Ij40OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj
bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TW9rLCBWLiBD
LjwvYXV0aG9yPjxhdXRob3I+TGFtLCBXLiBXLjwvYXV0aG9yPjxhdXRob3I+RmFuLCBZLiBILjwv
YXV0aG9yPjxhdXRob3I+V29uZywgQS48L2F1dGhvcj48YXV0aG9yPk5nLCBQLiBXLjwvYXV0aG9y
PjxhdXRob3I+VHNvaSwgVC4gSC48L2F1dGhvcj48YXV0aG9yPllldW5nLCBWLjwvYXV0aG9yPjxh
dXRob3I+V29uZywgSy4gUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt
YWRkcmVzcz5EZXBhcnRtZW50IG9mIE1lZGljaW5lIGFuZCBUaGVyYXBldXRpY3MsIFRoZSBDaGlu
ZXNlIFVuaXZlcnNpdHkgb2YgSG9uZyBLb25nLCBTaGF0aW4sIEhvbmcgS29uZyBTQVIsIENoaW5h
LiB2Y3Rtb2tAY3Voay5lZHUuaGs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5FZmZlY3Rz
IG9mIHN0YXRpbnMgb24gdGhlIHByb2dyZXNzaW9uIG9mIGNlcmVicmFsIHdoaXRlIG1hdHRlciBs
ZXNpb246IFBvc3QgaG9jIGFuYWx5c2lzIG9mIHRoZSBST0NBUyAoUmVncmVzc2lvbiBvZiBDZXJl
YnJhbCBBcnRlcnkgU3Rlbm9zaXMpIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogTmV1
cm9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBO
ZXVyb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz43NTAtNzwvcGFnZXM+PHZvbHVt
ZT4yNTY8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwv
a2V5d29yZD48a2V5d29yZD5CcmFpbiBNYXBwaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVicmFs
IEFydGVyaWVzLypkcnVnIGVmZmVjdHMvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlcmVi
cmFsIENvcnRleC9ibG9vZCBzdXBwbHkvKmRydWcgZWZmZWN0cy9wYXRob2xvZ3k8L2tleXdvcmQ+
PGtleXdvcmQ+RGVtZW50aWEsIFZhc2N1bGFyL2RydWcgdGhlcmFweS9wYXRob2xvZ3kvcHJldmVu
dGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgUHJvZ3Jlc3Npb248
L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5G
ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5ZHJveHlt
ZXRoeWxnbHV0YXJ5bC1Db0EgUmVkdWN0YXNlIEluaGliaXRvcnMvKnBoYXJtYWNvbG9neS90aGVy
YXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+SW1hZ2UgUHJvY2Vzc2luZywgQ29tcHV0ZXIt
QXNzaXN0ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+SW5mYXJjdGlvbiwgTWlkZGxlIENlcmVicmFsIEFy
dGVyeS8qZHJ1ZyB0aGVyYXB5L3BhdGhvbG9neS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtl
eXdvcmQ+SW50cmFjcmFuaWFsIEFydGVyaW9zY2xlcm9zaXMvKmRydWcgdGhlcmFweS9wYXRob2xv
Z3kvcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPk1hZ25ldGljIFJl
c29uYW5jZSBJbWFnaW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+
TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmVydmUgRmliZXJzLCBNeWVsaW5hdGVkLypk
cnVnIGVmZmVjdHMvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBsYWNlYm9zPC9rZXl3b3Jk
PjxrZXl3b3JkPlNldmVyaXR5IG9mIElsbG5lc3MgSW5kZXg8L2tleXdvcmQ+PGtleXdvcmQ+U2lt
dmFzdGF0aW4vcGhhcm1hY29sb2d5L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5U
cmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5PC95
ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+
MTQzMi0xNDU5IChFbGVjdHJvbmljKSYjeEQ7MDM0MC01MzU0IChMaW5raW5nKTwvaXNibj48YWNj
ZXNzaW9uLW51bT4xOTI1MjgxMTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1
cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xOTI1MjgxMTwvdXJsPjwvcmVs
YXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDA0MTUt
MDA5LTUwMDgtNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k
Tm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2s8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA [88] Statins might also have other therapeutic effects including anti-inflammatory and pro-endothelial activities. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>58</RecNum><DisplayText>[89]</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463795253">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, P. M.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>469-78</pages><volume>10</volume><number>4</number><keywords><keyword>Cerebral Small Vessel Diseases/*drug therapy/physiopathology</keyword><keyword>Humans</keyword><keyword>antithrombotics</keyword><keyword>blood brain barrier</keyword><keyword>blood pressure lowering</keyword><keyword>cyclic nucleotide inhibitors</keyword><keyword>nitric oxide</keyword><keyword>prostacyclin</keyword></keywords><dates><year>2015</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1747-4949 (Electronic)
1747-4930 (Linking)</isbn><accession-num>25727737</accession-num><urls><related-urls><url>;[89] Likewise, subgroup analysis of The VITAmins TO Prevent Stroke (VITATOPS) MRI-Substudy shows that B-vitamin supplementation may reduce WMH progression in patients with severe baseline CSVD.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXZhbGllcmk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXZhbGllcmk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy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ADDIN EN.CITE.DATA [90] Studies of treatment specifically targeting lacunar stroke are limited. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>58</RecNum><DisplayText>[89]</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463795253">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, P. M.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>469-78</pages><volume>10</volume><number>4</number><keywords><keyword>Cerebral Small Vessel Diseases/*drug therapy/physiopathology</keyword><keyword>Humans</keyword><keyword>antithrombotics</keyword><keyword>blood brain barrier</keyword><keyword>blood pressure lowering</keyword><keyword>cyclic nucleotide inhibitors</keyword><keyword>nitric oxide</keyword><keyword>prostacyclin</keyword></keywords><dates><year>2015</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1747-4949 (Electronic)
1747-4930 (Linking)</isbn><accession-num>25727737</accession-num><urls><related-urls><url>;[89] Apart from the SPS3 trial, there are very few clinical trials of antiplatelets where the results were reported by stroke subtype, and, except trials of cilostazolPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGlub2hhcmE8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGlub2hhcmE8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy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ADDIN EN.CITE.DATA [91, 92] which has weak antiplatelet effects ADDIN EN.CITE <EndNote><Cite><Author>Comerota</Author><Year>2005</Year><RecNum>114</RecNum><DisplayText>[93]</DisplayText><record><rec-number>114</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1472744210">114</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Comerota, A. J.</author></authors></contributors><auth-address>Jobst Vascular Center, Conrad Jobst Tower, Suite 400, 2109 Hughes Drive, Toledo, OH 43606, USA. acomerota@</auth-address><titles><title>Effect on platelet function of cilostazol, clopidogrel, and aspirin, each alone or in combination</title><secondary-title>Atheroscler Suppl</secondary-title></titles><periodical><full-title>Atheroscler Suppl</full-title></periodical><pages>13-9</pages><volume>6</volume><number>4</number><keywords><keyword>Aspirin/*pharmacology</keyword><keyword>Bleeding Time</keyword><keyword>Blood Platelets/*drug effects/physiology</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Humans</keyword><keyword>Intermittent Claudication/blood/drug therapy</keyword><keyword>Platelet Aggregation/drug effects</keyword><keyword>Platelet Aggregation Inhibitors/*pharmacology</keyword><keyword>Tetrazoles/*pharmacology</keyword><keyword>Ticlopidine/*analogs & derivatives/pharmacology</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2005</year><pub-dates><date>Dec 15</date></pub-dates></dates><isbn>1567-5688 (Print)
1567-5688 (Linking)</isbn><accession-num>16275168</accession-num><urls><related-urls><url>;[93], are especially scarce in Asian populations. Although some trials reported the proportion of lacunar stroke in their study population, the diagnostic criteria varied considerably and the results were not always reported by subgroup. A systematic review of randomised trials found that any single antiplatelet appeared beneficial for secondary prevention of lacunar stroke,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ld29rPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ld29rPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj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 EN.CITE.DATA [94] but the SPS3 trial showed that long-term dual antiplatelet treatment doubled the risk of bleeding without reducing the risk of stroke recurrence in patients with recent lacunar stroke. Also, blood pressure lowering did not show significant reduction in recurrent lacunar stroke in the SPS3 trial although it was consistent with a modest benefit. ADDIN EN.CITE <EndNote><Cite><Author>Group</Author><Year>2013</Year><RecNum>29</RecNum><DisplayText>[95]</DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463790362">29</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>S. P. S. Study Group</author><author>Benavente, O. R.</author><author>Coffey, C. S.</author><author>Conwit, R.</author><author>Hart, R. G.</author><author>McClure, L. A.</author><author>Pearce, L. A.</author><author>Pergola, P. E.</author><author>Szychowski, J. M.</author></authors></contributors><titles><title>Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>507-15</pages><volume>382</volume><number>9891</number><keywords><keyword>Antihypertensive Agents/*therapeutic use</keyword><keyword>Blood Pressure/drug effects</keyword><keyword>Cerebral Hemorrhage/prevention & control</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hypertension/physiopathology/*prevention & control</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Secondary Prevention</keyword><keyword>Stroke, Lacunar/physiopathology/*prevention & control</keyword><keyword>Systole</keyword><keyword>Time-to-Treatment</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug 10</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>23726159</accession-num><urls><related-urls><url>(13)60852-1</electronic-resource-num></record></Cite></EndNote>[95] Prevention and treatment of CSVD in the future should consider targeting the BBB, brain endothelium and microvascular function. There are multiple potential endothelial targets, such as nitric oxide/cyclic guanylate monophosphate (cGMP) system and prostacyclin/cyclic adenosine monophosphate (cAMP) system. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>58</RecNum><DisplayText>[89]</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463795253">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, P. M.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>469-78</pages><volume>10</volume><number>4</number><keywords><keyword>Cerebral Small Vessel Diseases/*drug therapy/physiopathology</keyword><keyword>Humans</keyword><keyword>antithrombotics</keyword><keyword>blood brain barrier</keyword><keyword>blood pressure lowering</keyword><keyword>cyclic nucleotide inhibitors</keyword><keyword>nitric oxide</keyword><keyword>prostacyclin</keyword></keywords><dates><year>2015</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1747-4949 (Electronic)
1747-4930 (Linking)</isbn><accession-num>25727737</accession-num><urls><related-urls><url>;[89] Therefore interventions that could induce cAMP or cGMP or reduce their degradation appear promising. There are several licensed drugs that have these properties like some nitric oxide donors and phosphodiesterases-5 inhibitors, ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>58</RecNum><DisplayText>[89]</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463795253">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, P. M.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>469-78</pages><volume>10</volume><number>4</number><keywords><keyword>Cerebral Small Vessel Diseases/*drug therapy/physiopathology</keyword><keyword>Humans</keyword><keyword>antithrombotics</keyword><keyword>blood brain barrier</keyword><keyword>blood pressure lowering</keyword><keyword>cyclic nucleotide inhibitors</keyword><keyword>nitric oxide</keyword><keyword>prostacyclin</keyword></keywords><dates><year>2015</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1747-4949 (Electronic)
1747-4930 (Linking)</isbn><accession-num>25727737</accession-num><urls><related-urls><url>;[89] while the others are still in development. More experimental studies should be encouraged. But meantime, management of these traditional risk factors according to guidelines should still be encouraged except to avoid long-term dual antiplatelet drugs.In conclusion, CSVD is not just a collection of individual brain lesions, but is both a ‘dynamic’ and ‘whole-brain’ disease. All CSVD subtypes might share some common intrinsic CSVD aetiologies. Some pathological changes at the early stage of the disease could be reversible, but will gradually worsen and become irreversible as the damage in vessels and tissues accumulates. Modification of traditional risk factors and a healthy lifestyle are currently the most important prophylactic and therapeutic approaches for CSVD indefinitely and until more specific treatments are available. Apart from the trials of cilostazol which have mostly been conducted in China or Japan, in general, large clinical trials of CSVD treatments targeting the Asian population are lacking, especially in lacunar stroke. Community-based studies of CSVD prevalence and progression are also needed to determine if prevalence genuinely differs in different world regions or ethnic groups. Future studies in CSVDs should stratify by stroke subtype and by MR imaging diagnosis and measure risk factors carefully. Clinical trials and experimental studies targeting endothelium and BBB integrity should be pursued. CONTRIBUTORSThis paper is based on a lecture given by J.M.W. at the Chinese Stroke Association Inaugural Conference in 2015, Beijing. Y.S. drafted the review which was then amended and approved by J.M.W.. FUNDINGY.S. is supported by China Scholarships Council. The work described in this paper was supported by the Wellcome Trust, the MRC, the Scottish Chief Scientist Office, Chest Heart Stroke Scotland, the UK HTA, etc. COMPETING INTERESTSNo. REFERENCES ADDIN EN.REFLIST 1 Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010,9:689-701.2 Tsai CF, Thomas B and Sudlow CL. Epidemiology of stroke and its subtypes in Chinese vs white populations: a systematic review. Neurology 2013,81:264-72.3 Fang XH, Wang WH, Zhang XQ, et al. Incidence and survival of symptomatic lacunar infarction in a Beijing population: a 6-year prospective study. Eur J Neurol 2012,19:1114-20.4 Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013,12:822-38.5 Vermeer SE, Longstreth WT, Jr. and Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol 2007,6:611-9.6 Mori E, Tabuchi M and Yamadori A. Lacunar syndrome due to intracerebral hemorrhage. Stroke 1985,16:454-9.7 Wardlaw JM, Smith C and Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013,12:483-97.8 Mead GE, Lewis SC, Wardlaw JM, et al. How well does the Oxfordshire community stroke project classification predict the site and size of the infarct on brain imaging? J Neurol Neurosurg Psychiatry 2000,68:558-62.9 Potter G, Doubal F, Jackson C, et al. Associations of clinical stroke misclassification ('clinical-imaging dissociation') in acute ischemic stroke. Cerebrovasc Dis 2010,29:395-402.10 Makin SD, Doubal FN, Dennis MS, et al. Clinically Confirmed Stroke With Negative Diffusion-Weighted Imaging Magnetic Resonance Imaging: Longitudinal Study of Clinical Outcomes, Stroke Recurrence, and Systematic Review. Stroke 2015,46:3142-8.11 Doubal FN, Dennis MS and Wardlaw JM. Characteristics of patients with minor ischaemic strokes and negative MRI: a cross-sectional study. J Neurol Neurosurg Psychiatry 2011,82:540-2.12 Kimberly WT, Gilson A, Rost NS, et al. Silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy. Neurology 2009,72:1230-5.13 Khan A, Kasner SE, Lynn MJ, et al. Risk factors and outcome of patients with symptomatic intracranial stenosis presenting with lacunar stroke. Stroke 2012,43:1230-3.14 Wardlaw JM, Doubal FN, Eadie E, et al. Little association between intracranial arterial stenosis and lacunar stroke. Cerebrovasc Dis 2011,31:12-8.15 Kim JS and Yoon Y. Single subcortical infarction associated with parental arterial disease: important yet neglected sub-type of atherothrombotic stroke. Int J Stroke 2013,8:197-203.16 de Jong G, Kessels F and Lodder J. Two types of lacunar infarcts: further arguments from a study on prognosis. Stroke 2002,33:2072-6.17 Asdaghi N, Pearce LA, Nakajima M, et al. Clinical correlates of infarct shape and volume in lacunar strokes: the Secondary Prevention of Small Subcortical Strokes trial. Stroke 2014,45:2952-8.18 Del Bene A, Makin SD, Doubal FN, et al. Variation in risk factors for recent small subcortical infarcts with infarct size, shape, and location. Stroke 2013,44:3000-6.19 Jackson CA, Hutchison A, Dennis MS, et al. Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy? Stroke 2010,41:624-9.20 Lodder J, Bamford JM, Sandercock PA, et al. Are hypertension or cardiac embolism likely causes of lacunar infarction? Stroke 1990,21:375-81.21 Potter GM, Doubal FN, Jackson CA, et al. Lack of association of white matter lesions with ipsilateral carotid artery stenosis. Cerebrovasc Dis 2012,33:378-84.22 Kwon HM, Lynn MJ, Turan TN, et al. Frequency, Risk Factors, and Outcome of Coexistent Small Vessel Disease and Intracranial Arterial Stenosis: Results From the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial. JAMA Neurol 2016,73:36-42.23 Macdonald RL, Kowalczuk A and Johns L. Emboli enter penetrating arteries of monkey brain in relation to their size. Stroke 1995,26:1247-50; discussion 1250-1.24 Jackson C and Sudlow C. Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and nonlacunar infarcts. Stroke 2005,36:891-901.25 Zhang B, Zhang W, Li X, et al. Admission markers predict lacunar and non-lacunar stroke in young patients. Thromb Res 2011,128:14-7.26 Lv P, Jin H, Liu Y, et al. Comparison of Risk Factor between Lacunar Stroke and Large Artery Atherosclerosis Stroke: A Cross-Sectional Study in China. PLoS One 2016,11:e0149605.27 Debette S and Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010,341:c3666.28 Madden DJ, Bennett IJ, Burzynska A, et al. Diffusion tensor imaging of cerebral white matter integrity in cognitive aging. Biochim Biophys Acta 2012,1822:386-400.29 Munoz DG, Hastak SM, Harper B, et al. Pathologic correlates of increased signals of the centrum ovale on magnetic resonance imaging. Arch Neurol 1993,50:492-7.30 Feigin I and Popoff N. Neuropathological Changes Late in Cerebral Edema: The Relationship to Trauma, Hypertensive Disease and Binswanger's Encephalopathy. J Neuropathol Exp Neurol 1963,22:500-11.31 Black S, Gao F and Bilbao J. Understanding white matter disease: imaging-pathological correlations in vascular cognitive impairment. Stroke 2009,40:S48-52.32 Maniega SM, Valdes Hernandez MC, Clayden JD, et al. White matter hyperintensities and normal-appearing white matter integrity in the aging brain. Neurobiol Aging 2015,36:909-18.33 Bastin ME, Clayden JD, Pattie A, et al. Diffusion tensor and magnetization transfer MRI measurements of periventricular white matter hyperintensities in old age. Neurobiol Aging 2009,30:125-36.34 Maillard P, Fletcher E, Lockhart SN, et al. White matter hyperintensities and their penumbra lie along a continuum of injury in the aging brain. Stroke 2014,45:1721-6.35 Shi Y, Thrippleton MJ, Makin SD, et al. Cerebral blood flow in small vessel disease: a systematic review and meta-analysis. J Cereb Blood Flow Metab Published online first: 5 August 2016. DOI: 10.1177/0271678X16662891.36 van der Veen PH, Muller M, Vincken KL, et al. Longitudinal relationship between cerebral small-vessel disease and cerebral blood flow: the second manifestations of arterial disease-magnetic resonance study. Stroke 2015,46:1233-8.37 Farrall AJ and Wardlaw JM. Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis. Neurobiol Aging 2009,30:337-52.38 Wardlaw JM, Doubal FN, Valdes-Hernandez M, et al. Blood-brain barrier permeability and long-term clinical and imaging outcomes in cerebral small vessel disease. Stroke 2013,44:525-7.39 Wardlaw JM, Doubal F, Armitage P, et al. Lacunar stroke is associated with diffuse blood-brain barrier dysfunction. Ann Neurol 2009,65:194-202.40 Topakian R, Barrick TR, Howe FA, et al. Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis. J Neurol Neurosurg Psychiatry 2010,81:192-7.41 Taheri S, Gasparovic C, Huisa BN, et al. Blood-brain barrier permeability abnormalities in vascular cognitive impairment. Stroke 2011,42:2158-63.42 Potter GM, Marlborough FJ and Wardlaw JM. Wide variation in definition, detection, and description of lacunar lesions on imaging. Stroke 2011,42:359-66.43 Franke CL, van Swieten JC and van Gijn J. Residual lesions on computed tomography after intracerebral hemorrhage. Stroke 1991,22:1530-3.44 Hernandez Mdel C, Piper RJ, Wang X, et al. Towards the automatic computational assessment of enlarged perivascular spaces on brain magnetic resonance images: a systematic review. J Magn Reson Imaging 2013,38:774-85.45 Snowdon DA, Greiner LH, Mortimer JA, et al. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 1997,277:813-7.46 Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003,348:1215-22.47 Fanning JP, Wong AA and Fraser JF. The epidemiology of silent brain infarction: a systematic review of population-based cohorts. BMC Med 2014,12:119.48 Braffman BH, Zimmerman RA, Trojanowski JQ, et al. Brain MR: pathologic correlation with gross and histopathology. 1. Lacunar infarction and Virchow-Robin spaces. AJR Am J Roentgenol 1988,151:551-8.49 Potter GM, Chappell FM, Morris Z, et al. Cerebral perivascular spaces visible on magnetic resonance imaging: development of a qualitative rating scale and its observer reliability. Cerebrovasc Dis 2015,39:224-31.50 Groeschel S, Chong WK, Surtees R, et al. Virchow-Robin spaces on magnetic resonance images: normative data, their dilatation, and a review of the literature. Neuroradiology 2006,48:745-54.51 Zhu YC, Tzourio C, Soumare A, et al. Severity of dilated Virchow-Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease: a population-based study. Stroke 2010,41:2483-90.52 Heier LA, Bauer CJ, Schwartz L, et al. Large Virchow-Robin spaces: MR-clinical correlation. AJNR Am J Neuroradiol 1989,10:929-36.53 Potter GM, Doubal FN, Jackson CA, et al. Enlarged perivascular spaces and cerebral small vessel disease. Int J Stroke 2015,10:376-81.54 Doubal FN, MacLullich AM, Ferguson KJ, et al. Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke 2010,41:450-4.55 Zhu YC, Dufouil C, Soumare A, et al. High degree of dilated Virchow-Robin spaces on MRI is associated with increased risk of dementia. J Alzheimers Dis 2010,22:663-72.56 Maclullich AM, Wardlaw JM, Ferguson KJ, et al. Enlarged perivascular spaces are associated with cognitive function in healthy elderly men. J Neurol Neurosurg Psychiatry 2004,75:1519-23.57 Wuerfel J, Haertle M, Waiczies H, et al. Perivascular spaces--MRI marker of inflammatory activity in the brain? Brain 2008,131:2332-40.58 Weller RO, Djuanda E, Yow HY, et al. Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 2009,117:1-14.59 Iliff JJ, Wang M, Zeppenfeld DM, et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 2013,33:18190-9.60 Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science 2013,342:373-7.61 Shoamanesh A, Kwok CS and Benavente O. Cerebral microbleeds: histopathological correlation of neuroimaging. Cerebrovasc Dis 2011,32:528-34.62 Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009,8:165-74.63 Cordonnier C, Al-Shahi Salman R and Wardlaw J. Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 2007,130:1988-2003.64 Martinez-Ramirez S, Greenberg SM and Viswanathan A. Cerebral microbleeds: overview and implications in cognitive impairment. Alzheimers Res Ther 2014,6:33.65 Sveinbjornsdottir S, Sigurdsson S, Aspelund T, et al. Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location. J Neurol Neurosurg Psychiatry 2008,79:1002-6.66 Poels MM, Vernooij MW, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke 2010,41:S103-6.67 Kakar P, Charidimou A and Werring DJ. Cerebral microbleeds: a new dilemma in stroke medicine. JRSM Cardiovasc Dis 2012,1:22.68 van Dijk EJ, Breteler MM, Schmidt R, et al. The association between blood pressure, hypertension, and cerebral white matter lesions: cardiovascular determinants of dementia study. Hypertension 2004,44:625-30.69 Wardlaw JM, Allerhand M, Doubal FN, et al. Vascular risk factors, large-artery atheroma, and brain white matter hyperintensities. Neurology 2014,82:1331-8.70 Ihara M and Yamamoto Y. Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease. Stroke 2016,47:554-60.71 van Dijk EJ, Prins ND, Vrooman HA, et al. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke 2008,39:2712-9.72 Staals J, Makin SD, Doubal FN, et al. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology 2014,83:1228-34.73 Gow AJ, Bastin ME, Munoz Maniega S, et al. Neuroprotective lifestyles and the aging brain: activity, atrophy, and white matter integrity. Neurology 2012,79:1802-8.74 Rost NS, Rahman RM, Biffi A, et al. White matter hyperintensity volume is increased in small vessel stroke subtypes. Neurology 2010,75:1670-7.75 Wardlaw JM, Lewis SC, Keir SL, et al. Cerebral microbleeds are associated with lacunar stroke defined clinically and radiologically, independently of white matter lesions. Stroke 2006,37:2633-6.76 Valdes Hernandez Mdel C, Maconick LC, Munoz Maniega S, et al. A comparison of location of acute symptomatic vs. 'silent' small vessel lesions. Int J Stroke 2015,10:1044-50.77 Potter GM, Doubal FN, Jackson CA, et al. Counting cavitating lacunes underestimates the burden of lacunar infarction. Stroke 2010,41:267-72.78 Schmidt R, Enzinger C, Ropele S, et al. Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. Lancet 2003,361:2046-8.79 Gouw AA, van der Flier WM, Fazekas F, et al. Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: the Leukoaraiosis and Disability study. Stroke 2008,39:1414-20.80 Schmidt R, Seiler S and Loitfelder M. Longitudinal change of small-vessel disease-related brain abnormalities. J Cereb Blood Flow Metab 2016,36:26-39.81 Munoz Maniega S, Chappell FM, Valdes Hernandez MC, et al. Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease. J Cereb Blood Flow Metab Published online first: 1 March 2016. DOI: 10.1177/0271678X16635657.82 Bouvy WH, Biessels GJ, Kuijf HJ, et al. Visualization of perivascular spaces and perforating arteries with 7 T magnetic resonance imaging. Invest Radiol 2014,49:307-13.83 Dufouil C, de Kersaint-Gilly A, Besancon V, et al. Longitudinal study of blood pressure and white matter hyperintensities: the EVA MRI Cohort. Neurology 2001,56:921-6.84 Dufouil C, Chalmers J, Coskun O, et al. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. Circulation 2005,112:1644-50.85 Weber R, Weimar C, Blatchford J, et al. Telmisartan on top of antihypertensive treatment does not prevent progression of cerebral white matter lesions in the prevention regimen for effectively avoiding second strokes (PRoFESS) MRI substudy. Stroke 2012,43:2336-42.86 Turner ST, Fornage M, Jack CR, Jr., et al. Genomic susceptibility loci for brain atrophy in hypertensive sibships from the GENOA study. Hypertension 2005,45:793-8.87 ten Dam VH, van den Heuvel DM, van Buchem MA, et al. Effect of pravastatin on cerebral infarcts and white matter lesions. Neurology 2005,64:1807-9.88 Mok VC, Lam WW, Fan YH, et al. Effects of statins on the progression of cerebral white matter lesion: Post hoc analysis of the ROCAS (Regression of Cerebral Artery Stenosis) study. J Neurol 2009,256:750-7.89 Bath PM and Wardlaw JM. Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions. Int J Stroke 2015,10:469-78.90 Cavalieri M, Schmidt R, Chen C, et al. B vitamins and magnetic resonance imaging-detected ischemic brain lesions in patients with recent transient ischemic attack or stroke: the VITAmins TO Prevent Stroke (VITATOPS) MRI-substudy. Stroke 2012,43:3266-70.91 Shinohara Y, Katayama Y, Uchiyama S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 2010,9:959-68.92 Huang Y, Cheng Y, Wu J, et al. Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol 2008,7:494-9.93 Comerota AJ. Effect on platelet function of cilostazol, clopidogrel, and aspirin, each alone or in combination. Atheroscler Suppl 2005,6:13-9.94 Kwok CS, Shoamanesh A, Copley HC, et al. Efficacy of antiplatelet therapy in secondary prevention following lacunar stroke: pooled analysis of randomized trials. Stroke 2015,46:1014-23.95 Group SPSS, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013,382:507-15.FIGURE LEGENDS:Figure 1. STRIVE: STandards for Reporting and Imaging of Small Vessel Disease: example findings (upper), schematic representation (middle) and a summary of imaging characteristics (lower) of MRI features for changes related to small vessel disease.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA [4] DWI: diffusion-weighted imaging; FLAIR: fluid-attenuated inversion recovery; SWI: susceptibility-weighted imaging; GRE: gradient-recalled echo.Figure 2. Four possible mechanisms that cause a lacunar infarct (from bottom to top): (a) An embolus from the big arteries or cardiac sources goes up to middle cerebral arteries (MCA) and ends up entering and occluding lenticulostriate arteries, resulting in a lacunar lesion in basal ganglia; (b) if the atheroma in the parent artery (i.e. MCA) is positioned at the opening of its penetrating branches, it could lead to an acute occlusion of one or several penetrating arteries hence causing a lacunar infarct; (c) a lacunar infarct could also be due to atheroma in the perforating artery if an acute occlusion happens; (d) intrinsic small vessel disease may lead to diffused disrupted blood brain barrier. If this happens at arteriolar level, plasma fluid components would enter and deposit in the vessel wall, resulting in narrowing of the arteriolar lumen, vessel wall thickening and eventually a secondary luminal occlusion and traditional infarct.Figure 3. Example of MR images of a lacune from a haemorrhagic source (A and B), and from a lacunar infarct (C and D). FLAIR: Fluid-attenuated inversion recovery; SWI: Susceptibility-weighted imaging; DWI: Diffusion-weighted imaging. Figure 4. Long-term appearances of lacunar infarcts (arrows: old stroke lesion on the follow-up scans). ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related searches
- icd 10 code for small vessel disease
- periventricular small vessel ischemic disease
- chronic small vessel ischemic changes brain
- small vessel brain disease prognosis
- chronic small vessel ischemic disease
- what is chronic small vessel disease
- chronic small vessel ischemic disease on mri
- chronic small vessel ischemia symptoms
- small vessel disease in brain
- small vessel heart disease lifespan
- small vessel disease brain prognosis
- small vessel disease brain treatment