University of Edinburgh Research Explorer
Title: Small vessel disease: mechanisms and clinical implications. . Authors: Joanna M Wardlaw, MD,1,2 University of EdinburghColin Smith, MD,1,3 University of EdinburghMartin Dichgans, PhD,3,4,5 Ludwig-Maximillians Universit?t LMU, MunichAffiliations:1 Center for Clinical Brain Sciences, Chancellor’s Building, University of Edinburgh2 UK Dementia Research Institute at the University of Edinburgh3 MRC Brain Tissue Bank, Edinburgh 4, Institute for Stroke and Dementia Research, Klinikum der Universit?t München, Ludwig-Maximilians-Universit?t LMU, Munich, Germany5 German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany.6 Munich Cluster for Systems Neurology (SyNergy), Munich, GermanyAddress for correspondence: JM Wardlaw, Center for Clinical Brain Sciences, University of Edinburgh, Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, UKWord count: abstract 145; text 4247; references 98; Tables 1; Figures 4. Panels: 3 (Search, Glossary, Future Directions) Key words: Small vessel diseases; stroke; dementia; lacunar stroke; vascular dementia; mechanisms; MRI; pathology; cerebral blood flow; blood-brain barrier;Glossary of terms: see PanelAbstract: Small vessel disease (SVD) is a disorder of cerebral microvessels that causes white matter hyperintensities and several other common abnormalities seen on brain imaging. Despite being a common cause of stroke and vascular dementia, the underlying pathogenesis is poorly understood. Recent research in patients has identified several manifestations of cerebral microvessel endothelial dysfunction including (in unknown order of importance) blood-brain barrier dysfunction, impaired vasodilation, vessel stiffening, dysfunctional blood flow and interstitial fluid drainage, white matter rarefaction, ischaemia, inflammation, myelin damage, and secondary neurodegeneration. The brain abnormalities are more dynamic and widespread than previously thought. Relationships between lesions and symptoms are highly variable but poorly understood. Major challenges are to determine which vascular dysfunction(s) are most important in pathogenesis, which abnormalities are reversible, and why lesion progression and symptomatology are so variable, so as to identify potential targets for intervention and improve risk prediction for individuals. IntroductionThe term ‘small vessel disease’ (SVD) describes a disorder of the brain’s small perforating arterioles, capillaries, and probably venules, ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2013</Year><RecNum>8983</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>8983</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815903">8983</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><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>483-497</pages><volume>12</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Cerebral</keyword><keyword>Vessel</keyword><keyword>Disease</keyword><keyword>neuroimaging</keyword><keyword>of</keyword></keywords><dates><year>2013</year><pub-dates><date>2013</date></pub-dates></dates><label>20434</label><urls></urls><electronic-resource-num>10.1016/S1474-4422(13)70060-7</electronic-resource-num></record></Cite></EndNote>1 that causes various lesions that are seen on pathology or brain imaging with magnetic resonance (MRI) or computed tomography (CT). The typical SVD lesions are white matter hyperintensities (WMH) of presumed vascular origin, lacunes, microbleeds, superficial siderosis, perivascular spaces (PVS) and microinfarcts.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 2,3 These may be clinically ‘silent’ individually, but increasing amounts of individual lesion types and combinations of lesions are associated with cognitive impairment, dementia, depression, mobility problems, increased risk of stroke, ADDIN EN.CITE <EndNote><Cite><Author>Debette</Author><Year>2018</Year><RecNum>11370</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>11370</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1548148413">11370</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Debette, S.</author><author>Schilling, S.</author><author>Duperron, M. G.</author><author>Larsson, S. C.</author><author>Markus, H. S.</author></authors></contributors><auth-address>University of Bordeaux, Inserm 1219, Bordeaux Population Health Research Center, Bordeaux, France.
Department of Neurology, Memory Clinic, Bordeaux University Hospital, Bordeaux, France.
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.</auth-address><titles><title>Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury: A Systematic Review and Meta-analysis</title><secondary-title>JAMA Neurol</secondary-title><alt-title>JAMA neurology</alt-title></titles><periodical><full-title>JAMA Neurol</full-title></periodical><alt-periodical><full-title>JAMA neurology</full-title></alt-periodical><edition>2018/11/14</edition><dates><year>2018</year><pub-dates><date>Oct 22</date></pub-dates></dates><isbn>2168-6149</isbn><accession-num>30422209</accession-num><urls></urls><electronic-resource-num>10.1001/jamaneurol.2018.3122</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>4 and worse outcome after stroke. ADDIN EN.CITE <EndNote><Cite><Author>Georgakis</Author><Year>2018</Year><RecNum>11313</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>11313</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1542209304">11313</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Georgakis, M.K.</author><author>Duering, M.</author><author>Wardlaw, J.M.</author><author>Dichgans, M. </author></authors></contributors><titles><title>WMH and long-term outcomes in ischemic stroke: a systematic review and meta-analysis</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><volume>In press</volume><dates><year>2018</year></dates><urls></urls><electronic-resource-num>In press</electronic-resource-num></record></Cite></EndNote>5 Other typical SVD lesions are recent small subcortical (or lacunar) infarcts and intracerebral haemorrhage, which typically present with stroke.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 4,7The brain damage is not confined to the visible lesions, which increasingly are recognised to represent just the ‘tip of the iceberg’. Newer MRI methods show that there are pathological changes in the so-called ‘normal appearing’ white matter (NWM) and grey matter, that worsen as the SVD lesions increase,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdW5veiBNYW5pZWdhPC9BdXRob3I+PFllYXI+MjAxNzwv
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ADDIN EN.CITE.DATA 8-10 Some MRI methods are exquisitely sensitive to small changes in fluid content and recent patient studies suggest that WMH, at least partly or in their early stages, represent areas of increased interstitial fluid,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWVyaW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA 8,11 not just demyelination. The SVD spectrum is increasingly diverse, including rare familial and common sporadic (ie non-familial) forms, with apparently different subtypes even amongst sporadic forms. For example, cerebral amyloid angiopathy with microbleeds and superficial siderosis has different pathology to predominantly non-haemorrhagic SVDs.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaW50ZXJzPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA 12 In this review, we focus on sporadic (ie non-familial) SVD as the commonest clinically-recognised form, focusing on causes and implications of white matter hyperintensities, lacunes, recent small subcortical infarcts and sub-visible findings. Microinfarcts, and haemorrhagic SVDs (cerebral amyloid angiopathy, microbleeds, superficial siderosis), were reviewed recently elsewhere.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gVmVsdXc8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy
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ADDIN EN.CITE.DATA 3,12,13 We discuss the evidence that sporadic SVD starts in the endothelium, , how this causes apparently focal lesions that are more dynamic than traditionally thought, and affects the whole brain. We consider potential explanations for the different clinical effects of SVDs, and potential therapeutic targets and interventions. SVD as a dynamic, whole brain disorderPathology studies of SVD mechanisms describe abnormalities in arterioles such as ‘arteriolosclerosis’, lipohyalinosis, or ‘fibrinoid necrosis’,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 1,12,14 and risk factors, particularly hypertension (reviewed in ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2013</Year><RecNum>8983</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>8983</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815903">8983</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><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>483-497</pages><volume>12</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Cerebral</keyword><keyword>Vessel</keyword><keyword>Disease</keyword><keyword>neuroimaging</keyword><keyword>of</keyword></keywords><dates><year>2013</year><pub-dates><date>2013</date></pub-dates></dates><label>20434</label><urls></urls><electronic-resource-num>10.1016/S1474-4422(13)70060-7</electronic-resource-num></record></Cite></EndNote>1). In arteriolosclerosis and fibrinoid necrosis the arteriolar wall is thickened and the lumen may be narrowed, occluded, or dilated. Capillaries and venules can also be abnormal and arteriolar abnormalities and SVD lesions can occur in individuals without hypertension.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaW50ZXJzPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA 12,13 Hence, in order to understand more fully the pathogenesis of SVD at the earliest stages, it is important also to consider how capillary endothelial cells (ECs) and pericytes interact with astrocytes, oligodendrocytes and microglia, which together form the neuro-glio-vascular unit. Better understanding of SVD mechanisms is essential in order to find ways to prevent damage to the brain, to delay worsening of damage, or preferably reverse the damage or enhance repair, so as to prevent or delay the damaging clinical consequences of SVD. Starting at the cellular level, the vascular endothelium, together with a specialised basement membrane, pericytes/mural cells, and astrocyte end-feet, forms the blood-brain barrier (BBB), Figure 1, which controls what enters and leaves the brain parenchyma. The vascular endothelium also affects brain oxygenation, metabolite transport and interstitial fluid balance via effects on cerebral blood flow, active and passive transporters, and fluid clearance, most of which depend on interactions between ECs, pericytes, astrocytes, and oligodendroglial cells (Figure 1). ADDIN EN.CITE <EndNote><Cite><Author>Iadecola</Author><Year>2017</Year><RecNum>10948</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>10948</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1513764539">10948</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Iadecola, C.</author></authors></contributors><auth-address>Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: coi2001@med.cornell.edu.</auth-address><titles><title>The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease</title><secondary-title>Neuron</secondary-title></titles><periodical><full-title>Neuron</full-title></periodical><pages>17-42</pages><volume>96</volume><number>1</number><keywords><keyword>Astrocytes/physiology</keyword><keyword>Brain/*blood supply</keyword><keyword>*Health</keyword><keyword>Humans</keyword><keyword>Models, Neurological</keyword><keyword>Neurodegenerative Diseases/*physiopathology</keyword><keyword>Neurons/physiology</keyword><keyword>Neurovascular Coupling/*physiology</keyword><keyword>Signal Transduction/physiology</keyword><keyword>astrocytes</keyword><keyword>cerebral blood flow</keyword><keyword>endothelium</keyword><keyword>functional hyperemia</keyword><keyword>neurodegeneration</keyword><keyword>neuroimaging</keyword><keyword>pericytes</keyword><keyword>smooth muscle cells</keyword></keywords><dates><year>2017</year><pub-dates><date>Sep 27</date></pub-dates></dates><isbn>1097-4199 (Electronic)
0896-6273 (Linking)</isbn><accession-num>28957666</accession-num><urls><related-urls><url> Oligodendrocytes form myelin which accelerates axonal signal conduction, but are highly interconnected and also support axons by supplying energy. Oligodendrocytes arise from oligodendrocyte precursor cells (OPC), and when injured are replaced through maturation of other OPC. It was shown recently in a rodent model of sporadic SVD and on histopathology of human WMH, that dysfunctional ECs can block OPC maturation thus impairing myelination and myelin repair. ADDIN EN.CITE <EndNote><Cite><Author>Rajani</Author><Year>2018</Year><RecNum>11151</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>11151</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1530788454">11151</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rajani, Rikesh M.</author><author>Quick, Sophie</author><author>Ruigrok, Silvie R.</author><author>Graham, Delyth</author><author>Harris, Sarah E.</author><author>Verhaaren, Benjamin F. J.</author><author>Fornage, Myriam</author><author>Seshadri, Sudha</author><author>Atanur, Santosh S.</author><author>Dominiczak, Anna F.</author><author>Smith, Colin</author><author>Wardlaw, Joanna M.</author><author>Williams, Anna</author></authors></contributors><titles><title>Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats</title><secondary-title>Sci Transl Med</secondary-title></titles><periodical><full-title>Sci Transl Med</full-title></periodical><pages>eaam9507</pages><volume>10</volume><number>448</number><dates><year>2018</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%"> In CARASAL (Cathepsin A-related arteriopathy with strokes and leukoencephalopathy), a rare familial SVD, endothelial dysfunction also blocked OPC maturation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdWdpYW5pPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48
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ADDIN EN.CITE.DATA 15,18 Astrocyte end-feet have special molecules called aquaporin-4 (AQP4) that normally face the capillary. AQP4 molecules are thought to be important in regulating fluid flow through the interstitial space, thus helping to maintain the interstitial milieu required for proper neuronal function. In areas of damage, AQP4 molecules may relocate to the outer side of the astrocyte end-foot, as seen in human WMH.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXNtdXNzZW48L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy
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ADDIN EN.CITE.DATA 18 At the tissue level, we think that failure of the BBB may have several adverse effects: the leakage of fluids, proteins and other plasma constituents into the perivascular tissues may increase interstitial fluid (oedema) and may thicken and stiffen arteriole walls, thus impairing further vasodilatation, oxygen and nutrient transport (summarised below). Blood constituents may be harmful in multiple ways, e.g. after crossing the BBB, fibrinogen is cleaved to fibrin which activates microglia and recruits peripheral macrophages, promoting inflammation. ADDIN EN.CITE <EndNote><Cite><Author>Petersen</Author><Year>2018</Year><RecNum>11212</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>11212</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1533890897">11212</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petersen, Mark A</author><author>Ryu, Jae Kyu</author><author>Akassoglou, Katerina</author></authors></contributors><titles><title>Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics</title><secondary-title>Nat Rev Neurosci</secondary-title></titles><periodical><full-title>Nat Rev Neurosci</full-title></periodical><pages>283</pages><volume>19</volume><number>5</number><keywords><keyword>review</keyword><keyword>blood-brain barrier</keyword><keyword>fibrinogen</keyword></keywords><dates><year>2018</year></dates><isbn>1471-0048</isbn><urls><related-urls><url><style face="underline" font="default" size="100%"> Fibrinogen blocks OPC maturation (inhibiting myelin maintenance and repair). It further binds amyloid-β, blocking its clearance and promoting amyloid-β plaques and pericyte loss. ADDIN EN.CITE <EndNote><Cite><Author>Petersen</Author><Year>2018</Year><RecNum>11212</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>11212</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1533890897">11212</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petersen, Mark A</author><author>Ryu, Jae Kyu</author><author>Akassoglou, Katerina</author></authors></contributors><titles><title>Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics</title><secondary-title>Nat Rev Neurosci</secondary-title></titles><periodical><full-title>Nat Rev Neurosci</full-title></periodical><pages>283</pages><volume>19</volume><number>5</number><keywords><keyword>review</keyword><keyword>blood-brain barrier</keyword><keyword>fibrinogen</keyword></keywords><dates><year>2018</year></dates><isbn>1471-0048</isbn><urls><related-urls><url><style face="underline" font="default" size="100%"> Perivascular fibrin deposits are increased in patients with AD, providing a potential mechanistic link between SVD and AD pathology. ADDIN EN.CITE <EndNote><Cite><Author>Petersen</Author><Year>2018</Year><RecNum>11212</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>11212</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1533890897">11212</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petersen, Mark A</author><author>Ryu, Jae Kyu</author><author>Akassoglou, Katerina</author></authors></contributors><titles><title>Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics</title><secondary-title>Nat Rev Neurosci</secondary-title></titles><periodical><full-title>Nat Rev Neurosci</full-title></periodical><pages>283</pages><volume>19</volume><number>5</number><keywords><keyword>review</keyword><keyword>blood-brain barrier</keyword><keyword>fibrinogen</keyword></keywords><dates><year>2018</year></dates><isbn>1471-0048</isbn><urls><related-urls><url><style face="underline" font="default" size="100%"> Subtle, very mild BBB dysfunction occurs with normal human ageing, ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2013</Year><RecNum>8983</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>8983</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815903">8983</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><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>483-497</pages><volume>12</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Cerebral</keyword><keyword>Vessel</keyword><keyword>Disease</keyword><keyword>neuroimaging</keyword><keyword>of</keyword></keywords><dates><year>2013</year><pub-dates><date>2013</date></pub-dates></dates><label>20434</label><urls></urls><electronic-resource-num>10.1016/S1474-4422(13)70060-7</electronic-resource-num></record></Cite></EndNote>1 but may be accelerated by genetic predisposition. 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ADDIN EN.CITE.DATA 20 Notch3R169C transgenic mice modelling CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) the commonest familial SVD, show changes in key BBB constituents (pericyte/mural cells, astrocytic end-feet, extracellular matrix (ECM).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaG9zaDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 21 BBB leak is worse in vascular dementia and AD. ADDIN EN.CITE <EndNote><Cite><Author>Nation</Author><Year>2019</Year><RecNum>11366</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>11366</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1547630567">11366</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nation, D.A.</author><author>Sweeney, M.D.</author><author>Montagne, A.</author><author>Sagare, A.P.</author><author>D’Orazio, L.M.</author><author>Pachicano, M.</author><author>Sepehrband, F.</author><author>Nelson, A.R.</author><author>Buennagel, D.P.</author><author>Harrington, M.G.</author><author>Benzinger, T.L.S.</author><author>Fagan, A.M.</author><author>Ringman, J.M.</author><author>Schneider, L.S.</author><author>Morris, J.C.</author><author>Chui, H.C.</author><author>Law, M.</author><author>Toga, A.W.</author><author>Zlokovic, B.V.</author></authors></contributors><titles><title>Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction</title><secondary-title>Nat Med</secondary-title></titles><periodical><full-title>Nat Med</full-title></periodical><dates><year>2019</year><pub-dates><date>2019/01/14</date></pub-dates></dates><isbn>1546-170X</isbn><urls><related-urls><url><style face="underline" font="default" size="100%"> Many clinical studies demonstrate BBB dysfunction in SVD in patients with stroke,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 26,28 using biochemical (CSF, blood), ADDIN EN.CITE <EndNote><Cite><Author>Nation</Author><Year>2019</Year><RecNum>11366</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>11366</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1547630567">11366</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nation, D.A.</author><author>Sweeney, M.D.</author><author>Montagne, A.</author><author>Sagare, A.P.</author><author>D’Orazio, L.M.</author><author>Pachicano, M.</author><author>Sepehrband, F.</author><author>Nelson, A.R.</author><author>Buennagel, D.P.</author><author>Harrington, M.G.</author><author>Benzinger, T.L.S.</author><author>Fagan, A.M.</author><author>Ringman, J.M.</author><author>Schneider, L.S.</author><author>Morris, J.C.</author><author>Chui, H.C.</author><author>Law, M.</author><author>Toga, A.W.</author><author>Zlokovic, B.V.</author></authors></contributors><titles><title>Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction</title><secondary-title>Nat Med</secondary-title></titles><periodical><full-title>Nat Med</full-title></periodical><dates><year>2019</year><pub-dates><date>2019/01/14</date></pub-dates></dates><isbn>1546-170X</isbn><urls><related-urls><url><style face="underline" font="default" size="100%"> neuroimaging or neuropathology methods.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaW50ZXJzPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA 8,25 and worsens with proximity to the WMH, ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2017</Year><RecNum>10693</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>10693</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1477654980">10693</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw, Joanna M.</author><author>Makin, Stephen J.</author><author>Valdés Hernández, Maria C.</author><author>Armitage, Paul A.</author><author>Heye, Anna K.</author><author>Chappell, Francesca M.</author><author>Mu?oz-Maniega, Susana</author><author>Sakka, Eleni</author><author>Shuler, Kirsten</author><author>Dennis, Martin S.</author><author>Thrippleton, Michael J.</author></authors></contributors><titles><title>Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study</title><secondary-title>Alzheimers Dement</secondary-title></titles><periodical><full-title>Alzheimers Dement</full-title></periodical><pages>634-643</pages><volume>13</volume><number>6</number><dates><year>2017</year></dates><isbn>15525260</isbn><label>22062</label><urls></urls><electronic-resource-num>10.1016/j.jalz.2016.09.006</electronic-resource-num></record></Cite></EndNote>28 a predilection site for future WMH expansion,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qcm9tanVueWFrdWw8L0F1dGhvcj48WWVhcj4yMDE4PC9Z
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ADDIN EN.CITE.DATA 30,31 and incident lacunes.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 32 In one study, BBB leak was worse in the perilesional NWM than in WMH,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWlzYTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 25 although others have found the opposite. ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2017</Year><RecNum>10693</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>10693</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1477654980">10693</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw, Joanna M.</author><author>Makin, Stephen J.</author><author>Valdés Hernández, Maria C.</author><author>Armitage, Paul A.</author><author>Heye, Anna K.</author><author>Chappell, Francesca M.</author><author>Mu?oz-Maniega, Susana</author><author>Sakka, Eleni</author><author>Shuler, Kirsten</author><author>Dennis, Martin S.</author><author>Thrippleton, Michael J.</author></authors></contributors><titles><title>Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study</title><secondary-title>Alzheimers Dement</secondary-title></titles><periodical><full-title>Alzheimers Dement</full-title></periodical><pages>634-643</pages><volume>13</volume><number>6</number><dates><year>2017</year></dates><isbn>15525260</isbn><label>22062</label><urls></urls><electronic-resource-num>10.1016/j.jalz.2016.09.006</electronic-resource-num></record></Cite></EndNote>28 BBB dysfunction was not found in some neuropathology studiesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWluc3dvcnRoPC9BdXRob3I+PFllYXI+MjAxNTwvWWVh
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ADDIN EN.CITE.DATA 35 suggesting that the decrease in WMH and brain volume was not atrophy from cell loss but clearance of excess interstitial fluid. Finally, three studies found that long-term outcomes were associated with BBB disruption at initial assessment: BBB leak in NWM predicted poor functional outcome three years later; ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2013</Year><RecNum>8790</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>8790</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815896">8790</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw,J.M.</author><author>Doubal,F.N.</author><author>Valdes-Hernandez,M.C.</author><author>Wang,X.</author><author>Chappell,F.M.</author><author>Shuler,K.</author><author>Armitage,P.</author><author>Carpenter,T.</author><author>Dennis,M.S.</author></authors></contributors><titles><title>Blood-brain barrier permeability and long term clinical and imaging outcomes in cerebral small vessel disease</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>525-527</pages><volume>44</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Blood-Brain Barrier</keyword><keyword>Permeability</keyword><keyword>and</keyword><keyword>imaging</keyword><keyword>outcome</keyword><keyword>Cerebral</keyword><keyword>Vessel</keyword><keyword>Disease</keyword></keywords><dates><year>2013</year><pub-dates><date>2013</date></pub-dates></dates><label>20240</label><urls></urls></record></Cite></EndNote>23 BBB leak in NWM predicted cognitive decline one year after lacunar stroke; ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2017</Year><RecNum>10693</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>10693</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1477654980">10693</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw, Joanna M.</author><author>Makin, Stephen J.</author><author>Valdés Hernández, Maria C.</author><author>Armitage, Paul A.</author><author>Heye, Anna K.</author><author>Chappell, Francesca M.</author><author>Mu?oz-Maniega, Susana</author><author>Sakka, Eleni</author><author>Shuler, Kirsten</author><author>Dennis, Martin S.</author><author>Thrippleton, Michael J.</author></authors></contributors><titles><title>Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study</title><secondary-title>Alzheimers Dement</secondary-title></titles><periodical><full-title>Alzheimers Dement</full-title></periodical><pages>634-643</pages><volume>13</volume><number>6</number><dates><year>2017</year></dates><isbn>15525260</isbn><label>22062</label><urls></urls><electronic-resource-num>10.1016/j.jalz.2016.09.006</electronic-resource-num></record></Cite></EndNote>28 and some areas with abnormal BBB permeability at baseline developed new WMH on follow-up scans.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWlzYTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 25 Compromise of cerebral blood flow (CBF) is another manifestation of endothelial function but the relationship between CBF and SVD lesion formation is complex. For example, in a meta-analysis, WMH were associated with lower resting CBF in cross-sectional studies, but this association disappears with proper age-matching and excluding patients with dementia, ADDIN EN.CITE <EndNote><Cite><Author>Shi</Author><Year>2016</Year><RecNum>10478</RecNum><DisplayText><style face="superscript">36</style></DisplayText><record><rec-number>10478</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815956">10478</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.I.</author><author>de Craen,A.J.</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><pages>1653-1667</pages><volume>36</volume><number>10</number><section>1653</section><reprint-edition>Not in File</reprint-edition><keywords><keyword>Cerebral</keyword><keyword>cerebral blood flow</keyword><keyword>blood</keyword><keyword>Blood Flow</keyword><keyword>BLOOD-FLOW</keyword><keyword>FLOW</keyword><keyword>Vessel</keyword><keyword>VESSEL DISEASE</keyword><keyword>Disease</keyword><keyword>systematic review</keyword><keyword>review</keyword><keyword>and</keyword><keyword>meta-analysis</keyword><keyword>METAANALYSIS</keyword></keywords><dates><year>2016</year><pub-dates><date>2016</date></pub-dates></dates><label>21949</label><urls></urls><electronic-resource-num>10.1177/0271678X16662891</electronic-resource-num></record></Cite></EndNote>36 reflecting that impaired CBF occurs early in AD. ADDIN EN.CITE <EndNote><Cite><Author>Kisler</Author><Year>2017</Year><RecNum>11308</RecNum><DisplayText><style face="superscript">37</style></DisplayText><record><rec-number>11308</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1541719095">11308</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kisler, Kassandra</author><author>Nelson, Amy R</author><author>Montagne, Axel</author><author>Zlokovic, Berislav V</author></authors></contributors><titles><title>Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease</title><secondary-title>Nature Reviews Neuroscience</secondary-title></titles><periodical><full-title>Nature Reviews Neuroscience</full-title></periodical><pages>419</pages><volume>18</volume><number>7</number><dates><year>2017</year></dates><isbn>1471-0048</isbn><urls><related-urls><url> Most larger longitudinal studies showed that high WMH burden predicts falling CBF, not vice versa,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 30 Furthermore, reduced resting CBF might reflect loss of viable tissue, rather than falling CBF causing tissue damage. A ‘mismatch’ between capillary flow and oxygen delivery, referred to as ‘capillary transit time heterogeneity’, has been observed in models and may occur in and around WMH. ADDIN EN.CITE <EndNote><Cite><Author>Ostergaard</Author><Year>2016</Year><RecNum>10078</RecNum><DisplayText><style face="superscript">39</style></DisplayText><record><rec-number>10078</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815941">10078</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ostergaard,L.</author><author>Sondergaard,T.</author><author>Moreton,F.</author><author>Hansen,M.B.</author><author>Wardlaw,J.M.</author><author>Dalkara,T.</author><author>Markus,H.S.</author><author>Muir,K.W.</author></authors></contributors><titles><title><style face="normal" font="TimesNewRoman,Bold" size="100%">Cerebral small vessel disease: capillary pathways to stroke and cognitive decline</style></title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><pages>302-325</pages><volume>36</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Cerebral</keyword><keyword>Vessel</keyword><keyword>VESSEL DISEASE</keyword><keyword>Disease</keyword><keyword>Capillaries</keyword><keyword>stroke</keyword><keyword>and</keyword></keywords><dates><year>2016</year><pub-dates><date>2016</date></pub-dates></dates><label>21544</label><urls></urls><electronic-resource-num>10.1177/0271678X15606723</electronic-resource-num></record></Cite></EndNote>39 The mechanism for increased CBF heterogeneity may reflect a failure to direct blood flow to exactly where it is needed, or as suggested by the authors, to shunting, but remains to be determined. Resting CBF is not a good indicator of oxygen extraction or of the ability to match tissue supply to demand. ADDIN EN.CITE <EndNote><Cite><Author>Ostergaard</Author><Year>2016</Year><RecNum>10078</RecNum><DisplayText><style face="superscript">39</style></DisplayText><record><rec-number>10078</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815941">10078</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ostergaard,L.</author><author>Sondergaard,T.</author><author>Moreton,F.</author><author>Hansen,M.B.</author><author>Wardlaw,J.M.</author><author>Dalkara,T.</author><author>Markus,H.S.</author><author>Muir,K.W.</author></authors></contributors><titles><title><style face="normal" font="TimesNewRoman,Bold" size="100%">Cerebral small vessel disease: capillary pathways to stroke and cognitive decline</style></title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><pages>302-325</pages><volume>36</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Cerebral</keyword><keyword>Vessel</keyword><keyword>VESSEL DISEASE</keyword><keyword>Disease</keyword><keyword>Capillaries</keyword><keyword>stroke</keyword><keyword>and</keyword></keywords><dates><year>2016</year><pub-dates><date>2016</date></pub-dates></dates><label>21544</label><urls></urls><electronic-resource-num>10.1177/0271678X15606723</electronic-resource-num></record></Cite></EndNote>39 A better indication of the adequacy of tissue-level CBF in SVD may be cerebrovascular reactivity (CVR), which is the ability of arterioles and capillaries to dilate in response to increased neuronal activity or a metabolic or vasodilatory challenge such as breathing 6% carbon dioxide in inspired air.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaHJpcHBsZXRvbjwvQXV0aG9yPjxZZWFyPjIwMTg8L1ll
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ADDIN EN.CITE.DATA 41 However, assessment of subcortical tissue-based CVR in patients is challenging and hence, so far, limited. ADDIN EN.CITE <EndNote><Cite><Author>Blair</Author><Year>2016</Year><RecNum>10227</RecNum><DisplayText><style face="superscript">42</style></DisplayText><record><rec-number>10227</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815946">10227</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Blair,G.</author><author>Doubal,F.N.</author><author>Thrippleton,M.J.</author><author>Marshall,I.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Magnetic resonance imaging for assessment of cerebrovascular reactivity in cerebral small vessel disease. A systematic review</title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><pages>833-841</pages><volume>36</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Magnetic Resonance</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>RESONANCE</keyword><keyword>imaging</keyword><keyword>of</keyword><keyword>Cerebral</keyword><keyword>Vessel</keyword><keyword>VESSEL DISEASE</keyword><keyword>Disease</keyword><keyword>systematic review</keyword><keyword>review</keyword></keywords><dates><year>2016</year><pub-dates><date>2016</date></pub-dates></dates><label>21696</label><urls></urls><electronic-resource-num>10.1177/0271678X16631756</electronic-resource-num></record></Cite></EndNote>42 Cross-sectional studies show that CVR declines with advancing age, hypertension, in lacunar versus non-lacunar stroke, and with increasing WMH burden. Longitudinally, reduced CVR may predict progression from NWM to WMH. ADDIN EN.CITE <EndNote><Cite><Author>Sam</Author><Year>2016</Year><RecNum>10635</RecNum><DisplayText><style face="superscript">43</style></DisplayText><record><rec-number>10635</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1472640242">10635</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sam, K.</author><author>Crawley, A. P.</author><author>Conklin, J.</author><author>Poublanc, J.</author><author>Sobczyk, O.</author><author>Mandell, D. M.</author><author>Venkatraghavan, L.</author><author>Duffin, J.</author><author>Fisher, J. A.</author><author>Black, S. E.</author><author>Mikulis, D. J.</author></authors></contributors><auth-address>Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Division of Neuroradiology, Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada.
Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada.
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
Department of Anesthesiology, University Health Network, Toronto, Ontario, Canada.
LC Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.</auth-address><titles><title>Development of white matter hyperintensity is preceded by reduced cerebrovascular reactivity</title><secondary-title>Ann Neurol</secondary-title></titles><periodical><full-title>Ann Neurol</full-title></periodical><pages>277-85</pages><volume>80</volume><number>2</number><dates><year>2016</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1531-8249 (Electronic)
0364-5134 (Linking)</isbn><accession-num>27352039</accession-num><label>21996</label><urls><related-urls><url> CVR declined in deep grey and white matter with increased systolic blood pressure, pulse pressure and intracranial vascular pulsatility, but reduced CVR was not associated with resting CBF, ADDIN EN.CITE <EndNote><Cite><Author>Shi</Author><Year>2018</Year><RecNum>11241</RecNum><DisplayText><style face="superscript">44</style></DisplayText><record><rec-number>11241</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1536138079">11241</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shi, Y.</author><author>Thrippleton, M.J.</author><author>Blair, G.W.</author><author>Dickie, D.A.</author><author>Marshall, I.</author><author>Hamilton, I.</author><author>Doubal, F.N.</author><author>Chappell, F.</author><author>Wardlaw, J.M.</author></authors></contributors><titles><title>Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow </title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><volume>38</volume><dates><year>2018</year></dates><urls></urls><electronic-resource-num>10.1177/0271678X18803956</electronic-resource-num></record></Cite></EndNote>44 similar to the dissociation of CVR from CBF seen in CADASIL.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdW5lYXU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 41 Patients with more WMH had lower CVR in white matter and higher intracranial vascular pulsatility, ADDIN EN.CITE <EndNote><Cite><Author>Shi</Author><Year>2018</Year><RecNum>11241</RecNum><DisplayText><style face="superscript">44</style></DisplayText><record><rec-number>11241</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1536138079">11241</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shi, Y.</author><author>Thrippleton, M.J.</author><author>Blair, G.W.</author><author>Dickie, D.A.</author><author>Marshall, I.</author><author>Hamilton, I.</author><author>Doubal, F.N.</author><author>Chappell, F.</author><author>Wardlaw, J.M.</author></authors></contributors><titles><title>Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow </title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><volume>38</volume><dates><year>2018</year></dates><urls></urls><electronic-resource-num>10.1177/0271678X18803956</electronic-resource-num></record></Cite></EndNote>44 independent of age or BP, suggesting that impaired CVR and high intracranial vascular pulsatility may be more strongly linked to formation of WMH than reduced resting CBF. However, the relationship between the different components of endothelial dysfunction (BBB leak, CVR, intracranial pulsatility and CBF) and the order in which they occur, is unknown in humans. Studies measuring all these parameters simultaneously are ongoing (e.g. ISRCTN10514229) and should provide answers soon. Fluid and compounds that enter the brain, and the waste generated, must be removed to maintain normal brain function. The main drainage conduits are the perivascular, or paravascular, spaces (PVS) which surround brain microvessels (Figure 1)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccm93bjwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 18 In rodents, glymphatic dynamic function demonstrated with optical imaging via cranial windows or MRI with intrathecal gadolinium showed that CSF from the basal cisterns and cerebral convexities enters the peri-arteriolar PVS to flush the interstitial space.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXNtdXNzZW48L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy
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ADDIN EN.CITE.DATA 18 In humans, PVS are visible on T2- and T1-weighted MRI as thin linear or round CSF-intensity structures that run parallel with perforating vesselsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 46 There have been fewer studies of PVS than of the other SVD features to date, consequently PVS are not yet universally accepted as an SVD marker. ADDIN EN.CITE <EndNote><Cite><Author>Debette</Author><Year>2018</Year><RecNum>11370</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>11370</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1548148413">11370</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Debette, S.</author><author>Schilling, S.</author><author>Duperron, M. G.</author><author>Larsson, S. C.</author><author>Markus, H. S.</author></authors></contributors><auth-address>University of Bordeaux, Inserm 1219, Bordeaux Population Health Research Center, Bordeaux, France.
Department of Neurology, Memory Clinic, Bordeaux University Hospital, Bordeaux, France.
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.</auth-address><titles><title>Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury: A Systematic Review and Meta-analysis</title><secondary-title>JAMA Neurol</secondary-title><alt-title>JAMA neurology</alt-title></titles><periodical><full-title>JAMA Neurol</full-title></periodical><alt-periodical><full-title>JAMA neurology</full-title></alt-periodical><edition>2018/11/14</edition><dates><year>2018</year><pub-dates><date>Oct 22</date></pub-dates></dates><isbn>2168-6149</isbn><accession-num>30422209</accession-num><urls></urls><electronic-resource-num>10.1001/jamaneurol.2018.3122</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>4 However, in patients, PVS as seen on MRI are associated with several SVD-related factors: hypertension,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWJhLUxsZW5hPC9BdXRob3I+PFllYXI+MjAxODwvWWVh
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ADDIN EN.CITE.DATA 44,47,51,52 In rodents, perivascular CSF flow depends on normal ‘elastic’ arteriolar pulsation and becomes slower and irregular if arteriolar pulsatility increases, such as with raised blood pressure, leading to fluid stagnation in PVS and impaired interstitial flushing.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXNtdXNzZW48L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy
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ADDIN EN.CITE.DATA 12) from tissues. Indeed, some investigators have described Alzheimer’s disease, CAA and several monogenic SVDs as ‘protein elimination failure angiopathies’.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaW50ZXJzPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA 12 The increased interstitial fluid would also increase the distance over which oxygen and nutrients have to diffuse to reach neurons, thus propagating a worsening cycle of tissue injury. While the precise sequence of endothelial dysfunctions in humans is currently unknown, we suggest that BBB leakage may increase interstitial fluid, arteriolar wall and tissue damage. Arteriolar wall thickening and stiffening, including when secondary to vascular risk factors, increases pulsatility and restricts vasodilation, impairs normal perivascular fluid flushing and removal of waste. Together these effects reduce oxygen and nutrient supply (Figure 1). Although speculative, drawing these elements together provides a unifying explanation for the common microscopic and in vivo vascular and brain lesions found in humans, while retaining consistency with information emerging from relevant rodent models.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXNtdXNzZW48L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy
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ADDIN EN.CITE.DATA 18 circadian and physical activity, and may have hampered understanding of SVD.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWVyaW5nPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA 10,54,55 Currently, SVD lesions are considered to be ‘permanent’, with WMH representing demyelination, axon loss, and gliosis, lacunes being cavities replacing destroyed tissue, and microbleeds being fixed haemorrhages. Many longitudinal studies document WMH progression,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2htaWR0PC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48
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Tm90ZT5=
ADDIN EN.CITE.DATA 56 although some change included small WMH decreases.Two recent studies demonstrate that SVD lesions can shrink or disappear as well as grow.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gTGVpanNlbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1ll
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ADDIN EN.CITE.DATA 35,57 The RUN DMC study assessed older community-dwelling subjects three times over nine years: WMH volume decreased in 9.4%, lacunes disappeared in 2.6% and microbleeds in 5.7% of participants between two assessments.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gTGVpanNlbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1ll
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ADDIN EN.CITE.DATA 32 In addition, quantitative MRI methods such as DTI, T1 mapping, or DCE-MRI, reveal increasingly abnormal tissue (increased MD, reduced FA, increased T1) in a perilesional zone of NWM around WMHPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdW5veiBNYW5pZWdhPC9BdXRob3I+PFllYXI+MjAxNzwv
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ADDIN EN.CITE.DATA 8,28 Longitudinal DTI studies demonstrate progressive loss of tissue integrity in perilesional tissue over time and conversion of NWM to WMH: lower CBF, CVR, ADDIN EN.CITE <EndNote><Cite><Author>Sam</Author><Year>2016</Year><RecNum>10635</RecNum><DisplayText><style face="superscript">43</style></DisplayText><record><rec-number>10635</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1472640242">10635</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sam, K.</author><author>Crawley, A. P.</author><author>Conklin, J.</author><author>Poublanc, J.</author><author>Sobczyk, O.</author><author>Mandell, D. M.</author><author>Venkatraghavan, L.</author><author>Duffin, J.</author><author>Fisher, J. A.</author><author>Black, S. E.</author><author>Mikulis, D. J.</author></authors></contributors><auth-address>Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Division of Neuroradiology, Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada.
Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada.
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
Department of Anesthesiology, University Health Network, Toronto, Ontario, Canada.
LC Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.</auth-address><titles><title>Development of white matter hyperintensity is preceded by reduced cerebrovascular reactivity</title><secondary-title>Ann Neurol</secondary-title></titles><periodical><full-title>Ann Neurol</full-title></periodical><pages>277-85</pages><volume>80</volume><number>2</number><dates><year>2016</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1531-8249 (Electronic)
0364-5134 (Linking)</isbn><accession-num>27352039</accession-num><label>21996</label><urls><related-urls><url> FA, and higher MD in perilesional tissue independently predicted conversion of NWM to WMH.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qcm9tanVueWFrdWw8L0F1dGhvcj48WWVhcj4yMDE4PC9Z
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ADDIN EN.CITE.DATA 13,58 The focus of SVD research on MRI visible lesions may have distracted attention from the ‘whole brain effects’ of SVD. These include the diffuse changes in NWM and grey matter detailed above,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdW5veiBNYW5pZWdhPC9BdXRob3I+PFllYXI+MjAxNzwv
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ADDIN EN.CITE.DATA 59,60 Considering global visible and subvisible SVD effects together may better predict conversion to dementia, ADDIN EN.CITE <EndNote><Cite><Author>Ter Telgte</Author><Year>2018</Year><RecNum>11081</RecNum><DisplayText><style face="superscript">59</style></DisplayText><record><rec-number>11081</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1529506998">11081</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ter Telgte, A.</author><author>van Leijsen, E. M. C.</author><author>Wiegertjes, K.</author><author>Klijn, C. J. M.</author><author>Tuladhar, A. M.</author><author>de Leeuw, F. E.</author></authors></contributors><auth-address>Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands. FrankErik.deLeeuw@radboudumc.nl.</auth-address><titles><title>Cerebral small vessel disease: from a focal to a global perspective</title><secondary-title>Nat Rev Neurol</secondary-title></titles><periodical><full-title>Nat Rev Neurol</full-title></periodical><pages>387-398</pages><volume>14</volume><dates><year>2018</year><pub-dates><date>May 25</date></pub-dates></dates><isbn>1759-4766 (Electronic)
1759-4758 (Linking)</isbn><accession-num>29802354</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%"> relationships with vascular risk, ADDIN EN.CITE <EndNote><Cite><Author>Staals</Author><Year>2014</Year><RecNum>9530</RecNum><DisplayText><style face="superscript">61</style></DisplayText><record><rec-number>9530</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815921">9530</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Staals,J.</author><author>Makin,S.D.J.</author><author>Doubal,F.</author><author>Dennis,M.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Stroke subtype, vascular risk factors and total MRI brain small vessel disease burden</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>1228-1234</pages><volume>83</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>stroke</keyword><keyword>subtype</keyword><keyword>Risk</keyword><keyword>Risk Factors</keyword><keyword>RISK-FACTORS</keyword><keyword>and</keyword><keyword>MRI</keyword><keyword>Brain</keyword><keyword>Vessel</keyword><keyword>Disease</keyword></keywords><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><label>20987</label><urls></urls></record></Cite></EndNote>61 concurrent cognition,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYW5lcmplZTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+
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ADDIN EN.CITE.DATA 62 although optimal combination and weighting of features remains unclear. ADDIN EN.CITE <EndNote><Cite><Author>Paradise</Author><Year>2018</Year><RecNum>11187</RecNum><DisplayText><style face="superscript">63</style></DisplayText><record><rec-number>11187</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1532439887">11187</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Paradise, Matthew B</author><author>Shepherd, Claire E</author><author>Wen, Wei</author><author>Sachdev, Perminder S</author></authors></contributors><titles><title>Neuroimaging and neuropathology indices of cerebrovascular disease burden: A systematic review</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>310-320</pages><volume>91</volume><number>7</number><dates><year>2018</year></dates><isbn>0028-3878</isbn><urls></urls></record></Cite></EndNote>63 Clinical implications Many of the clinical manifestations of SVD, including stroke, cognitive decline,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5zbWE8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 66 depression, ADDIN EN.CITE <EndNote><Cite><Author>van Agtmaal</Author><Year>2017</Year><RecNum>10836</RecNum><DisplayText><style face="superscript">67</style></DisplayText><record><rec-number>10836</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1499678859">10836</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Agtmaal, M. J. M.</author><author>Houben, Ajhm</author><author>Pouwer, F.</author><author>Stehouwer, C. D. A.</author><author>Schram, M. T.</author></authors></contributors><auth-address>Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands2Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
Department of Psychology, University of Southern Denmark, Odense, Denmark.
Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands2Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands4Heart and Vascular Center, Maastricht University Medical Center, Maastricht, the Netherlands.</auth-address><titles><title>Association of microvascular dysfunction with late-life depression: a systematic review and meta-analysis</title><secondary-title>JAMA Psychiatry</secondary-title></titles><periodical><full-title>JAMA Psychiatry</full-title><abbr-1>JAMA psychiatry</abbr-1></periodical><pages>729-739</pages><volume>74</volume><number>7</number><edition>2017/06/01</edition><dates><year>2017</year><pub-dates><date>Jul 01</date></pub-dates></dates><isbn>2168-622x</isbn><accession-num>28564681</accession-num><urls></urls><electronic-resource-num>10.1001/jamapsychiatry.2017.0984</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>67 and extrapyramidal symptoms,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIEhvbHN0PC9BdXRob3I+PFllYXI+MjAxNTwv
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ADDIN EN.CITE.DATA 68 relate to functions with structural and functional underpinnings in widely distributed neuronal networks, consistent with diffuse effects of SVD on the brain, and important when considering mechanisms and interventions. The presenting symptoms and clinical course of SVD are highly variable. We suggest that this relates to several factors, which we discuss below. These include: (i) variations in the vascular injury (location, type, and extent); (ii) variable degrees of secondary neurodegeneration; (iii) resilience factors such as brain reserve, and (iv) comorbid conditions (Figure 4). Associations between typical acute lacunar motor and sensory syndromes and recent small subcortical infarcts in specific anatomical locations, and between sudden cognitive deficits and strategic infarcts in the thalamus, are well established. ADDIN EN.CITE <EndNote><Cite><Author>Valdes Hernandez</Author><Year>2015</Year><RecNum>9887</RecNum><DisplayText><style face="superscript">69</style></DisplayText><record><rec-number>9887</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815934">9887</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Valdes Hernandez,M.C.</author><author>Maconick,L.C.</author><author>Munoz Maniega,S.</author><author>Wang,X.</author><author>Wiseman,S.</author><author>Armitage,P.A.</author><author>Doubal,F.N.</author><author>Makin,S.</author><author>Sudlow,C.L.</author><author>Dennis,M.S.</author><author>Deary,I.J.</author><author>Bastin,M.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>A comparison of location of acute symptomatic versus 'silent' small vessel lesions</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>1044-1050</pages><volume><style face="normal" font="Frutiger-Light" size="100%">10</style></volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>of</keyword><keyword>Acute</keyword><keyword>Vessel</keyword><keyword>LESIONS</keyword><keyword>lesion</keyword></keywords><dates><year>2015</year><pub-dates><date>2015</date></pub-dates></dates><label>21352</label><urls></urls><electronic-resource-num>10.1111/ijs.12558</electronic-resource-num></record></Cite></EndNote>69 Lesion-symptom associations may reflect the total burden of lesions, preponderance in specific brain subregions, or sub-visible changes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWVyaW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA 3 However, more studies are needed to determine the effects of co-morbidities and whether this also applies to unselected patients attending typical cognition or mobility clinics. ADDIN EN.CITE <EndNote><Cite><Author>Quinn</Author><Year>2017</Year><RecNum>10908</RecNum><DisplayText><style face="superscript">74</style></DisplayText><record><rec-number>10908</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1506520373">10908</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Quinn, T. J.</author><author>McCleery, J.</author></authors></contributors><auth-address>Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K. terry.quinn@glasgow.ac.uk.
Cochrane Dementia and Cognitive Improvement Group, Cochrane, Oxford, U.K.</auth-address><titles><title>Diagnosis in vascular dementia, applying 'Cochrane diagnosis rules' to 'dementia diagnostic tools'</title><secondary-title>Clin Sci (Lond)</secondary-title><alt-title>Clinical science (London, England : 1979)</alt-title></titles><periodical><full-title>Clin Sci (Lond)</full-title></periodical><pages>729-732</pages><volume>131</volume><number>8</number><edition>2017/04/08</edition><keywords><keyword>Biomarkers</keyword><keyword>Brain</keyword><keyword>Dementia</keyword><keyword>*Dementia, Vascular</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>*Sensitivity and Specificity</keyword><keyword>*biomarkers</keyword><keyword>*dementia</keyword><keyword>*sensitivity/specificity</keyword><keyword>*test accuracy</keyword><keyword>*vascular cognitive impairment</keyword></keywords><dates><year>2017</year><pub-dates><date>Apr 25</date></pub-dates></dates><isbn>0143-5221</isbn><accession-num>28385828</accession-num><urls></urls><electronic-resource-num>10.1042/cs20170025</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>74Recent studies further emphasise a role of secondary neurodegeneration in determining clinical status. Discrete subcortical infarcts induce loss of connected cortex remote from the infarct via degeneration of white matter tracts.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWVyaW5nPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA 10 Increasing WMH burden associates with worse whole brain atrophy, cortex thinning overlying areas of high WMH density, ADDIN EN.CITE <EndNote><Cite><Author>Ter Telgte</Author><Year>2018</Year><RecNum>11081</RecNum><DisplayText><style face="superscript">59</style></DisplayText><record><rec-number>11081</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1529506998">11081</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ter Telgte, A.</author><author>van Leijsen, E. M. C.</author><author>Wiegertjes, K.</author><author>Klijn, C. J. M.</author><author>Tuladhar, A. M.</author><author>de Leeuw, F. E.</author></authors></contributors><auth-address>Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands. FrankErik.deLeeuw@radboudumc.nl.</auth-address><titles><title>Cerebral small vessel disease: from a focal to a global perspective</title><secondary-title>Nat Rev Neurol</secondary-title></titles><periodical><full-title>Nat Rev Neurol</full-title></periodical><pages>387-398</pages><volume>14</volume><dates><year>2018</year><pub-dates><date>May 25</date></pub-dates></dates><isbn>1759-4766 (Electronic)
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ADDIN EN.CITE.DATA 75 although the precise relationship between WMH progression and brain volume loss remains controversial. ADDIN EN.CITE <EndNote><Cite><Author>Dickie</Author><Year>2016</Year><RecNum>10178</RecNum><DisplayText><style face="superscript">55</style></DisplayText><record><rec-number>10178</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815945">10178</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dickie,D.A.</author><author>Karama,S.</author><author>Ritchie,S.J.</author><author>Cox,S.R.</author><author>Sakka,E.</author><author>Royle,N.A.</author><author>Aribisala,B.S.</author><author>Valdes-Hernandez,M.</author><author>Munoz Maniega,S.</author><author>Pattie,A.</author><author>Corley,J.</author><author>Starr,J.M.</author><author>Bastin,M.E.</author><author>Evans,A.C.</author><author>Deary,I.J.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Progression of white matter disease and cortical thinning are not related in older community-dwelling subjects</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>410-416</pages><volume>47</volume><keywords><keyword>of</keyword><keyword>White Matter</keyword><keyword>WHITE-MATTER</keyword><keyword>Disease</keyword><keyword>and</keyword></keywords><dates><year>2016</year><pub-dates><date>2016</date></pub-dates></dates><label>21646</label><urls></urls><electronic-resource-num>10.1161/STROKEAHA.115.011229</electronic-resource-num></record></Cite></EndNote>55 Importantly, brain atrophy is a strong independent predictor of clinical status and progression in SVD, ADDIN EN.CITE <EndNote><Cite><Author>Chabriat</Author><Year>2016</Year><RecNum>11129</RecNum><DisplayText><style face="superscript">76</style></DisplayText><record><rec-number>11129</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1530177148">11129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chabriat, Hugues</author><author>Hervé, Dominique</author><author>Duering, Marco</author><author>Godin, Ophelia</author><author>Jouvent, Eric</author><author>Opherk, Christian</author><author>Alili, Nassira</author><author>Reyes, Sonia</author><author>Jabouley, Aude</author><author>Zieren, Nikola</author></authors></contributors><titles><title>Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: prospective cohort study</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>4-11</pages><volume>47</volume><number>1</number><dates><year>2016</year></dates><isbn>0039-2499</isbn><urls></urls></record></Cite></EndNote>76 and path analyses demonstrate that the effects of SVD-related vascular lesions on clinical status are in part mediated by changes in brain atrophy and cortex morphology.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UZXIgVGVsZ3RlPC9BdXRob3I+PFllYXI+MjAxODwvWWVh
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ADDIN EN.CITE.DATA 59,77 It may be that prevention of secondary atrophy may help delay the clinical effects of SVD. Another factor contributing to the clinical expression of SVD is ‘resilience’, which refers to the capacity to cope with brain pathology. ‘Brain reserve’ refers to inter-individual differences in brain structure, whereas ‘cognitive reserve’ refers to differences in the way the brain processes specific tasks. Both reserves are influenced by experiences, including early in life, ADDIN EN.CITE <EndNote><Cite><Author>Backhouse</Author><Year>2017</Year><RecNum>10727</RecNum><DisplayText><style face="superscript">78</style></DisplayText><record><rec-number>10727</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1482500454">10727</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Backhouse, E. V.</author><author>McHutchison, C. A.</author><author>Cvoro, V.</author><author>Shenkin, S. D.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>From the Centre for Clinical Brain Sciences (E.V.B., C.A.M., V.C., J.M.W.), Centre for Cognitive Ageing and Cognitive Epidemiology (C.A.M., V.C., S.D.S., J.M.W.), and Geriatric Medicine, Department of Clinical and Surgical Sciences (S.D.S.), University of Edinburgh; and Scottish Imaging Network (V.C., S.D.S., J.M.W.), A Platform for Scientific Excellence (SINAPSE), UK.
From the Centre for Clinical Brain Sciences (E.V.B., C.A.M., V.C., J.M.W.), Centre for Cognitive Ageing and Cognitive Epidemiology (C.A.M., V.C., S.D.S., J.M.W.), and Geriatric Medicine, Department of Clinical and Surgical Sciences (S.D.S.), University of Edinburgh; and Scottish Imaging Network (V.C., S.D.S., J.M.W.), A Platform for Scientific Excellence (SINAPSE), UK. joanna.wardlaw@ed.ac.uk.</auth-address><titles><title>Early life risk factors for cerebrovascular disease: A systematic review and meta-analysis</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>976-984</pages><volume>88</volume><number>10</number><dates><year>2017</year><pub-dates><date>Mar 07</date></pub-dates></dates><isbn>1526-632X (Electronic)
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ADDIN EN.CITE.DATA 79-81), influences motor functions, ADDIN EN.CITE <EndNote><Cite><Author>Elbaz</Author><Year>2013</Year><RecNum>11139</RecNum><DisplayText><style face="superscript">82</style></DisplayText><record><rec-number>11139</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1530178116">11139</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elbaz, Alexis</author><author>Vicente-Vytopilova, Pavla</author><author>Tavernier, Béatrice</author><author>Sabia, Séverine</author><author>Dumurgier, Julien</author><author>Mazoyer, Bernard</author><author>Singh-Manoux, Archana</author><author>Tzourio, Christophe</author></authors></contributors><titles><title>Motor function in the elderly Evidence for the reserve hypothesis</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>417-426</pages><volume>81</volume><number>5</number><dates><year>2013</year></dates><isbn>0028-3878</isbn><urls></urls></record></Cite></EndNote>82 and age at stroke. ADDIN EN.CITE <EndNote><Cite><Author>Makin</Author><Year>2018</Year><RecNum>11199</RecNum><DisplayText><style face="superscript">80</style></DisplayText><record><rec-number>11199</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1532610779">11199</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Makin, Stephen DJ</author><author>Doubal, Fergus N</author><author>Shuler, Kirsten</author><author>Chappell, Francesca M</author><author>Staals, Julie</author><author>Dennis, Martin S</author><author>Wardlaw, Joanna M</author></authors></contributors><titles><title>The impact of early-life intelligence quotient on post stroke cognitive impairment</title><secondary-title>Eur Stroke J</secondary-title></titles><periodical><full-title>Eur Stroke J</full-title></periodical><pages>145-156</pages><volume>3</volume><number>2</number><dates><year>2018</year></dates><isbn>2396-9873</isbn><urls></urls></record></Cite></EndNote>80 ‘Brain resilience’ may depend on white matter structural integrity and network connectivity, since global white matter network efficiency mediated the effects of SVD lesions on cognition and progression to dementia. ADDIN EN.CITE <EndNote><Cite><Author>Ter Telgte</Author><Year>2018</Year><RecNum>11081</RecNum><DisplayText><style face="superscript">59</style></DisplayText><record><rec-number>11081</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1529506998">11081</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ter Telgte, A.</author><author>van Leijsen, E. M. C.</author><author>Wiegertjes, K.</author><author>Klijn, C. J. M.</author><author>Tuladhar, A. M.</author><author>de Leeuw, F. E.</author></authors></contributors><auth-address>Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands. FrankErik.deLeeuw@radboudumc.nl.</auth-address><titles><title>Cerebral small vessel disease: from a focal to a global perspective</title><secondary-title>Nat Rev Neurol</secondary-title></titles><periodical><full-title>Nat Rev Neurol</full-title></periodical><pages>387-398</pages><volume>14</volume><dates><year>2018</year><pub-dates><date>May 25</date></pub-dates></dates><isbn>1759-4766 (Electronic)
1759-4758 (Linking)</isbn><accession-num>29802354</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%"> Premorbid cognitive ability (ie peak intelligence, a measure of ‘cognitive reserve’) can be estimated using tests such as the National Adult Reading Test, influences risk of SVD lesions in later life, ADDIN EN.CITE <EndNote><Cite><Author>Backhouse</Author><Year>2017</Year><RecNum>10727</RecNum><DisplayText><style face="superscript">78</style></DisplayText><record><rec-number>10727</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1482500454">10727</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Backhouse, E. V.</author><author>McHutchison, C. A.</author><author>Cvoro, V.</author><author>Shenkin, S. D.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>From the Centre for Clinical Brain Sciences (E.V.B., C.A.M., V.C., J.M.W.), Centre for Cognitive Ageing and Cognitive Epidemiology (C.A.M., V.C., S.D.S., J.M.W.), and Geriatric Medicine, Department of Clinical and Surgical Sciences (S.D.S.), University of Edinburgh; and Scottish Imaging Network (V.C., S.D.S., J.M.W.), A Platform for Scientific Excellence (SINAPSE), UK.
From the Centre for Clinical Brain Sciences (E.V.B., C.A.M., V.C., J.M.W.), Centre for Cognitive Ageing and Cognitive Epidemiology (C.A.M., V.C., S.D.S., J.M.W.), and Geriatric Medicine, Department of Clinical and Surgical Sciences (S.D.S.), University of Edinburgh; and Scottish Imaging Network (V.C., S.D.S., J.M.W.), A Platform for Scientific Excellence (SINAPSE), UK. joanna.wardlaw@ed.ac.uk.</auth-address><titles><title>Early life risk factors for cerebrovascular disease: A systematic review and meta-analysis</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>976-984</pages><volume>88</volume><number>10</number><dates><year>2017</year><pub-dates><date>Mar 07</date></pub-dates></dates><isbn>1526-632X (Electronic)
0028-3878 (Linking)</isbn><accession-num>28188307</accession-num><label>22093</label><urls><related-urls><url> and could explain some of the variation in SVD and cognitive function. ADDIN EN.CITE <EndNote><Cite><Author>Makin</Author><Year>2018</Year><RecNum>11199</RecNum><DisplayText><style face="superscript">80</style></DisplayText><record><rec-number>11199</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1532610779">11199</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Makin, Stephen DJ</author><author>Doubal, Fergus N</author><author>Shuler, Kirsten</author><author>Chappell, Francesca M</author><author>Staals, Julie</author><author>Dennis, Martin S</author><author>Wardlaw, Joanna M</author></authors></contributors><titles><title>The impact of early-life intelligence quotient on post stroke cognitive impairment</title><secondary-title>Eur Stroke J</secondary-title></titles><periodical><full-title>Eur Stroke J</full-title></periodical><pages>145-156</pages><volume>3</volume><number>2</number><dates><year>2018</year></dates><isbn>2396-9873</isbn><urls></urls></record></Cite></EndNote>80 Comorbid conditions are common in older patients, particularly in patients diagnosed with dementia. The most frequent finding in patients with dementia is mixed vascular and AD-type pathology, with individuals with multiple versus one pathology being more likely to have dementia. ADDIN EN.CITE <EndNote><Cite><Author>Kapasi</Author><Year>2017</Year><RecNum>10981</RecNum><DisplayText><style face="superscript">6</style></DisplayText><record><rec-number>10981</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1516362882">10981</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kapasi, A.</author><author>DeCarli, C.</author><author>Schneider, J. A.</author></authors></contributors><auth-address>Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, USA.
Department of Pathology, Rush University Medical Center, Chicago, USA.
Department of Neurology, University of California, Davis, Sacramento, USA.
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, USA. julie_a_schneider@rush.edu.
Department of Pathology, Rush University Medical Center, Chicago, USA. julie_a_schneider@rush.edu.
Department of Neurological Sciences, Rush University Medical Center, Chicago, USA. julie_a_schneider@rush.edu.</auth-address><titles><title>Impact of multiple pathologies on the threshold for clinically overt dementia</title><secondary-title>Acta Neuropathol</secondary-title></titles><periodical><full-title>Acta Neuropathol</full-title></periodical><pages>171-186</pages><volume>134</volume><number>2</number><keywords><keyword>Alzheimer's disease</keyword><keyword>Biomarkers</keyword><keyword>Dementia</keyword><keyword>Mixed dementia</keyword><keyword>Mixed pathologies</keyword><keyword>Neuroimaging</keyword></keywords><dates><year>2017</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1432-0533 (Electronic)
0001-6322 (Linking)</isbn><accession-num>28488154</accession-num><urls><related-urls><url> As such, comorbid neurodegenerative disease or other vascular lesions (e.g. large artery stroke) may also modify clinical expressions of SVD. The mechanisms and clinical effects of co-morbidities are subject to intensive research. Pharmacological and Lifestyle Interventions Evidence on prevention and treatment of SVD comes from completed trials of contemporary vascular risk modifying agents, drugs used in other fields with relevant modes of action, ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>9537</RecNum><DisplayText><style face="superscript">83</style></DisplayText><record><rec-number>9537</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815922">9537</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><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>469-478</pages><volume><style face="normal" font="Frutiger-Light" size="100%">10</style></volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>treatment</keyword><keyword>and</keyword><keyword>prevention</keyword><keyword>of</keyword><keyword>Cerebral</keyword><keyword>Vessel</keyword><keyword>Disease</keyword><keyword>review</keyword></keywords><dates><year>2015</year><pub-dates><date>2015</date></pub-dates></dates><label>20995</label><urls></urls><electronic-resource-num><style face="normal" font="Frutiger-Light" size="100%">10.1111/ijs.12466</style></electronic-resource-num></record></Cite></EndNote>83 and lifestyle factors that can be modified (Table 1). In the Secondary Prevention of Small Subcortical Stroke (SPS3) trial, long-term dual versus single antiplatelet therapy increased bleeding and death without reducing recurrent stroke.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ld29rPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 86 PRESERVE (n=70, hypertension and SVD, mean age 69 years, duration three months) found no difference in CBF with BP reduction; ADDIN EN.CITE <EndNote><Cite><Author>Croall</Author><Year>2018</Year><RecNum>11145</RecNum><DisplayText><style face="superscript">87</style></DisplayText><record><rec-number>11145</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1530178471">11145</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Croall, Iain D</author><author>Tozer, Daniel J</author><author>Moynihan, Barry</author><author>Khan, Usman</author><author>O’brien, John T</author><author>Morris, Robin G</author><author>Cambridge, Victoria C</author><author>Barrick, Thomas R</author><author>Blamire, Andrew M</author><author>Ford, Gary A</author><author>Markus, Hugh S.</author></authors></contributors><titles><title>Effect of standard vs intensive blood pressure control on cerebral blood flow in small vessel disease: The PRESERVE randomized clinical trial</title><secondary-title>JAMA Neurol</secondary-title></titles><periodical><full-title>JAMA Neurol</full-title></periodical><pages>720-727</pages><volume>75</volume><number>6</number><dates><year>2018</year></dates><isbn>2168-6149</isbn><urls></urls></record></Cite></EndNote>87 full publication of SPRINT MIND (Systolic Blood Pressure Intervention Trial Memory and cognition IN Decreased hypertension, mean age 67.9) is awaited. While supporting rigorous BP control in patients with lacunar stroke or WMH who are in their 60s, WMH are commonest in patients aged over 80. Some believe that too rapid or large BP reductions in the over 80s, in whom brain perfusion may depend on elevated BP,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWJheWFuPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 89 may lead to hypoperfusion. While the PRESERVE CBF substudy provides reassurance that intensive BP reduction did not affect CBF, the mean age was only 69. Hence, while rigorous BP control is important, data are lacking on optimal individual BP targets in older patients with severe WMH. Statins are now guideline therapy for secondary stroke/cardiovascular disease prevention, with no evidence of different effects in lacunar ischaemic stroke. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>9537</RecNum><DisplayText><style face="superscript">83</style></DisplayText><record><rec-number>9537</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815922">9537</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><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>469-478</pages><volume><style face="normal" font="Frutiger-Light" size="100%">10</style></volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>treatment</keyword><keyword>and</keyword><keyword>prevention</keyword><keyword>of</keyword><keyword>Cerebral</keyword><keyword>Vessel</keyword><keyword>Disease</keyword><keyword>review</keyword></keywords><dates><year>2015</year><pub-dates><date>2015</date></pub-dates></dates><label>20995</label><urls></urls><electronic-resource-num><style face="normal" font="Frutiger-Light" size="100%">10.1111/ijs.12466</style></electronic-resource-num></record></Cite></EndNote>83 Low dose rosuvastatin may delay WMH progression, particularly in patients with the APOE-4 allele,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KaTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 92 Emerging targets include BBB integrity, vasoreactivity, vascular compliance, perivascular inflammation or myelin repair.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXRoPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXRoPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 16,83 Several drugs approved for other indications have relevant modes of action (Table 1). Cilostazol, a phosphodiesterase 3’ (PDE3) inhibitor is used for stroke prevention in Asia-Pacific countries, may reduce cognitive decline,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 93 reduce endothelial dysfunction, inflammation and enhance myelin repair, ADDIN EN.CITE <EndNote><Cite><Author>Rajani</Author><Year>2018</Year><RecNum>11151</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>11151</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1530788454">11151</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rajani, Rikesh M.</author><author>Quick, Sophie</author><author>Ruigrok, Silvie R.</author><author>Graham, Delyth</author><author>Harris, Sarah E.</author><author>Verhaaren, Benjamin F. J.</author><author>Fornage, Myriam</author><author>Seshadri, Sudha</author><author>Atanur, Santosh S.</author><author>Dominiczak, Anna F.</author><author>Smith, Colin</author><author>Wardlaw, Joanna M.</author><author>Williams, Anna</author></authors></contributors><titles><title>Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats</title><secondary-title>Sci Transl Med</secondary-title></titles><periodical><full-title>Sci Transl Med</full-title></periodical><pages>eaam9507</pages><volume>10</volume><number>448</number><dates><year>2018</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%"> with supporting genetic data.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWxpazwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 95 High dietary sodium increases stroke risk, worsens WMH and total SVD burden. ADDIN EN.CITE <EndNote><Cite><Author>Hankey</Author><Year>2017</Year><RecNum>10921</RecNum><DisplayText><style face="superscript">96</style></DisplayText><record><rec-number>10921</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1507729070">10921</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hankey, G. J.</author></authors></contributors><auth-address>From the Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth; Sir Charles Gairdner Hospital, Perth, Australia; and Perron Institute for Neurological and Translational Science, Perth, Australia. graeme.hankey@uwa.edu.au.</auth-address><titles><title>The role of nutrition in the risk and burden of stroke: an update of the evidence</title><secondary-title>Stroke</secondary-title><alt-title>Stroke</alt-title></titles><periodical><full-title>Stroke</full-title></periodical><alt-periodical><full-title>Stroke</full-title></alt-periodical><pages>3168-3174</pages><volume>48</volume><number>11</number><edition>2017/09/25</edition><keywords><keyword>diet</keyword><keyword>epidemiology</keyword><keyword>risk</keyword><keyword>stroke</keyword></keywords><dates><year>2017</year><pub-dates><date>Sep 22</date></pub-dates></dates><isbn>0039-2499</isbn><accession-num>28939673</accession-num><urls></urls><electronic-resource-num>10.1161/strokeaha.117.016993</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>96 A ‘Mediterranean’ diet and B12/folate may limit WMH. ADDIN EN.CITE <EndNote><Cite><Author>Hankey</Author><Year>2017</Year><RecNum>10921</RecNum><DisplayText><style face="superscript">96</style></DisplayText><record><rec-number>10921</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1507729070">10921</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hankey, G. J.</author></authors></contributors><auth-address>From the Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth; Sir Charles Gairdner Hospital, Perth, Australia; and Perron Institute for Neurological and Translational Science, Perth, Australia. graeme.hankey@uwa.edu.au.</auth-address><titles><title>The role of nutrition in the risk and burden of stroke: an update of the evidence</title><secondary-title>Stroke</secondary-title><alt-title>Stroke</alt-title></titles><periodical><full-title>Stroke</full-title></periodical><alt-periodical><full-title>Stroke</full-title></alt-periodical><pages>3168-3174</pages><volume>48</volume><number>11</number><edition>2017/09/25</edition><keywords><keyword>diet</keyword><keyword>epidemiology</keyword><keyword>risk</keyword><keyword>stroke</keyword></keywords><dates><year>2017</year><pub-dates><date>Sep 22</date></pub-dates></dates><isbn>0039-2499</isbn><accession-num>28939673</accession-num><urls></urls><electronic-resource-num>10.1161/strokeaha.117.016993</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>96 Common sense should include good sleep hygiene, since brain interstitial fluid and waste clearance via PVS may accelerate during sleep.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXNtdXNzZW48L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy
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ADDIN EN.CITE.DATA 18,45Conclusions and future directions Small vessel disease causes a quarter to a fifth of strokes, age-related cognitive, physical and mood decline and about half of all dementias. This burden of disease has only been appreciated recently, so a complete understanding of the pathophysiology has been lacking. Much recent understanding of pathophysiological mechanisms in humans derives from advanced neuroimaging methods, which demonstrate dysfunctions of the cerebrovascular endothelium including subtle but diffuse BBB dysfunction, ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2017</Year><RecNum>10693</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>10693</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1477654980">10693</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw, Joanna M.</author><author>Makin, Stephen J.</author><author>Valdés Hernández, Maria C.</author><author>Armitage, Paul A.</author><author>Heye, Anna K.</author><author>Chappell, Francesca M.</author><author>Mu?oz-Maniega, Susana</author><author>Sakka, Eleni</author><author>Shuler, Kirsten</author><author>Dennis, Martin S.</author><author>Thrippleton, Michael J.</author></authors></contributors><titles><title>Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study</title><secondary-title>Alzheimers Dement</secondary-title></titles><periodical><full-title>Alzheimers Dement</full-title></periodical><pages>634-643</pages><volume>13</volume><number>6</number><dates><year>2017</year></dates><isbn>15525260</isbn><label>22062</label><urls></urls><electronic-resource-num>10.1016/j.jalz.2016.09.006</electronic-resource-num></record></Cite></EndNote>28 impaired vasoreactivity, ADDIN EN.CITE <EndNote><Cite><Author>Sam</Author><Year>2016</Year><RecNum>10635</RecNum><DisplayText><style face="superscript">43</style></DisplayText><record><rec-number>10635</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1472640242">10635</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sam, K.</author><author>Crawley, A. P.</author><author>Conklin, J.</author><author>Poublanc, J.</author><author>Sobczyk, O.</author><author>Mandell, D. M.</author><author>Venkatraghavan, L.</author><author>Duffin, J.</author><author>Fisher, J. A.</author><author>Black, S. E.</author><author>Mikulis, D. J.</author></authors></contributors><auth-address>Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Division of Neuroradiology, Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada.
Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada.
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
Department of Anesthesiology, University Health Network, Toronto, Ontario, Canada.
LC Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.</auth-address><titles><title>Development of white matter hyperintensity is preceded by reduced cerebrovascular reactivity</title><secondary-title>Ann Neurol</secondary-title></titles><periodical><full-title>Ann Neurol</full-title></periodical><pages>277-85</pages><volume>80</volume><number>2</number><dates><year>2016</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1531-8249 (Electronic)
0364-5134 (Linking)</isbn><accession-num>27352039</accession-num><label>21996</label><urls><related-urls><url> increased intracranial vascular pulsatility, ADDIN EN.CITE <EndNote><Cite><Author>Shi</Author><Year>2018</Year><RecNum>11241</RecNum><DisplayText><style face="superscript">44</style></DisplayText><record><rec-number>11241</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1536138079">11241</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shi, Y.</author><author>Thrippleton, M.J.</author><author>Blair, G.W.</author><author>Dickie, D.A.</author><author>Marshall, I.</author><author>Hamilton, I.</author><author>Doubal, F.N.</author><author>Chappell, F.</author><author>Wardlaw, J.M.</author></authors></contributors><titles><title>Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow </title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><volume>38</volume><dates><year>2018</year></dates><urls></urls><electronic-resource-num>10.1177/0271678X18803956</electronic-resource-num></record></Cite></EndNote>44 early white matter oedema, ADDIN EN.CITE <EndNote><Cite><Author>De Guio</Author><Year>2015</Year><RecNum>9973</RecNum><DisplayText><style face="superscript">34</style></DisplayText><record><rec-number>9973</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815937">9973</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>De Guio,F.</author><author>Mangin,J.F.</author><author>Duering,M.</author><author>Ropele,S.</author><author>Chabriat,H.</author><author>Jouvent,E.</author></authors></contributors><titles><title>White matter edema at the early stage of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>258-261</pages><volume>46</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>White Matter</keyword><keyword>WHITE-MATTER</keyword><keyword>Edema</keyword><keyword>of</keyword><keyword>Cerebral</keyword><keyword>Infarct</keyword><keyword>and</keyword><keyword>Leukoencephalopathies</keyword></keywords><dates><year>2015</year><pub-dates><date>2015</date></pub-dates></dates><label>21438</label><urls></urls><electronic-resource-num>10.1161/STROKEAHA.114.007018</electronic-resource-num></record></Cite></EndNote>34 lesion regression as well as progression,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gTGVpanNlbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1ll
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ADDIN EN.CITE.DATA 57 and diffuse structural effects throughout normal appearing white matter ADDIN EN.CITE <EndNote><Cite><Author>Rost</Author><Year>2018</Year><RecNum>11100</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>11100</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1530097378">11100</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rost, N.S.</author><author>Cougo, P.</author><author>Lorenzano, S.</author><author>Li, H.</author><author>Cloonan, L.</author><author>Bouts, M.J.</author><author>Lauer, A.</author><author>Etherton, M.R.</author><author>Karadeli, H.H.</author><author>Musolino, P.L.</author><author>Copen, W.A.</author><author>Arai, K.</author><author>Lo, E.H.</author><author>Feske, S.K.</author><author>Furie, K.L.</author><author>Wu, O.</author></authors></contributors><titles><title>Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke.</title><secondary-title>J Cereb Blood Flow Metab </secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><pages>75-86</pages><volume>38</volume><number>1</number><dates><year>2018</year></dates><urls></urls><electronic-resource-num><style face="underline" font="default" size="100%"> face="normal" font="default" size="100%"> </style></electronic-resource-num></record></Cite></EndNote>29 and secondary remote tissue atrophy.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXJlczwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 16,20 Improved awareness of the dynamic, whole brain effects, balance of primary versus secondary injury, balance of risk factor exposure versus resilience and complex disease patterns should inform future clinical trials, observational human studies, experimental models, and clinical practice. Future studies should address the order of, and interactions between, BBB failure, impaired vasoreactivity, increased pulsatility, vessel wall damage, impaired interstitial fluid drainage and PVS function in sporadic SVDs. Trials of agents that maintain endothelial function, improve risk factors and of lifestyle improvements should be encouraged. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>9537</RecNum><DisplayText><style face="superscript">83</style></DisplayText><record><rec-number>9537</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815922">9537</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><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>469-478</pages><volume><style face="normal" font="Frutiger-Light" size="100%">10</style></volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>treatment</keyword><keyword>and</keyword><keyword>prevention</keyword><keyword>of</keyword><keyword>Cerebral</keyword><keyword>Vessel</keyword><keyword>Disease</keyword><keyword>review</keyword></keywords><dates><year>2015</year><pub-dates><date>2015</date></pub-dates></dates><label>20995</label><urls></urls><electronic-resource-num><style face="normal" font="Frutiger-Light" size="100%">10.1111/ijs.12466</style></electronic-resource-num></record></Cite></EndNote>83 An approach that integrates from cells to tissues to systems, and across clinical specialties, would facilitate progress in SVD and should be encouraged. Since humans are their own best model, better pathology-imaging correlations,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaW50ZXJzPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA 12 and brain banking with data linkage, are needed. ADDIN EN.CITE <EndNote><Cite><Author>Humphreys</Author><Year>2018</Year><RecNum>11152</RecNum><DisplayText><style face="superscript">97</style></DisplayText><record><rec-number>11152</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1531222085">11152</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Humphreys, C.A.</author><author>Jansen, M.A.</author><author>Munoz-Maniega, S.</author><author>González-Castro, V.</author><author>Pernet, C.</author><author>Deary, I.J.</author><author>Al-Shahi Salman, R.</author><author>Wardlaw, J.M.</author><author>Smith, C.</author></authors></contributors><titles><title>A protocol for precise comparisons of small vessel disease lesions between ex vivo MRI and histopathology.</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><volume>In press.</volume><dates><year>2018</year></dates><urls></urls></record></Cite></EndNote>97Panel: Search strategy and selection criteriaWe searched PubMed, Google Scholar, , Cochrane library, from 01/12/2012–31/12/2018, using search terms ‘lacunar’, ‘stroke’, ‘dementia’, ‘small vessel disease’ and its terminologies (‘white matter hyperintensities’, ‘white matter lesions’, ‘leukoaraiosis’, ‘lacune’, ‘microbleed’, ‘perivascular space’, ‘Virchow-Robin space’), ‘meta-analysis’, ‘systematic review’, and ‘randomised clinical trial’, restricting to ‘human’ studies, published in English, German, Spanish, French, Mandarin. We checked reference lists of reviews. The final reference list included systematic reviews where available, high quality observational studies and clinical trials. Panel: Definitions of terminology used in Small Vessel Diseases Small vessel diseasesRefers to neuroimaging and neuropathological abnormalities in the cerebral white and deep grey matter that are thought to arise from abnormalities in the microscopic perforating cerebral arterioles, capillaries and venules. Many affected individuals do not have symptoms but the brain damage can lead to stroke (25% of ischaemic and most haemorrhagic strokes), cognitive decline or dementia (the commonest cause of vascular dementia and common in mixed dementias), gait and balance problems and mood disorders in older people. Most small vessel disease is ‘sporadic’, perhaps related to hypertension or other vascular risk factors, but a small proportion are due to rare genetic variants of which the commonest is CADASIL.White matter hyperintensities, lacunes, microbleeds, perivascular spaces, recent small subcortical infarctsAre the common types of small vessel lesions seen on neuroimaging or neuropathology where the brain is most damaged. Many lesions gradually worsen although some lesions may improve for unknown reasons. Normal appearing brain is often abnormal if assessed with sensitive imaging methods, especially as the number of lesions increases and in the tissue around the visible lesions. Endothelial dysfunctionWhen the layer of cells that line the blood vessels in the brain are not functioning properly. This is manifest in several ways. The cells lining the capillaries should regulate transport of fluid, nutrients and waste in and out of the brain, but they become leaky leading to perivascular tissue and arteriolar wall damage. The arterioles lose the ability to contract and dilate so as to match blood supply to demand in the brain. The vessels stiffen so that the pulsatility of the pulse wave increases, and this in turn diminishes the flow of fluid in the perivascular spaces which is thought to affect interstitial fluid flushing. Neurogliovascular unitRefers to the way in which the common types of vascular and brain cells - endothelial cells, pericytes, astrocytes, oligodendrocytes and neurons - are organised and linked together into millions of functional units in the brain. In these groupings, the cells interact to regulate entry of fluid and nutrients into the interstitium, manage blood supply, maintain and repair myelin, clear fluid and waste, and maintain the interstitial milieu for proper cell function.Panel: Future PrioritiesResearch is needed to determine the relative contribution(s) of different manifestations of endothelial dysfunctions to brain damage in patients with small vessel diseases and their timescales. Longitudinal studies with detailed risk factor assessment and lesion monitoring are needed to determine reasons for the wide variation in rates of progression of SVD lesions, why some lesions regress, and why some lesions lead to secondary damage in remote brain regions. This knowledge would help predict disease impact on clinical, physical and cognitive outcomes. Understanding the reasons for the variable symptomologies, and the role of ‘brain reserve’ and ‘cognitive reserve’, would improve detection, diagnosis and in future also help tailor the clinical management of individual patients. Understanding the role of genetic susceptibilities versus environment and risk factor exposures, from birth to later life, is also important to understand variation in SVD lesion development and clinical expression. Clinical trials should test the numerous licenced drugs that have relevant effects. New interventions are needed to target the molecular underpinnings of the endothelial dysfunction(s) seen in SVD. Declarations of interestJW reports grants from Wellcome Trust, Scottish Executive Chief Scientist Office, Row Fogo Charitable Trust, Medical Research Council, Age UK, Chest Heart Stroke Scotland, Alzheimer's Society, Stroke Association, Fondation Leducq, EU Horizon 2020, and British Heart Foundation. CS reports grants from the Medical Research Council and Alzheimer’s Research UK. MD reports grants from the Fondation Leducq, EU Horizon 2020 and the Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. There are no other competing interests.Authors’ contributionsJMW, MD and CS each drafted sections of text. JMW combined the text. All three authors edited the text, helped to prepare the figures, provided insight, context and balanced interpretation of evidence through discussion and approved the final version for submission.AcknowledgementWe thank Antonia Weingart for artistic preparation of Figure1, Figure 2 and Figure 4. References ADDIN EN.REFLIST 1.Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013; 12: 483-97.2.Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration: a united approach. 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Stroke 2017; 48(11): 3168-74.97.Humphreys CA, Jansen MA, Munoz-Maniega S, et al. A protocol for precise comparisons of small vessel disease lesions between ex vivo MRI and histopathology. Int J Stroke 2018; In press.98.The ENOS Trial Investigators. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial. Lancet 2015; 385: 617-28.Table 1. Summary of pharmacological and lifestyle interventions in small vessel disease. Meta-analyses are cited where available, otherwise randomised controlled trials (RCT). A ‘ – ‘ in the N column or ‘analysing’ indicates that the trial is ongoing. Trial registration numbers or published protocols are cited for ongoing studies where more details of trial protocols may be found. References are cited for main trial results papers. 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ADDIN EN.CITE.DATA 84Patients with lacunar stroke4223464.4Includes SPS3; follow-up 4 weeks to 3.5 years; single vs no antiplatelet reduced recurrent stroke; no difference between several antiplatelet drugs; long term dual antiplatelet in SPS3 increased ICH.Anti-hyper-tensiveRCTSPS3; ADDIN EN.CITE <EndNote><Cite><Author>Pearce</Author><Year>2014</Year><RecNum>9626</RecNum><DisplayText><style face="superscript">85</style></DisplayText><record><rec-number>9626</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815925">9626</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pearce,L.A.</author><author>McClure,L.A.</author><author>Anderson,D.C.</author><author>Jacova,C.</author><author>Sharma,M.</author><author>Hart,R.G.</author><author>Benavente,O.R.</author><author>for the SPS3 Investigators,</author></authors></contributors><titles><title>Effects of long-term blood pressure lowering and dual antiplatelet treatment on cognitive function in patients with recent lacunar stroke: a secondary analysis from the SPS3 randomised trial</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>1177-1185</pages><volume>13</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>of</keyword><keyword>blood</keyword><keyword>blood pressure</keyword><keyword>Pressure</keyword><keyword>and</keyword><keyword>treatment</keyword><keyword>COGNITIVE FUNCTION</keyword><keyword>Patients</keyword><keyword>Patient</keyword><keyword>stroke</keyword><keyword>secondary</keyword><keyword>analysis</keyword><keyword>Randomised</keyword><keyword>trial</keyword></keywords><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><label>21085</label><urls></urls></record></Cite></EndNote>85 Meta-analysisACCORD-MIND, PRoFESS, PROGRESS, SCOPEPEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gTWlkZGVsYWFyPC9BdXRob3I+PFllYXI+MjAxODwv
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ADDIN EN.CITE.DATA 86RCT substudyPRESERVEPatients with lacunar strokeAny strokeHT, lacunar stroke, severe WMH 30201369 6263±1162±566±861±1277±4 69 Different BP lowering agents at the discretion of the treating clinician. No reduction in stroke, cognitive decline with intensive vs usual BP reduction;Follow-up 28-47months; less WMH progression with intensive vs usual BP reduction.CBF did not fall with BP reductionStatinsRCT SubstudyVITATOPSPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YaW9uZzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 91 RCT substudy in Shandong, ChinaPatients with stroke and pre-stroke statin, rosuvastatin 81668>60Less WMH progression with pre-stroke statin Follow-up 61.8 (SD: 2.2) months; less WMH progression with statin than non statin and in non APO-e4 v APOE-4 carriersNovel pharmacology: endothelial and other effects – ongoing unless otherwise statedNitric OxideRCTENOSRIGHT-2(ISRCTN26986053)LACI trials (LACI-1 (EudraCT 2015‐001953‐33); LACI-2, EudraCT 2016-002277-35)Patients with stroke including lacunar stroke ADDIN EN.CITE <EndNote><Cite><Author>The ENOS Trial Investigators</Author><Year>2015</Year><RecNum>9572</RecNum><DisplayText><style face="superscript">98</style></DisplayText><record><rec-number>9572</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815923">9572</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>The ENOS Trial Investigators,</author></authors></contributors><titles><title>Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>617-628</pages><volume>385</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Acute</keyword><keyword>Acute stroke</keyword><keyword>blood</keyword><keyword>blood pressure</keyword><keyword>Controlled trial</keyword><keyword>EFFICACY</keyword><keyword>NITRIC-OXIDE</keyword><keyword>Nitric Oxide</keyword><keyword>of</keyword><keyword>Pressure</keyword><keyword>Randomised</keyword><keyword>stroke</keyword><keyword>treatment</keyword><keyword>trial</keyword></keywords><dates><year>2015</year><pub-dates><date>2015</date></pub-dates></dates><label>21030</label><urls></urls><electronic-resource-num>10.1016/S0140-6736(14)61121-1</electronic-resource-num></record></Cite></EndNote>98Patients with stroke including lacunar strokePatients with lacunar strokePatients with lacunar stroke40111050 57 -70±12Analysing66±11Effect of short term GTN on neurological, functional, cognitive outcomes; analysing 1397 with lacunar stroke of whom 41% had WMHEffect of short term GTN on neurological, functional, cognitive outcomes Effect of isosorbide mononitrate on recurrent stroke, cognitive decline, SVD lesion burden.PDE3’ inhibitor (Cilostazol) Meta-analysisTrials of stroke preventionRCTLACI trials (LACI-1 (EudraCT 2015‐001953‐33); LACI-2, EudraCT 2016-002277-35)ObservationalNational Registry TaiwanPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 93Patients with ischaemic strokePatients with lacunar strokePatients with lacunar strokePatients in central hospital registry600057 -9148 67 66±11 - >40Reduced recurrent strokeEffect of cilostazol on recurrent stroke, cognitive decline, SVD lesion burden.Effect of cilostazol on recurrent stroke, cognitive decline, SVD lesion burdenCilostazol use was associated with a reduction in incident dementia, xanthine oxidase inhibitor (Allopurinol)RCTXYLO-FIST (NCT02122718) Ischaemic stroke - -Effect of Allopurinol on WMH progression and recurrent stroke, PDE5’ inhibitorsRCTPASTIS (EudraCT 2015-001235-20) Patients with WMH - -Effect of Tadalafil single dose on resting CBF, B12/FolateSubstudies in RCT VITATOPS ADDIN EN.CITE <EndNote><Cite><Author>Hankey</Author><Year>2017</Year><RecNum>10921</RecNum><DisplayText><style face="superscript">96</style></DisplayText><record><rec-number>10921</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1507729070">10921</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hankey, G. J.</author></authors></contributors><auth-address>From the Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth; Sir Charles Gairdner Hospital, Perth, Australia; and Perron Institute for Neurological and Translational Science, Perth, Australia. graeme.hankey@uwa.edu.au.</auth-address><titles><title>The role of nutrition in the risk and burden of stroke: an update of the evidence</title><secondary-title>Stroke</secondary-title><alt-title>Stroke</alt-title></titles><periodical><full-title>Stroke</full-title></periodical><alt-periodical><full-title>Stroke</full-title></alt-periodical><pages>3168-3174</pages><volume>48</volume><number>11</number><edition>2017/09/25</edition><keywords><keyword>diet</keyword><keyword>epidemiology</keyword><keyword>risk</keyword><keyword>stroke</keyword></keywords><dates><year>2017</year><pub-dates><date>Sep 22</date></pub-dates></dates><isbn>0039-2499</isbn><accession-num>28939673</accession-num><urls></urls><electronic-resource-num>10.1161/strokeaha.117.016993</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>96Patients with stroke359 64Vitamin supplements for 2 years reduced WMH progression in patients with the worst WMH at baseline; LifestyleSmoking ObservationalMSS2 ADDIN EN.CITE <EndNote><Cite><Author>Staals</Author><Year>2014</Year><RecNum>9530</RecNum><DisplayText><style face="superscript">61</style></DisplayText><record><rec-number>9530</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815921">9530</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Staals,J.</author><author>Makin,S.D.J.</author><author>Doubal,F.</author><author>Dennis,M.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Stroke subtype, vascular risk factors and total MRI brain small vessel disease burden</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>1228-1234</pages><volume>83</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>stroke</keyword><keyword>subtype</keyword><keyword>Risk</keyword><keyword>Risk Factors</keyword><keyword>RISK-FACTORS</keyword><keyword>and</keyword><keyword>MRI</keyword><keyword>Brain</keyword><keyword>Vessel</keyword><keyword>Disease</keyword></keywords><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><label>20987</label><urls></urls></record></Cite></EndNote>61Paris-Munich CADASIL ADDIN EN.CITE <EndNote><Cite><Author>Chabriat</Author><Year>2016</Year><RecNum>11129</RecNum><DisplayText><style face="superscript">76</style></DisplayText><record><rec-number>11129</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1530177148">11129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chabriat, Hugues</author><author>Hervé, Dominique</author><author>Duering, Marco</author><author>Godin, Ophelia</author><author>Jouvent, Eric</author><author>Opherk, Christian</author><author>Alili, Nassira</author><author>Reyes, Sonia</author><author>Jabouley, Aude</author><author>Zieren, Nikola</author></authors></contributors><titles><title>Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: prospective cohort study</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>4-11</pages><volume>47</volume><number>1</number><dates><year>2016</year></dates><isbn>0039-2499</isbn><urls></urls></record></Cite></EndNote>76Lothian Birth Cohort ADDIN EN.CITE <EndNote><Cite><Author>Karama</Author><Year>2015</Year><RecNum>9735</RecNum><DisplayText><style face="superscript">94</style></DisplayText><record><rec-number>9735</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815929">9735</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Karama,S.</author><author>Ducharme,S.</author><author>Corley,J.</author><author>Chouinard-Decorte,F.</author><author>Starr,J.</author><author>Wardlaw,J.</author><author>Bastin,M.</author><author>Deary,I.</author></authors></contributors><titles><title>Cigarette smoking and thinning of the brain's cortex</title><secondary-title>Mol Psychiatry</secondary-title></titles><periodical><full-title>Mol Psychiatry</full-title></periodical><pages>778-785</pages><volume>20</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Smoking</keyword><keyword>and</keyword><keyword>of</keyword><keyword>CORTEX</keyword></keywords><dates><year>2015</year><pub-dates><date>2015</date></pub-dates></dates><label>21195</label><urls></urls><electronic-resource-num>10.1038/mp.2014.187</electronic-resource-num></record></Cite></EndNote>94Patients with stroke; 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ADDIN EN.CITE.DATA 95Older subjects at risk of dementia1260 69.5Dietary, exercise encouragement and medical risk factor reduction versus usual health messages and guideline vascular risk factor reduction, reduced cognitive decline, and WMH progression in substudyDiet: sodium chlorideObservationalMSS-2 ADDIN EN.CITE <EndNote><Cite><Author>Hankey</Author><Year>2017</Year><RecNum>10921</RecNum><DisplayText><style face="superscript">96</style></DisplayText><record><rec-number>10921</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1507729070">10921</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hankey, G. J.</author></authors></contributors><auth-address>From the Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth; Sir Charles Gairdner Hospital, Perth, Australia; and Perron Institute for Neurological and Translational Science, Perth, Australia. graeme.hankey@uwa.edu.au.</auth-address><titles><title>The role of nutrition in the risk and burden of stroke: an update of the evidence</title><secondary-title>Stroke</secondary-title><alt-title>Stroke</alt-title></titles><periodical><full-title>Stroke</full-title></periodical><alt-periodical><full-title>Stroke</full-title></alt-periodical><pages>3168-3174</pages><volume>48</volume><number>11</number><edition>2017/09/25</edition><keywords><keyword>diet</keyword><keyword>epidemiology</keyword><keyword>risk</keyword><keyword>stroke</keyword></keywords><dates><year>2017</year><pub-dates><date>Sep 22</date></pub-dates></dates><isbn>0039-2499</isbn><accession-num>28939673</accession-num><urls></urls><electronic-resource-num>10.1161/strokeaha.117.016993</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>96Patients with stroke 264 67High dietary sodium increased risk of: stroke, lacunar versus cortical stroke, WMH & total SVD burden. SPS3: Secondary prevention of small subcortical stroke trial. ACCORD-MIND: Action to Control Cardiovascular Risk in Diabetes: Memory in Diabetes (MIND) substudy. PRoFESS: Prevention Regimen for Effectively Avoiding Second Strokes. PROGRESS: Peridopril protection against recurrent stroke study. SCOPE: Study on Cognition and Prognosis in the Elderly. VITATOPS: VITAmins TO Prevent Stroke trial. ENOS Efficacy of Nitric Oxide in Stroke. RIGHT-2: Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial. LACI: Lacunar Intervention Trial. XYLO-FIST: Xanthine Oxidase Inhibition for Improvement of Long-term Outcomes Following Ischaemic Stroke and Transient Ischaemic Attack. PASTIS: Perfusion by Arterial Spin Labelling Following Single Dose Tadalafil in Small Vessel Disease (PASTIS) Trial. MSS2 Mild Stroke Study. CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. FINGER: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability.Figure legends Figure 1. Key constituents of the vascular-glio-neuronal unit and possible entry points for disease mechanisms in cerebral SVD. Arterioles penetrate the brain and ultimately branch into capillaries. They are each surrounded by a perivascular space (PVS) that is connected to the cerebrospinal fluid (CSF). Capillary endothelial cells (EC) including their connecting tight junctions (TJ), a specialized basement membrane (BM), pericytes/mural cells (PC), and astrocyte endfeet collectively form the blood-brain barrier (BBB). The latter is essential for maintaining the interstitial milieu. Astrocytes maintain the interstitial fluid balance, provide energy to neurons and relay signals between neurons and other cells to the vasculature to adapt blood flow to energy demand. Oligodendrocytes form and repair myelin around axons to which they also provide metabolic and trophic support. At cellular level, EC dysfunction and BBB leak increase interstitial fluid and proteins, disrupt astrocyte end feet impairing interstitial fluid exchange, block oligodendrocyte precursor cell (OPC) maturation impairing myelination and repair and energy support to axons, and impedes normal astrocyte function decreasing neuronal energy supply. The order of these events is not yet determined. Several of the cellular and functional constituents of the vasculo-glio-neuronal unit represent possible entry points for disease mechanisms in cerebral small vessel disease (SVD). For further explanations see text. Graphics provided by Antonia Weingart. Figure 2. Cerebral SVD lesions, their long-term fate and the perilesional zone. White matter hyperintensities (WMH, detectable on FLAIR or T2 weighted MR sequences at conventional field strengths), represented by the grey circles, may (from top down) regress (arrow), expand (arrow), remain stable, develop incident lacunes at the edge of the WMH (arrow), or cavitate (i.e. turn into a lacune, arrow). Examples of initial and follow-up MRI are shown on the right hand of the image, initial MRI in the left-hand and follow-up MRI in the right-hand columns. WMH and other SVD lesions are typically surrounded by a zone of increasingly abnormal tissue (indicated in orange) that appears normal on conventional FLAIR or T2-weighed MRI or pathology (normal appearing white matter, NWM) but shows altered signal characteristics on several MRI modalities including diffusion tensor imaging (DTI) and at pathology. Figure 3. Cerebral SVD affects the whole brain. Shown left to right is a progression of SVD lesions detectable on MRI. Note that incident lesions such as infarcts and microbleeds may occur at variable time points during disease progression, or be absent. Acute infarcts and white matter hyperintensities (WMH; visible on FLAIR and T2 weighted MR sequences) cause secondary loss of grey and white matter in connected brain regions, and regions with less obvious direct connections, resulting in cortical thinning, brain atrophy and neurodegeneration. Left: interstitial fluid increases produce subtle changes in normal white matter (WM) leading to WMH formation. Middle: WMH progress leading to secondary cortical thinning, acute small subcortical infarcts may appear. Right: WMH, lacunes, microbleeds worsen, secondary cortical thinning and long tract degeneration worsens. Figure graphics provided by Antonia Weingart.Figure 4. Factors influencing the clinical expression of cerebral SVD. The clinical presentation and course of cerebral SVD is highly variable. 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ADDIN EN.CITE.DATA 69,73 lesion type and extent. ADDIN EN.CITE <EndNote><Cite><Author>Ter Telgte</Author><Year>2018</Year><RecNum>11081</RecNum><DisplayText><style face="superscript">59</style></DisplayText><record><rec-number>11081</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1529506998">11081</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ter Telgte, A.</author><author>van Leijsen, E. M. C.</author><author>Wiegertjes, K.</author><author>Klijn, C. J. M.</author><author>Tuladhar, A. M.</author><author>de Leeuw, F. E.</author></authors></contributors><auth-address>Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands. FrankErik.deLeeuw@radboudumc.nl.</auth-address><titles><title>Cerebral small vessel disease: from a focal to a global perspective</title><secondary-title>Nat Rev Neurol</secondary-title></titles><periodical><full-title>Nat Rev Neurol</full-title></periodical><pages>387-398</pages><volume>14</volume><dates><year>2018</year><pub-dates><date>May 25</date></pub-dates></dates><isbn>1759-4766 (Electronic)
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