Www.research.ed.ac.uk
Full title: William M Feinberg Award for Excellence in Clinical Stroke: Small vessel disease; a big problem, but fixable108 charAuthor: Joanna M Wardlaw, FRCR, MDAffiliation: Division of Neuroimaging Science, Centre for Clinical Brain Science, Edinburgh Imaging and UK Dementia Research Institute at the University of Edinburgh, Address: Centre for Clinical Brain Science, Chancellor’s Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.Tel: +44 (0)131 465 9599Email: Joanna.wardlaw@ed.ac.ukCover title: Small vessel disease; a big problem, but fixable48 charTotal tables and figures: no tables, 2 figures.Key words: stroke; cerebral infarction: lacunar; lacunes; white matter disease; cerebral small vessel disease; blood-brain barrier; cerebral blood flow.Subject terms: lacunar stroke; small vessel disease; stroke; dementia; blood-brain barrier.Word count: text 2956, whole document 4993, references 57.Like much in stroke, this research journey started with a clot. Although this clot, and this stroke, were different.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48
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ADDIN EN.CITE.DATA 1 Small vessel disease (SVD) is now recognised to cause 20-25% of strokes, to be the second commonest cause of dementia, to cause cognitive decline, physical frailty and late onset depression. In addition to acute small subcortical (lacunar) ischaemic strokes, SVD includes lesions seen commonly on brain imaging: white matter hypertensities (WMH), lacunes, microbleeds, perivascular spaces (PVS), brain shrinkage,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 3 However, when this research started, the strokes, cognitive presentations and neuroimaging features of SVD were thought generally to be unrelated, silent, permanent, and lacunar stroke was a ‘small’ version of large artery stroke. How did it start? In 2000 A.D., a 70-year-old man presented to our hospital with a recent lacunar stroke. His CT scan showed a small, low attenuation area, consistent with a recent small subcortical (lacunar) infarct. There were three odd features. In the centre was a small white dot, like a ‘mini’ version of the hyperattenuated middle cerebral artery (MCA) commonly seen in patients with hyperacute cardio- or athero- thromboembolic ischemic stroke, an appearance not described previously.Brain MRI immediately after the CT scan confirmed the recent lacunar infarct including the odd central line/dot, except that there also appeared to be some blood in the arteriole wall. While a few small cardiac or carotid atheromatous emboli can enter the basal perforating arterioles, about 6% in experimental models, ADDIN EN.CITE <EndNote><Cite><Author>Macdonald</Author><Year>1995</Year><RecNum>3517</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>3517</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815594">3517</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Macdonald,R.L.</author><author>Kowalczuk,A.</author><author>Johns,L.</author></authors></contributors><titles><title>Emboli enter penetrating arteries of monkey brain in relation to their size</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>1247-1251</pages><volume>26</volume><reprint-edition>In File</reprint-edition><keywords><keyword>Arteries</keyword><keyword>Brain</keyword></keywords><dates><year>1995</year><pub-dates><date>1995</date></pub-dates></dates><label>7381</label><urls></urls></record></Cite></EndNote>4 and no more than 11% in patients, ADDIN EN.CITE <EndNote><Cite><Author>Del Bene</Author><Year>2012</Year><RecNum>8676</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>8676</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815893">8676</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Del Bene,A.</author><author>Makin,S.D.J.</author><author>Doubal,F.N.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Do risk factors for lacunar ischaemic stroke vary with the location or appearance of the lacunar infarct?</title><secondary-title>Cerebrovasc Dis</secondary-title></titles><periodical><full-title>Cerebrovasc Dis</full-title></periodical><pages>21</pages><volume>33</volume><number>Suppl 1</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>etiology</keyword><keyword>of</keyword><keyword>stroke</keyword><keyword>and</keyword><keyword>Risk</keyword><keyword>Risk Factors</keyword><keyword>RISK-FACTORS</keyword></keywords><dates><year>2012</year><pub-dates><date>2012</date></pub-dates></dates><label>20121</label><urls></urls></record></Cite></EndNote>5 an embolus would not explain the blood in the arteriole wall. The ‘infarct’ was around the affected arteriolar segment, not at the end of it, as would be expected in, e.g., an infarct occurring secondary to an acute MCA occlusion. What was going on? Most strokes are thought to result from blocked or bleeding vessels. The thrombus in the arteriole lumen, the wall abnormality and the ‘infarct’ location suggested some different process. Was the surrounding tissue change ‘ischaemic’ or another process? And what were the implications for other small subcortical lesions commonly seen in stroke, particularly in lacunar stroke,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 2 such as WMH? Then, and now, WMH are commonly labelled ‘ischaemic’ and attributed to low cerebral blood flow (CBF). But, is every WMH at the end of a diseased arteriole?We examined scans of all our patients with acute lacunar stroke in the previous four years and found a similar arteriole appearance in the symptomatic recent lacunar infarct in about 10%.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48
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ADDIN EN.CITE.DATA 1 Detailed examination of the few papers on lacunar stroke pathology was informative, particularly C Miller Fisher’s meticulous dissections of the perforating arterioles leading to lacunar strokes in the 1950s and 1960s. ADDIN EN.CITE <EndNote><Cite><Author>Fisher</Author><Year>1969</Year><RecNum>1980</RecNum><DisplayText><style face="superscript">6, 7</style></DisplayText><record><rec-number>1980</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815545">1980</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fisher,C.M.</author></authors></contributors><titles><title>The arterial lesions underlying lacunes</title><secondary-title>Acta Neuropathol</secondary-title></titles><periodical><full-title>Acta Neuropathol</full-title></periodical><pages>1-15</pages><volume>12</volume><reprint-edition>In File</reprint-edition><keywords><keyword>lesion</keyword></keywords><dates><year>1969</year><pub-dates><date>1969</date></pub-dates></dates><label>5718</label><urls></urls></record></Cite><Cite><Author>Bailey</Author><Year>2012</Year><RecNum>8094</RecNum><record><rec-number>8094</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815874">8094</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bailey,E.L.</author><author>Smith,C.</author><author>Sudlow,C.L.M.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Pathology of lacunar ischaemic stroke in humans - a systematic review</title><secondary-title>Brain Pathol</secondary-title></titles><periodical><full-title>Brain Pathol</full-title></periodical><pages>583-591</pages><volume>22</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>pathology</keyword><keyword>of</keyword><keyword>ischaemic stroke</keyword><keyword>stroke</keyword><keyword>Humans</keyword><keyword>Human</keyword><keyword>systematic review</keyword><keyword>review</keyword></keywords><dates><year>2012</year><pub-dates><date>2012</date></pub-dates></dates><label>12442</label><urls></urls></record></Cite></EndNote>6, 7 Reading original observations is always valuable, since subsequent interpretations may drift from the original over time. Fisher described the arterioles in and around lacunes in four patients with hypertension and small strokes in life as ‘segmental arteriolar disorganisation’ consisting of local dilatation and narrowing of the arteriole, thickened disintegrating wall, and leakage of fibrinoid material and blood into and around the wall. Others have called this process ‘fibrinoid necrosis’ or ‘hyalinosis’ amongst other names. Interestingly, some of his histological images of the arteriolar pathology looked similar to our ‘macroscopic’ MRI images (Figure 1). Not just midlife atheroma or vascular risk factors.Much has been written about the causes of lacunar stroke and its distinct clinical syndromes pointing to an intrinsic process, ADDIN EN.CITE <EndNote><Cite><Author>Bamford</Author><Year>1988</Year><RecNum>1999</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>1999</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815546">1999</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bamford,J.M.</author><author>Warlow,C.P.</author></authors></contributors><titles><title>Evolution and testing of the lacunar hypothesis</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>1074</pages><volume>19</volume><number>9</number><reprint-edition>In File</reprint-edition><dates><year>1988</year><pub-dates><date>1988</date></pub-dates></dates><label>5737</label><urls></urls></record></Cite></EndNote>8 yet embolic processes and atheroma remain strong in stroke thinking. Fisher’s lesions were mostly not embolic, but they might have been a ‘micro-atheroma’ and MCA atheroma can obstruct the ostea of perforating arterioles. However, much research, from large epidemiological to small intensive studies, confirms a lack of direct association between embolic sources or atheroma and most small subcortical infarctsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWNrc29uPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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ADDIN EN.CITE.DATA 10-13 Consistent with this, long term intensive versus single antiplatelet agents not only did not prevent recurrent lacunar stroke in the 3000+ patient Secondary Prevention of Small Subcortical Stroke (SPS3) trial, but found that long-term dual antiplatelet drugs were hazardous. ADDIN EN.CITE <EndNote><Cite><Author>The SPS3 Investigators</Author><Year>2012</Year><RecNum>8693</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>8693</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815893">8693</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>The SPS3 Investigators,</author></authors></contributors><titles><title>Effects of clopidogrel added to aspirin in patients with recent lacunar stroke</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>817-825</pages><volume>367</volume><reprint-edition>In File</reprint-edition><keywords><keyword>of</keyword><keyword>clopidogrel</keyword><keyword>aspirin</keyword><keyword>Patients</keyword><keyword>Patient</keyword><keyword>stroke</keyword></keywords><dates><year>2012</year><pub-dates><date>2012</date></pub-dates></dates><label>20141</label><urls></urls></record></Cite></EndNote>14 Furthermore, although hypertension is a major risk factor for stroke, including lacunar stroke, ADDIN EN.CITE <EndNote><Cite><Author>Jackson</Author><Year>2010</Year><RecNum>6878</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>6878</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815835">6878</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jackson,C.A.</author><author>Hutchison,A.</author><author>Dennis,M.S.</author><author>Wardlaw,J.M.</author><author>Lindgren,A.</author><author>Norrving,B.</author><author>Anderson,C.S.</author><author>Hankey,G.J.</author><author>Jamrozik,K.</author><author>Appelros,P.</author><author>Sudlow,C.L.M.</author></authors></contributors><titles><title>Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy?</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>624-629</pages><volume>41</volume><reprint-edition>In File</reprint-edition><keywords><keyword>Risk</keyword><keyword>ischemic</keyword><keyword>Ischemic stroke</keyword><keyword>stroke</keyword><keyword>subtype</keyword></keywords><dates><year>2010</year><pub-dates><date>2010</date></pub-dates></dates><label>10796</label><urls></urls><electronic-resource-num>10.1161/STROKEAHA.109.558809</electronic-resource-num></record></Cite></EndNote>9 it and other common vascular risk factors are not the only cause. For example, in about 750 community-dwelling subjects aged 72, and separately in about 150 patients with non-disabling ischaemic stroke, all common vascular risk factors combined (hypertension, smoking, diabetes, hypercholesterolaemia, measured blood pressure, cholesterol, HbA1c), accounted for less than 2% of the variance in WMH burden. ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2014</Year><RecNum>9377</RecNum><DisplayText><style face="superscript">12</style></DisplayText><record><rec-number>9377</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815916">9377</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw,J.M.</author><author>Allerhand,M.</author><author>Doubal,F.N.</author><author>Valdes Hernandez,M.</author><author>Morris,Z.</author><author>Gow,A.J.</author><author>Bastin,M.</author><author>Starr,J.M.</author><author>Dennis,M.S.</author><author>Deary,I.J.</author></authors></contributors><titles><title>Vascular risk factors, large artery atheroma and brain white matter hyperintensities</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>1331-1338</pages><volume>82</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Risk</keyword><keyword>Risk Factors</keyword><keyword>RISK-FACTORS</keyword><keyword>Artery</keyword><keyword>Arteries</keyword><keyword>and</keyword><keyword>Brain</keyword><keyword>White Matter</keyword></keywords><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><label>20832</label><urls></urls><electronic-resource-num>10.1212/WNL.0000000000000312</electronic-resource-num></record></Cite></EndNote>12 Of this 2%, hypertension and smoking were the strongest risk factors. The unavoidable conclusion is that 98%, ie most, of the variance in WMH is not explained by common vascular risk factors, also consistent with the SPS3 trial in which intensive (versus guideline) blood pressure reduction did not prevent recurrent stroke, WMH progression, or cognitive decline, in over 3000 patients with lacunar stroke. ADDIN EN.CITE <EndNote><Cite><Author>SPS3 Study Group</Author><Year>2013</Year><RecNum>8970</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>8970</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815902">8970</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>SPS3 Study Group,</author><author>Benavente,O.R.</author><author>Coffey,C.S.</author><author>Conwit,R.</author><author>Hart,R.G.</author><author>McClure,L.A.</author><author>Pearce,L.A.</author><author>Pergola,P.E.</author><author>Szychowski,J.M.</author></authors></contributors><titles><title>Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>507-515</pages><volume>382</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>secondary</keyword><keyword>secondary prevention</keyword><keyword>prevention</keyword><keyword>of</keyword><keyword>stroke</keyword><keyword>trial</keyword><keyword>blood</keyword><keyword>blood pressure</keyword><keyword>Pressure</keyword><keyword>Patients</keyword><keyword>Patient</keyword><keyword>Randomised</keyword></keywords><dates><year>2013</year><pub-dates><date>2013</date></pub-dates></dates><label>20421</label><urls></urls></record></Cite></EndNote>15 These results do not mean that common vascular risk factor avoidance is not important. 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ADDIN EN.CITE.DATA 17 indicate that genes are important, yet genetic studies have so far identified relatively few SVD-related genes. However, their detailed discussion is beyond the scope of this short paper which focuses on unravelling SVD pathophysiological pathways through direct human studies. Since SVD develops in the brain over many years, long before the lacunar stroke or cognitive decline starts, what about risk-factors earlier in adulthood? Long-term adult lifestyle habits, such as taking less exercise ADDIN EN.CITE <EndNote><Cite><Author>Gow</Author><Year>2012</Year><RecNum>8453</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>8453</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815886">8453</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gow,A.J.</author><author>Bastin,M.E.</author><author>Munoz Maniega,S.</author><author>Valdes Hernandez,M.C.</author><author>Morris,Z.</author><author>Murray,C.</author><author>Royle,N.A.</author><author>Starr,J.M.</author><author>Deary,I.J.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Neuroprotective lifestyles and the aging brain: activity, atrophy and white matter integrity</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>1802-1808</pages><volume>79</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>and</keyword><keyword>Aging</keyword><keyword>Brain</keyword><keyword>Atrophy</keyword><keyword>White Matter</keyword></keywords><dates><year>2012</year><pub-dates><date>2012</date></pub-dates></dates><label>19898</label><urls></urls></record></Cite></EndNote>18 and more dietary salt,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXllPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 19, 20 are associated independently with more WMH and lacunar (vs non-lacunar) ischemic stroke. The overall health benefits of exercise, and detrimental effects of dietary salt, are well established, but their specific effects on brain microvascular health are less appreciated. These invite public health approaches to preventing SVD, since that will help prevent dementia as well as stroke.What about factors occurring even earlier in life? Interestingly, a large published literature indicates that lower childhood intelligence, socioeconomic status and educational attainment each predict increased lifetime risk of all types of SVD lesions, ADDIN EN.CITE <EndNote><Cite><Author>Backhouse</Author><Year>2017</Year><RecNum>10727</RecNum><DisplayText><style face="superscript">21</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> as well as stroke, ADDIN EN.CITE <EndNote><Cite><Author>McHutchison</Author><Year>2017</Year><RecNum>10683</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>10683</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1477311512">10683</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McHutchison, C. A.</author><author>Backhouse, E. V.</author><author>Cvoro, V.</author><author>Shenkin, S. D.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>From the aCentre for Clinical Brain Sciences, University of Edinburgh, The Chancellors Building, Edinburgh, United Kingdom; bCentre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, The University of Edinburgh, United Kingdom; and cGeriatric Medicine, Department of Clinical and Surgical Sciences, The University of Edinburgh, Edinburgh, United Kingdom.</auth-address><titles><title>Education, Socioeconomic Status, and Intelligence in Childhood and Stroke Risk in Later Life: A Meta-analysis</title><secondary-title>Epidemiology</secondary-title><alt-title>Epidemiology</alt-title></titles><periodical><full-title>Epidemiology</full-title></periodical><alt-periodical><full-title>Epidemiology</full-title></alt-periodical><pages>608-618</pages><volume>28</volume><number>4</number><dates><year>2017</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1531-5487 (Electronic)
1044-3983 (Linking)</isbn><accession-num>28410350</accession-num><label>22056</label><urls><related-urls><url> independent of adult risk factors. Since these three factors are inter-related, and few studies which examined all three simultaneously, their independent contribution to SVD or stroke risk is unclear. However, the magnitude of effect of any one of them is similar and important on a population basis. For example, expect 3.5/1000 more strokes in those who completed full-time education to high school level versus those with university education, ADDIN EN.CITE <EndNote><Cite><Author>McHutchison</Author><Year>2017</Year><RecNum>10683</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>10683</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1477311512">10683</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McHutchison, C. A.</author><author>Backhouse, E. V.</author><author>Cvoro, V.</author><author>Shenkin, S. D.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>From the aCentre for Clinical Brain Sciences, University of Edinburgh, The Chancellors Building, Edinburgh, United Kingdom; bCentre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, The University of Edinburgh, United Kingdom; and cGeriatric Medicine, Department of Clinical and Surgical Sciences, The University of Edinburgh, Edinburgh, United Kingdom.</auth-address><titles><title>Education, Socioeconomic Status, and Intelligence in Childhood and Stroke Risk in Later Life: A Meta-analysis</title><secondary-title>Epidemiology</secondary-title><alt-title>Epidemiology</alt-title></titles><periodical><full-title>Epidemiology</full-title></periodical><alt-periodical><full-title>Epidemiology</full-title></alt-periodical><pages>608-618</pages><volume>28</volume><number>4</number><dates><year>2017</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1531-5487 (Electronic)
1044-3983 (Linking)</isbn><accession-num>28410350</accession-num><label>22056</label><urls><related-urls><url> or 17% relative increase in SVD lesions ADDIN EN.CITE <EndNote><Cite><Author>Backhouse</Author><Year>2017</Year><RecNum>10727</RecNum><DisplayText><style face="superscript">21</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> for the same education difference, moving responsibility for stroke and SVD prevention from purely medical or public health onto Government policies. Consider the blood-brain barrierSporadic SVD is a complex disorder that develops over many years. While genetics, childhood factors and adult lifestyle may raise the SVD risk, they do not explain what actually goes wrong. The pathology described by Miller Fisher and others tends to reflect late stage features, ADDIN EN.CITE <EndNote><Cite><Author>Bailey</Author><Year>2012</Year><RecNum>8094</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>8094</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815874">8094</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bailey,E.L.</author><author>Smith,C.</author><author>Sudlow,C.L.M.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Pathology of lacunar ischaemic stroke in humans - a systematic review</title><secondary-title>Brain Pathol</secondary-title></titles><periodical><full-title>Brain Pathol</full-title></periodical><pages>583-591</pages><volume>22</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>pathology</keyword><keyword>of</keyword><keyword>ischaemic stroke</keyword><keyword>stroke</keyword><keyword>Humans</keyword><keyword>Human</keyword><keyword>systematic review</keyword><keyword>review</keyword></keywords><dates><year>2012</year><pub-dates><date>2012</date></pub-dates></dates><label>12442</label><urls></urls></record></Cite></EndNote>7 but preventing development or progression requires consideration of the earliest disease stages. A possible unifying hypothesis to explain all three odd features observed in our original case, was dysfunction of the endothelium and subtle blood-brain barrier (BBB) leakage. ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2003</Year><RecNum>3297</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>3297</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815587">3297</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw,J.M.</author><author>Sandercock,P.A.</author><author>Dennis,M.S.</author><author>Starr,J.</author></authors></contributors><auth-address>Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK jmw@skulldcnedacuk</auth-address><titles><title>Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>806-812</pages><volume>34</volume><number>3</number><reprint-edition>In File</reprint-edition><keywords><keyword>Aging</keyword><keyword>Alzheimer Disease</keyword><keyword>Animal</keyword><keyword>Blood-Brain Barrier</keyword><keyword>Brain</keyword><keyword>Brain Diseases</keyword><keyword>Brain Infarction</keyword><keyword>Cerebrovascular Accident</keyword><keyword>Dementia</keyword><keyword>Disease Progression</keyword><keyword>etiology</keyword><keyword>Human</keyword><keyword>MRI</keyword><keyword>physiopathology</keyword><keyword>review</keyword><keyword>stroke</keyword><keyword>Syndrome</keyword><keyword>treatment</keyword><keyword>United States</keyword></keywords><dates><year>2003</year><pub-dates><date>2003</date></pub-dates></dates><label>7160</label><urls><related-urls><url> held by Ann Deary</remote-database-provider></record></Cite></EndNote>23 If there was leakage, then it would have to be subtle, otherwise it would have been obvious given the widespread clinical use of contrast-enhanced brain imaging. In studies including about 3000 subjects up to the mid 2000s, BBB leak, mostly detected using the CSF:plasma albumin ratio, increased with age, was worse in any dementia versus healthy controls, in vascular versus Alzheimer’s disease, and in patients with more WMH. ADDIN EN.CITE <EndNote><Cite><Author>Farrall</Author><Year>2009</Year><RecNum>6233</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>6233</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815815">6233</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Farrall,A.J.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Blood brain barrier: ageing and microvascular disease - systemic review and meta-analysis</title><secondary-title>Neurobiol Aging</secondary-title></titles><periodical><full-title>Neurobiol Aging</full-title></periodical><pages>337-352</pages><volume>30</volume><number>3</number><reprint-edition>In File</reprint-edition><keywords><keyword>blood</keyword><keyword>Brain</keyword><keyword>Disease</keyword><keyword>review</keyword><keyword>meta-analysis</keyword></keywords><dates><year>2009</year><pub-dates><date>2009</date></pub-dates></dates><label>10106</label><urls></urls><electronic-resource-num> 10.1161/STROKEAHA.112.669994</electronic-resource-num></record></Cite></EndNote>24 However the CSF:plasma albumin ratio could not locate or quantify the leakage. 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ADDIN EN.CITE.DATA 25, 26 Gradually, as MRI and image processing improved, scan times shortened and methods to calculate permeability improved. ADDIN EN.CITE <EndNote><Cite><Author>Heye</Author><Year>2016</Year><RecNum>10129</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>10129</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815943">10129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Heye,A.K.</author><author>Thrippleton,M.J.</author><author>Armitage,P.A.</author><author>Valdes Hernandez,M.C.</author><author>Makin,S.D.</author><author>Glatz,A.</author><author>Sakka,E.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Tracer kinetic modelling for DCE-MRI quantification of subtle blood-brain barrier permeability</title><secondary-title>Neuroimage</secondary-title></titles><periodical><full-title>Neuroimage</full-title></periodical><pages>446-455</pages><volume>125</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>of</keyword><keyword>Blood-Brain Barrier</keyword><keyword>Permeability</keyword></keywords><dates><year>2016</year><pub-dates><date>2016</date></pub-dates></dates><label>21597</label><urls></urls><electronic-resource-num>10.1016/j.neuroimage.2015.10.018</electronic-resource-num></record></Cite></EndNote>27 The details are beyond the scope of the present paper, but suffice to note that the methods are complex, involving correction for several factors (pre-contrast tissue T1, ADDIN EN.CITE <EndNote><Cite><Author>Armitage</Author><Year>2011</Year><RecNum>7347</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>7347</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815849">7347</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Armitage,P.A.</author><author>Farrall,A.J.</author><author>Carpenter,T.K.</author><author>Doubal,F.N.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Use of dynamic contrast-enhanced MRI to measure subtle blood-brain barrier abnormalities</title><secondary-title>Magn Reson Imaging</secondary-title></titles><periodical><full-title>Magn Reson Imaging</full-title></periodical><pages>305-314</pages><volume>29</volume><reprint-edition>In File</reprint-edition><keywords><keyword>of</keyword><keyword>MRI</keyword><keyword>Blood-Brain Barrier</keyword><keyword>abnormalities</keyword></keywords><dates><year>2011</year><pub-dates><date>2011</date></pub-dates></dates><label>11608</label><urls></urls></record></Cite></EndNote>28 haematocrit, ADDIN EN.CITE <EndNote><Cite><Author>Heye</Author><Year>2016</Year><RecNum>10129</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>10129</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815943">10129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Heye,A.K.</author><author>Thrippleton,M.J.</author><author>Armitage,P.A.</author><author>Valdes Hernandez,M.C.</author><author>Makin,S.D.</author><author>Glatz,A.</author><author>Sakka,E.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Tracer kinetic modelling for DCE-MRI quantification of subtle blood-brain barrier permeability</title><secondary-title>Neuroimage</secondary-title></titles><periodical><full-title>Neuroimage</full-title></periodical><pages>446-455</pages><volume>125</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>of</keyword><keyword>Blood-Brain Barrier</keyword><keyword>Permeability</keyword></keywords><dates><year>2016</year><pub-dates><date>2016</date></pub-dates></dates><label>21597</label><urls></urls><electronic-resource-num>10.1016/j.neuroimage.2015.10.018</electronic-resource-num></record></Cite></EndNote>27 repeated measures to overcome background noise, a reliable estimate of vascular input function ADDIN EN.CITE <EndNote><Cite><Author>Heye</Author><Year>2016</Year><RecNum>10129</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>10129</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815943">10129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Heye,A.K.</author><author>Thrippleton,M.J.</author><author>Armitage,P.A.</author><author>Valdes Hernandez,M.C.</author><author>Makin,S.D.</author><author>Glatz,A.</author><author>Sakka,E.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Tracer kinetic modelling for DCE-MRI quantification of subtle blood-brain barrier permeability</title><secondary-title>Neuroimage</secondary-title></titles><periodical><full-title>Neuroimage</full-title></periodical><pages>446-455</pages><volume>125</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>of</keyword><keyword>Blood-Brain Barrier</keyword><keyword>Permeability</keyword></keywords><dates><year>2016</year><pub-dates><date>2016</date></pub-dates></dates><label>21597</label><urls></urls><electronic-resource-num>10.1016/j.neuroimage.2015.10.018</electronic-resource-num></record></Cite></EndNote>27) and detailed image processing that avoids tissue cross-contamination especially by large vessels. ADDIN EN.CITE <EndNote><Cite><Author>Armitage</Author><Year>2011</Year><RecNum>7347</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>7347</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815849">7347</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Armitage,P.A.</author><author>Farrall,A.J.</author><author>Carpenter,T.K.</author><author>Doubal,F.N.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Use of dynamic contrast-enhanced MRI to measure subtle blood-brain barrier abnormalities</title><secondary-title>Magn Reson Imaging</secondary-title></titles><periodical><full-title>Magn Reson Imaging</full-title></periodical><pages>305-314</pages><volume>29</volume><reprint-edition>In File</reprint-edition><keywords><keyword>of</keyword><keyword>MRI</keyword><keyword>Blood-Brain Barrier</keyword><keyword>abnormalities</keyword></keywords><dates><year>2011</year><pub-dates><date>2011</date></pub-dates></dates><label>11608</label><urls></urls></record></Cite></EndNote>28 Despite this, all current ‘permeability’ calculations rely on several assumptions, including that microvessel density and surface area do not change with age, disease, or tissue type (clearly untrue). Thus careful between-group comparisons of signal change to assess ‘leak’ may be safer. Accumulating human cross-sectional analyses indicate that BBB leakage increases with age, in lacunar vs non-lacunar stroke, with increasing visibility of PVS, ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2009</Year><RecNum>6508</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>6508</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815823">6508</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw,J.M.</author><author>Doubal,F.</author><author>Armitage,P.</author><author>Chappell,F.</author><author>Carpenter,T.</author><author>Maniega,S.M.</author><author>Farrall,A.</author><author>Sudlow,C.</author><author>Dennis,M.</author><author>Dhillon,B.</author></authors></contributors><titles><title>Lacunar stroke is associated with diffuse blood-brain barrier dysfunction</title><secondary-title>Ann Neurol</secondary-title></titles><periodical><full-title>Ann Neurol</full-title></periodical><pages>194-202</pages><volume>65</volume><number>2</number><reprint-edition>In File</reprint-edition><keywords><keyword>stroke</keyword><keyword>Blood-Brain Barrier</keyword></keywords><dates><year>2009</year><pub-dates><date>2009</date></pub-dates></dates><label>10412</label><urls></urls></record></Cite></EndNote>25 in WMH versus apparently normal tissue,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWlzYTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 32 in white matter in Alzheimer’s disease, ADDIN EN.CITE <EndNote><Cite><Author>Starr</Author><Year>2009</Year><RecNum>6661</RecNum><DisplayText><style face="superscript">33</style></DisplayText><record><rec-number>6661</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815828">6661</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Starr,J.M.</author><author>Farrall,A.J.</author><author>Armitage,P.</author><author>McGurn,B.</author><author>Wardlaw,J.</author></authors></contributors><auth-address>Geriatric Medicine Unit, University of Edinburgh, Scotland, UK</auth-address><titles><title>Blood-brain barrier permeability in Alzheimer's disease: a case-control MRI study</title><secondary-title>Psychiatry Res</secondary-title></titles><periodical><full-title>Psychiatry Res</full-title></periodical><pages>232-241</pages><volume>171</volume><number>3</number><reprint-edition>In File</reprint-edition><keywords><keyword>Arteries</keyword><keyword>Artery</keyword><keyword>Article</keyword><keyword>Blood-Brain Barrier</keyword><keyword>Bolus Injection</keyword><keyword>Carotid Arteries</keyword><keyword>Carotid Artery</keyword><keyword>Disease</keyword><keyword>imaging</keyword><keyword>Injection</keyword><keyword>Internal Carotid Artery</keyword><keyword>Kinetics</keyword><keyword>Magnetic Resonance</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Model</keyword><keyword>MRI</keyword><keyword>Permeability</keyword><keyword>Risk</keyword><keyword>Scotland</keyword><keyword>Study</keyword><keyword>temporal</keyword><keyword>Time</keyword><keyword>Universities</keyword><keyword>White Matter</keyword></keywords><dates><year>2009</year><pub-dates><date>2009</date></pub-dates></dates><label>10577</label><urls><related-urls><url> and vascular dementia.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWhlcmk8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 29, 34, 35 Furthermore, in longitudinal studies, BBB leakage predicts recurrent stroke, worsening of WMH, ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2013</Year><RecNum>8790</RecNum><DisplayText><style face="superscript">36</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>36 and cognitive decline in patients with lacunar stroke. ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2017</Year><RecNum>10693</RecNum><DisplayText><style face="superscript">30</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>Alzheimer's & Dementia</secondary-title></titles><periodical><full-title>Alzheimer's & Dementia</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>30Might a leaky arteriole and increased periarteriolar interstitial fluid also explain the location of the ‘infarct’ around, rather than at the end of, the arteriole in our patient with acute lacunar stroke? Perhaps the ‘infarct’ is increased extracellular fluid, not just ischaemia, a speculation that needs more research. Unfortunately the chances of scanning someone just before they develop a lacunar stroke are remote, although there is one example: a patient had gadolinium-enhanced MRI the day prior to presenting with a lacunar stroke; examination showed gadolinium enhancement in the thalamus where the stroke developed. ADDIN EN.CITE <EndNote><Cite><Author>Iwata</Author><Year>1999</Year><RecNum>5622</RecNum><DisplayText><style face="superscript">37</style></DisplayText><record><rec-number>5622</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815658">5622</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Iwata,A.</author><author>Koike,F.</author><author>Arasaki,K.</author><author>Tamaki,M.</author></authors></contributors><titles><title>Blood brain barrier destruction in hyperglycemic chorea in a patient with poorly controlled diabetes</title><secondary-title>J Neurol Sci</secondary-title></titles><periodical><full-title>J Neurol Sci</full-title></periodical><pages>90-93</pages><volume>163</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>blood</keyword><keyword>Brain</keyword><keyword>Patient</keyword></keywords><dates><year>1999</year><pub-dates><date>1999</date></pub-dates></dates><label>9489</label><urls></urls></record></Cite></EndNote>37 Further evidence for BBB leak comes from sensitive MRI methods that show that increased interstitial fluid present in WMH, before demyelination and axonal loss typically seen pathologically.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdW5veiBNYW5pZWdhPC9BdXRob3I+PFllYXI+MjAxNTwv
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ADDIN EN.CITE.DATA 39 Why the discrepancy between MRI and pathology? They are sensitive to different factors: conventional MRI relies on hydrogen, a major component of water, so is very sensitive to shifting water content; pathology generally removes water from the specimen during processing leaving rarefied axons visible, in part explaining why WMH until recently were conventionally thought to indicate demyelination and axonal loss. What about ischemia?If WMH are areas of increased fluid, what role does CBF play? In upwards of 10 cross-sectional studies so far, in about 400 subjects, resting CBF is lower in people with more versus less WMH (standardised mean difference, SMD: -0.73, 95%CI -1.16, -0.31). ADDIN EN.CITE <EndNote><Cite><Author>Shi</Author><Year>2016</Year><RecNum>10478</RecNum><DisplayText><style face="superscript">41</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>41 However, many studies did not have age-matched controls, or included patients with Alzheimer’s disease. Excluding patients with Alzheimer’s dementia renders the CBF-WMH association non-significant (SMD: -0.32, 95%CI -0.67, 0.02); focusing on studies with age-matched controls removes any residual CBF-WMH association (SMD: -0.78, 95%CI -2.04, 0.49). ADDIN EN.CITE <EndNote><Cite><Author>Shi</Author><Year>2016</Year><RecNum>10478</RecNum><DisplayText><style face="superscript">41</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>41 What does this mean? Are WMH ‘ischaemic’ or not, or might the falling CBF reflect having less brain to supply, perhaps explaining the association with Alzheimer’s disease a classic feature of which is brain atrophy? The six longitudinal studies of WMH and CBF to date, overall show that low baseline CBF does not lead to increasing WMH burden; instead, a high WMH burden at baseline leads to falling CBF at follow-up,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 41, 42 suggesting the reduction in CBF reflects having less brain to supply. Resting CBF may not reflect CBF during brain activity. The brain has a highly responsive vascular system designed to match the complex, rapid demands for increased oxygen, glucose and removal of metabolic waste, the failure of which results rapidly in neurological dysfunction. Cerebrovascular vasoreactivity (CVR), measured with Doppler ultrasound in the MCA, falls with age and is worse in patients with stroke, and in lacunar versus non-lacunar stroke, or with more WMH. ADDIN EN.CITE <EndNote><Cite><Author>Stevenson</Author><Year>2010</Year><RecNum>7048</RecNum><DisplayText><style face="superscript">43</style></DisplayText><record><rec-number>7048</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815840">7048</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stevenson,S.F.</author><author>Doubal,F.N.</author><author>Shuler,K.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>A systematic review of dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>e434-e442</pages><volume>41</volume><reprint-edition>In File</reprint-edition><keywords><keyword>systematic review</keyword><keyword>review</keyword><keyword>Cerebral</keyword><keyword>stroke</keyword></keywords><dates><year>2010</year><pub-dates><date>2010</date></pub-dates></dates><label>10973</label><urls></urls></record></Cite></EndNote>43 To measure individual tissue-level vasoreactivity requires techniques such as blood oxygen level dependent (BOLD) MRI,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaHJpcHBsZXRvbjwvQXV0aG9yPjxZZWFyPjIwMTg8L1ll
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ADDIN EN.CITE.DATA 44 although results of most studies to date are limited by not adjusting for age or hypertension. ADDIN EN.CITE <EndNote><Cite><Author>Blair</Author><Year>2016</Year><RecNum>10227</RecNum><DisplayText><style face="superscript">45</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>45 In 60 patients with varied severities of WMH, CVR fell independently with increasing WMH and basal ganglia PVS visibility, ADDIN EN.CITE <EndNote><Cite><Author>Blair</Author><Year>2017</Year><RecNum>10940</RecNum><DisplayText><style face="superscript">46</style></DisplayText><record><rec-number>10940</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1512553995">10940</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Blair, G. W.</author><author>Shi, Y.</author><author>Thrippleton, M. J.</author><author>Hamilton, I.</author><author>Dickie, D.</author><author>Doubal, F.</author><author>Marshall, I.</author><author>Wardlaw, J. M.</author></authors></contributors><titles><title>Impairment of white matter cerebrovascular reactivity is associated with increased white matter hyperintensity and perivascular space burdens in patients with minor ischaemic stroke presentations of small vessel disease. UK Stroke Forum Abstracts, 2017</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>12</pages><volume>12</volume><number>5_suppl</number><dates><year>2017</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1747-4949 (Electronic)
1747-4930 (Linking)</isbn><accession-num>29153049</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%"> and CVR was not related to resting CBF but was related to increased intracranial vascular pulsatility. Increased intracranial pulsatility was also related to increased WMH and PVS visibility. These findings concur with the established relationship between systemic arterial pulse pressure, which is strongly associated longitudinally with increased WMH and PVS, independent of BP, ADDIN EN.CITE <EndNote><Cite><Author>Aribisala</Author><Year>2014</Year><RecNum>9378</RecNum><DisplayText><style face="superscript">47</style></DisplayText><record><rec-number>9378</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815916">9378</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aribisala,B.S.</author><author>Morris,Z.</author><author>Eadie,E.</author><author>Thomas,A.</author><author>Gow,A.</author><author>Valdes Hernandez,M.C.</author><author>Royle,N.A.</author><author>Bastin,M.E.</author><author>Starr,J.</author><author>Deary,I.J.</author><author>Wardlaw,J.M.</author></authors></contributors><titles><title>Blood pressure, internal carotid artery flow parameters and age-related white matter hyperintensities</title><secondary-title>Hypertension</secondary-title></titles><periodical><full-title>Hypertension</full-title></periodical><pages>1011-1018</pages><volume>63</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>blood</keyword><keyword>blood pressure</keyword><keyword>Pressure</keyword><keyword>Internal Carotid Artery</keyword><keyword>Carotid Artery</keyword><keyword>Carotid Arteries</keyword><keyword>Artery</keyword><keyword>Arteries</keyword><keyword>FLOW</keyword><keyword>Parameter</keyword><keyword>and</keyword><keyword>White Matter</keyword></keywords><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><label>20833</label><urls></urls></record></Cite></EndNote>47 and implicates impaired CVR and vessel stiffness in the endothelial dysfunction contributing to SVD pathogenesis (Figure 2). PVS deserve further mention. Visible on MRI as thin linear or round CSF-intensity structures parallel with perforating microvessels, they are important conduits for brain interstitial fluid balance, waste management and immune competence. Their enlargement (best seen on T2 or T1 MRI) is associated with hypertension, inflammation, BBB leakage, increased WMH, and lacunar stroke. Close inspection of T2 and FLAIR MRI shows deep WMH forming around PVS, consistent with growing evidence above on BBB leak ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2009</Year><RecNum>6508</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>6508</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815823">6508</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw,J.M.</author><author>Doubal,F.</author><author>Armitage,P.</author><author>Chappell,F.</author><author>Carpenter,T.</author><author>Maniega,S.M.</author><author>Farrall,A.</author><author>Sudlow,C.</author><author>Dennis,M.</author><author>Dhillon,B.</author></authors></contributors><titles><title>Lacunar stroke is associated with diffuse blood-brain barrier dysfunction</title><secondary-title>Ann Neurol</secondary-title></titles><periodical><full-title>Ann Neurol</full-title></periodical><pages>194-202</pages><volume>65</volume><number>2</number><reprint-edition>In File</reprint-edition><keywords><keyword>stroke</keyword><keyword>Blood-Brain Barrier</keyword></keywords><dates><year>2009</year><pub-dates><date>2009</date></pub-dates></dates><label>10412</label><urls></urls></record></Cite></EndNote>25 and implying impaired interstitial fluid drainage in SVD pathogenesis (Figure 2). Rodent studies suggest that tissue clearance and drainage via PVS may increase during sleep,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YaWU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO
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Tm90ZT4A
ADDIN EN.CITE.DATA 49, 50 We followed 200 subjects to one year after non-disabling ischemic stroke and found that WMH volume clearly decreased in about 20%, increased in about 20% and either did not change at all or only by a small amount in the remainder.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA 50 It appears that the pathology underlying SVD is not permanent and lesions are much more dynamic than previously thought.What to do?What can be done to prevent or correct subtle BBB leakage, stiff vessels and poor vasoreactivity? Might any current therapies, licenced for other purposes but with relevant modes of action, be helpful? There are many established cardiovascular drugs with relevant effects, which might also help mitigate the cognitive effects of SVD, thereby addressing a huge unmet societal burden of dementia and stroke, buying time for more specific novel agents to be developed.A detailed literature search identified several agents with potentially relevant modes of action, of which two oral agents had the most encouraging human data: isosorbide mononitrate (ISMN) and cilostazol. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>9537</RecNum><DisplayText><style face="superscript">51</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>51 The animal literature supported the same conclusion. ADDIN EN.CITE <EndNote><Cite><Author>Pedder</Author><Year>2014</Year><RecNum>9335</RecNum><DisplayText><style face="superscript">52</style></DisplayText><record><rec-number>9335</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815914">9335</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pedder,H.</author><author>Vesterinen,H.</author><author>Macleod,M.</author><author>Wardlaw,J.</author></authors></contributors><titles><title>A systematic review and meta-analysis of interventions tested in animal models of lacunar stroke</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>563-570</pages><volume>45</volume><number>2</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>systematic review</keyword><keyword>review</keyword><keyword>and</keyword><keyword>meta-analysis</keyword><keyword>METAANALYSIS</keyword><keyword>of</keyword><keyword>Animal</keyword><keyword>Animal models</keyword><keyword>MODELS</keyword><keyword>Model</keyword><keyword>stroke</keyword></keywords><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><label>20790</label><urls></urls></record></Cite></EndNote>52 Why these two drugs? Most importantly, they are both widely used, have known safety profiles, and limited but encouraging data in lacunar stroke. ISMN, a nitric oxide (NO) donor. NO is reduced in acute, chronic and possibly lacunar stroke; given acutely after stroke, NO donors improved cognitive test scores at 90 days in the 4000-patient ENOS trial.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb29kaG91c2U8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFy
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ADDIN EN.CITE.DATA 51, 54 although data on ISMN in lacunar stroke are sparse since ischemic heart disease (its main therapeutic indication) is uncommon in these patients. ADDIN EN.CITE <EndNote><Cite><Author>Jackson</Author><Year>2010</Year><RecNum>6878</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>6878</rec-number><foreign-keys><key app="EN" db-id="0ptze0td4at9vmepzscxd5vnx9e5xttse55r" timestamp="1470815835">6878</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jackson,C.A.</author><author>Hutchison,A.</author><author>Dennis,M.S.</author><author>Wardlaw,J.M.</author><author>Lindgren,A.</author><author>Norrving,B.</author><author>Anderson,C.S.</author><author>Hankey,G.J.</author><author>Jamrozik,K.</author><author>Appelros,P.</author><author>Sudlow,C.L.M.</author></authors></contributors><titles><title>Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy?</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>624-629</pages><volume>41</volume><reprint-edition>In File</reprint-edition><keywords><keyword>Risk</keyword><keyword>ischemic</keyword><keyword>Ischemic stroke</keyword><keyword>stroke</keyword><keyword>subtype</keyword></keywords><dates><year>2010</year><pub-dates><date>2010</date></pub-dates></dates><label>10796</label><urls></urls><electronic-resource-num>10.1161/STROKEAHA.109.558809</electronic-resource-num></record></Cite></EndNote>9 Cilostazol, a phosphodiesterase 3’ inhibitor, has multiple potential relevant beneficial effects, including that: in humans, it improved blood-brain barrier integrity and vasodilation, reduced vessel stiffnessPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 56 Cilostazol trials include over 6000 patients in Japan, Korea and China, many with lacunar stroke, but cilostazol is little used in Europe or North America. Since both ISMN and cilostazol combined may be synergistic, they are being tested factorially in the LACunar Intervention (LACI) trials: LACI-1 (ISRCTN12580546), recruited 57 patients in two centres to test short-term tolerability, safety, intermediary endpoints and trial feasibility;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbGFpcjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 57 LACI-2 (ISRCTN14911850), planned n=400 in 20 centres, now ongoing, tests longer-term tolerability, trial feasibility, safety and efficacy on patient relevant outcomes preparatory to large phase III trials. More generally, hypertension is common in lacunar stroke. Some antihypertensive drugs may have more relevant endothelial effects, and BP targets remain unclear especially in frailer older people, providing ongoing justification for trials (e.g. PRESERVE, TREAT@SVDs) testing specific antihypertensive strategies in specific patient populations. Other agents such as allopurinol also have relevant vascular effects and are being tested (e.g. XYLOFIST). Meanwhile, general advice to patients should include common sense: stop smoking, take regular exercise, eat a well-balanced diet, avoid excess dietary salt, and adhere to prescribed treatment for hypertension, hypercholesterolemia and diabetes where relevant.The futureSVD is not silent, permanent, or untreatable. Importantly, advances made in recent years open new insights, offering new therapeutic targets. SVD is a common cause of stroke and worsens all stroke outcomes. As Hachinksi has said, the commonest form of cerebrovascular disease is dementia not stroke, vascular dementia is the second commonest dementia with SVD as the commonest cause, vascular dysfunction occurs early in Alzheimer’s disease, and dementia prevention and treatment are currently very limited, yet many drugs with known vascular effects might prevent or delay progression of dementia. Stroke, dementia and cardiovascular experts should combine their strengths since a united approach offers hope not just for stroke but also for dementia.AcknowledgementsI am grateful to the many mentors, clinical and science colleagues and early stage researchers with whom I have been fortunate to work over many years, whose collective thoughts have contributed to this work. I was very privileged to receive the William M Feinberg award in the company of many of them and the wider stroke community that continues to work tirelessly towards mitigating the personal and societal global burden of cerebrovascular disease.FundingThe work described was funded by the Chief Scientist Office (CZB/4/281), Wellcome Trust (WT088134/Z/09/A), the Row Fogo Charitable Trust (BRO-D.FID3668413), Chest Heart Stroke Scotland (Res14/A157), Medical Research Council (G0701120, G1001245, MR/M013111/1, MR/K026992/1), AgeUK, Alzheimer Society (AS-PG-14-033), EU Horizon 2020, (PHC-03-15, No 666881), Fondation Leducq (16 CVD 05).DisclosuresNone.FiguresFigure 1. CT (A) and MR (B sagittal T1, C axial T2, D axial T2*) images from a 70 year old man who presented shortly after a left hemisphere lacunar syndrome (adapted from Wardlaw et al, Ann Neurol 2001, Fig 1,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48
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ADDIN EN.CITE.DATA 1 publ. John Wyllie and Sons, with permission, license number 4351401429541). Note the ‘infarct’ (arrows, A) with the central hyperattenuated ‘dot’ in cross-section like a ‘mini hyperattenuated artery sign’; this appears linear on the sagittal T1 (B) consistent with the orientation of the perforating arteriole. The arteriole wall appears thickened with blood signal within it (C, D) particularly striking on the T2* blood-sensitive sequence (D). The ‘infarct’ is around about the mid arteriole, not at its end. A tiny side branch is visible in D (short arrow).Figure 2. Diagram illustrating dynamic relationships between small vessel function, and SVD lesions. A, Resting CBF is weakly related to intracranial vascular pulsatility but not to cerebrovascular reactivity while increasing pulsatility is strongly related to declining cerebrovascular reactivity. 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