Update on small vessel diseases - University of Edinburgh
Update on cerebral small vessel disease – a dynamic, whole-brain diseaseYulu Shi, MBBS, MNeurol; Joanna M Wardlaw, MDAffiliations and address:Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (Y.S., J.M.W.); Department of Neurology, Zhongnan Hospital, Wuhan University, Wuhan, China (Y.S.).Correspondence to: Prof Joanna M Wardlaw, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom. Joanna.Wardlaw@ed.ac.uk. Phone: +44-(0)131-465-958Word counts: 4810 words Figs: 4Key words: Cerebral Small Vessel Disease; Lacunar Infarct; White Matter Hyperintensities; Blood Brain Barrier; Microvascular dysfunctionList of abbreviationsAbbreviationDefinitionASCOAtherosclerosis - Small-vessel disease - Cardiac pathology - Other causesBBBBlood brain barrierCADASIL Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and LeukoencephalopathycAMPProstacyclin/cyclic adenosine monophosphateCBFCerebral blood flowcGMPNitric oxide/cyclic guanylate monophosphateCMBCerebral microbleedCSFCerebrospinal fluidCSVDCerebral small vessel diseaseDTIDiffusion-tensor imagingDWIDiffusion-weighted imagingFLAIRFluid-attenuated inversion recoveryISFInterstitial fluidMRIMagnetic resonance imagingNAWMNormal appearing white matterOCSPthe Oxfordshire Community Stroke ProjectPVSPerivascular spacesSPS3the Secondary Prevention of Small Subcortical Stokes TrialSWISusceptibility-weighted imagingTOASTthe Trial of Org 10172 in Acute Stroke TreatmentVITATOPSThe VITAmins TO Prevent Stroke studyWASIDthe Warfarin Aspirin Symptomatic Intracranial Disease studyWMHWhite matter hyperintensitiesABTRACTCerebral small vessel disease (CSVD) is a very common neurological disease in older people. It causes stroke and dementia, mood disturbance and gait problems. Since it is difficult to visualise CSVD pathologies in vivo, the diagnosis of CSVD has relied on imaging findings including white matter hyperintensities, lacunar ischaemic stroke, lacunes, microbleeds, visible perivascular spaces, and many haemorrhagic strokes. However, variations in the use of definition and terms of these features has probably caused confusion and difficulties in interpreting results of previous studies. A standardised use of terms should be encouraged in CSVD research. These CSVD features have long been regarded as different lesions, but emerging evidence has indicated that they might share some common intrinsic microvascular pathologies and therefore, because of its diffuse nature, CSVD should be regarded as a ‘whole-brain disease’. Single antiplatelet (for acute lacunar ischaemic stroke) and management of traditional risk factors still remain the most important therapeutic and preventive approach, due to limited understanding of pathophysiology in CSVD. Increasing evidence suggests that new studies should consider drugs that target endothelium and blood brain barrier to prevent and treat CSVD. Epidemiology of CSVD might differ in Asian compared to Western populations (where most results and guidelines about CSVD and stroke originate), but more community-based data and clear stratification of stroke types are required to address this. INTRODUCTIONThe term “cerebral small vessel disease (CSVD)” refers to a syndrome of clinical and imaging findings that are thought to result from pathologies in perforating cerebral arterioles, capillaries, and venules. CSVD causes up to 45% of dementia, and accounts for about 20% of all stroke worldwide, 25% of ischaemic (or lacunar strokes), of whom about 20% are left disabled. ADDIN EN.CITE <EndNote><Cite><Author>Pantoni</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463785719">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pantoni, L.</author></authors></contributors><auth-address>Department of Neurological and Psychiatric Sciences, University of Florence, Italy. pantoni@unifi.it</auth-address><titles><title>Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>689-701</pages><volume>9</volume><number>7</number><keywords><keyword>Age Factors</keyword><keyword>Anticoagulants/therapeutic use</keyword><keyword>Blood Vessels/*pathology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cerebrovascular Disorders/classification/*etiology/*pathology/*therapy</keyword><keyword>Cognition Disorders/physiopathology</keyword><keyword>Diagnostic Imaging/methods</keyword><keyword>Endarterectomy, Carotid/methods</keyword><keyword>Humans</keyword><keyword>Thrombolytic Therapy/methods</keyword></keywords><dates><year>2010</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1474-4465 (Electronic)
1474-4422 (Linking)</isbn><accession-num>20610345</accession-num><urls><related-urls><url>(10)70104-6</electronic-resource-num></record></Cite></EndNote>[1] Cognitive impairment, depression and gait problems are also frequently seen in patients with CSVD. The prevalence of lacunar stroke may be higher in patients in China where recent studies have suggested that lacunar infarction accounts for 38-46% of ischaemic stroke.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Uc2FpPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
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AG==
ADDIN EN.CITE.DATA [2, 3] Generally, including in this review, CSVD is used to describe a series of imaging changes in white matter and subcortical grey matter, including recent small subcortical infarct, lacunes, white matter hyperintensities (WMH), prominent perivascular spaces (PVS), cerebral microbleeds (CMB), and atrophy.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA [4] Usually, recent small subcortical infarcts cause acute stroke symptoms, whereas other CSVD lesions are clinically more insidious and thus referred to as ‘silent’ lesions. However, the definitions and terms of these lesions have varied greatly among studies. For example, a recent review identified 159 different names for recent small subcortical infarcts, but these names like “lacunar infarct” were also frequently used to describe lacunes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXJtZWVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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ADDIN EN.CITE.DATA [4] We will also use these terms in this review.The different features of CSVD have long been regarded as different types of tissue changes. However, recent studies show that these features are correlated, are more likely to share common diffuse intrinsic small vessel pathologies, and are probably also more ‘dynamic’ than previously thought. Advances in imaging techniques have brought new insights into mechanisms of CSVD. In this review, we will summarise findings in recent clinical studies on CSVD, discuss CSVD mechanisms, and explore emerging prevention and treatment options. Clinical lacunar stroke A lacunar clinical syndrome could be due to either ischaemia or a small haemorrhage. ADDIN EN.CITE <EndNote><Cite><Author>Mori</Author><Year>1985</Year><RecNum>97</RecNum><DisplayText>[6]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468589276">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mori, E.</author><author>Tabuchi, M.</author><author>Yamadori, A.</author></authors></contributors><titles><title>Lacunar syndrome due to intracerebral hemorrhage</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>454-9</pages><volume>16</volume><number>3</number><keywords><keyword>Ataxia/*etiology/radiography</keyword><keyword>Cerebral Hemorrhage/*complications/radiography</keyword><keyword>Hemiplegia/*etiology/radiography</keyword><keyword>Humans</keyword><keyword>Pons/blood supply</keyword><keyword>Putamen/blood supply</keyword><keyword>Syndrome</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>1985</year><pub-dates><date>May-Jun</date></pub-dates></dates><isbn>0039-2499 (Print)
0039-2499 (Linking)</isbn><accession-num>4002260</accession-num><urls><related-urls><url>;[6] Many haemorrhagic strokes in older people are also due to CSVD pathology. ADDIN EN.CITE <EndNote><Cite><Author>Pantoni</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463785719">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pantoni, L.</author></authors></contributors><auth-address>Department of Neurological and Psychiatric Sciences, University of Florence, Italy. pantoni@unifi.it</auth-address><titles><title>Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>689-701</pages><volume>9</volume><number>7</number><keywords><keyword>Age Factors</keyword><keyword>Anticoagulants/therapeutic use</keyword><keyword>Blood Vessels/*pathology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cerebrovascular Disorders/classification/*etiology/*pathology/*therapy</keyword><keyword>Cognition Disorders/physiopathology</keyword><keyword>Diagnostic Imaging/methods</keyword><keyword>Endarterectomy, Carotid/methods</keyword><keyword>Humans</keyword><keyword>Thrombolytic Therapy/methods</keyword></keywords><dates><year>2010</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1474-4465 (Electronic)
1474-4422 (Linking)</isbn><accession-num>20610345</accession-num><urls><related-urls><url>(10)70104-6</electronic-resource-num></record></Cite></EndNote>[1] In this review, we will focus mainly on ischaemic CSVD. Lacunar ischaemic stroke is defined as a stroke that is attributable to a recent small infarct less than 1.5 (or some say 2) cm diameter in white matter, basal ganglia, pons or brainstem, and is consistent with a lacunar clinical syndrome. ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2013</Year><RecNum>7</RecNum><DisplayText>[7]</DisplayText><record><rec-number>7</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463787133">7</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw, J. M.</author><author>Smith, C.</author><author>Dichgans, M.</author></authors></contributors><auth-address>Neuroimaging Sciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. joanna.wardlaw@ed.ac.uk</auth-address><titles><title>Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>483-97</pages><volume>12</volume><number>5</number><keywords><keyword>Brain/*blood supply/pathology</keyword><keyword>Cerebral Small Vessel Diseases/*pathology</keyword><keyword>Dementia, Vascular/*pathology</keyword><keyword>Humans</keyword><keyword>Neuroimaging</keyword></keywords><dates><year>2013</year><pub-dates><date>May</date></pub-dates></dates><isbn>1474-4465 (Electronic)
1474-4422 (Linking)</isbn><accession-num>23602162</accession-num><urls><related-urls><url>(13)70060-7</electronic-resource-num></record></Cite></EndNote>[7] It is commonly attributed to an abnormality in a single small deep perforating (or lenticulostriate) artery. On magnetic resonance imaging (MRI), an acute lacunar infarct is shown as hyperintense on diffusion-weighted imaging (DWI), hypointense on apparent diffusion coefficient map, hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR), hypointense on T1, and hypoattenuated on CT. (Figure 1) It can be rounded, ovoid, or tubular.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA [4] Generally, the Oxfordshire Community Stroke Project (OCSP) classification, which uses only clinical features to diagnose the stroke subtype, can predict correctly the size and location of a recent brain infarct on imaging in 75-80% of stroke patients. ADDIN EN.CITE <EndNote><Cite><Author>Mead</Author><Year>2000</Year><RecNum>10</RecNum><DisplayText>[8]</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463787630">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mead, G. E.</author><author>Lewis, S. C.</author><author>Wardlaw, J. M.</author><author>Dennis, M. S.</author><author>Warlow, C. P.</author></authors></contributors><auth-address>Neurosciences Trials Unit, Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK.</auth-address><titles><title>How well does the Oxfordshire community stroke project classification predict the site and size of the infarct on brain imaging?</title><secondary-title>J Neurol Neurosurg Psychiatry</secondary-title></titles><periodical><full-title>J Neurol Neurosurg Psychiatry</full-title></periodical><pages>558-62</pages><volume>68</volume><number>5</number><keywords><keyword>Aged</keyword><keyword>Brain/*pathology</keyword><keyword>Cerebral Infarction/*classification/diagnosis</keyword><keyword>Cohort Studies</keyword><keyword>*Diagnostic Imaging</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prognosis</keyword><keyword>Stroke/*classification/diagnosis</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>2000</year><pub-dates><date>May</date></pub-dates></dates><isbn>0022-3050 (Print)
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ADDIN EN.CITE.DATA [9] One explanation is that lacunar infarcts closer to the cortex are more likely to cause cortical symptoms.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3R0ZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [9] Therefore, in studies where stroke diagnosis relied mainly on the clinical presentations, this ‘mismatch’ may have added ‘noise’. Thus in epidemiology, mechanistic studies or clinical trials, it is important to verify stroke lesions using sensitive imaging wherever possible. However, even with sensitive imaging like DWI, about 30% of patients with clinically definite stroke did not show any recent ischaemic change on MRI;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [10] when followed-up for a year, the DWI-negative patients had just as much recurrent stroke, dependency and cognitive impairment as the DWI-positive patients. Therefore, negative DWI/MRI cannot exclude stroke diagnosis. Rapid access to scanning after stroke onset can increase the chance of positive findings. ADDIN EN.CITE <EndNote><Cite><Author>Doubal</Author><Year>2011</Year><RecNum>9</RecNum><DisplayText>[11]</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463787396">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Doubal, F. N.</author><author>Dennis, M. S.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Bramwell Dott Building, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. fergus.doubal@ed.ac.uk</auth-address><titles><title>Characteristics of patients with minor ischaemic strokes and negative MRI: a cross-sectional study</title><secondary-title>J Neurol Neurosurg Psychiatry</secondary-title></titles><periodical><full-title>J Neurol Neurosurg Psychiatry</full-title></periodical><pages>540-2</pages><volume>82</volume><number>5</number><keywords><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Brain/*pathology</keyword><keyword>Brain Infarction/diagnosis/pathology</keyword><keyword>Cross-Sectional Studies</keyword><keyword>False Negative Reactions</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Multivariate Analysis</keyword><keyword>Sex Factors</keyword><keyword>Stroke/diagnosis/*pathology</keyword><keyword>Time Factors</keyword></keywords><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1468-330X (Electronic)
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ADDIN EN.CITE.DATA [12] In some clinical stroke classifications such as the Trial of Org 10172 in Acute Stroke Treatment (TOAST) or the ASCO (A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other causes), another term “small vessel/artery disease” rather than “lacunar stroke” is used to represent a stroke that is supposed to be due to a small artery occlusion. However, these classifications use risk factors to decide the stroke subtype not just the clinical presentation, so as to distinguish “small vessel/artery disease” from strokes caused by large artery atherosclerosis, cardiac emboli or other unknown reasons. However, a small embolus, or atheroma in the middle cerebral artery (MCA) or perforating arterioles can all block the perforating arteriole, and any of these can cause a lacunar ischaemic stroke (see Figure 2). Therefore it might be better to focus on the clinical presentation to assign the stroke syndrome and separately focus on the risk factors for patient management. Risk factors and causes of lacunar infarctsFour possible main aetiologies for lacunar ischaemic stroke have been proposed (Figure 2): atheroma of parent arteries (usually MCA) or perforating arterioles, embolism from heart or carotid arteries, and intrinsic small vessel disease (lipohyalinosis or fibrinoid necrosis). Atheroma in MCA appears to cause less than 20% of lacunar ischaemic stroke. In the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial, only 11% (38/347) of all stroke patients were lacunar type,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGFuPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [13] which is surprising if MCA stenosis is supposed to be a common cause of lacunar stroke. A recent study also did not find any association between lacunar stroke and MCA stenosis.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA [14] A systematic review of Asian studies showed that parent artery atherosclerosis accounted for 20% of single lacunar infarcts in anterior circulation territory, however these hospital-based studies were rather small (n=71-118) and some were even retrospective. ADDIN EN.CITE <EndNote><Cite><Author>Kim</Author><Year>2013</Year><RecNum>21</RecNum><DisplayText>[15]</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463789611">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim, J. S.</author><author>Yoon, Y.</author></authors></contributors><auth-address>Stroke Center and Department of Neurology, University of Ulsan, Asan Medical Center, Seoul, South Korea. jongskim@amc.seoul.kr</auth-address><titles><title>Single subcortical infarction associated with parental arterial disease: important yet neglected sub-type of atherothrombotic stroke</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>197-203</pages><volume>8</volume><number>3</number><keywords><keyword>Cerebral Arteries/pathology</keyword><keyword>Cerebral Infarction/*etiology/pathology</keyword><keyword>Diagnosis, Differential</keyword><keyword>Humans</keyword><keyword>Intracranial Arteriosclerosis/*complications/pathology</keyword><keyword>Magnetic Resonance Angiography</keyword><keyword>Stroke/classification/*etiology/pathology</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1747-4949 (Electronic)
1747-4930 (Linking)</isbn><accession-num>22568537</accession-num><urls><related-urls><url>;[15] Larger and tubular lacunar infarcts might be more likely to be caused by proximal artery diseases. ADDIN EN.CITE <EndNote><Cite><Author>de Jong</Author><Year>2002</Year><RecNum>98</RecNum><DisplayText>[16]</DisplayText><record><rec-number>98</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468597089">98</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Jong, G.</author><author>Kessels, F.</author><author>Lodder, J.</author></authors></contributors><auth-address>Department of Neurology, Isala Clinics Location Weezenlanden, Zwolle, The Netherlands.</auth-address><titles><title>Two types of lacunar infarcts: further arguments from a study on prognosis</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>2072-6</pages><volume>33</volume><number>8</number><keywords><keyword>Arteriosclerosis/diagnosis/pathology</keyword><keyword>Brain/blood supply/pathology</keyword><keyword>Brain Infarction/*classification/*diagnosis/mortality/pathology</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Diagnosis, Differential</keyword><keyword>Disease-Free Survival</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Hypertension/complications</keyword><keyword>Logistic Models</keyword><keyword>Microcirculation/pathology</keyword><keyword>Odds Ratio</keyword><keyword>Prognosis</keyword><keyword>Prospective Studies</keyword><keyword>Recurrence</keyword><keyword>Risk Factors</keyword><keyword>Survival Rate</keyword><keyword>Tomography, X-Ray Computed</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2002</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1524-4628 (Electronic)
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWNrc29uPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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ADDIN EN.CITE.DATA [19, 20] Few if any associations were found between ipsilateral carotid stenosis and lacunar ischaemic stroke or other features of CSVD.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3R0ZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [21, 22] In primate models, less than 6% of emboli injected into carotid arteries entered the lenticulostriate arteries, while the majority entered cortical arteries. ADDIN EN.CITE <EndNote><Cite><Author>Macdonald</Author><Year>1995</Year><RecNum>28</RecNum><DisplayText>[23]</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463790171">28</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Macdonald, R. L.</author><author>Kowalczuk, A.</author><author>Johns, L.</author></authors></contributors><auth-address>Department of Surgery, University of Chicago Medical Center, IL 60637, USA.</auth-address><titles><title>Emboli enter penetrating arteries of monkey brain in relation to their size</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>1247-50; discussion 1250-1</pages><volume>26</volume><number>7</number><keywords><keyword>Acrylic Resins</keyword><keyword>Animals</keyword><keyword>Basilar Artery/pathology</keyword><keyword>Brain/pathology</keyword><keyword>Carotid Artery, Internal/pathology</keyword><keyword>Cerebral Arteries/*pathology</keyword><keyword>Cerebral Infarction/pathology</keyword><keyword>Cerebrovascular Circulation</keyword><keyword>Image Processing, Computer-Assisted</keyword><keyword>Injections, Intra-Arterial</keyword><keyword>Intracranial Embolism and Thrombosis/*pathology</keyword><keyword>Macaca fascicularis</keyword><keyword>Microspheres</keyword><keyword>Particle Size</keyword><keyword>Polymers</keyword><keyword>Sepharose</keyword><keyword>Triazines</keyword></keywords><dates><year>1995</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0039-2499 (Print)
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ADDIN EN.CITE.DATA [18] Intrinsic small vessel pathologies remain the most common cause of lacunar ischaemic stroke, although the underlying mechanism is unclear. Fisher attributed the lipohyalinosis in small arteries to hypertension. However, the diagnosis and treatment of hypertension were less good when Fisher was working in the 1950s and 1960s and he may have seen some particularly severe cases of hypertension. Now, epidemiology data show that hypertension is equally common in non-lacunar as in lacunar ischaemic stroke; ADDIN EN.CITE <EndNote><Cite><Author>Jackson</Author><Year>2010</Year><RecNum>24</RecNum><DisplayText>[19]</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463789910">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jackson, C. A.</author><author>Hutchison, A.</author><author>Dennis, M. S.</author><author>Wardlaw, J. M.</author><author>Lindgren, A.</author><author>Norrving, B.</author><author>Anderson, C. S.</author><author>Hankey, G. J.</author><author>Jamrozik, K.</author><author>Appelros, P.</author><author>Sudlow, C. L.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, University of Edinburgh, United Kingdom.</auth-address><titles><title>Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy?</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>624-9</pages><volume>41</volume><number>4</number><keywords><keyword>Aged</keyword><keyword>*Brain/anatomy & histology/pathology</keyword><keyword>*Brain Infarction/classification/epidemiology/pathology</keyword><keyword>*Brain Ischemia/classification/epidemiology/pathology</keyword><keyword>Cerebral Arteries/*pathology</keyword><keyword>Cerebrovascular Circulation</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Registries</keyword><keyword>Risk Factors</keyword><keyword>*Stroke/classification/epidemiology/pathology</keyword></keywords><dates><year>2010</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>20150553</accession-num><urls><related-urls><url>;[19] and many lacunar stroke patients are normotensive. Similarly, other traditional risk factors like diabetes mellitus, hypercholesterolaemia and smoking were as frequent in lacunar stroke as in other ischaemic strokes. ADDIN EN.CITE <EndNote><Cite><Author>Jackson</Author><Year>2005</Year><RecNum>99</RecNum><DisplayText>[24]</DisplayText><record><rec-number>99</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468597991">99</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jackson, C.</author><author>Sudlow, C.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, University of Edinburgh, United Kingdom.</auth-address><titles><title>Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and nonlacunar infarcts</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>891-901</pages><volume>36</volume><number>4</number><keywords><keyword>Aged</keyword><keyword>Atrial Fibrillation/complications</keyword><keyword>Blood Pressure</keyword><keyword>Brain Infarction/*diagnosis/pathology</keyword><keyword>Carotid Stenosis/complications</keyword><keyword>Diabetes Complications/diagnosis</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hypertension/complications</keyword><keyword>Ischemia</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Risk</keyword><keyword>Risk Factors</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Stroke/*diagnosis/pathology</keyword></keywords><dates><year>2005</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>15761206</accession-num><urls><related-urls><url>;[24] Risk factor profiles of lacunar stroke seemed different in China, but it might be too early to say so. The Beijing stroke registry (n=1184) showed a higher proportion of hypertension in lacunar (acute stroke symptoms + subcortical lesion <2 cm diameter on acute CT/MRI) than in non-lacunar stroke after adjusting for age and gender. ADDIN EN.CITE <EndNote><Cite><Author>Fang</Author><Year>2012</Year><RecNum>30</RecNum><DisplayText>[3]</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463790458">30</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fang, X. H.</author><author>Wang, W. H.</author><author>Zhang, X. Q.</author><author>Liu, H. J.</author><author>Zhang, H. M.</author><author>Qin, X. M.</author><author>Wang, Z. C.</author><author>Ji, X. M.</author><author>Li, L. M.</author></authors></contributors><auth-address>Department of Evidence-based Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.</auth-address><titles><title>Incidence and survival of symptomatic lacunar infarction in a Beijing population: a 6-year prospective study</title><secondary-title>Eur J Neurol</secondary-title></titles><periodical><full-title>Eur J Neurol</full-title></periodical><pages>1114-20</pages><volume>19</volume><number>8</number><keywords><keyword>Adult</keyword><keyword>Age Distribution</keyword><keyword>Aged</keyword><keyword>China/epidemiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Sex Distribution</keyword><keyword>Stroke, Lacunar/*epidemiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1468-1331 (Electronic)
1351-5101 (Linking)</isbn><accession-num>22494183</accession-num><urls><related-urls><url>;[3] Some other studies had similar findings, but the stroke diagnosis varied: in some studies the differentiation between lacunar stroke and “large artery atherosclerosis” stroke relied only on lesion size, and clinical classification included risk factors.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [25, 26] Additionally, most studies were hospital-based. Hence population-scale data on lacunar stroke are lacking. It is important to distinguish lacunar stroke from other subtypes because the mechanism, hence prevention and treatment might differ. More data and careful separation of lacunar stroke from other subtypes are required in future studies. Clinically ‘Silent CSVD’White matter hyperintensitiesWMH of presumed vascular origin are very common in older individuals and regarded as typical signs of CSVD. Symptoms of WMH develop insidiously, such as cognitive impairment, dementia and depression; ADDIN EN.CITE <EndNote><Cite><Author>Pantoni</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463785719">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pantoni, L.</author></authors></contributors><auth-address>Department of Neurological and Psychiatric Sciences, University of Florence, Italy. pantoni@unifi.it</auth-address><titles><title>Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>689-701</pages><volume>9</volume><number>7</number><keywords><keyword>Age Factors</keyword><keyword>Anticoagulants/therapeutic use</keyword><keyword>Blood Vessels/*pathology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cerebrovascular Disorders/classification/*etiology/*pathology/*therapy</keyword><keyword>Cognition Disorders/physiopathology</keyword><keyword>Diagnostic Imaging/methods</keyword><keyword>Endarterectomy, Carotid/methods</keyword><keyword>Humans</keyword><keyword>Thrombolytic Therapy/methods</keyword></keywords><dates><year>2010</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1474-4465 (Electronic)
1474-4422 (Linking)</isbn><accession-num>20610345</accession-num><urls><related-urls><url>(10)70104-6</electronic-resource-num></record></Cite></EndNote>[1] but it almost triples the risk of stroke, doubles the risk of dementia and increases the risk of death. ADDIN EN.CITE <EndNote><Cite><Author>Debette</Author><Year>2010</Year><RecNum>32</RecNum><DisplayText>[27]</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463791069">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Debette, S.</author><author>Markus, H. S.</author></authors></contributors><auth-address>Clinical Neuroscience, St George's University of London, London. sdebette@bu.edu</auth-address><titles><title>The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis</title><secondary-title>BMJ</secondary-title></titles><periodical><full-title>BMJ</full-title></periodical><pages>c3666</pages><volume>341</volume><keywords><keyword>Cerebrovascular Disorders/*pathology</keyword><keyword>Cognition Disorders/*pathology/prevention & control</keyword><keyword>Dementia, Vascular/pathology/prevention & control</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Longitudinal Studies</keyword><keyword>Magnetic Resonance Angiography</keyword><keyword>Microcirculation</keyword><keyword>Prognosis</keyword><keyword>Risk Factors</keyword><keyword>Stroke/pathology/prevention & control</keyword></keywords><dates><year>2010</year></dates><isbn>1756-1833 (Electronic)
0959-535X (Linking)</isbn><accession-num>20660506</accession-num><urls><related-urls><url>;[27] WMH are usually symmetrically and bilaterally distributed in white matter including pons and brain stem, and also occur in deep grey matter. They appear hyperintense to normal brain on T2 or FLAIR MRI,(Figure 1) and can be patchy or confluent depending on their stage in development and severity. Due to limited pathology studies the underlying pathology of WMH remains imprecise. Demyelination, loss of oligodendrocytes and axonal damage were often reported. Diffusion tensor imaging (DTI) studies provided indirect evidence for axonal damage and impaired white matter integrity in WMH. ADDIN EN.CITE <EndNote><Cite><Author>Madden</Author><Year>2012</Year><RecNum>35</RecNum><DisplayText>[28]</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463791493">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Madden, D. J.</author><author>Bennett, I. J.</author><author>Burzynska, A.</author><author>Potter, G. G.</author><author>Chen, N. K.</author><author>Song, A. W.</author></authors></contributors><auth-address>Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC 27710, USA. madden@biac.duke.edu</auth-address><titles><title>Diffusion tensor imaging of cerebral white matter integrity in cognitive aging</title><secondary-title>Biochim Biophys Acta</secondary-title></titles><periodical><full-title>Biochim Biophys Acta</full-title></periodical><pages>386-400</pages><volume>1822</volume><number>3</number><keywords><keyword>Age Factors</keyword><keyword>Cerebrum/pathology/*physiology</keyword><keyword>Cognition/*physiology</keyword><keyword>Cognition Disorders/*pathology</keyword><keyword>Diffusion Tensor Imaging/methods</keyword><keyword>Humans</keyword><keyword>Nerve Fibers, Myelinated/*pathology</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0006-3002 (Print)
0006-3002 (Linking)</isbn><accession-num>21871957</accession-num><urls><related-urls><url>;[28] Indeed, recent evidence indicates that WMH are rather heterogeneous, perhaps reflecting different disease stages. Reduced density of glia and vacuolation were observed in severe WMH suggesting end stage disease. ADDIN EN.CITE <EndNote><Cite><Author>Munoz</Author><Year>1993</Year><RecNum>34</RecNum><DisplayText>[29]</DisplayText><record><rec-number>34</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463791281">34</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Munoz, D. G.</author><author>Hastak, S. M.</author><author>Harper, B.</author><author>Lee, D.</author><author>Hachinski, V. C.</author></authors></contributors><auth-address>Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada.</auth-address><titles><title>Pathologic correlates of increased signals of the centrum ovale on magnetic resonance imaging</title><secondary-title>Arch Neurol</secondary-title></titles><periodical><full-title>Arch Neurol</full-title></periodical><pages>492-7</pages><volume>50</volume><number>5</number><keywords><keyword>Aged</keyword><keyword>Cerebral Cortex/blood supply/*pathology</keyword><keyword>Cerebral Hemorrhage/pathology</keyword><keyword>Cerebral Infarction/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Vacuoles/pathology</keyword></keywords><dates><year>1993</year><pub-dates><date>May</date></pub-dates></dates><isbn>0003-9942 (Print)
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ADDIN EN.CITE.DATA [34]. Multiple mechanisms underlying WMH such as incomplete infarct, chronic hypoperfusion and venous collagenous have been proposed but evidence for each is limited. In a pathology study (n=15), no incomplete infarct was found in WMH. ADDIN EN.CITE <EndNote><Cite><Author>Munoz</Author><Year>1993</Year><RecNum>34</RecNum><DisplayText>[29]</DisplayText><record><rec-number>34</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463791281">34</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Munoz, D. G.</author><author>Hastak, S. M.</author><author>Harper, B.</author><author>Lee, D.</author><author>Hachinski, V. C.</author></authors></contributors><auth-address>Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada.</auth-address><titles><title>Pathologic correlates of increased signals of the centrum ovale on magnetic resonance imaging</title><secondary-title>Arch Neurol</secondary-title></titles><periodical><full-title>Arch Neurol</full-title></periodical><pages>492-7</pages><volume>50</volume><number>5</number><keywords><keyword>Aged</keyword><keyword>Cerebral Cortex/blood supply/*pathology</keyword><keyword>Cerebral Hemorrhage/pathology</keyword><keyword>Cerebral Infarction/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Vacuoles/pathology</keyword></keywords><dates><year>1993</year><pub-dates><date>May</date></pub-dates></dates><isbn>0003-9942 (Print)
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ADDIN EN.CITE.DATA [36] In post-mortem study, some non-inflammatory, periventricular venulopathy were observed in periventricular WMH, suggesting that venous collagenosis might cause tissue damage by vasogenic oedema and impede interstitial fluid circulation. ADDIN EN.CITE <EndNote><Cite><Author>Black</Author><Year>2009</Year><RecNum>43</RecNum><DisplayText>[31]</DisplayText><record><rec-number>43</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463793058">43</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Black, S.</author><author>Gao, F.</author><author>Bilbao, J.</author></authors></contributors><auth-address>FRCP(C), Brill Professor of Neurology, Cognitive Neurology, A421, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5. sandra.black@sunnybrook.ca</auth-address><titles><title>Understanding white matter disease: imaging-pathological correlations in vascular cognitive impairment</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>S48-52</pages><volume>40</volume><number>3 Suppl</number><keywords><keyword>Aging/*pathology</keyword><keyword>Alzheimer Disease/pathology</keyword><keyword>Cognition Disorders/*pathology</keyword><keyword>Dementia, Vascular/*pathology</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Magnetic Resonance Spectroscopy</keyword><keyword>Positron-Emission Tomography</keyword></keywords><dates><year>2009</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1524-4628 (Electronic)
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ADDIN EN.CITE.DATA [29, 30] which was corroborated by studies using cerebrospinal fluid (CSF)/plasma albumin ratio ADDIN EN.CITE <EndNote><Cite><Author>Farrall</Author><Year>2009</Year><RecNum>103</RecNum><DisplayText>[37]</DisplayText><record><rec-number>103</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468790051">103</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Farrall, A. J.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK. Andrew.Farrall@ed.ac.uk</auth-address><titles><title>Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis</title><secondary-title>Neurobiol Aging</secondary-title></titles><periodical><full-title>Neurobiol Aging</full-title></periodical><pages>337-52</pages><volume>30</volume><number>3</number><keywords><keyword>*Aging/physiology</keyword><keyword>Alzheimer Disease/metabolism/physiopathology</keyword><keyword>Animals</keyword><keyword>Blood-Brain Barrier/*metabolism/*physiopathology</keyword><keyword>Capillary Permeability/physiology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cerebrovascular Disorders/metabolism/physiopathology</keyword><keyword>Dementia, Vascular/metabolism/physiopathology</keyword><keyword>Humans</keyword><keyword>Microvessels/*metabolism/*physiopathology</keyword></keywords><dates><year>2009</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1558-1497 (Electronic)
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ADDIN EN.CITE.DATA [38-41]. It is hypothesized that the disrupted BBB would result in leakage of fluid, plasma components and cells and eventually lead to perivascular inflammation, demyelination and gliosis. Indeed, the formation of WMH is likely to be multi-factorial. Hypoperfusion, venous pathologies and BBB impairment might all play critical roles in WMH initiation or progression and interact with each other, but which one is the key initial factor remains unknown. LacunesThe term “lacune” was used by Fisher to describe a small fluid cavity in the brain which he thought was a healed lacunar infarct. Therefore in CSVD research, it is very common that terms like “lacunar infarction”, “lacunar stroke”, “silent brain infarct” were used to refer to the CSF-filled cavities on brain MRI or autopsy. ADDIN EN.CITE <EndNote><Cite><Author>Potter</Author><Year>2011</Year><RecNum>11</RecNum><DisplayText>[42]</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463787790">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Potter, G. M.</author><author>Marlborough, F. J.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK.</auth-address><titles><title>Wide variation in definition, detection, and description of lacunar lesions on imaging</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>359-66</pages><volume>42</volume><number>2</number><keywords><keyword>Brain Infarction/*classification/*diagnosis</keyword><keyword>Diagnostic Imaging/*methods/*standards</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/methods/standards</keyword><keyword>Random Allocation</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>21193752</accession-num><urls><related-urls><url>;[42] In fact, lacunes are not always “ischaemic”. They can also be the residual lesion of a small haemorrhage. ADDIN EN.CITE <EndNote><Cite><Author>Franke</Author><Year>1991</Year><RecNum>14</RecNum><DisplayText>[43]</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463788062">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Franke, C. L.</author><author>van Swieten, J. C.</author><author>van Gijn, J.</author></authors></contributors><auth-address>Department of Neurology, De Wever-Ziekenhuis, Heerlen, The Netherlands.</auth-address><titles><title>Residual lesions on computed tomography after intracerebral hemorrhage</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>1530-3</pages><volume>22</volume><number>12</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Basal Ganglia/radiography</keyword><keyword>Caudate Nucleus/radiography</keyword><keyword>Cerebral Hemorrhage/*radiography</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Putamen/radiography</keyword><keyword>Rupture, Spontaneous</keyword><keyword>Thalamus/radiography</keyword><keyword>*Tomography, X-Ray Computed</keyword></keywords><dates><year>1991</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0039-2499 (Print)
0039-2499 (Linking)</isbn><accession-num>1962328</accession-num><urls><related-urls><url>;[43] (Figure 3) Also it is common that many non-cavitated lacunar ischaemic strokes were not counted as ‘lacunar infarcts’. Therefore, in order to avoid more confusion, the term “lacune of presumed vascular origin” was proposed to replace “lacune” and the term ‘lacunar infarct’ should NOT be used to describe ‘lacunes’ any more. Lacunes of presumed vascular origin are round or ovoid, subcortical, fluid-filled cavities, with a diameter of 3-15 mm. These can occur without any prior symptoms, but can also result from a previous acute small subcortical infarct or haemorrhage.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA [44] Large PVS might have also been miscounted as lacunes in many studies. ADDIN EN.CITE <EndNote><Cite><Author>Potter</Author><Year>2011</Year><RecNum>11</RecNum><DisplayText>[42]</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463787790">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Potter, G. M.</author><author>Marlborough, F. J.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK.</auth-address><titles><title>Wide variation in definition, detection, and description of lacunar lesions on imaging</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>359-66</pages><volume>42</volume><number>2</number><keywords><keyword>Brain Infarction/*classification/*diagnosis</keyword><keyword>Diagnostic Imaging/*methods/*standards</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/methods/standards</keyword><keyword>Random Allocation</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1524-4628 (Electronic)
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ADDIN EN.CITE.DATA [5, 45, 46] In the general elderly population, the prevalence of lacunes ranges from 8% to 28% (mean age = 50 -75 years). ADDIN EN.CITE <EndNote><Cite><Author>Vermeer</Author><Year>2007</Year><RecNum>16</RecNum><DisplayText>[5]</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463788342">16</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vermeer, S. E.</author><author>Longstreth, W. T., Jr.</author><author>Koudstaal, P. J.</author></authors></contributors><auth-address>Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. s.vermeer@erasmusmc.nl</auth-address><titles><title>Silent brain infarcts: a systematic review</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>611-9</pages><volume>6</volume><number>7</number><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain Infarction/*etiology/*pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/methods</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Risk</keyword><keyword>Sex Factors</keyword><keyword>Stroke/*complications</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1474-4422 (Print)
1474-4422 (Linking)</isbn><accession-num>17582361</accession-num><urls><related-urls><url>(07)70170-9</electronic-resource-num></record></Cite></EndNote>[5] A systematic review suggests that silent brain infarcts (another term sometimes used for lacune) are more prevalent in Asian than in non-Asian population. ADDIN EN.CITE <EndNote><Cite><Author>Fanning</Author><Year>2014</Year><RecNum>18</RecNum><DisplayText>[47]</DisplayText><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463788810">18</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fanning, J. P.</author><author>Wong, A. A.</author><author>Fraser, J. F.</author></authors></contributors><titles><title>The epidemiology of silent brain infarction: a systematic review of population-based cohorts</title><secondary-title>BMC Med</secondary-title></titles><periodical><full-title>BMC Med</full-title></periodical><pages>119</pages><volume>12</volume><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain Infarction/*epidemiology/etiology/pathology/prevention & control</keyword><keyword>Cohort Studies</keyword><keyword>Ethnic Groups</keyword><keyword>Female</keyword><keyword>Global Health</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2014</year></dates><isbn>1741-7015 (Electronic)
1741-7015 (Linking)</isbn><accession-num>25012298</accession-num><urls><related-urls><url>;[47] However it is noteworthy that most of these Asian studies were hospital-based whereas all non-Asian studies were community-based, therefore more relevant comparisons are needed to determine if the prevalence of lacunes and other CSVD features does differ between world regions and ethnic groups. PVSPVS are the extension of subarachnoid spaces that surround cerebral microvessels. ADDIN EN.CITE <EndNote><Cite><Author>Braffman</Author><Year>1988</Year><RecNum>64</RecNum><DisplayText>[48]</DisplayText><record><rec-number>64</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1464951360">64</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Braffman, B. H.</author><author>Zimmerman, R. A.</author><author>Trojanowski, J. Q.</author><author>Gonatas, N. K.</author><author>Hickey, W. F.</author><author>Schlaepfer, W. W.</author></authors></contributors><auth-address>Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia 19104.</auth-address><titles><title>Brain MR: pathologic correlation with gross and histopathology. 1. Lacunar infarction and Virchow-Robin spaces</title><secondary-title>AJR Am J Roentgenol</secondary-title></titles><periodical><full-title>AJR Am J Roentgenol</full-title></periodical><pages>551-8</pages><volume>151</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Basal Ganglia/pathology</keyword><keyword>Blood Vessels/pathology</keyword><keyword>Brain/blood supply/*pathology</keyword><keyword>Cerebral Infarction/*diagnosis</keyword><keyword>Cranial Fossa, Posterior</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Thalamus/pathology</keyword></keywords><dates><year>1988</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0361-803X (Print)
0361-803X (Linking)</isbn><accession-num>3261517</accession-num><urls><related-urls><url>;[48] They are fluid-filled spaces that follow the course of a vessel through the brain parenchyma. ADDIN EN.CITE <EndNote><Cite><Author>Braffman</Author><Year>1988</Year><RecNum>65</RecNum><DisplayText>[48]</DisplayText><record><rec-number>65</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465233515">65</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Braffman, B. H.</author><author>Zimmerman, R. A.</author><author>Trojanowski, J. Q.</author><author>Gonatas, N. K.</author><author>Hickey, W. F.</author><author>Schlaepfer, W. W.</author></authors></contributors><auth-address>Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia 19104.</auth-address><titles><title>Brain MR: pathologic correlation with gross and histopathology. 1. Lacunar infarction and Virchow-Robin spaces</title><secondary-title>AJR Am J Roentgenol</secondary-title></titles><periodical><full-title>AJR Am J Roentgenol</full-title></periodical><pages>551-8</pages><volume>151</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Basal Ganglia/pathology</keyword><keyword>Blood Vessels/pathology</keyword><keyword>Brain/blood supply/*pathology</keyword><keyword>Cerebral Infarction/*diagnosis</keyword><keyword>Cranial Fossa, Posterior</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Thalamus/pathology</keyword></keywords><dates><year>1988</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0361-803X (Print)
0361-803X (Linking)</isbn><accession-num>3261517</accession-num><urls><related-urls><url>;[48] PVS are usually microscopic and not detected on CT or conventional MRIs. When enlarged, PVS are commonly seen as hyperintense on T2 MRI , either punctuate with a diameter less than 3 mm if imaged perpendicular to the course of the vessel, or linear if imaged parallel to the course of the vessel. ADDIN EN.CITE <EndNote><Cite><Author>Potter</Author><Year>2015</Year><RecNum>87</RecNum><DisplayText>[49]</DisplayText><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468399521">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Potter, G. M.</author><author>Chappell, F. M.</author><author>Morris, Z.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Brain Imaging Research Centre, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Cerebral perivascular spaces visible on magnetic resonance imaging: development of a qualitative rating scale and its observer reliability</title><secondary-title>Cerebrovasc Dis</secondary-title></titles><periodical><full-title>Cerebrovasc Dis</full-title></periodical><pages>224-31</pages><volume>39</volume><number>3-4</number><keywords><keyword>Age Distribution</keyword><keyword>Blood-Brain Barrier/pathology</keyword><keyword>Brain/*pathology</keyword><keyword>Cerebral Small Vessel Diseases/*pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging/methods</keyword><keyword>Male</keyword><keyword>Reproducibility of Results</keyword></keywords><dates><year>2015</year></dates><isbn>1421-9786 (Electronic)
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ADDIN EN.CITE.DATA [4] PVS usually do not have a hyperintense rim on T2-weighted or FLAIR unless passing through a WMH area, which can help the discrimination between PVS and lacunes. Whether PVS should be regarded as ‘lesions’ is still controversial, as their clinical significance remains unclear. Although a few PVS can be normal, ADDIN EN.CITE <EndNote><Cite><Author>Groeschel</Author><Year>2006</Year><RecNum>66</RecNum><DisplayText>[50]</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465234555">66</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Groeschel, S.</author><author>Chong, W. K.</author><author>Surtees, R.</author><author>Hanefeld, F.</author></authors></contributors><auth-address>Department of Pediatrics and Child Neurology, Georg-August-University, Goettingen, Germany.</auth-address><titles><title>Virchow-Robin spaces on magnetic resonance images: normative data, their dilatation, and a review of the literature</title><secondary-title>Neuroradiology</secondary-title></titles><periodical><full-title>Neuroradiology</full-title></periodical><pages>745-54</pages><volume>48</volume><number>10</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Brain/*blood supply/*pathology/physiopathology</keyword><keyword>Brain Diseases/*pathology/physiopathology</keyword><keyword>Case-Control Studies</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Dilatation, Pathologic/pathology</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Microcirculation/physiology</keyword><keyword>Reference Values</keyword></keywords><dates><year>2006</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0028-3940 (Print)
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ADDIN EN.CITE.DATA [57] In CSVD, it might be a sign of impaired BBB. ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2009</Year><RecNum>73</RecNum><DisplayText>[39]</DisplayText><record><rec-number>73</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465553815">73</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw, J. M.</author><author>Doubal, F.</author><author>Armitage, P.</author><author>Chappell, F.</author><author>Carpenter, T.</author><author>Munoz Maniega, S.</author><author>Farrall, A.</author><author>Sudlow, C.</author><author>Dennis, M.</author><author>Dhillon, B.</author></authors></contributors><auth-address>University of Edinburgh, United Kingdom. joanna.wardlaw@ed.ac.uk</auth-address><titles><title>Lacunar stroke is associated with diffuse blood-brain barrier dysfunction</title><secondary-title>Ann Neurol</secondary-title></titles><periodical><full-title>Ann Neurol</full-title></periodical><pages>194-202</pages><volume>65</volume><number>2</number><keywords><keyword>Aged</keyword><keyword>Blood-Brain Barrier/pathology/*physiopathology</keyword><keyword>Brain Infarction/pathology/*physiopathology</keyword><keyword>Diffusion Magnetic Resonance Imaging/methods</keyword><keyword>Female</keyword><keyword>Gadolinium</keyword><keyword>Humans</keyword><keyword>Image Processing, Computer-Assisted/methods</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Retrospective Studies</keyword><keyword>Stroke/classification/pathology/physiopathology</keyword><keyword>Time Factors</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1531-8249 (Electronic)
0364-5134 (Linking)</isbn><accession-num>19260033</accession-num><urls><related-urls><url>;[39] There is also hypothesis that visible PVSs are associated with blockage of drainage of interstitial fluid (ISF) ADDIN EN.CITE <EndNote><Cite><Author>Weller</Author><Year>2009</Year><RecNum>76</RecNum><DisplayText>[58]</DisplayText><record><rec-number>76</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465555877">76</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weller, R. O.</author><author>Djuanda, E.</author><author>Yow, H. Y.</author><author>Carare, R. O.</author></authors></contributors><auth-address>Clinical Neurosciences, Southampton General Hospital, University of Southampton School of Medicine, LD74, South Lab and Path Block, Southampton, SO16 6YD, UK. row@soton.ac.uk</auth-address><titles><title>Lymphatic drainage of the brain and the pathophysiology of neurological disease</title><secondary-title>Acta Neuropathol</secondary-title></titles><periodical><full-title>Acta Neuropathol</full-title></periodical><pages>1-14</pages><volume>117</volume><number>1</number><keywords><keyword>Animals</keyword><keyword>Brain/metabolism/*physiopathology</keyword><keyword>Cerebral Arteries/metabolism/physiopathology</keyword><keyword>Cerebrospinal Fluid/metabolism</keyword><keyword>Extracellular Fluid/metabolism</keyword><keyword>Humans</keyword><keyword>Lymph/metabolism</keyword><keyword>Lymphatic System/metabolism/*physiopathology</keyword><keyword>Models, Biological</keyword><keyword>Nervous System Diseases/metabolism/*physiopathology</keyword></keywords><dates><year>2009</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1432-0533 (Electronic)
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ADDIN EN.CITE.DATA [60]CMBCMBs are regarded as small round and homogeneous foci of hypointensity on T2*-weighted (gradient echo) MRI and susceptibility-weighted imaging (SWI).(Figure 1) In the very few studies of radiological-pathological correlation, perivascular hemosiderin-laden macrophages were found underlying most of the CMBs shown on MRI. Other possible pathologies include old hematomas, intact erythrocytes, and very rarely vascular pseudocalcification, microaneurysm and distended dissected vessels. ADDIN EN.CITE <EndNote><Cite><Author>Shoamanesh</Author><Year>2011</Year><RecNum>80</RecNum><DisplayText>[61]</DisplayText><record><rec-number>80</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465982391">80</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shoamanesh, A.</author><author>Kwok, C. S.</author><author>Benavente, O.</author></authors></contributors><auth-address>Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, B.C., Canada. ashkan.sho@</auth-address><titles><title>Cerebral microbleeds: histopathological correlation of neuroimaging</title><secondary-title>Cerebrovasc Dis</secondary-title></titles><periodical><full-title>Cerebrovasc Dis</full-title></periodical><pages>528-34</pages><volume>32</volume><number>6</number><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain Neoplasms/complications</keyword><keyword>Cerebral Arteries/pathology</keyword><keyword>Cerebral Hemorrhage/etiology/*pathology</keyword><keyword>Cerebral Small Vessel Diseases/pathology</keyword><keyword>Cerebral Veins/pathology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cerebrovascular Disorders/pathology</keyword><keyword>Female</keyword><keyword>Hemosiderin/metabolism</keyword><keyword>Histocytochemistry</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neuroimaging</keyword></keywords><dates><year>2011</year></dates><isbn>1421-9786 (Electronic)
1015-9770 (Linking)</isbn><accession-num>22104448</accession-num><urls><related-urls><url>;[61] Lipofibrohyalinosis and amyloid angiopathy are the most common vascular findings in relation to CMB. These two vasculopathies are thought to have different patterns of CMBs distribution: CMBs in basal ganglia, thalamus, brainstem, and cerebellum are typically attributed to lipofibrohyalinosis; whereas amyloid angiopathy is more associated with lobar CMBs. ADDIN EN.CITE <EndNote><Cite><Author>Greenberg</Author><Year>2009</Year><RecNum>81</RecNum><DisplayText>[62]</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465985480">81</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Greenberg, S. M.</author><author>Vernooij, M. W.</author><author>Cordonnier, C.</author><author>Viswanathan, A.</author><author>Al-Shahi Salman, R.</author><author>Warach, S.</author><author>Launer, L. J.</author><author>Van Buchem, M. A.</author><author>Breteler, M. M.</author><author>Microbleed Study, Group</author></authors></contributors><auth-address>Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. sgreenberg@</auth-address><titles><title>Cerebral microbleeds: a guide to detection and interpretation</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title></periodical><pages>165-74</pages><volume>8</volume><number>2</number><keywords><keyword>Aged</keyword><keyword>Cerebral Hemorrhage/*diagnosis/epidemiology/pathology</keyword><keyword>Humans</keyword><keyword>Image Processing, Computer-Assisted</keyword><keyword>Magnetic Resonance Imaging</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1474-4422 (Print)
1474-4422 (Linking)</isbn><accession-num>19161908</accession-num><urls><related-urls><url>(09)70013-4</electronic-resource-num></record></Cite></EndNote>[62] However some studies suggest there may be more overlap and larger studies are awaited to confirm the specificity of CMB distribution for particular pathologies. Most CMBs are asymptomatic; they can be found in healthy adults but are more often a marker of vascular risk factor exposure or amyloid deposition. ADDIN EN.CITE <EndNote><Cite><Author>Cordonnier</Author><Year>2007</Year><RecNum>82</RecNum><DisplayText>[63]</DisplayText><record><rec-number>82</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465990156">82</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cordonnier, C.</author><author>Al-Shahi Salman, R.</author><author>Wardlaw, J.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. c-cordonnier@chru-lille.fr</auth-address><titles><title>Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>1988-2003</pages><volume>130</volume><number>Pt 8</number><keywords><keyword>Adult</keyword><keyword>Cerebral Hemorrhage/diagnosis/epidemiology/*etiology</keyword><keyword>Cerebrovascular Disorders/complications</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>Prognosis</keyword><keyword>Research Design/standards</keyword><keyword>Risk Factors</keyword><keyword>Stroke/complications</keyword></keywords><dates><year>2007</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1460-2156 (Electronic)
0006-8950 (Linking)</isbn><accession-num>17322562</accession-num><urls><related-urls><url>;[63] In addition to its potential association with stroke, CMBs also contribute to cognitive impairment and dementia, and to transient neurological deficits. ADDIN EN.CITE <EndNote><Cite><Author>Martinez-Ramirez</Author><Year>2014</Year><RecNum>83</RecNum><DisplayText>[64]</DisplayText><record><rec-number>83</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465998930">83</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martinez-Ramirez, S.</author><author>Greenberg, S. M.</author><author>Viswanathan, A.</author></authors></contributors><auth-address>Philip J. Kistler Stroke Research Center, Massachusetts General Hospital, 175 Cambridge Street Suite 300, Boston, MA 02114, USA.</auth-address><titles><title>Cerebral microbleeds: overview and implications in cognitive impairment</title><secondary-title>Alzheimers Res Ther</secondary-title></titles><periodical><full-title>Alzheimers Res Ther</full-title></periodical><pages>33</pages><volume>6</volume><number>3</number><dates><year>2014</year></dates><isbn>1758-9193 (Electronic)</isbn><accession-num>24987468</accession-num><urls><related-urls><url>;[64] The prevalence of CMBs detected in community-dwelling subjects in the Rotterdam Scan study (n=3979, mean age= 60.3 years) and AGES-Reykjavik study (n=1962, mean age=76 years) was 11.1-15.3%PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdmVpbmJqb3Juc2RvdHRpcjwvQXV0aG9yPjxZZWFyPjIw
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ADDIN EN.CITE.DATA [65, 66] and increased with age ADDIN EN.CITE <EndNote><Cite><Author>Poels</Author><Year>2010</Year><RecNum>79</RecNum><DisplayText>[66]</DisplayText><record><rec-number>79</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465982040">79</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Poels, M. M.</author><author>Vernooij, M. W.</author><author>Ikram, M. A.</author><author>Hofman, A.</author><author>Krestin, G. P.</author><author>van der Lugt, A.</author><author>Breteler, M. M.</author></authors></contributors><auth-address>Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.</auth-address><titles><title>Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>S103-6</pages><volume>41</volume><number>10 Suppl</number><keywords><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain/*blood supply/pathology</keyword><keyword>Cerebral Hemorrhage/*epidemiology/pathology</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prevalence</keyword><keyword>Risk</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2010</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>20876479</accession-num><urls><related-urls><url>;[66]. In patients with ischaemic stroke and non-traumatic intracerebral haemorrhage (ICH), the prevalence of CMBs could be as high as 33.5-67.5%. ADDIN EN.CITE <EndNote><Cite><Author>Cordonnier</Author><Year>2007</Year><RecNum>82</RecNum><DisplayText>[63]</DisplayText><record><rec-number>82</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1465990156">82</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cordonnier, C.</author><author>Al-Shahi Salman, R.</author><author>Wardlaw, J.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. c-cordonnier@chru-lille.fr</auth-address><titles><title>Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>1988-2003</pages><volume>130</volume><number>Pt 8</number><keywords><keyword>Adult</keyword><keyword>Cerebral Hemorrhage/diagnosis/epidemiology/*etiology</keyword><keyword>Cerebrovascular Disorders/complications</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>Prognosis</keyword><keyword>Research Design/standards</keyword><keyword>Risk Factors</keyword><keyword>Stroke/complications</keyword></keywords><dates><year>2007</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1460-2156 (Electronic)
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ADDIN EN.CITE.DATA [68] A recent study shows that vascular risk factors and large artery disease explained only 2% of the variance in WMH, leaving 98% of the variance unexplained, providing further evidence that WMH are mostly nonathromatous.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA [69] This finding may give a clue as to why risk factor modifications so far have very limited effects on preventing WMH progression. Other important risk factors for CSVD include other high risk lifestyles: lack of exercise, poor diet, and smoking. High salt intake is associated with more severe WMH, not only through causing high blood pressure but may also have direct effects on the endothelium. ADDIN EN.CITE <EndNote><Cite><Author>Ihara</Author><Year>2016</Year><RecNum>52</RecNum><DisplayText>[70]</DisplayText><record><rec-number>52</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463794644">52</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ihara, M.</author><author>Yamamoto, Y.</author></authors></contributors><auth-address>From the Departments of Stroke and Cerebrovascular Diseases (M.I.) and Regenerative Medicine and Tissue Engineering (M.I., Y.Y.), National Cerebral and Cardiovascular Center, Suita, Japan. ihara@ncvc.go.jp.
From the Departments of Stroke and Cerebrovascular Diseases (M.I.) and Regenerative Medicine and Tissue Engineering (M.I., Y.Y.), National Cerebral and Cardiovascular Center, Suita, Japan.</auth-address><titles><title>Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>554-60</pages><volume>47</volume><number>2</number><keywords><keyword>blood pressure</keyword><keyword>cerebral small vessel diseases</keyword><keyword>endothelium</keyword><keyword>hypertension</keyword><keyword>infection</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>26742799</accession-num><urls><related-urls><url>;[70] Current smoking is also an independent predictor of WMH progression ADDIN EN.CITE <EndNote><Cite><Author>van Dijk</Author><Year>2008</Year><RecNum>53</RecNum><DisplayText>[71]</DisplayText><record><rec-number>53</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463794724">53</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Dijk, E. J.</author><author>Prins, N. D.</author><author>Vrooman, H. A.</author><author>Hofman, A.</author><author>Koudstaal, P. J.</author><author>Breteler, M. M.</author></authors></contributors><auth-address>Department of Epidemiology &Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.</auth-address><titles><title>Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>2712-9</pages><volume>39</volume><number>10</number><keywords><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Blood Pressure/physiology</keyword><keyword>Brain/*blood supply/pathology</keyword><keyword>Brain Infarction/*complications/*pathology</keyword><keyword>Cognition Disorders/*etiology/*pathology/psychology</keyword><keyword>Disease Progression</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neuropsychological Tests</keyword><keyword>Risk Factors</keyword><keyword>Sex Factors</keyword><keyword>Smoking/adverse effects</keyword></keywords><dates><year>2008</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1524-4628 (Electronic)
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ADDIN EN.CITE.DATA [4] visible PVS were frequently seen in patients with lacunar stroke, WMH and lacunes; CMBs were also associated with WMH and lacunar stroke. ADDIN EN.CITE <EndNote><Cite><Author>Cordonnier</Author><Year>2007</Year><RecNum>56</RecNum><DisplayText>[63]</DisplayText><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463795018">56</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cordonnier, C.</author><author>Al-Shahi Salman, R.</author><author>Wardlaw, J.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. c-cordonnier@chru-lille.fr</auth-address><titles><title>Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title></periodical><pages>1988-2003</pages><volume>130</volume><number>Pt 8</number><keywords><keyword>Adult</keyword><keyword>Cerebral Hemorrhage/diagnosis/epidemiology/*etiology</keyword><keyword>Cerebrovascular Disorders/complications</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>Prognosis</keyword><keyword>Research Design/standards</keyword><keyword>Risk Factors</keyword><keyword>Stroke/complications</keyword></keywords><dates><year>2007</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1460-2156 (Electronic)
0006-8950 (Linking)</isbn><accession-num>17322562</accession-num><urls><related-urls><url>;[63] When counting the presence of any CSVD as total CSVD score, patients with lacunar stroke had significantly higher CSVD burden than those with cortical stroke.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFhbHM8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [78, 79] with little progression in punctuate WMH but rapid progression in confluent WMHs. ADDIN EN.CITE <EndNote><Cite><Author>Schmidt</Author><Year>2016</Year><RecNum>85</RecNum><DisplayText>[80]</DisplayText><record><rec-number>85</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1466520405">85</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schmidt, R.</author><author>Seiler, S.</author><author>Loitfelder, M.</author></authors></contributors><titles><title>Longitudinal change of small-vessel disease-related brain abnormalities</title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><pages>26-39</pages><volume>36</volume><number>1</number><keywords><keyword>Brain/*blood supply/pathology</keyword><keyword>Cerebral Hemorrhage/pathology</keyword><keyword>Cerebral Small Vessel Diseases/*pathology</keyword><keyword>Dementia, Vascular/pathology</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Microvessels/*pathology</keyword><keyword>Stroke, Lacunar/pathology</keyword><keyword>Time Factors</keyword><keyword>White Matter/blood supply/pathology</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1559-7016 (Electronic)
0271-678X (Linking)</isbn><accession-num>25899293</accession-num><urls><related-urls><url>;[80] The Austrian Stroke Prevention Study, a community-based study, reported WMH progression in about 18% of subjects with vascular risk factors. ADDIN EN.CITE <EndNote><Cite><Author>Schmidt</Author><Year>2003</Year><RecNum>40</RecNum><DisplayText>[78]</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463792415">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schmidt, R.</author><author>Enzinger, C.</author><author>Ropele, S.</author><author>Schmidt, H.</author><author>Fazekas, F.</author><author>Austrian Stroke Prevention, Study</author></authors></contributors><auth-address>Department of Neurology, Karl-Franzens University Graz, A-8036, Graz, Austria. reinhold.schmidt@kfunigraz.ac.at</auth-address><titles><title>Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>2046-8</pages><volume>361</volume><number>9374</number><keywords><keyword>Aged</keyword><keyword>Aging/*pathology</keyword><keyword>Brain/*pathology</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2003</year><pub-dates><date>Jun 14</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>12814718</accession-num><urls><related-urls><url>;[78] WMH can also cavitate to take on the appearance of lacunes and they can also disappear – these dynamic features are only now being realised. Though early microstructural impairment could be detected in NAWM contouring WMH, not all NAWM will eventually develop into WMH. ADDIN EN.CITE <EndNote><Cite><Author>Munoz Maniega</Author><Year>Published online first: 1 March 2016 </Year><RecNum>92</RecNum><DisplayText>[81]</DisplayText><record><rec-number>92</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1468401740">92</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Munoz Maniega, S.</author><author>Chappell, F. M.</author><author>Valdes Hernandez, M. C.</author><author>Armitage, P. A.</author><author>Makin, S. D.</author><author>Heye, A. K.</author><author>Thrippleton, M. J.</author><author>Sakka, E.</author><author>Shuler, K.</author><author>Dennis, M. S.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK joanna.wardlaw@ed.ac.uk.</auth-address><titles><title>Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease</title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><volume>DOI: 10.1177/0271678X16635657.</volume><keywords><keyword>Magnetic resonance imaging</keyword><keyword>ageing</keyword><keyword>blood-brain barrier</keyword><keyword>cerebrovascular disease</keyword><keyword>diffusion tensor imaging</keyword></keywords><dates><year>Published online first: 1 March 2016 </year><pub-dates><date>Mar 1</date></pub-dates></dates><isbn>1559-7016 (Electronic)
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ADDIN EN.CITE.DATA [82] Treatments for CSVDManagement of traditional risk factors is still the main approach for treating or preventing CSVD, despite the fact that most of these treatments have not yet shown ideal effects on long-term outcome. Antihypertensive treatment produced contradicting results: it reduced WMH progression in some observational studies ADDIN EN.CITE <EndNote><Cite><Author>Dufouil</Author><Year>2001</Year><RecNum>46</RecNum><DisplayText>[83]</DisplayText><record><rec-number>46</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463793426">46</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dufouil, C.</author><author>de Kersaint-Gilly, A.</author><author>Besancon, V.</author><author>Levy, C.</author><author>Auffray, E.</author><author>Brunnereau, L.</author><author>Alperovitch, A.</author><author>Tzourio, C.</author></authors></contributors><auth-address>Institut National de la Sante et de la Recherche Medicale U360, Hopital la Salpetriere, Paris, France. carole.dufouil@chups.jussieu.fr</auth-address><titles><title>Longitudinal study of blood pressure and white matter hyperintensities: the EVA MRI Cohort</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>921-6</pages><volume>56</volume><number>7</number><keywords><keyword>Aged</keyword><keyword>Blood Pressure/*physiology</keyword><keyword>Brain/*pathology/physiopathology</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Hypertension/*pathology/*physiopathology</keyword><keyword>Longitudinal Studies</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr 10</date></pub-dates></dates><isbn>0028-3878 (Print)
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ADDIN EN.CITE.DATA [84, 85]. Although hypertension has been reported highly associated with CSVD, other factors may be involved, or be influenced by genetic factors,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdXJuZXI8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS
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AG==
ADDIN EN.CITE.DATA [86] yet more evidences are required. Likewise, most lipid-lowering treatment had neutral results in preventing WMH, like pravastatin.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj50ZW4gRGFtPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48
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ADDIN EN.CITE.DATA [88] Statins might also have other therapeutic effects including anti-inflammatory and pro-endothelial activities. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>58</RecNum><DisplayText>[89]</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463795253">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, P. M.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>469-78</pages><volume>10</volume><number>4</number><keywords><keyword>Cerebral Small Vessel Diseases/*drug therapy/physiopathology</keyword><keyword>Humans</keyword><keyword>antithrombotics</keyword><keyword>blood brain barrier</keyword><keyword>blood pressure lowering</keyword><keyword>cyclic nucleotide inhibitors</keyword><keyword>nitric oxide</keyword><keyword>prostacyclin</keyword></keywords><dates><year>2015</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1747-4949 (Electronic)
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ADDIN EN.CITE.DATA [90] Studies of treatment specifically targeting lacunar stroke are limited. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>58</RecNum><DisplayText>[89]</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463795253">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, P. M.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>469-78</pages><volume>10</volume><number>4</number><keywords><keyword>Cerebral Small Vessel Diseases/*drug therapy/physiopathology</keyword><keyword>Humans</keyword><keyword>antithrombotics</keyword><keyword>blood brain barrier</keyword><keyword>blood pressure lowering</keyword><keyword>cyclic nucleotide inhibitors</keyword><keyword>nitric oxide</keyword><keyword>prostacyclin</keyword></keywords><dates><year>2015</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1747-4949 (Electronic)
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ADDIN EN.CITE.DATA [91, 92] which has weak antiplatelet effects ADDIN EN.CITE <EndNote><Cite><Author>Comerota</Author><Year>2005</Year><RecNum>114</RecNum><DisplayText>[93]</DisplayText><record><rec-number>114</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1472744210">114</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Comerota, A. J.</author></authors></contributors><auth-address>Jobst Vascular Center, Conrad Jobst Tower, Suite 400, 2109 Hughes Drive, Toledo, OH 43606, USA. acomerota@</auth-address><titles><title>Effect on platelet function of cilostazol, clopidogrel, and aspirin, each alone or in combination</title><secondary-title>Atheroscler Suppl</secondary-title></titles><periodical><full-title>Atheroscler Suppl</full-title></periodical><pages>13-9</pages><volume>6</volume><number>4</number><keywords><keyword>Aspirin/*pharmacology</keyword><keyword>Bleeding Time</keyword><keyword>Blood Platelets/*drug effects/physiology</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Humans</keyword><keyword>Intermittent Claudication/blood/drug therapy</keyword><keyword>Platelet Aggregation/drug effects</keyword><keyword>Platelet Aggregation Inhibitors/*pharmacology</keyword><keyword>Tetrazoles/*pharmacology</keyword><keyword>Ticlopidine/*analogs & derivatives/pharmacology</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2005</year><pub-dates><date>Dec 15</date></pub-dates></dates><isbn>1567-5688 (Print)
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ADDIN EN.CITE.DATA [94] but the SPS3 trial showed that long-term dual antiplatelet treatment doubled the risk of bleeding without reducing the risk of stroke recurrence in patients with recent lacunar stroke. Also, blood pressure lowering did not show significant reduction in recurrent lacunar stroke in the SPS3 trial although it was consistent with a modest benefit. ADDIN EN.CITE <EndNote><Cite><Author>Group</Author><Year>2013</Year><RecNum>29</RecNum><DisplayText>[95]</DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463790362">29</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>S. P. S. Study Group</author><author>Benavente, O. R.</author><author>Coffey, C. S.</author><author>Conwit, R.</author><author>Hart, R. G.</author><author>McClure, L. A.</author><author>Pearce, L. A.</author><author>Pergola, P. E.</author><author>Szychowski, J. M.</author></authors></contributors><titles><title>Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>507-15</pages><volume>382</volume><number>9891</number><keywords><keyword>Antihypertensive Agents/*therapeutic use</keyword><keyword>Blood Pressure/drug effects</keyword><keyword>Cerebral Hemorrhage/prevention & control</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hypertension/physiopathology/*prevention & control</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Secondary Prevention</keyword><keyword>Stroke, Lacunar/physiopathology/*prevention & control</keyword><keyword>Systole</keyword><keyword>Time-to-Treatment</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug 10</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>23726159</accession-num><urls><related-urls><url>(13)60852-1</electronic-resource-num></record></Cite></EndNote>[95] Prevention and treatment of CSVD in the future should consider targeting the BBB, brain endothelium and microvascular function. There are multiple potential endothelial targets, such as nitric oxide/cyclic guanylate monophosphate (cGMP) system and prostacyclin/cyclic adenosine monophosphate (cAMP) system. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>58</RecNum><DisplayText>[89]</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463795253">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, P. M.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>469-78</pages><volume>10</volume><number>4</number><keywords><keyword>Cerebral Small Vessel Diseases/*drug therapy/physiopathology</keyword><keyword>Humans</keyword><keyword>antithrombotics</keyword><keyword>blood brain barrier</keyword><keyword>blood pressure lowering</keyword><keyword>cyclic nucleotide inhibitors</keyword><keyword>nitric oxide</keyword><keyword>prostacyclin</keyword></keywords><dates><year>2015</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1747-4949 (Electronic)
1747-4930 (Linking)</isbn><accession-num>25727737</accession-num><urls><related-urls><url>;[89] Therefore interventions that could induce cAMP or cGMP or reduce their degradation appear promising. There are several licensed drugs that have these properties like some nitric oxide donors and phosphodiesterases-5 inhibitors, ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>58</RecNum><DisplayText>[89]</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="p2250d9x4w0wxretxs3pz0x6rzvwvwaxzddx" timestamp="1463795253">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, P. M.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions</title><secondary-title>Int J Stroke</secondary-title></titles><periodical><full-title>Int J Stroke</full-title></periodical><pages>469-78</pages><volume>10</volume><number>4</number><keywords><keyword>Cerebral Small Vessel Diseases/*drug therapy/physiopathology</keyword><keyword>Humans</keyword><keyword>antithrombotics</keyword><keyword>blood brain barrier</keyword><keyword>blood pressure lowering</keyword><keyword>cyclic nucleotide inhibitors</keyword><keyword>nitric oxide</keyword><keyword>prostacyclin</keyword></keywords><dates><year>2015</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1747-4949 (Electronic)
1747-4930 (Linking)</isbn><accession-num>25727737</accession-num><urls><related-urls><url>;[89] while the others are still in development. More experimental studies should be encouraged. But meantime, management of these traditional risk factors according to guidelines should still be encouraged except to avoid long-term dual antiplatelet drugs.In conclusion, CSVD is not just a collection of individual brain lesions, but is both a ‘dynamic’ and ‘whole-brain’ disease. All CSVD subtypes might share some common intrinsic CSVD aetiologies. Some pathological changes at the early stage of the disease could be reversible, but will gradually worsen and become irreversible as the damage in vessels and tissues accumulates. Modification of traditional risk factors and a healthy lifestyle are currently the most important prophylactic and therapeutic approaches for CSVD indefinitely and until more specific treatments are available. Apart from the trials of cilostazol which have mostly been conducted in China or Japan, in general, large clinical trials of CSVD treatments targeting the Asian population are lacking, especially in lacunar stroke. Community-based studies of CSVD prevalence and progression are also needed to determine if prevalence genuinely differs in different world regions or ethnic groups. Future studies in CSVDs should stratify by stroke subtype and by MR imaging diagnosis and measure risk factors carefully. Clinical trials and experimental studies targeting endothelium and BBB integrity should be pursued. CONTRIBUTORSThis paper is based on a lecture given by J.M.W. at the Chinese Stroke Association Inaugural Conference in 2015, Beijing. Y.S. drafted the review which was then amended and approved by J.M.W.. FUNDINGY.S. is supported by China Scholarships Council. 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ADDIN EN.CITE.DATA [4] DWI: diffusion-weighted imaging; FLAIR: fluid-attenuated inversion recovery; SWI: susceptibility-weighted imaging; GRE: gradient-recalled echo.Figure 2. Four possible mechanisms that cause a lacunar infarct (from bottom to top): (a) An embolus from the big arteries or cardiac sources goes up to middle cerebral arteries (MCA) and ends up entering and occluding lenticulostriate arteries, resulting in a lacunar lesion in basal ganglia; (b) if the atheroma in the parent artery (i.e. MCA) is positioned at the opening of its penetrating branches, it could lead to an acute occlusion of one or several penetrating arteries hence causing a lacunar infarct; (c) a lacunar infarct could also be due to atheroma in the perforating artery if an acute occlusion happens; (d) intrinsic small vessel disease may lead to diffused disrupted blood brain barrier. If this happens at arteriolar level, plasma fluid components would enter and deposit in the vessel wall, resulting in narrowing of the arteriolar lumen, vessel wall thickening and eventually a secondary luminal occlusion and traditional infarct.Figure 3. Example of MR images of a lacune from a haemorrhagic source (A and B), and from a lacunar infarct (C and D). FLAIR: Fluid-attenuated inversion recovery; SWI: Susceptibility-weighted imaging; DWI: Diffusion-weighted imaging. Figure 4. Long-term appearances of lacunar infarcts (arrows: old stroke lesion on the follow-up scans). ................
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