Consensus statement for diagnosis of subcortical small ...
Consensus statement for diagnosis of subcortical small vessel disease1Gary A. Rosenberg, 2Anders Wallin, 3Joanna Wardlaw, 4Hugh S. Markus, 5Joan Montaner, 6Leslie Wolfson, 7Costantino Iadecola, 8Berislav V. Zlokovic, 9Anne Joutel, 10Martin Dichgans, 11Marco Duering, 11Reinhold Schmidt, 12Amos Koczyn, 13Lea T. Grinberg, 14Helena C. Chui, 15Vladimir Hachinski1Department of Neurology, University of New Mexico, Albuquerque, NM, 2Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Sweden, 3Centre for Clinical Brain Sciences, University of Edinburgh, UK, 4Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK, 5Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain, 6Department of Neurology, University of Connecticut Health Center, Farmington, CT, 7Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 8Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los?Angeles, CA, 9INSERM, U1161, Paris, France, 10Institute for Stroke and Dementia Research, Klinikum der Universit?t München, Munich, Germany, 11 Department of Neurology, Medical University of Graz, Graz, Austria, 12Tel-Aviv University Medical School, Ramat Aviv, Israel 13Department of Neurology, Memory and Aging Center and Department of Pathology, University of California, San Francisco, CA, and University of Sao Paulo Medical School, Sao Paulo, Brazil, 14Department of Neurology, University of Southern California Medical School, Los Angeles, CA 15Department of Clinical Neurological Sciences, University Hospital, University of Western Ontario, London, ONRunning Title: Consensus statement for SVDAddress correspondence to:Gary A. Rosenberg, MDDepartment of NeurologyUniversity of New Mexico Health Sciences CenterAlbuquerque, NM 87131Email: grosenberg@salud.unm.eduTel: (505) 272-3315Abstract: 144 words; Text: 6,690 words; References: 154; Tables: 4; Figures 6 (5 in color) AbstractVascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as Binswanger’s disease (BD), constitute a spectrum from pure vascular disease to a mixture with neurodegenerative changes. BD patients are a relatively homogeneous subgroup with hypoxic hypoperfusion, lacunar infarcts and inflammation that act synergistically to disrupt the blood-brain barrier (BBB) and break down myelin. Identification of this subgroup can be facilitated by multimodal disease markers obtained from clinical, cerebrospinal fluid (CSF), neuropsychological, and imaging studies. This consensus statement identifies a potential set of biomarkers based on underlying pathological changes that could facilitate diagnosis and aid patient selection for future collaborative treatment trials.Keywords: Binswanger’s disease, vascular cognitive impairment, mixed dementia, blood-brain barrier permeability, MRI, leukoaraiosis, cerebrospinal fluid, inflammationIntroductionVascular cognitive impairment (VCI) refers to cognitive alterations caused by vascular disease.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWNoaW5za2k8L0F1dGhvcj48WWVhcj4xOTkzPC9ZZWFy
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ADDIN EN.CITE.DATA 1, 2 The aging of the populations worldwide and the increase in vascular disease with age has led to projections of major growth in the numbers of patients with VCI over the next 30 years. ADDIN EN.CITE <EndNote><Cite><Author>Gorelick</Author><Year>2011</Year><RecNum>20085</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>20085</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1317413532">20085</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gorelick, P. B.</author><author>Scuteri, A.</author><author>Black, S. E.</author><author>Decarli, C.</author><author>Greenberg, S. M.</author><author>Iadecola, C.</author><author>Launer, L. J.</author><author>Laurent, S.</author><author>Lopez, O. L.</author><author>Nyenhuis, D.</author><author>Petersen, R. C.</author><author>Schneider, J. A.</author><author>Tzourio, C.</author><author>Arnett, D. K.</author><author>Bennett, D. A.</author><author>Chui, H. C.</author><author>Higashida, R. T.</author><author>Lindquist, R.</author><author>Nilsson, P. M.</author><author>Roman, G. C.</author><author>Sellke, F. W.</author><author>Seshadri, S.</author></authors></contributors><titles><title>Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title><abbr-1>Stroke; a journal of cerebral circulation</abbr-1></periodical><pages>2672-2713</pages><volume>42</volume><number>9</number><edition>2011/07/23</edition><dates><year>2011</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>21778438</accession-num><urls><related-urls><url> [pii]
10.1161/STR.0b013e3182299496</electronic-resource-num><language>Eng</language></record></Cite></EndNote>2 However, in spite of its growing importance, very few specific treatments, apart from treatments for stroke, have been tested in VCI. In addition, there is increased awareness of the role played by vascular disease and neuroinflammation in accelerating the course of Alzheimer’s disease (AD),PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tbm93ZG9uPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48
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ADDIN EN.CITE.DATA 7-9 Several factors have impeded progress in organizing treatment trials in VCI, including heterogeneity of clinical presentations, and lack of pathological consensus, making identification of homogeneous subpopulations of VCI patients a critical unmet need. ADDIN EN.CITE <EndNote><Cite><Author>Grinberg</Author><Year>2010</Year><RecNum>24431</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>24431</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1422745150">24431</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grinberg, L. T.</author><author>Heinsen, H.</author></authors></contributors><auth-address>Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 941143, USA. lea.grinberg@ucsf.edu</auth-address><titles><title>Toward a pathological definition of vascular dementia</title><secondary-title>J Neurol Sci</secondary-title><alt-title>Journal of the neurological sciences</alt-title></titles><periodical><full-title>J Neurol Sci</full-title><abbr-1>Journal of the neurological sciences</abbr-1></periodical><alt-periodical><full-title>J Neurol Sci</full-title><abbr-1>Journal of the neurological sciences</abbr-1></alt-periodical><pages>136-8</pages><volume>299</volume><number>1-2</number><edition>2010/10/06</edition><keywords><keyword>Aging/pathology</keyword><keyword>Blood Vessels/*pathology</keyword><keyword>Brain/*pathology</keyword><keyword>Cognition Disorders/etiology/pathology</keyword><keyword>Dementia, Vascular/etiology/*pathology</keyword><keyword>Humans</keyword></keywords><dates><year>2010</year><pub-dates><date>Dec 15</date></pub-dates></dates><isbn>1878-5883 (Electronic)
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ADDIN EN.CITE.DATA 11, 12 Large vessel strokes result in a sporadic pattern of brain damage, making it difficult to predict the natural history. On the contrary, damage to small vessels, involving the subcortical white and gray matter nuclei often follows a progressive course with gradual changes over several years, providing information on the natural history, which can be used in treatment trials.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2htaWR0PC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48
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ADDIN EN.CITE.DATA 13-15 Since changes in the subcortical and periventricular white matter accrue over time in the elderly, the deep white matter is a common site for ischemic and inflammatory injury. Patients with subcortical lesions have been separated from the larger group of VCI patients and referred to as subcortical small vessel disease (SVD). The challenge is to identify patients with similar underlying pathological processes at an early stage through the use of disease markers derived from clinical, imaging and biochemical studies in order to establish a relatively homogeneous population to test treatments developed in animal models. This special issue is a consensus statement for treatment guidelines in patients with progressive SVD of the white matter. Historical PerspectiveIn the early 1900s, clinical/pathology studies by Otto Binswanger, Oskar Fischer and Alois Alzheimer separated arteriosclerotic dementia with multiple lacunar strokes, état criblé, dilated perivascular spaces, and cortical and periventricular white matter atrophy from neurodegeneration with senile plaques. ADDIN EN.CITE <EndNote><Cite><Author>Roman</Author><Year>2002</Year><RecNum>23908</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>23908</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1421522313">23908</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Roman, G. C.</author></authors></contributors><auth-address>University of Texas Health Science Center at San Antonio, Tex 78229, USA. romang@uthscsa.edu</auth-address><titles><title>On the history of lacunes, etat crible, and the white matter lesions of vascular dementia</title><secondary-title>Cerebrovasc Dis</secondary-title><alt-title>Cerebrovascular diseases</alt-title></titles><periodical><full-title>Cerebrovasc Dis</full-title><abbr-1>Cerebrovascular diseases (Basel, Switzerland)</abbr-1></periodical><pages>1-6</pages><volume>13 Suppl 2</volume><edition>2002/03/20</edition><keywords><keyword>Aged</keyword><keyword>Brain/*pathology</keyword><keyword>Dementia, Multi-Infarct/*history/pathology</keyword><keyword>Dementia, Vascular/*history/pathology</keyword><keyword>History, 17th Century</keyword><keyword>History, 18th Century</keyword><keyword>History, 19th Century</keyword><keyword>History, 20th Century</keyword><keyword>Humans</keyword></keywords><dates><year>2002</year></dates><isbn>1015-9770 (Print)
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ADDIN EN.CITE.DATA 21, 22 Currently, there is general agreement about the diagnosis of VCI in patients with large vessel strokes either due to thrombosis or embolism, which can be readily seen on neuroimaging. ADDIN EN.CITE <EndNote><Cite><Author>Gorelick</Author><Year>2011</Year><RecNum>20085</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>20085</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1317413532">20085</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gorelick, P. B.</author><author>Scuteri, A.</author><author>Black, S. E.</author><author>Decarli, C.</author><author>Greenberg, S. M.</author><author>Iadecola, C.</author><author>Launer, L. J.</author><author>Laurent, S.</author><author>Lopez, O. L.</author><author>Nyenhuis, D.</author><author>Petersen, R. C.</author><author>Schneider, J. A.</author><author>Tzourio, C.</author><author>Arnett, D. K.</author><author>Bennett, D. A.</author><author>Chui, H. C.</author><author>Higashida, R. T.</author><author>Lindquist, R.</author><author>Nilsson, P. M.</author><author>Roman, G. C.</author><author>Sellke, F. W.</author><author>Seshadri, S.</author></authors></contributors><titles><title>Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title><abbr-1>Stroke; a journal of cerebral circulation</abbr-1></periodical><pages>2672-2713</pages><volume>42</volume><number>9</number><edition>2011/07/23</edition><dates><year>2011</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>21778438</accession-num><urls><related-urls><url> [pii]
10.1161/STR.0b013e3182299496</electronic-resource-num><language>Eng</language></record></Cite></EndNote>2 Some of these multi-infarct patients show a cognitive decline with each stroke. ADDIN EN.CITE <EndNote><Cite><Author>Tatemichi</Author><Year>1993</Year><RecNum>1937</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>1937</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">1937</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tatemichi, T. K.</author><author>Desmond, D. W.</author><author>Paik, M.</author><author>Figueroa, M.</author><author>Gropen, T. I.</author><author>Stern, Y.</author><author>Sano, M.</author><author>Remien, R.</author><author>Williams, J. B.</author><author>Mohr, J. P.</author><author>et al.,</author></authors></contributors><titles><title>Clinical determinants of dementia related to stroke</title><secondary-title>Ann.Neurol.</secondary-title></titles><pages>568-575</pages><volume>33</volume><keywords><keyword>dementia</keyword><keyword>stroke</keyword><keyword>history</keyword><keyword>diabetes mellitus</keyword><keyword>HYPERTENSION</keyword><keyword>INFARCTION</keyword><keyword>LATERALITY</keyword><keyword>CEREBRAL ARTERIES</keyword><keyword>ARTERIES</keyword><keyword>syndrome</keyword><keyword>RISK</keyword><keyword>RISK FACTORS</keyword><keyword>CEREBROVASCULAR DISORDERS</keyword><keyword>AGE FACTORS</keyword><keyword>AGED</keyword><keyword>AGED 80 AND OVER</keyword><keyword>COMPARATIVE STUDY</keyword><keyword>EDUCATION</keyword><keyword>FEMALE</keyword><keyword>HUMAN</keyword><keyword>MALE</keyword><keyword>MIDDLE AGE</keyword><keyword>ODDS RATIO</keyword><keyword>RACIAL STOCKS</keyword><keyword>regression analysis</keyword><keyword>SUPPORT U S GOVT P H S</keyword><keyword>TIME FACTORS</keyword></keywords><dates><year>1993</year></dates><accession-num>1291</accession-num><urls></urls></record></Cite></EndNote>23, PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbGlwZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 24 On the other hand, diagnosis of vascular dementia due to SVD was more controversial because of the frequent occurrence of white matter changes in normal elderly, the high incidence of overlap with other neurodegenerative disorders, and the lack of consensus on the use of clinical, CSF, neuroimaging and neuropathological findings in the diagnosis. ADDIN EN.CITE <EndNote><Cite><Author>Grinberg</Author><Year>2010</Year><RecNum>24431</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>24431</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1422745150">24431</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grinberg, L. T.</author><author>Heinsen, H.</author></authors></contributors><auth-address>Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 941143, USA. lea.grinberg@ucsf.edu</auth-address><titles><title>Toward a pathological definition of vascular dementia</title><secondary-title>J Neurol Sci</secondary-title><alt-title>Journal of the neurological sciences</alt-title></titles><periodical><full-title>J Neurol Sci</full-title><abbr-1>Journal of the neurological sciences</abbr-1></periodical><alt-periodical><full-title>J Neurol Sci</full-title><abbr-1>Journal of the neurological sciences</abbr-1></alt-periodical><pages>136-8</pages><volume>299</volume><number>1-2</number><edition>2010/10/06</edition><keywords><keyword>Aging/pathology</keyword><keyword>Blood Vessels/*pathology</keyword><keyword>Brain/*pathology</keyword><keyword>Cognition Disorders/etiology/pathology</keyword><keyword>Dementia, Vascular/etiology/*pathology</keyword><keyword>Humans</keyword></keywords><dates><year>2010</year><pub-dates><date>Dec 15</date></pub-dates></dates><isbn>1878-5883 (Electronic)
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ADDIN EN.CITE.DATA 1, 25 Large vessel strokes involve the cortex and deep white matter with multiple etiologies, while SVD occurs mainly secondary to vascular risk factors, including hypertension, diabetes, hyperlipidemia, obesity, smoking, sleep apnea, and hereditary blood vessel diseases, resulting in activation of endothelial cells with thrombosis and inflammation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWxsZW5iZWNrPC9BdXRob3I+PFllYXI+MjAxMDwvWWVh
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ADDIN EN.CITE.DATA 26 SVD includes both lacunar infarcts in the basal ganglia and thalamus as well as white matter damage. Occasionally single lacunar infarcts in strategic locations, particularly the thalamus, can result in cognitive impairment, but more generally multiple basal ganglia lacunes result in cognitive impairment.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GaXNoZXI8L0F1dGhvcj48WWVhcj4xOTgyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 29, 30Multi-infarct Dementia (MID)Atherosclerosis of the carotids, vertebral and major intracranial arteries mainly cause large vessel strokes. Emboli from the heart, particularly with atrial fibrillation and from the atherosclerotic aortic arch and carotid generally lead to large strokes, but on occasion showers of small emboli can occur. Initial attempts to standardize diagnostic criteria for MID required the temporal relationship of the stroke to the decline in cognition, which failed to occur in many patients with a progressive course, which more closely resembled neurodegeneration. ADDIN EN.CITE <EndNote><Cite><Author>Chui</Author><Year>1992</Year><RecNum>2111</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>2111</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">2111</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chui, H. C.</author><author>Victoroff, J. I.</author><author>Margolin, D.</author><author>Jagust, W.</author><author>Shankle, R.</author><author>Katzman, R.</author></authors></contributors><titles><title>Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer's Disease Diagnostic and Treatment Centers</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title><abbr-1>Neurology</abbr-1></periodical><pages>473-480</pages><volume>42</volume><keywords><keyword>vascular dementia</keyword><keyword>dementia</keyword><keyword>incidence</keyword><keyword>stroke</keyword><keyword>cerebral ischemia</keyword><keyword>DEMENTIA VASCULAR</keyword><keyword>CEREBROVASCULAR DISORDERS</keyword><keyword>cognition disorders</keyword><keyword>HUMAN</keyword><keyword>SUPPORT NON U S GOVT</keyword><keyword>SUPPORT U S GOVT NON P H S</keyword><keyword>SUPPORT U S GOVT P H S</keyword></keywords><dates><year>1992</year></dates><accession-num>1253</accession-num><urls></urls></record></Cite></EndNote>21, ADDIN EN.CITE <EndNote><Cite><Author>Roman</Author><Year>1993</Year><RecNum>1938</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>1938</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">1938</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Roman, G. C.</author><author>Tatemichi, T. K.</author><author>Erkinjuntti, T.</author><author>Cummings, J. L.</author><author>Masdeu, J. C.</author><author>Garcia, J. H.</author><author>Amaducci, L.</author><author>Orgogozo, J. M.</author><author>Brun, A.</author><author>Hofman, A.</author><author>et al.,</author></authors></contributors><titles><title>Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop [see comments]</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title><abbr-1>Neurology</abbr-1></periodical><pages>250-260</pages><volume>43</volume><keywords><keyword>vascular dementia</keyword><keyword>dementia</keyword><keyword>stroke</keyword><keyword>syndrome</keyword><keyword>GAIT</keyword><keyword>BRAIN</keyword><keyword>DEMENTIA VASCULAR</keyword><keyword>FEMALE</keyword><keyword>HUMAN</keyword><keyword>INTERNATIONAL COOPERATION</keyword><keyword>MAGNETIC RESONANCE IMAGING</keyword><keyword>MALE</keyword><keyword>NATIONAL INSTITUTES OF HEALTH U S</keyword><keyword>neuropsychological tests</keyword><keyword>TOMOGRAPHY X RAY COMPUTED</keyword><keyword>UNITED STATES</keyword></keywords><dates><year>1993</year></dates><accession-num>1292</accession-num><urls></urls></record></Cite></EndNote>22 Although temporal relationship between the infarct and the loss of cognitive function was considered critical for diagnosis, it was soon realized that many patients with vascular causes of dementia had a progressive course that overlapped in the early stages with AD, while MRI showed that many of these patients had abnormal signal in the white matter, suggesting possible cerebrovascular disease.Subcortical small vessel disease (SVD)SVD is a broad term that includes lesions in subcortical gray and white matter. Small strokes produce lacunes, which can be seen in the basal ganglia and deep white matter. Isolated infarcts in the basal ganglia and thalamus cause stroke-like events with an unpredictable course, and have been classified in the multiple stroke category. Diffuse white matter lesions, which may have a different pathophysiology, tend to enlarge over time, making it possible to determine a natural history that could potentially be altered by treatment. Lacunes are often present along with extensive white matter changes, which are often the case in hypertensive SVD.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GaXNoZXI8L0F1dGhvcj48WWVhcj4xOTgyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 32 Microinfarcts in the cortex, which are being identified with pathological studies and 7T MRI, are associated with acceleration of AD, but their role in white matter pathology remains to be established. ADDIN EN.CITE <EndNote><Cite><Author>Smith</Author><Year>2012</Year><RecNum>24446</RecNum><DisplayText><style face="superscript">33</style></DisplayText><record><rec-number>24446</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1423796128">24446</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smith, E. E.</author><author>Schneider, J. A.</author><author>Wardlaw, J. M.</author><author>Greenberg, S. M.</author></authors></contributors><auth-address>Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.</auth-address><titles><title>Cerebral microinfarcts: the invisible lesions</title><secondary-title>Lancet Neurol</secondary-title><alt-title>The Lancet. Neurology</alt-title></titles><periodical><full-title>Lancet Neurol</full-title><abbr-1>Lancet neurology</abbr-1></periodical><pages>272-82</pages><volume>11</volume><number>3</number><edition>2012/02/22</edition><keywords><keyword>Brain/*pathology</keyword><keyword>Brain Infarction/complications/*pathology</keyword><keyword>Cognition Disorders/etiology/*pathology</keyword><keyword>Humans</keyword><keyword>Nerve Fibers, Myelinated/pathology</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1474-4465 (Electronic)
1474-4422 (Linking)</isbn><accession-num>22341035</accession-num><work-type>Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review</work-type><urls><related-urls><url>(11)70307-6</electronic-resource-num></record></Cite></EndNote>33 Many of the patients with sleep apnea have cognitive impairment, but the relationship of sleep apnea to WMHs needs further study.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYWZmZTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 34Binswanger’s disease (BD) Binswanger’s disease (BD) prior to CT and MRI was an infrequent pathological diagnosis that was made when there was extensive demyelination associated with arteriolosclerosis of deep white matter vessels. ADDIN EN.CITE <EndNote><Cite><Author>Olszewski</Author><Year>1962</Year><RecNum>3509</RecNum><DisplayText><style face="superscript">35, 36</style></DisplayText><record><rec-number>3509</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">3509</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Olszewski, J.</author></authors></contributors><titles><title>Subcortical arteriosclerotic encephalopathy: review of the literature on the so-called Binswanger's disease and presentation of 2 cases</title><secondary-title>World Neurology</secondary-title></titles><pages>359-375</pages><volume>3</volume><dates><year>1962</year></dates><accession-num>772</accession-num><urls></urls></record></Cite><Cite><Author>Feigin</Author><Year>1963</Year><RecNum>3503</RecNum><record><rec-number>3503</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">3503</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Feigin, I.</author><author>Popoff, N.</author></authors></contributors><titles><title>Neuropathological changes late in cerebral edema: The relationship to trauma, hypertensive disease and Binswanger's encephalopathy</title><secondary-title>J Neuropathol Exp Neurol.</secondary-title></titles><pages>500-511</pages><volume>22</volume><keywords><keyword>binswanger</keyword><keyword>BRAIN DISEASES</keyword><keyword>BRAIN INJURIES</keyword><keyword>cerebral edema</keyword><keyword>Disease</keyword><keyword>EDEMA</keyword><keyword>encephalopathy</keyword><keyword>HYPERTENSION</keyword><keyword>INTRACRANIAL PRESSURE</keyword><keyword>Neurologic Manifestations</keyword></keywords><dates><year>1963</year><pub-dates><date>07</date></pub-dates></dates><accession-num>3775</accession-num><urls></urls></record></Cite></EndNote>35, 36 Diagnosis prior to death is now possible from clinical, imaging and biochemical features; the typical patient with BD has an insidious onset suggestive of small strokes and clinical findings of executive dysfunction on neuropsychological testing, early onset of motor findings with prominent gait impairment, apathy, incontinence, and in the advanced stages, pseudobulbar findings with full-blown dementia.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXBsYW48L0F1dGhvcj48WWVhcj4xOTc4PC9ZZWFyPjxS
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AD==
ADDIN EN.CITE.DATA 34 Congestive heart failure can lead to intermittent symptoms, depending on the cardiac output. Atrial fibrillation with episodic hypoperfusion may be present. Medical diseases, such as hypothyroidism, B12 deficiency, collagen vascular disease, and hematological disorders, need to be ruled out. CSF should be tested to exclude infections and in younger patients to rule out multiple sclerosis. BD is a spectrum disorder; a collection of clinical, imaging and molecular markers will be needed to approach diagnostic certainty. Diagnosis of BD is complicated by the overlap with AD and white matter changes of aging (FIGURE 1). Age related white matter damagePeriventricular WMHs are commonly observed in older persons on FLAIR MRI. Population-based and cohort studies have helped to define the course and clinical significance of WMHs in the periventricular and deep white matter. The conclusions reached are highly dependent upon study design, demographics and definition of WMHs. In community dwelling individuals over the age of 75, using a quantitative definition of WMHs (> 0.5% of intracranial volume), periventricular WMHs were found in 2/3 of an age-stratified cohort (75-89 y/o) selected for mobility (stratified from normal to impaired) with relatively normal cognition. Over 4-years, the most important risk factors for progression were age, hypertension and WMH volume at baseline with the cohort demonstrating significant decrements of mobility and measures of cognitive processing speed with periventricular WMH accrual from 0.99 to 1.74% of intracranial contents volume. ADDIN EN.CITE <EndNote><Cite><Author>Wolfson</Author><Year>2013</Year><RecNum>21855</RecNum><DisplayText><style face="superscript">42</style></DisplayText><record><rec-number>21855</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1377381017">21855</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wolfson, L.</author><author>Wakefield, D. B.</author><author>Moscufo, N.</author><author>Kaplan, R. F.</author><author>Hall, C. B.</author><author>Schmidt, J. A.</author><author>Guttmann, C. R.</author><author>White, W. B.</author></authors></contributors><auth-address>Professor and Chair, Department of Neurology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030. wolfson@nso.uchc.edu.</auth-address><titles><title>Rapid Buildup of Brain White Matter Hyperintensities Over 4 Years Linked to Ambulatory Blood Pressure, Mobility, Cognition, and Depression in Old Persons</title><secondary-title>J Gerontol A Biol Sci Med Sci</secondary-title><alt-title>The journals of gerontology. Series A, Biological sciences and medical sciences</alt-title></titles><periodical><full-title>J Gerontol A Biol Sci Med Sci</full-title></periodical><edition>2013/06/15</edition><dates><year>2013</year><pub-dates><date>Jun 13</date></pub-dates></dates><isbn>1758-535X (Electronic)
1079-5006 (Linking)</isbn><accession-num>23766429</accession-num><urls><related-urls><url> The growth of WMHs occurred by expansion of pre-existing periventricular lesions, generally extending outward from the anterior and posterior horns of the lateral ventricles, making it less likely that they were due to acute ischemic pathophysiology.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaGl0ZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 43 One explanation is that periventricular WMHs are caused by benign venous collagenosis as opposed to deep WMHs that are related to reduced blood flow with hypoxia.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb29keTwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 44 Although this condition and BD are linked with hypertension and likely microvascular disease, the age of onset, prevalence, clinical manifestations, rate of progression and site of lesions differ, suggesting other factors are also operative. Separation of elderly individuals with age-related periventricular WMHs from those related to BD will aid treatment trials by reducing the numbers of patients to treat. Inherited forms of small vessel diseaseThere are several recognized forms of inherited SVD. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited SVD, which is a systemic vascular disorder characterized by recurrent subcortical strokes leading to vascular dementia, will be the focus of this review. CADASIL is due to a mutation in the NOTCH3 gene, encoding a transmembrane receptor protein. Granular osmiophilic material (GOM) deposition around vascular smooth muscle cells is a specific diagnostic feature of CADASIL. The clinical presentation of CADASIL is characterized by migraine with aura, subcortical ischemic events, mood disturbances, apathy, and cognitive impairment.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFicmlhdDwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA 45 Migraine with aura is usually the first symptom. Transient ischemic attacks and ischemic strokes are the most frequent manifestations in CADASIL, often occurring in the absence of conventional vascular risk factors. However, in one series, hypertension was present in 20% of patients and the risk factors of high cholesterol concentrations and smoking were present in 50%, with an association between current smoking and earlier stroke onset. Eventually, multiple strokes cause gait problems, urinary incontinence, depression and pseudobulbar palsy.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaWtrYTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 45, 46LeukoaraiosisLeukoaraiosis was derived from the Greek words for “white” and “rarified”, and was originally proposed to describe the low signal seen on CT in the white matter for which a concise etiology was lacking. ADDIN EN.CITE <EndNote><Cite><Author>Hachinski</Author><Year>1987</Year><RecNum>2747</RecNum><DisplayText><style face="superscript">47</style></DisplayText><record><rec-number>2747</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">2747</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hachinski, V. C.</author><author>Potter, P.</author><author>Merskey, H.</author></authors></contributors><titles><title>Leuko-araiosis</title><secondary-title>Archives of Neurology</secondary-title></titles><pages>21-23</pages><volume>44</volume><number>1</number><keywords><keyword>UNITED STATES</keyword><keyword>BRAIN</keyword><keyword>white matter</keyword><keyword>Binswanger's disease</keyword><keyword>Alzheimer's Disease</keyword><keyword>Pathology</keyword><keyword>BRAIN DISEASES</keyword><keyword>Diagnosis</keyword><keyword>dementia</keyword><keyword>HUMAN</keyword><keyword>myelin sheath</keyword><keyword>nomenclature</keyword><keyword>NUCLEAR MAGNETIC RESONANCE</keyword><keyword>Diagnostic Use</keyword><keyword>Support,Non-U.'t</keyword><keyword>Tomography,X-Ray Computed.</keyword></keywords><dates><year>1987</year></dates><accession-num>1633</accession-num><urls></urls></record></Cite></EndNote>47 The attenuated signal on CT corresponds to high signal on T2- weighted MRI. The impetus for the use of this descriptive term was originally to avoid the over use of the association of white matter changes, which were seen in some normal individuals, with the pathological process in BD. It is a “neutral” term to be used when neither a definite pathological change nor a specific clinical deficit has been linked with the CT and MR changes. The use of a purely descriptive term was to preclude “premature presuppositions” and encourage the search for causes.Mixed dementiaWhile relatively pure forms of BD and AD are found, it appears that the largest group of patients has a combination of both diseases.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2huZWlkZXI8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFy
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ADDIN EN.CITE.DATA 5, 6, 48 This important group of patients has remained essentially undefined, until the advent of amyloid PET imaging. ADDIN EN.CITE <EndNote><Cite><Author>Chui</Author><Year>2015</Year><RecNum>24536</RecNum><DisplayText><style face="superscript">49</style></DisplayText><record><rec-number>24536</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1426532249">24536</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chui, H. C.</author><author>Ramirez-Gomez, L.</author></authors></contributors><auth-address>Department of Neurology, University of Southern California, 1570 Alcazar Street, Suite 215, Los Angeles, CA 90033 USA.</auth-address><titles><title>Clinical and imaging features of mixed Alzheimer and vascular pathologies</title><secondary-title>Alzheimers Res Ther</secondary-title><alt-title>Alzheimer's research & therapy</alt-title></titles><periodical><full-title>Alzheimers Res Ther</full-title></periodical><pages>21</pages><volume>7</volume><number>1</number><edition>2015/02/28</edition><dates><year>2015</year></dates><isbn>1758-9193 (Electronic)</isbn><accession-num>25722748</accession-num><urls><related-urls><url> These patients generally are older than the typical patient with vascular disease. Often memory impairment is present along with executive dysfunction. White matter changes are present on the MRI, which may be difficult to differentiate between those accruing over time in the elderly from those due to hypoxic hypoperfusion with incomplete ischemia due to arteriolosclerosis or cerebral amyloid angiopathy (CAA); this is an important distinction because the latter group could have both AD and SVD. In the patients with AD, CAA results in microbleeds that tend to be localized to the posterior white matter, and which are suggestive of mixed type pathology. This group most likely will require multiple treatments related to the vascular and AD aspects of the pathology. The key will be to determine the dominant features early in the course and to initiate treatment directed to the major factors. Pathophysiology of white matter injury in SVD The deep white matter is a watershed region that is vulnerable to reductions in CBF and oxygen delivery. ADDIN EN.CITE <EndNote><Cite><Author>De Reuck</Author><Year>1980</Year><RecNum>3187</RecNum><DisplayText><style face="superscript">50</style></DisplayText><record><rec-number>3187</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">3187</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>De Reuck, J.</author><author>Crevits, L.</author><author>De Coster, W.</author><author>Sieben, G.</author><author>vander Eecken, H.</author></authors></contributors><titles><title>Pathogenesis of Binswanger chronic progressive subcortical encephalopathy</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title><abbr-1>Neurology</abbr-1></periodical><pages>920-928</pages><volume>30</volume><keywords><keyword>binswanger</keyword><keyword>encephalopathy</keyword><keyword>dementia</keyword><keyword>BRAIN</keyword><keyword>dementia presenile</keyword><keyword>AGED</keyword><keyword>BASAL GANGLIA</keyword><keyword>CASE REPORT</keyword><keyword>FEMALE</keyword><keyword>HUMAN</keyword><keyword>MALE</keyword><keyword>MIDDLE AGE</keyword><keyword>OCCIPITAL LOBE</keyword><keyword>PARIETAL LOBE</keyword></keywords><dates><year>1980</year></dates><accession-num>1271</accession-num><urls></urls></record></Cite></EndNote>50 The vasculature supplying the subcortical white matter originates on the cortical surface and narrows as the vessels descend into the deeper regions, leaving white matter around the ventricles vulnerable. ADDIN EN.CITE <EndNote><Cite><Author>De Reuck</Author><Year>1971</Year><RecNum>7400</RecNum><DisplayText><style face="superscript">51</style></DisplayText><record><rec-number>7400</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1254682598">7400</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>De Reuck, J.</author></authors></contributors><titles><title>The human periventricular arterial blood supply and the anatomy of cerebral infarctions</title><secondary-title>Eur Neurol</secondary-title></titles><periodical><full-title>Eur Neurol</full-title><abbr-1>European neurology</abbr-1></periodical><pages>321-34</pages><volume>5</volume><number>6</number><edition>1971/01/01</edition><keywords><keyword>Cerebral Arteries/*pathology</keyword><keyword>Cerebral Ventricles/*blood supply</keyword><keyword>Cerebrovascular Disorders/etiology/*pathology</keyword><keyword>Collateral Circulation</keyword><keyword>Humans</keyword><keyword>Microcirculation</keyword></keywords><dates><year>1971</year></dates><isbn>0014-3022 (Print)</isbn><accession-num>5141149</accession-num><urls><related-urls><url> Brun has described the damage to the region as “incomplete infarction”. ADDIN EN.CITE <EndNote><Cite><Author>Brun</Author><Year>1986</Year><RecNum>2852</RecNum><DisplayText><style face="superscript">52</style></DisplayText><record><rec-number>2852</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">2852</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brun, A.</author><author>Englund, E.</author></authors></contributors><titles><title>A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study</title><secondary-title>Ann.Neurol.</secondary-title></titles><pages>253-262</pages><volume>19</volume><keywords><keyword>white matter</keyword><keyword>dementia</keyword><keyword>INFARCTION</keyword><keyword>axons</keyword><keyword>CELLS</keyword><keyword>gliosis</keyword><keyword>MACROPHAGES</keyword><keyword>ARTERIOLES</keyword><keyword>hypotension</keyword><keyword>BRAIN</keyword><keyword>WHITE MATTER LESIONS</keyword><keyword>alzheimers disease</keyword><keyword>AGED</keyword><keyword>CARDIOVASCULAR DISEASES</keyword><keyword>CEREBRAL INFARCTION</keyword><keyword>DEMENTIA SENILE</keyword><keyword>HUMAN</keyword><keyword>MIDDLE AGE</keyword><keyword>PERIAQUEDUCTAL GRAY</keyword><keyword>severity of illness index</keyword></keywords><dates><year>1986</year></dates><accession-num>1252</accession-num><urls></urls></record></Cite></EndNote>52 Hypertension has the major effect of narrowing the vessel lumen and thickening the vessel outer wall; in spontaneously hypertensive rats (SHR), spironolactone, a potassium-sparing diuretic, used as an antihypertensive, reverses these changes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWdzYnk8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 55, ADDIN EN.CITE <EndNote><Cite><Author>Faraco</Author><Year>2013</Year><RecNum>22062</RecNum><DisplayText><style face="superscript">56</style></DisplayText><record><rec-number>22062</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1390280220">22062</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Faraco, G.</author><author>Iadecola, C.</author></authors></contributors><auth-address>Brain and Mind Research Institute, Weill Cornell Medical College, 407 E 61st St, RR-303, New York, NY 10065. coi2001@med.cornell.edu.</auth-address><titles><title>Hypertension: a harbinger of stroke and dementia</title><secondary-title>Hypertension</secondary-title><alt-title>Hypertension</alt-title></titles><periodical><full-title>Hypertension</full-title><abbr-1>Hypertension</abbr-1></periodical><alt-periodical><full-title>Hypertension</full-title><abbr-1>Hypertension</abbr-1></alt-periodical><pages>810-7</pages><volume>62</volume><number>5</number><edition>2013/08/28</edition><keywords><keyword>Brain/*physiopathology</keyword><keyword>Dementia/*etiology/physiopathology</keyword><keyword>Humans</keyword><keyword>Hypertension/*complications/physiopathology</keyword><keyword>Stroke/*etiology/physiopathology</keyword></keywords><dates><year>2013</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1524-4563 (Electronic)
0194-911X (Linking)</isbn><accession-num>23980072</accession-num><work-type>Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
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ADDIN EN.CITE.DATA 60 The combination of free radicals and proteases produces a non-immunologic attack on the myelinated fibers of the white matter, resulting in “by-stander” inflammatory demyelination. ADDIN EN.CITE <EndNote><Cite><Author>Cammer</Author><Year>1978</Year><RecNum>3253</RecNum><DisplayText><style face="superscript">61</style></DisplayText><record><rec-number>3253</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">3253</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cammer, W.</author><author>Bloom, B. R.</author><author>Norton, W. T.</author><author>Gordon, S.</author></authors></contributors><titles><title>Degradation of basic protein in myelin by neutral proteases secreted by stimulated macrophages: a possible mechanism of inflammatory demyelination</title><secondary-title>Proc.Natl.Acad.Sci.U.S.A.</secondary-title></titles><pages>1554-1558</pages><volume>75</volume><keywords><keyword>collagenase</keyword><keyword>EXTRACELLULAR MATRIX</keyword><keyword>proteinases</keyword><keyword>PROTEINS</keyword><keyword>MACROPHAGES</keyword><keyword>demyelination</keyword><keyword>myelin proteins</keyword><keyword>PEPTIDE HYDROLASES</keyword><keyword>ANIMAL</keyword><keyword>ascitic fluid</keyword><keyword>fibrinolysin</keyword><keyword>isoelectric point</keyword><keyword>MICE</keyword><keyword>PLASMINOGEN ACTIVATORS</keyword><keyword>SUPPORT U S GOVT P H S</keyword><keyword>thioglycolates</keyword></keywords><dates><year>1978</year></dates><accession-num>1033</accession-num><urls></urls></record></Cite></EndNote>61Elevated levels of albumin suggest blood-derived protein crossed a disrupted BBB. ADDIN EN.CITE <EndNote><Cite><Author>Wallin</Author><Year>1990</Year><RecNum>2405</RecNum><DisplayText><style face="superscript">62</style></DisplayText><record><rec-number>2405</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">2405</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wallin, A.</author><author>Blennow, K.</author><author>Fredman, P.</author><author>Gottfries, C. G.</author><author>Karlsson, I.</author><author>Svennerholm, L.</author></authors></contributors><titles><title>Blood brain barrier function in vascular dementia</title><secondary-title>Acta Neurologica Scandinavica</secondary-title></titles><periodical><full-title>Acta Neurol Scand</full-title><abbr-1>Acta neurologica Scandinavica</abbr-1></periodical><pages>318-322</pages><volume>81</volume><number>4</number><keywords><keyword>NEUROCHEMISTRY</keyword><keyword>SWEDEN</keyword><keyword>BLOOD</keyword><keyword>BLOOD BRAIN BARRIER</keyword><keyword>BRAIN</keyword><keyword>vascular dementia</keyword><keyword>dementia</keyword><keyword>blood-brain barrier</keyword><keyword>BBB</keyword><keyword>ALBUMINS</keyword><keyword>AGED</keyword><keyword>Aged,80 and over</keyword><keyword>Dementia,Vascular</keyword><keyword>Physiopathology</keyword><keyword>FEMALE</keyword><keyword>HUMAN</keyword><keyword>MALE</keyword><keyword>SERUM ALBUMIN</keyword><keyword>Pharmacokinetics</keyword><keyword>Support,Non-U.'t.</keyword></keywords><dates><year>1990</year></dates><accession-num>2209</accession-num><urls></urls></record></Cite></EndNote>62 Pathological studies showed blood-derived proteins in the brains of patients with SVD. ADDIN EN.CITE <EndNote><Cite><Author>Tomimoto</Author><Year>2011</Year><RecNum>21296</RecNum><DisplayText><style face="superscript">63</style></DisplayText><record><rec-number>21296</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1330190060">21296</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tomimoto, H.</author></authors></contributors><auth-address>Department of Neurology, Graduate School of Medicine, Mie University, Tsu, Japan. tomimoto@clin.medic.mie-u.ac.jp</auth-address><titles><title>Subcortical vascular dementia</title><secondary-title>Neurosci Res</secondary-title><alt-title>Neuroscience research</alt-title></titles><periodical><full-title>Neurosci Res</full-title></periodical><pages>193-9</pages><volume>71</volume><number>3</number><edition>2011/08/09</edition><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1872-8111 (Electronic)
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ADDIN EN.CITE.DATA 64-67 Patients with lacunar strokes have increased permeability in deep white matter remote from the lacunar infarct, and the increased BBB permeability shortened the time to functional dependency as measured three years later.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 68 By the time of death, brain tissue shows multiple pathologies, which may or may not reflect the early events, making it necessary to use neuroimaging and CSF markers to identify initiating events. In CADASIL, pathogenetic mutations in NOTCH3 gene alter the number of cysteine residues in the extracellular domain, leading to accumulation of the protein within GOM deposits in small arteries, veins and capillaries throughout the brain.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb3V0ZWw8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 69 There is degeneration of smooth muscle cells with fibrosis of small arteries in the white matter. Immunostaining for blood-derived proteins, as a proxy for BBB permeability, demonstrated focal breaches of the BBB at the sites of microbleeds or infarcts, but did not show generalized BBB leakage. ADDIN EN.CITE <EndNote><Cite><Author>Tikka</Author><Year>2014</Year><RecNum>23911</RecNum><DisplayText><style face="superscript">46</style></DisplayText><record><rec-number>23911</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1421596633">23911</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tikka, S.</author><author>Baumann, M.</author><author>Siitonen, M.</author><author>Pasanen, P.</author><author>Poyhonen, M.</author><author>Myllykangas, L.</author><author>Viitanen, M.</author><author>Fukutake, T.</author><author>Cognat, E.</author><author>Joutel, A.</author><author>Kalimo, H.</author></authors></contributors><auth-address>Protein Chemistry Unit, Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland.</auth-address><titles><title>CADASIL and CARASIL</title><secondary-title>Brain Pathol</secondary-title><alt-title>Brain pathology</alt-title></titles><periodical><full-title>Brain Pathol</full-title><abbr-1>Brain pathology (Zurich, Switzerland)</abbr-1></periodical><pages>525-44</pages><volume>24</volume><number>5</number><edition>2014/10/18</edition><keywords><keyword>Cadasil</keyword><keyword>Carasil</keyword></keywords><dates><year>2014</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1750-3639 (Electronic)
1015-6305 (Linking)</isbn><accession-num>25323668</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url> Functional neuroimaging studies have provided evidence of compromised cerebral hemodynamics in CADASIL patients; studies of cerebrovascular reactivity, as determined by measurement of cerebral blood flow (CBF) changes after exposure to inhaled CO2 or injected acetazolamide, indicate that cerebral blood vessels are dysfunctional in CADASIL patients.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFicmlhdDwvQXV0aG9yPjxZZWFyPjIwMDA8L1llYXI+
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ADDIN EN.CITE.DATA 70, 71 Notably, an association was reported between a lower cerebrovascular reactivity at baseline and a larger increase of WMHs at follow up, suggesting a role for impaired cerebrovascular reactivity in progression of white matter lesions. Positron emission tomography studies have documented a significant decrease in CBF in the white matter, consistent with a chronic ischemia of white matter or decreased demand for oxygen and blood supply consequent upon having fewer normal cells to supply. The finding that CBF was reduced in young patients prior to the occurrence of clinical symptoms indicates that ischemia could be occurring early in the disease course.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdW9taW5lbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+
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ADDIN EN.CITE.DATA 78, 79 Neuropathological validation of imaging findings is complicated by alterations of postmortem brain tissue.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmluYmVyZzwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA 82 Microstructural changes with DTI in normal appearing brain tissue relate more closely to the patients’ clinical presentation than the volume of visible white matter abnormalities on FLAIR. ADDIN EN.CITE <EndNote><Cite><Author>Schmidt</Author><Year>2003</Year><RecNum>7786</RecNum><DisplayText><style face="superscript">83</style></DisplayText><record><rec-number>7786</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1257008588">7786</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></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><edition>2003/06/20</edition><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)</isbn><accession-num>12814718</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>83 These observations clearly indicate that age-related SVD of the brain is a diffuse process affecting the entire brain. In addition, population based studies have shown that the WMHs, which increase in size over 3 years, are related to cognitive impairment, and increase the risk of stroke.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2htaWR0PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48
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ZT48L0VuZE5vdGU+AAAA
ADDIN EN.CITE.DATA 13, 83-85 Population studies using MRI provide important cohort information of population, but are less useful in identifying pathological changes in individual patients, and other MR modalities augment the information (TABLE 2). NMR Spectroscopy and diffusion tensor imaging Other MR techniques that are more sensitive to pathological changes in the white matter are proton NMR spectroscopy (1H-MRS) and diffusion tensor imaging (DTI). 1H-MRS, which shows reductions in N-acetylaspartate (NAA) and creatine (Cr) in ischemic tissue, is a marker of axonal and neuronal injury.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWdvdHRpPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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AD==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWdvdHRpPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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AD==
ADDIN EN.CITE.DATA 86 Patients with BD have reduced NAA in the white matter, while WMHs in normal elderly have normal NAA levels.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXBwZXkgTWFyaW5pZXI8L0F1dGhvcj48WWVhcj4xOTky
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ADDIN EN.CITE.DATA 87, 88 There is lack of consensus on the relationship of the level of NAA and cognitive function with one report failing to find a correlation, ADDIN EN.CITE <EndNote><Cite><Author>Nitkunan</Author><Year>2009</Year><RecNum>3786</RecNum><DisplayText><style face="superscript">89</style></DisplayText><record><rec-number>3786</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">3786</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nitkunan, A.</author><author>Charlton, R. A.</author><author>Barrick, T. R.</author><author>McIntyre, D. J.</author><author>Howe, F. A.</author><author>Markus, H. S.</author></authors></contributors><auth-address>Centre for Clinical Neuroscience, St George's, University of London, London, UK. a.nitkunan@sgul.ac.uk</auth-address><titles><title>Reduced N-acetylaspartate is consistent with axonal dysfunction in cerebral small vessel disease</title><secondary-title>NMR Biomed</secondary-title><alt-title>NMR in biomedicine</alt-title></titles><periodical><full-title>NMR Biomed</full-title><abbr-1>NMR in biomedicine</abbr-1></periodical><alt-periodical><full-title>NMR Biomed</full-title><abbr-1>NMR in biomedicine</abbr-1></alt-periodical><pages>285-91</pages><volume>22</volume><number>3</number><dates><year>2009</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0952-3480 (Print)</isbn><accession-num>19009567</accession-num><urls><related-urls><url> </url></related-urls></urls><language>eng</language></record></Cite></EndNote>89 and another showing that the level of white matter NAA and Cr correlates with executive function on neuropsychological testing, which may be related to differences in populations studied or MR techniques.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXNwYXJvdmljPC9BdXRob3I+PFllYXI+MjAxMzwvWWVh
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ADDIN EN.CITE.DATA 91 DTI allows measurements of fractional anisotropy and mean diffusivity. ADDIN EN.CITE <EndNote><Cite><Author>Alexander</Author><Year>2007</Year><RecNum>23575</RecNum><DisplayText><style face="superscript">92</style></DisplayText><record><rec-number>23575</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1419270169">23575</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Alexander, A. L.</author><author>Lee, J. E.</author><author>Lazar, M.</author><author>Field, A. S.</author></authors></contributors><auth-address>Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. alalexander2@wisc.edu</auth-address><titles><title>Diffusion tensor imaging of the brain</title><secondary-title>Neurotherapeutics</secondary-title><alt-title>Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics</alt-title></titles><periodical><full-title>Neurotherapeutics</full-title></periodical><pages>316-29</pages><volume>4</volume><number>3</number><edition>2007/06/30</edition><keywords><keyword>Anisotropy</keyword><keyword>Brain/*anatomy & histology</keyword><keyword>*Diffusion Magnetic Resonance Imaging</keyword><keyword>Image Processing, Computer-Assisted</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1933-7213 (Print)
1878-7479 (Linking)</isbn><accession-num>17599699</accession-num><work-type>Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review</work-type><urls><related-urls><url> Quantification of DTI may be confounded by the heterogeneity of white matter regions with crossing fiber tracts, which can often be overcome with appropriate image processing methods. Methods are needed to standardize groups of patients, and atlases of controls are used to normalize regional variations.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWlsbGFyZDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+
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ADDIN EN.CITE.DATA 93 A penumbra surrounds WMHs where DTI is less severely affected than in the center of the lesions, but more affected than normal appearing white matter.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWlsbGFyZDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+
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ADDIN EN.CITE.DATA 93, 94 Similar changes in DTI in the penumbral region around the WMHs were seen in CADASIL patients who had incident lacunes that arose along the perforating arteries at the edges of the WMHs.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWVyaW5nPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 32 Blood-brain barrier permeability measurementsMeasurement of BBB permeability is possible with contrast-enhanced MRI.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ub2Z0czwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
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AAA=
ADDIN EN.CITE.DATA 68, 95, 96 Quantitative transfer constants for BBB permeability can be obtained with dynamic contrast-enhanced MRI (DCEMRI), using the Graphical Method of Patlak, originally developed for calculation of transfer constants with isotopes and autoradiography, and adapted to human studies with MRI.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXRsYWs8L0F1dGhvcj48WWVhcj4xOTgzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 99Biochemical markers in diagnosis of small vessel diseaseBiochemical studies of blood and CSF provide important information in patients with SVD (TABLE 3). CSF studies have been most useful and are indicated particularly in patients with BD. The CSF eliminates nonvascular causes, such as inflammation secondary to infection, vasculitis and multiple sclerosis. This is essential in younger patients with white matter lesions. Measurements of CSF protein levels as reflected in the albumin ratio (albumincsf/albuminblood) can indicate BBB disruption when the albumin ratio is elevated, which makes it more likely for the patient to have VCI than AD. ADDIN EN.CITE <EndNote><Cite><Author>Wallin</Author><Year>1990</Year><RecNum>2405</RecNum><DisplayText><style face="superscript">62</style></DisplayText><record><rec-number>2405</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">2405</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wallin, A.</author><author>Blennow, K.</author><author>Fredman, P.</author><author>Gottfries, C. G.</author><author>Karlsson, I.</author><author>Svennerholm, L.</author></authors></contributors><titles><title>Blood brain barrier function in vascular dementia</title><secondary-title>Acta Neurologica Scandinavica</secondary-title></titles><periodical><full-title>Acta Neurol Scand</full-title><abbr-1>Acta neurologica Scandinavica</abbr-1></periodical><pages>318-322</pages><volume>81</volume><number>4</number><keywords><keyword>NEUROCHEMISTRY</keyword><keyword>SWEDEN</keyword><keyword>BLOOD</keyword><keyword>BLOOD BRAIN BARRIER</keyword><keyword>BRAIN</keyword><keyword>vascular dementia</keyword><keyword>dementia</keyword><keyword>blood-brain barrier</keyword><keyword>BBB</keyword><keyword>ALBUMINS</keyword><keyword>AGED</keyword><keyword>Aged,80 and over</keyword><keyword>Dementia,Vascular</keyword><keyword>Physiopathology</keyword><keyword>FEMALE</keyword><keyword>HUMAN</keyword><keyword>MALE</keyword><keyword>SERUM ALBUMIN</keyword><keyword>Pharmacokinetics</keyword><keyword>Support,Non-U.'t.</keyword></keywords><dates><year>1990</year></dates><accession-num>2209</accession-num><urls></urls></record></Cite></EndNote>62 In addition to indicators of BBB opening, the CSF can show neuroinflammation and by-products of myelin breakdown. MMPs participate in the neuroinflammatory response by attacking the proteins in the basal lamina around cerebral blood vessels and breaking down the tight junction proteins.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Zb25nPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 59, 100, 101 During an inflammatory response, there is a shift of the constitutive MMPs to the inducible MMPs that are more disruptive. Inflammation increases the levels of MMP-9 and MMP-3 in the CSF, while the constitutive MMP-2 that is normally present in a proform is reduced in the CSF, most likely due to activation; MMP-3 and -9 are not normally present in CSF, making them readily detectable when elevated in inflammation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZGFpcjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 102-104 MMPs exist in the blood and move into the CSF when there is disruption of the BBB, contributing to the CSF level. To determine the intrathecal production of MMPs, an index can be calculated by creating ratios with the albumin in the CSF and blood, which is similar to the IgG Index used in the diagnosis of multiple sclerosis. ADDIN EN.CITE <EndNote><Cite><Author>Liuzzi</Author><Year>2002</Year><RecNum>450</RecNum><DisplayText><style face="superscript">105</style></DisplayText><record><rec-number>450</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">450</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liuzzi, G. M.</author><author>Trojano, M.</author><author>Fanelli, M.</author><author>Avolio, C.</author><author>Fasano, A.</author><author>Livrea, P.</author><author>Riccio, P.</author></authors></contributors><titles><title>Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis</title><secondary-title>Mult.Scler.</secondary-title></titles><pages>222-228</pages><volume>8</volume><number>3</number><keywords><keyword>ADULT</keyword><keyword>BBB</keyword><keyword>BLOOD</keyword><keyword>BLOOD BRAIN BARRIER</keyword><keyword>blood-brain barrier</keyword><keyword>CEREBROSPINAL FLUID</keyword><keyword>csf</keyword><keyword>England</keyword><keyword>ENZYME LINKED IMMUNOSORBENT ASSAY</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Etiology</keyword><keyword>FEMALE</keyword><keyword>Gelatinase A</keyword><keyword>Gelatinase B</keyword><keyword>HUMAN</keyword><keyword>MALE</keyword><keyword>MIDDLE AGE</keyword><keyword>Multiple Sclerosis</keyword><keyword>Multiple Sclerosis,Relapsing-Remitting</keyword><keyword>PERMEABILITY</keyword><keyword>Sclerosis</keyword><keyword>Support,Non-U.'t</keyword><keyword>Tissue-Inhibitor of Metalloproteinase-1</keyword><keyword>zymography</keyword></keywords><dates><year>2002</year><pub-dates><date>05</date></pub-dates></dates><accession-num>3107</accession-num><urls></urls></record></Cite></EndNote>105 The index is formed as follows: MMP Index=[(MMP/albumin)CSF]/[(MMP/albumin)blood]. Combining the MMP-2 index and the MMP-3 activity effectively separates BD from controls (FIGURE 4).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYW5kZWxhcmlvLUphbGlsPC9BdXRob3I+PFllYXI+MjAx
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AAAA
ADDIN EN.CITE.DATA 104 MMPs are latent and once activated are rapidly removed. Measurements of active MMPs is possible with either gel zymography or immunocapture and fluorometric assays, which are available for the active forms for MMP-3 and MMP-9.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXdraW5zPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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AA==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXdraW5zPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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AA==
ADDIN EN.CITE.DATA 106 Other CSF biomarkers include neurofilament light, myelin basic protein and heart fatty acid binding protein.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CamVya2U8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 107 Separation of SVD from AD has been shown to be possible in studies of CSF biomarkers. The CSF biomarkers that perform well in differentiating AD and white matter pathology are phosphylated-tau (p-tau) and amyloid-1-42 for AD and neurofilament light, myelin basic protein, MMPs and tissue inhibitor of metalloproteinases-1 for white matter inflammation and myelin break down. The results of a single-center study are shown in FIGURE 5.There are no validated blood biomarkers for BD. However, studies using blood have indicated that a systemic low-grade inflammation leading to endothelial dysfunction is involved in SVD pathophysiology. Several blood-derived biomarkers have been studied, including C-reactive protein, interleukin-6 (IL-6), ICAM-1 and thrombomodulin. IL-6 appears to be strongly associated with silent infarctions.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXRpemFiYWw8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy
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ADDIN EN.CITE.DATA 111 Homocysteine, which has been shown to cause endothelial dysfunction, was elevated in patients with lacunar stroke and leukoaraiois, and this association was attenuated after controlling for circulating markers of endothelial activation suggesting it was mediated via endothelial dysfunction.Amyloid-1-42 (A42) and phosphorylated-tau181 (p-tau181) are markers for AD in the CSF. Low values of A42 are suggestive of AD. However, there is evidence that the presence of WMHs may lower A42 in the CSF by interfering with perivascular drainage. ADDIN EN.CITE <EndNote><Cite><Author>Weller</Author><Year>2015</Year><RecNum>24177</RecNum><DisplayText><style face="superscript">112</style></DisplayText><record><rec-number>24177</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1422150963">24177</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weller, R. O.</author><author>Hawkes, C. A.</author><author>Kalaria, R. N.</author><author>Werring, D. J.</author><author>Carare, R. O.</author></authors></contributors><auth-address>Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.</auth-address><titles><title>White matter changes in dementia: role of impaired drainage of interstitial fluid</title><secondary-title>Brain Pathol</secondary-title><alt-title>Brain pathology</alt-title></titles><periodical><full-title>Brain Pathol</full-title><abbr-1>Brain pathology (Zurich, Switzerland)</abbr-1></periodical><pages>63-78</pages><volume>25</volume><number>1</number><edition>2014/12/19</edition><keywords><keyword>Alzheimer's disease</keyword><keyword>Cadasil</keyword><keyword>amyloid-β</keyword><keyword>cerebral amyloid angiopathy</keyword><keyword>perivascular drainage</keyword><keyword>perivascular spaces</keyword><keyword>protein elimination failure angiopathy (PEFA)</keyword><keyword>white matter hyperintensities</keyword></keywords><dates><year>2015</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1750-3639 (Electronic)
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ADDIN EN.CITE.DATA 118, 119 In addition to the white matter there is cellular damage in the hippocampus. CBF is reduced in white matter, hippocampus and some areas of the cortex shortly after the vessels are occluded; there is restoration of CBF over time. A drawback of the BCAO model is that the changes in the CBF occur acutely and resolve chronically. To overcome this limitation, gradual occlusion of the carotids with a device that constricts over time has been used. Gradual narrowing of the both common carotid arteries using the ameroid constrictor device instead of ligation circumvents the acute phase of CBF reduction and acute inflammatory response observed in the BCAO model.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXRhbXVyYTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+
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ADDIN EN.CITE.DATA 120Spontaneously hypertensive/stroke prone rats SHR/SP develop pathological changes that resemble those in SVD.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWdzYnk8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 121 Bred originally from Wistar-Kyoto rats, they evolved into a hypertensive species and finally into the current SHR/SP. ADDIN EN.CITE <EndNote><Cite><Author>Yamori</Author><Year>1976</Year><RecNum>3298</RecNum><DisplayText><style face="superscript">122</style></DisplayText><record><rec-number>3298</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">3298</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yamori, Y.</author><author>Horie, R.</author><author>Handa, H.</author><author>Sato, M.</author><author>Fukase, M.</author></authors></contributors><titles><title>Pathogenetic similarity of strokes in stroke-prone spontaneously hypertensive rats and humans</title><secondary-title>Stroke.</secondary-title></titles><pages>46-53</pages><volume>7</volume><keywords><keyword>collagenase</keyword><keyword>collagen</keyword><keyword>hemorrhage</keyword><keyword>collagenase.text</keyword><keyword>CEREBROVASCULAR DISORDERS</keyword><keyword>DISEASE MODELS ANIMAL</keyword><keyword>HYPERTENSION</keyword><keyword>ANIMAL</keyword><keyword>BASAL GANGLIA</keyword><keyword>BLOOD PRESSURE</keyword><keyword>BRAIN</keyword><keyword>CEREBRAL ANGIOGRAPHY</keyword><keyword>COMPARATIVE STUDY</keyword><keyword>HUMAN</keyword><keyword>RATS</keyword><keyword>SPECIES SPECIFICITY</keyword><keyword>THALAMUS</keyword></keywords><dates><year>1976</year></dates><accession-num>552</accession-num><urls></urls></record></Cite></EndNote>122 Without modifications SHR/SP generally live for over one year, developing strokes and intracerebral bleeding prior to death. In addition to a diffuse brain SVD that closely mimics human sporadic SVD, they have damaged blood vessels in the kidneys. Dietary modifications with high salt or low protein diets (Japanese Permissive Diet) accelerate the pathological changes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaXJvbmk8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 123 Recently, occlusion of one carotid artery to increase the hypoxic injury was added to the Japanese permissive diet in the SHR/SP animals.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWxhbDwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 124 Depending on the purpose of the study, various modifications can be made. For example, in studies involving intracerebral hemorrhage, the high salt or Japanese Permissive diet are introduced at age 6 weeks, which is four weeks prior to the onset of severe hypertension; this results in hemorrhages around 6 to 8 weeks later. If the dietary changes are delayed until the twelfth week, there are prominent changes in the white matter that resemble those seen in BD and aging. Both BCAO in the normotensive rats, and low protein, high salt diets with unilateral carotid artery occlusion (UCAO) in the SHR/SP, damage neurons and white matter through hypoxic hypoperfusion. Measurements of the level of oxygen in the white matter over an extended period of time have been done using the minimally invasive technique of electron paramagnetic resonance.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWF2ZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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Tm90ZT4AAAA=
ADDIN EN.CITE.DATA 125 The oxygen content in the white matter begins to gradually increase by the 9th week reaching a maximum at 12 weeks after birth. Following UCAO and abnormal diet, which are started at 12 weeks, the oxygen content in the white matter falls precipitously to hypoxic levels where it remains until the animal dies around week 16. Therapeutic manipulations with BBB-directed strategies, such as with activated protein C analogs eliminated post-ischemic microbleeds in SHR, suggesting that enhancing BBB integrity might have beneficial in ischemic model in SHR.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 126 CADASIL mouse models Transgenic mice expressing mutated NOTCH3 protein in the extracellular domain (ECD) recapitulate the preclinical stage of the disease with NOTCH3ECD and GOM deposits and white matter lesions. ADDIN EN.CITE <EndNote><Cite><Author>Joutel</Author><Year>2011</Year><RecNum>23990</RecNum><DisplayText><style face="superscript">127</style></DisplayText><record><rec-number>23990</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1421598026">23990</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joutel, A.</author></authors></contributors><auth-address>INSERM U740, Paris, France. anne.joutel@univ-paris-diderot.fr</auth-address><titles><title>Pathogenesis of CADASIL: transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature</title><secondary-title>Bioessays</secondary-title><alt-title>BioEssays : news and reviews in molecular, cellular and developmental biology</alt-title></titles><periodical><full-title>Bioessays</full-title></periodical><pages>73-80</pages><volume>33</volume><number>1</number><edition>2010/10/23</edition><keywords><keyword>Adult</keyword><keyword>Animals</keyword><keyword>Arteries/*metabolism/pathology/physiopathology</keyword><keyword>Brain/pathology/physiology/physiopathology</keyword><keyword>*CADASIL/genetics/pathology/physiopathology</keyword><keyword>Disease Models, Animal</keyword><keyword>Gene Expression</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Mice, Transgenic</keyword><keyword>Mutation/physiology</keyword><keyword>*Receptors, Notch/genetics/metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1521-1878 (Electronic)
0265-9247 (Linking)</isbn><accession-num>20967782</accession-num><work-type>Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review</work-type><urls><related-urls><url> Vascular accumulation of NOTCH3ECD is the earliest pathological change, a finding, which was suspected from the immunohistochemical analysis of skin biopsies from asymptomatic NOTCH3 mutation carriers.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb3V0ZWw8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 127, 128 Mutant mice have a lower threshold for cortical spreading depression, which could explain the higher incidence of migraine with aura in CADASIL patients.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FaWtlcm1hbm4tSGFlcnRlcjwvQXV0aG9yPjxZZWFyPjIw
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ADDIN EN.CITE.DATA 129 Also, mutant mice have impaired cerebrovascular reactivity, with reduced functional hyperemia and compromised autoregulation of CBF. Myogenic responses play a major role in normal hemodynamic processes in the brain, modulating vascular resistance and contributing to local and global CBF regulation. Notably, analysis of isolated vessels have demonstrated reduced myogenic responses in both pial and parenchymal arteries in mutant mice, a finding which could account for the impaired cerebrovascular reactivity in these mice.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb3V0ZWw8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 130 Importantly, the data indicate that cerebral arteries are dysfunctional in the absence of overt smooth muscle degeneration and fibrosis, and that cerebrovascular dysfunction is detectable prior to the appearance of white matter lesions, suggesting that the former could cause the latter.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb3V0ZWw8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 133 A number of anti-inflammatory agents and free radical scavenging agents have shown benefit. ADDIN EN.CITE <EndNote><Cite><Author>Farkas</Author><Year>2007</Year><RecNum>4</RecNum><DisplayText><style face="superscript">114</style></DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Farkas, E.</author><author>Luiten, P. G.</author><author>Bari, F.</author></authors></contributors><titles><title>Permanent, bilateral common carotid artery occlusion in the rat: A model for chronic cerebral hypoperfusion-related neurodegenerative diseases</title><secondary-title>Brain Res.Brain Res.Rev.</secondary-title></titles><keywords><keyword>AGING</keyword><keyword>Alzheimer's Disease</keyword><keyword>ANIMAL</keyword><keyword>ARTERIES</keyword><keyword>BLOOD</keyword><keyword>CAROTID ARTERIES</keyword><keyword>cerebral blood flow</keyword><keyword>Disease</keyword><keyword>EYE</keyword><keyword>HIPPOCAMPUS</keyword><keyword>HUMAN</keyword><keyword>Injuries</keyword><keyword>injury</keyword><keyword>MEMORY</keyword><keyword>Neurodegenerative Diseases</keyword><keyword>rat</keyword><keyword>RATS</keyword><keyword>Research</keyword><keyword>white matter</keyword></keywords><dates><year>2007</year><pub-dates><date>01/18/</date></pub-dates></dates><accession-num>3872</accession-num><urls></urls></record></Cite></EndNote>114 Treatments with minocycline significantly attenuated the hypoxia-ischemia-induced brain injury and improved neurobehavioral performance; the protection of minocycline was associated with its ability to reduce microglial activation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GYW48L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 134 In the SHR/SP with the Japanese permissive diet and UCAO, treatment with minocycline blocked the full development of white matter injuries seen on MRI and improved behavior in the Morris water maze. ADDIN EN.CITE <EndNote><Cite><Author>Jalal</Author><Year>2015</Year><RecNum>24514</RecNum><DisplayText><style face="superscript">135</style></DisplayText><record><rec-number>24514</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1425259649">24514</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jalal, F. Y.</author><author>Yang, Y.</author><author>Thompson, J. F.</author><author>Roitbak, T.</author><author>Rosenberg, G. A.</author></authors></contributors><auth-address>Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
Department of Neurosurgery, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
1] Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA [2] Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA [3] Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.</auth-address><titles><title>Hypoxia-induced neuroinflammatory white-matter injury reduced by minocycline in SHR/SP</title><secondary-title>J Cereb Blood Flow Metab</secondary-title><alt-title>Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism</alt-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><edition>2015/02/26</edition><dates><year>2015</year><pub-dates><date>Feb 25</date></pub-dates></dates><isbn>1559-7016 (Electronic)
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ADDIN EN.CITE.DATA 136 Up regulation of Kv1 channels in cerebral arteries has been shown to be the molecular mechanism underlying the diminished myogenic responses in mutant mice.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYWJlcnRyYW5kPC9BdXRob3I+PFllYXI+MjAxNTwvWWVh
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ADDIN EN.CITE.DATA 137 Treatment of hypertension and other vascular risk factors, anti-aggregants and anti-inflammatory drugs are other possible avenues.Multimodal Approach to Biomarkers in VCI DiagnosisMultiple pathological processes produce the final changes in the brains of patients with VCI. Depending on the time of encountering the patient, there may be one or more pathologies present. Autopsy, is of less use in VCI since by the time of death the majority of patients have a variety of diseases, ranging from cerebral infarctions to AD.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb25uZW48L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 6, 138 A more practical approach based on the need to identify the initiating factors in a multiple disease process is to use biomarkers that would ideally reflect the brain pathology in the early stages of the disease.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYWNjYWk8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYWNjYWk8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS
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dGU+AAA=
ADDIN EN.CITE.DATA 139 Since the natural history can be determined in BD, this is most likely the optimal form to use biomarkers to separate from other forms for the purpose of treatment trials. Although there are a number of potential disease markers from the clinical, imaging and biochemical perspective, none of them is diagnostic, making it necessary to use a combination of these markers.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3NlbmJlcmc8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy
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ADDIN EN.CITE.DATA 140 Biomarkers derived from MRI are the best studied with both growth of WMHs on FLAIR and of FA decrease on DTI, indicating progressive damage. ADDIN EN.CITE <EndNote><Cite><Author>Poggesi</Author><Year>2013</Year><RecNum>21793</RecNum><DisplayText><style face="superscript">141</style></DisplayText><record><rec-number>21793</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1375243957">21793</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Poggesi, A.</author><author>Gouw, A.</author><author>van der Flier, W.</author><author>Pracucci, G.</author><author>Chabriat, H.</author><author>Erkinjuntti, T.</author><author>Fazekas, F.</author><author>Ferro, J. M.</author><author>Hennerici, M.</author><author>Langhorne, P.</author><author>O'Brien, J. T.</author><author>Visser, M. C.</author><author>Wahlund, L. O.</author><author>Waldemar, G.</author><author>Wallin, A.</author><author>Scheltens, P.</author><author>Inzitari, D.</author><author>Pantoni, L.</author></authors></contributors><auth-address>Department of Neurological and Psychiatric Sciences, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.</auth-address><titles><title>Cerebral white matter changes are associated with abnormalities on neurological examination in non-disabled elderly: the LADIS study</title><secondary-title>J Neurol</secondary-title><alt-title>Journal of neurology</alt-title></titles><periodical><full-title>J Neurol</full-title></periodical><pages>1014-21</pages><volume>260</volume><number>4</number><edition>2012/11/28</edition><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1432-1459 (Electronic)
0340-5354 (Linking)</isbn><accession-num>23180181</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url> Information on the use of a number of biomarkers of diagnosis of BD is available, but most have not been used in longitudual studies. For diagnosis, there are studies showing that clinical and neuropsychological testing, 1H-MRS, and CSF measurements of albumin, MMPs, and neurofilament light can be used. It is possible to create a diagnostic scale by summing a series of biomarkers, which when a given number of factors are present, the likelihood of the diagnosis being BD is increased. A statistical approach can be used to optimize the diagnostic set through use of exploratory factor analysis. Two processes are involved: initially, diagnostic biomarkers need to be determined, and secondarily, the biomarkers that can be followed to show progressive tissue damage need to be selected. Biomarkers to be used in diagnosis should be obtained at the early stages with the diagnoses confirmed after a period of follow-up. A potential multimodal approach would include three groups of possible markers: clinical, imaging, and biochemical, which are like three axes with grades of closeness to the full diagnosis of BD at points along each axis. Clinical factors come from the neurological examination and the neuropsychological testing: features from the examination include vascular risk factors, hyperreflexia and gait impairment; neuropsychological testing includes impaired executive function with relative preservation of memory and language; imaging features based primarily on MRI include reduced NAA on 1H-MRS, increased BBB permeability with DCEMRI, reduced FA and increased MD on DTI. CSF measures include increased albumin ratio, reduced MMP-2 index, elevated neurofilament light, and absence of AD biomarkers. A complicating factor is that there is considerable overlap between AD and VCI, which is not always be possible to document by clinical or imaging means alone. ADDIN EN.CITE <EndNote><Cite><Author>Iadecola</Author><Year>2013</Year><RecNum>22060</RecNum><DisplayText><style face="superscript">54</style></DisplayText><record><rec-number>22060</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1390280220">22060</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Iadecola, C.</author></authors></contributors><auth-address>Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10021, USA. Electronic address: coi2001@med.cornell.edu.</auth-address><titles><title>The pathobiology of vascular dementia</title><secondary-title>Neuron</secondary-title><alt-title>Neuron</alt-title></titles><periodical><full-title>Neuron</full-title></periodical><alt-periodical><full-title>Neuron</full-title></alt-periodical><pages>844-66</pages><volume>80</volume><number>4</number><edition>2013/11/26</edition><keywords><keyword>Alzheimer Disease/pathology/physiopathology</keyword><keyword>Atherosclerosis/complications/pathology</keyword><keyword>Cerebrovascular Circulation/physiology</keyword><keyword>Cognition Disorders/pathology/psychology</keyword><keyword>Dementia, Vascular/etiology/immunology/*pathology/*physiopathology</keyword><keyword>Humans</keyword><keyword>Stroke/psychology</keyword></keywords><dates><year>2013</year><pub-dates><date>Nov 20</date></pub-dates></dates><isbn>1097-4199 (Electronic)
0896-6273 (Linking)</isbn><accession-num>24267647</accession-num><work-type>Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review</work-type><urls><related-urls><url> Identifying an optimal set of markers will be challenging since different investigators may have access to a limited number of the possible biomarkers. It may be necessary to have a “high tech” set of markers done by a limited number of investigators with the goal of selecting optimal ones, and a “low tech” group of markers that are available at all research sites. Additional factors such as age will need to be taken into consideration. An approach to targeted treatment trials Treatment trials in VCI have used drugs designed to treat AD with limited success in heterogeneous populations.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb21hbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 142 This has lead to a reassessment of the normal range of blood pressure at various ages since it may be beneficial to aggressively lower blood pressure in the younger hypertensive patients, while avoiding excessive blood pressure lowering in the very old, although the age boundaries are still to be determined. ADDIN EN.CITE <EndNote><Cite><Author>Soros</Author><Year>2013</Year><RecNum>24367</RecNum><DisplayText><style face="superscript">143</style></DisplayText><record><rec-number>24367</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1422154845">24367</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Soros, P.</author><author>Whitehead, S.</author><author>Spence, J. D.</author><author>Hachinski, V.</author></authors></contributors><auth-address>Department of Clinical Neurological Sciences, London Health Sciences Centre, 339 Windermere Road, London, ON N6A 5A5, Canada.</auth-address><titles><title>Antihypertensive treatment can prevent stroke and cognitive decline</title><secondary-title>Nat Rev Neurol</secondary-title><alt-title>Nature reviews. Neurology</alt-title></titles><periodical><full-title>Nat Rev Neurol</full-title></periodical><pages>174-8</pages><volume>9</volume><number>3</number><edition>2012/12/19</edition><keywords><keyword>Cognition Disorders/etiology/*prevention & control</keyword><keyword>Humans</keyword><keyword>Hypertension/*complications/*drug therapy</keyword><keyword>Stroke/etiology/*prevention & control</keyword></keywords><dates><year>2013</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1759-4766 (Electronic)
1759-4758 (Linking)</isbn><accession-num>23247612</accession-num><urls><related-urls><url> it remains a challenge to separate inflammation from multiple lacunar strokes as the primary mechanism of injury to the white matter, the interaction between ischemia and Inflammation is an emerging concept that may be relevant in those individuals with progressive decline rather than discreet strokes. ADDIN EN.CITE <EndNote><Cite><Author>Iadecola</Author><Year>2011</Year><RecNum>24427</RecNum><DisplayText><style face="superscript">144</style></DisplayText><record><rec-number>24427</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1422155248">24427</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Iadecola, C.</author><author>Anrather, J.</author></authors></contributors><auth-address>Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA. coi2001@med.cornell.edu</auth-address><titles><title>The immunology of stroke: from mechanisms to translation</title><secondary-title>Nat Med</secondary-title><alt-title>Nature medicine</alt-title></titles><periodical><full-title>Nat Med</full-title><abbr-1>Nature medicine</abbr-1></periodical><alt-periodical><full-title>Nat Med</full-title><abbr-1>Nature medicine</abbr-1></alt-periodical><pages>796-808</pages><volume>17</volume><number>7</number><edition>2011/07/09</edition><keywords><keyword>Adaptive Immunity/immunology</keyword><keyword>Anti-Inflammatory Agents/therapeutic use</keyword><keyword>Brain Infarction/immunology</keyword><keyword>Brain Ischemia/immunology</keyword><keyword>Cell Death/immunology</keyword><keyword>Humans</keyword><keyword>Immunity, Innate/immunology</keyword><keyword>Inflammation/drug therapy/immunology</keyword><keyword>Lymphocytes/immunology</keyword><keyword>Stroke/drug therapy/*immunology</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1546-170X (Electronic)
1078-8956 (Linking)</isbn><accession-num>21738161</accession-num><work-type>Research Support, N.I.H., Extramural
Review</work-type><urls><related-urls><url> It is likely that the extensive white matter injury evolves from either small strokes that trigger an inflammatory response around the vessels or an inflammatory response is initiated in the vessels damaged by hypertension or diabetes. Since the disruption of the BBB suggests inflammation, reducing permeability may be beneficial and could be tested. Although the inflammatory cascade causes damage in the early stages of an injury, in the secondary stage when recovery with angiogenesis is beginning, inflammation appears to be necessary for recovery, which could compromise treatment with anti-inflammatory agents. These studies have been done in the acute injury models and they need to be done in the chronic injury models to determine the long-term effects of agents that block inflammation. A major challenge will be to identify the optimal biomarkers both for diagnosis and surrogate endpoints for treatment trials. Rather than attempt to categorize patients solely on the basis of one diagnostic test, developing operational definitions based on combinations of features may help. This requires understanding the contribution of each of the factors to the clinical presentation. For example, in the clinical examination it is well known that motor findings are uncommon in the early stages of AD, where memory loss and language problems are the dominant factors. On the other hand, motor findings, such as hemiparesis and asymmetric hyperreflexia can be frequently present at the onset in SVD. Similarly, executive dysfunction occurs early in SVD. Confluent WMHs on MRI are highly suggestive of BD, although it can be seen in AD and normal elderly. Biochemical measurements of NAA with 1H-MRS are more specific for ischemic damage to the white matter, and DTI provides a more sensitive measure of white matter damage than FLAIR or T2-weighted images. DTI has the advantage that it can be done in a shorter time and is readily available on most MRI machines.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 145, 146 Currently, confluent WMHs are the only MRI correlates of cerebral SVD for which the requirement of a surrogate marker are fulfilled; progression of confluent white matter lesions correlate with cognitive decline.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2htaWR0PC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48
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ADDIN EN.CITE.DATA 145, with the caveat that amyloid deposits can also be present in cognitively normal individuals. ADDIN EN.CITE <EndNote><Cite><Author>Cohen</Author><Year>2014</Year><RecNum>24152</RecNum><DisplayText><style face="superscript">146</style></DisplayText><record><rec-number>24152</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1421639247">24152</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cohen, A. D.</author><author>Klunk, W. E.</author></authors></contributors><auth-address>Department of Psychiatry, University of Pittsburgh School of Medicine, USA. Electronic address: cohenad@upmc.edu.
Department of Psychiatry, University of Pittsburgh School of Medicine, USA; Department of Neurology, University of Pittsburgh School of Medicine, USA.</auth-address><titles><title>Early detection of Alzheimer's disease using PiB and FDG PET</title><secondary-title>Neurobiol Dis</secondary-title><alt-title>Neurobiology of disease</alt-title></titles><periodical><full-title>Neurobiol Dis</full-title><abbr-1>Neurobiology of disease</abbr-1></periodical><alt-periodical><full-title>Neurobiol Dis</full-title><abbr-1>Neurobiology of disease</abbr-1></alt-periodical><pages>117-122</pages><volume>72PA</volume><edition>2014/05/16</edition><keywords><keyword>Alzheimer's disease</keyword><keyword>Amyloid</keyword><keyword>Fdg</keyword><keyword>Glucose metabolism</keyword><keyword>Neuroimaging</keyword><keyword>Pittsburgh compound B</keyword></keywords><dates><year>2014</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1095-953X (Electronic)
0969-9961 (Linking)</isbn><accession-num>24825318</accession-num><work-type>Review</work-type><urls><related-urls><url> CSF studies provide the third axis of diagnosis; elevated albumin ratio indicates that the BBB is compromised, which is more likely to occur in SVD than in AD. Furthermore, CSF shows changes in proteins associated with AD, including A42 and p-Tau. In addition to the clinical, imaging and CSF results that are generally available in the clinic there are number of research investigations that can be helpful.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 77 Promising biomarkers in the CSF include neurofilament light, as indicator of myelin breakdown, and MMPs as a measure of inflammation. Finally, elevation of BBB permeability is a marker of inflammation. Discreet cut-points for the factors used to diagnose BD are difficult to determine since it is a spectrum disorder with AD at one end and BD at the other, and a large group of patients with overlapping disease in the middle (FIGURE 6). Utilizing a combination of these factors it is possible to construct scales that reflect the underlying pathophysiological changes occurring in the brain. One such scale is shown in TABLE 4, which is based on a single center study, using cut-points that have been determined in studies of individual factors in patients and controls. High or low scores on these scales would suggest the “pure” forms, while intermediate scores would indicate “mixed” pathological processes. Furthermore, since these biomarkers are dynamic and change at different stages of the disease, it would be possible to stage the disease process and modify treatments based on the stage.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3NlbmJlcmc8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFy
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ADDIN EN.CITE.DATA 148Clarification of the optimal factors to include in classification scales would require a concerted effort of multiple centers and a harmonization of the data collection methods. ADDIN EN.CITE <EndNote><Cite><Author>Hachinski</Author><Year>2006</Year><RecNum>42</RecNum><DisplayText><style face="superscript">149</style></DisplayText><record><rec-number>42</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">42</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hachinski, V.</author><author>Iadecola, C.</author><author>Petersen, R. C.</author><author>Breteler, M. M.</author><author>Nyenhuis, D. L.</author><author>Black, S. E.</author><author>Powers, W. J.</author><author>DeCarli, C.</author><author>Merino, J. G.</author><author>Kalaria, R. N.</author><author>Vinters, H. V.</author><author>Holtzman, D. M.</author><author>Rosenberg, G. A.</author><author>Dichgans, M.</author><author>Marler, J. R.</author><author>Leblanc, G. G.</author></authors></contributors><titles><title>National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards</title><secondary-title>Stroke.</secondary-title></titles><pages>2220-2241</pages><volume>37</volume><number>9</number><keywords><keyword>Alzheimer Disease</keyword><keyword>BRAIN</keyword><keyword>CEREBROVASCULAR DISORDERS</keyword><keyword>CLINICAL TRIALS</keyword><keyword>cognition</keyword><keyword>cognition disorders</keyword><keyword>Complications</keyword><keyword>dementia</keyword><keyword>Diagnosis</keyword><keyword>Disease</keyword><keyword>Epidemiology</keyword><keyword>Etiology</keyword><keyword>Genetics</keyword><keyword>Humans</keyword><keyword>MAGNETIC RESONANCE IMAGING</keyword><keyword>METHODS</keyword><keyword>neuropsychological tests</keyword><keyword>Pathology</keyword><keyword>Psychology</keyword><keyword>Research</keyword><keyword>standards</keyword><keyword>stroke</keyword></keywords><dates><year>2006</year><pub-dates><date>09</date></pub-dates></dates><accession-num>3813</accession-num><urls></urls></record></Cite></EndNote>149 Such large data sets could be mined statistically to identify best classification features. An even more important exercise for such an endeavor to succeed would require agreement as to diagnoses. These would have to be made after several years of follow-up at each center based on the clinical picture. Using this iterative approach it would be possible to construct retrospective databases that then could be used prospectively to identify patients for targeted treatment trials. Recommendations for Future DirectionsTreatment trials in animal models can help identify agents to test in patients. Ideally, the drugs to be tested would show benefits in several models and both sexes as now required for acute drug studies in stroke. ADDIN EN.CITE <EndNote><Cite><Author>Saver</Author><Year>2009</Year><RecNum>16192</RecNum><DisplayText><style face="superscript">150</style></DisplayText><record><rec-number>16192</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1278344583">16192</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saver, J. L.</author><author>Albers, G. W.</author><author>Dunn, B.</author><author>Johnston, K. C.</author><author>Fisher, M.</author></authors></contributors><auth-address>Department of Neurology, Geffen School of Medicine, UCLA, Los Angeles, CA, USA.</auth-address><titles><title>Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for extended window acute stroke therapy trials</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title><abbr-1>Stroke; a journal of cerebral circulation</abbr-1></periodical><pages>2594-600</pages><volume>40</volume><number>7</number><edition>2009/05/30</edition><keywords><keyword>Controlled Clinical Trials as Topic/standards</keyword><keyword>Fibrinolytic Agents/*therapeutic use</keyword><keyword>*Health Planning Guidelines</keyword><keyword>Humans</keyword><keyword>Stroke/*drug therapy</keyword><keyword>Thrombolytic Therapy</keyword><keyword>Time Factors</keyword><keyword>Tissue Plasminogen Activator/*therapeutic use</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>19478212</accession-num><urls><related-urls><url> [pii]
10.1161/STROKEAHA.109.552554</electronic-resource-num><language>eng</language></record></Cite></EndNote>150 Drugs that have been approved for other uses, for example, the anti-inflammatory agents and free radical scavengers, minocycline and simvastatin, all of which have been shown to have beneficial effects in animals models and could be tested in humans.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYWk8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 151, 152 A biological product, E-selectin, has been shown to reduce inflammation after induction of nasal tolerance in the hypertensive rat.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWtpdGE8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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Lancet neurology 2014;13:419-428.TABLE 1: Major Diagnostic Categories for Vascular Cognitive Impairment PatientsDiagnostic CategoriesDescriptionMultiple InfarctsLarge vessel thrombotic occlusion or emboli to major arteries involving gray and white matter regions. MRI indicatesthe regions of infarction in the cortex. These patients have a step-wise course.Lacunar Infarcts and Single Strategic InfarctsSmall strokes in basal ganglia and white matter; single stroke in thalamic region likely to impair cognition. These lesions are considered as a separate entity since they may have a different pathophysiology than involved in the extensive white matter diseaseBinswanger disease (BD)Progressive form of SVD with extensive white matter ischemic changes with or without lacunar strokes secondary to vascular disease with arteriolosclerosis. Patients have gait disturbances, executive dysfunction, evidence of small strokes (hyperreflexia), apathy and depression.CADASIL a representative inherited SVDFamilial form of small vessel disease involving vessel smooth muscle NOTCH 3 accumulation with migraines, multiple strokes and dementiaTABLE 2: Magnetic Resonance Neuroimaging Diagnostic Tests Useful in Evaluation of patients with VCIMR TechniqueVariable measuredAdvantages/disadvantagesFluid Attenuated Inversion Recovery (FLAIR)Volume and location of white matter hyperintensitiesVery sensitive to white matter changes, but not specific for ischemic pathogenesis Proton Magnetic Resonance Spectroscopy (1H-MRS)NAA and CrDetects ischemia or demyelination, more sensitive and specific than FLAIR in identifying injured white matterDiffusion Tensor Imaging (DTI)Structural changes in the white matter related to axial and radial diffusionMore specific for injury than FLAIRDiffusion Tensor Tractography (DTT)Extension of DTI that shows actual white matter tractsIdentifies regions of damaged white matter and potential for lost connectivityDynamic Contrast-Enhanced MRI (DCEMRI) Gadolinium blood-brain transfer constantIndicates disruption of the blood-brain barrierAtrophy/brain volume 3D T1 sequencesCorrelates with cognition in sporadic disease and CADASILTABLE 3: Cerebrospinal fluid findings in patients with white matter injury in VCITestInterpretationAlbumin Ratio increased (CSF/serum)Albumin made in the liver and found in very low concentrations in CSF except when BBB is leakyReduced matrix metalloproteinase-2 index, elevated MMP-3, and -9)Inflammatory molecules that disrupt the BBB by attacking the basal lamina and tight junction proteinsCytokines (TNF-alpha and IL-1beta)Expressed in blood and CSF during inflammatory responsesMultiple sclerosis Panel (IgG index, Oligoclonal bands, myelin basic protein)Necessary to rule out MS as a cause of the s on FLAIR and may be expressed in neuroinfections due to viruses, bacteria, fungal infections, or immunological reactionsAlzheimer proteins (A and PhosphoTau)Reduced A found in CSF of AD patients along with elevated Tau making them important to rule out ADTABLE 4: Potential biomarkers and other features to create BD scale for diagnosis. I. Clinical Features (4 points) 1. Hypertension (HTN) 2. Diabetes mellitus (DM) 3. Hyperreflexia (REF) 4. Imbalance (GAIT)II. Neuropsychological testing (1 point) 5. Executive < 45 (Exec T score)III. Metabolites in WM (1H-MRS) and FA in DTI (1 point) 6. N-acetylasparate (NAA)<12PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXNwYXJvdmljPC9BdXRob3I+PFllYXI+MjAxMzwvWWVh
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ADDIN EN.CITE.DATA 90 or decreased FAIV. Inflammation and BBB (3 points) 7. Albumin ratio (albuminCSF/albuminblood> 6.0 ADDIN EN.CITE <EndNote><Cite><Author>Wallin</Author><Year>1990</Year><RecNum>2405</RecNum><DisplayText><style face="superscript">62</style></DisplayText><record><rec-number>2405</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="0">2405</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wallin, A.</author><author>Blennow, K.</author><author>Fredman, P.</author><author>Gottfries, C. G.</author><author>Karlsson, I.</author><author>Svennerholm, L.</author></authors></contributors><titles><title>Blood brain barrier function in vascular dementia</title><secondary-title>Acta Neurologica Scandinavica</secondary-title></titles><periodical><full-title>Acta Neurol Scand</full-title><abbr-1>Acta neurologica Scandinavica</abbr-1></periodical><pages>318-322</pages><volume>81</volume><number>4</number><keywords><keyword>NEUROCHEMISTRY</keyword><keyword>SWEDEN</keyword><keyword>BLOOD</keyword><keyword>BLOOD BRAIN BARRIER</keyword><keyword>BRAIN</keyword><keyword>vascular dementia</keyword><keyword>dementia</keyword><keyword>blood-brain barrier</keyword><keyword>BBB</keyword><keyword>ALBUMINS</keyword><keyword>AGED</keyword><keyword>Aged,80 and over</keyword><keyword>Dementia,Vascular</keyword><keyword>Physiopathology</keyword><keyword>FEMALE</keyword><keyword>HUMAN</keyword><keyword>MALE</keyword><keyword>SERUM ALBUMIN</keyword><keyword>Pharmacokinetics</keyword><keyword>Support,Non-U.'t.</keyword></keywords><dates><year>1990</year></dates><accession-num>2209</accession-num><urls></urls></record></Cite></EndNote>62 8. BBB permeability by DCEMRI (Ki> 0.0018) ADDIN EN.CITE <EndNote><Cite><Author>Taheri</Author><Year>2011</Year><RecNum>21372</RecNum><DisplayText><style face="superscript">67</style></DisplayText><record><rec-number>21372</rec-number><foreign-keys><key app="EN" db-id="w2szftrzysaaw1ex59tx0pssfer29ptettwe" timestamp="1339015207">21372</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Taheri, S.</author><author>Gasparovic, C.</author><author>Huisa, B. N.</author><author>Adair, J. C.</author><author>Edmonds, E.</author><author>Prestopnik, J.</author><author>Grossetete, M.</author><author>Shah, N. J.</author><author>Wills, J.</author><author>Qualls, C.</author><author>Rosenberg, G. A.</author></authors></contributors><auth-address>Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.</auth-address><titles><title>Blood-brain barrier permeability abnormalities in vascular cognitive impairment</title><secondary-title>Stroke</secondary-title><alt-title>Stroke; a journal of cerebral circulation</alt-title></titles><periodical><full-title>Stroke</full-title><abbr-1>Stroke; a journal of cerebral circulation</abbr-1></periodical><alt-periodical><full-title>Stroke</full-title><abbr-1>Stroke; a journal of cerebral circulation</abbr-1></alt-periodical><pages>2158-63</pages><volume>42</volume><number>8</number><edition>2011/07/02</edition><dates><year>2011</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1524-4628 (Electronic)
0039-2499 (Linking)</isbn><accession-num>21719768</accession-num><work-type>Research Support, N.I.H., Extramural
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ADDIN EN.CITE.DATA 113Components of the scoring system used to select patients most likely to have BD. Points can be given for each feature to create the BD scaleFIGURE LEGENDSFigure 1: Venn diagram of the various categories of small vessel VCI. White matter changes of aging or leukoaraiosis indicates that the etiology is uncertain. White matter changes of aging can overlap with small vessel disease (SVD) in patients with Binswanger’s disease. When Alzheimer’s disease overlaps with SVD, mixed dementia is the appropriate term. Hereditary forms of SVD (ISVD), such as CADASIL, are a separate category of SVD.Figure 2: Hypothetical pathophysiological mechanisms for white matter damage secondary to vascular risk factors (hypertension, diabetes etc.). Damage to the blood vessels leads to fibrosis with narrowing of the vessel lumen and thickening of the walls. There is reduction of cerebral blood flow with hypoxia/ischemia that triggers a molecular injury cascade, beginning with hypoxia inducible factor-1. The fur gene forms Furin, which is the activator of pro-membrane type metalloproteinase-1 (MT—MMP), the activator of proMMP-2. Proteolytic disruption of the blood-brain barrier (BBB), vasoconstriction due to activation of endothelin-1, ad demyelination, edema, and white matter damage. HIF also activates a repair cascade that leads to angiogenesis and neurogenesis. (From Rosenberg Lancet Neuorlogy, permission pending).Figure 3: Representative permeability maps in the white matter obtained with dynamic contrast-enhanced MRI (DCEMRI). White matter hyperintensities (WMHs) are colored in green and are derived from FLAIR MRI. The color scale in the right indicates the amount of permeability change with yellow being the highest values and red being the lowest. A) Upper row shows representative permeability maps for normal subjects. Scattered areas of red show that mild increases in permeability can be seen in normal some of whom have WMHs (white arrows). B) Lower row shows white matter permeability maps from several BD patients. The large amount of green indicates that they have extensive WMHs. Areas of high permeability, which were not seen in the normal are seen as yellow areas at the edges of the WMHs (white arrows). Normal appearing white matter shows increased permeability. (Figure courtesy of Arvind Caprihan,PhD, MIND Research Network, Albuquerque,NM).Figure 4: Relationship of MMP-2 index to MMP-3 activity for the SVD and control groups. A) Scatter plot of MMP-2 index and MMP-3 activity shows that the controls clustered in the high MMP-2 index and low MMP-3 activity quadrant (black dots). The SVD group clustered in the low MMP-2 index and high MMP-3 activity (red dots). B) A density plot of the ratio of MMP-2 index to MMP-3 activity shows that the two groups could be separated based on their means with a p-value of 0.0005.Figure 5: Scatter plots showing univariate analyses of CSF biomarkers for controls, SVD, and AD. The SVD patient group consists of MD (filled diamonds) and VaD (open diamonds). Error bars are represented by median and interquartile range. A) neurofilament light (NF-L), note the broken axis; B) myelin basic protein (MBP); C) heart fatty acid binding protein (H-FABP); D) total tau (T-tau), one missing value (mv) in controls; E) tau phosphorylated at threonine 181 (P-tau181), two mv in controls and one in MD; F) amyloid beta 1–42 (A?1-42); G) matrix metalloproteinase 9 (MMP?9), lowest detection limit set to 40 ng/L; H) matrix metalloproteinase 10 (MMP?10); I) tissue inhibitor of metalloproteinases 1 (TIMP?1); J) matrix metalloproteinase 2 (MMP?2); K) matrix metalloproteinase 3 (MMP?3), one mv in MD and one in VaD; L) tissue inhibitor of metalloproteinases 2 (TIMP?2). AD = Alzheimer’s disease; SVD = subcortical vascular disease; MD = mixed dementia; VaD = vascular dementia. (From M. Bjerke et. al, J Alzheimer’s disease, permission pending)Figure 6: The spectrum nature of Binswanger’s disease is illustrated. At one end of the spectrum on the left side is Alzheimer’s disease with high levels of amyloid and tau proteins. At the other end (right) is Binswanger’s disease with vascular risk factors and without amyloid and tau. In the middle are the mixed dementia patients, which represent the majority of the patients with relative levels of pathology of both diseases. ................
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