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Etiology, clinical manifestations, and diagnosis of vascular dementia

Clinton B Wright, MD, MS
Section Editors
Steven T DeKosky, MD, FAAN, FACP, FANA
Scott E Kasner, MD
Deputy Editor
April F Eichler, MD, MPH


Vascular dementia (VaD) has a long history. VaD was first described in the late 19th century by Binswanger and Alzheimer who also recognized and described a variety of underlying pathologic mechanisms including the role of multiple infarctions and chronic ischemia. For nearly 50 years this was held to be the predominant form of dementia. Subsequently, pathologic studies demonstrated that the amyloid plaques and neurofibrillary tangles of Alzheimer disease (AD) were much more common in the brains of the demented elderly than previously thought [1]; chronic ischemic injury was thought to be quite rare, and VaD was understood as the sequelae of recurrent strokes or "multi-infarct dementia" (MID) [2]. With the advent of sophisticated neuroimaging techniques, computed tomography (CT) and magnetic resonance imaging (MRI), in the latter part of the twentieth century, the high prevalence of chronic vascular injury in the brain was appreciated, and interest in the role of vascular disease, including the role of progressive ischemic injury, on cognitive decline reemerged.

Despite this surge of interest, certain issues impede progress. There are no pathologic criteria for the diagnosis of VaD, as there are for AD. A number of clinical diagnostic criteria exist but are poorly validated and inconsistently applied.

Even basic terminology requires clarification. As an example, the traditional definition of dementia was originally developed in the context of AD in which memory loss occurs prominently and early on in the disease. However, in patients with cognitive deficits ultimately attributable to VaD, memory impairment appears somewhat later, and these patients may have significant cognitive disability long before they meet criteria for dementia.

This has led to the proposed concept of "vascular cognitive impairment" or VCI [3,4]. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards, recognizing the limitations of current diagnostic criteria for both AD and VaD, promulgate the use of VCI as "cognitive impairment that is caused by or associated with vascular factors" [5]. Cognitive deficits associated with vascular disease that don't meet criteria for dementia is labelled "vascular cognitive impairment, no dementia" (vCIND). This is somewhat analogous to the more accepted term "mild cognitive impairment" or MCI, also known as "cognitive impairment, no dementia" or CIND [6]. Criteria as to what deficits qualify as cognitive impairment are ill-defined [6]. Use of the term Binswanger's disease to apply to VaD characterized by severe white matter disease associated with longstanding hypertension is no longer accepted; the volume of the white matter damage sufficient to cause VaD is not known and there are no accepted diagnostic criteria for this entity.

At the foundation of some of these problems is the fact that cerebrovascular disease is itself a heterogeneous disorder, with a variety of pathophysiologic mechanisms and clinical manifestations. At present, the entity of VaD is best understood as a heterogeneous syndrome rather than a distinct disorder, in which the underlying cause is cerebrovascular disease in some form and its ultimate manifestation is dementia.


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Literature review current through: Sep 2016. | This topic last updated: Jul 11, 2016.
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  1. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970; 11:205.
  2. Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia. A cause of mental deterioration in the elderly. Lancet 1974; 2:207.
  3. Hachinski VC, Bowler JV. Vascular dementia. Neurology 1993; 43:2159.
  4. O'Brien JT, Erkinjuntti T, Reisberg B, et al. Vascular cognitive impairment. Lancet Neurol 2003; 2:89.
  5. Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 2006; 37:2220.
  6. Román GC, Sachdev P, Royall DR, et al. Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci 2004; 226:81.
  7. Lobo A, Launer LJ, Fratiglioni L, et al. Prevalence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 2000; 54:S4.
  8. Fratiglioni L, Launer LJ, Andersen K, et al. Incidence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 2000; 54:S10.
  9. Sonnen JA, Larson EB, Crane PK, et al. Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann Neurol 2007; 62:406.
  10. Ikeda M, Hokoishi K, Maki N, et al. Increased prevalence of vascular dementia in Japan: a community-based epidemiological study. Neurology 2001; 57:839.
  11. Ikejima C, Yasuno F, Mizukami K, et al. Prevalence and causes of early-onset dementia in Japan: a population-based study. Stroke 2009; 40:2709.
  12. Sekita A, Ninomiya T, Tanizaki Y, et al. Trends in prevalence of Alzheimer's disease and vascular dementia in a Japanese community: the Hisayama Study. Acta Psychiatr Scand 2010; 122:319.
  13. Hébert R, Brayne C. Epidemiology of vascular dementia. Neuroepidemiology 1995; 14:240.
  14. Rockwood K, Wentzel C, Hachinski V, et al. Prevalence and outcomes of vascular cognitive impairment. Vascular Cognitive Impairment Investigators of the Canadian Study of Health and Aging. Neurology 2000; 54:447.
  15. Hébert R, Lindsay J, Verreault R, et al. Vascular dementia : incidence and risk factors in the Canadian study of health and aging. Stroke 2000; 31:1487.
  16. Fitzpatrick AL, Kuller LH, Ives DG, et al. Incidence and prevalence of dementia in the Cardiovascular Health Study. J Am Geriatr Soc 2004; 52:195.
  17. Jorm AF, Jolley D. The incidence of dementia: a meta-analysis. Neurology 1998; 51:728.
  18. Kuller LH, Lopez OL, Jagust WJ, et al. Determinants of vascular dementia in the Cardiovascular Health Cognition Study. Neurology 2005; 64:1548.
  19. Andersen K, Launer LJ, Dewey ME, et al. Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group. Neurology 1999; 53:1992.
  20. Suryadevara V, Storey SG, Aronow WS, Ahn C. Association of abnormal serum lipids in elderly persons with atherosclerotic vascular disease and dementia, atherosclerotic vascular disease without dementia, dementia without atherosclerotic vascular disease, and no dementia or atherosclerotic vascular disease. J Gerontol A Biol Sci Med Sci 2003; 58:M859.
  21. Reitz C, Tang MX, Luchsinger J, Mayeux R. Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol 2004; 61:705.
  22. Posner HB, Tang MX, Luchsinger J, et al. The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology 2002; 58:1175.
  23. Ross GW, Petrovitch H, White LR, et al. Characterization of risk factors for vascular dementia: the Honolulu-Asia Aging Study. Neurology 1999; 53:337.
  24. Ott A, Stolk RP, Hofman A, et al. Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia 1996; 39:1392.
  25. Geroldi C, Frisoni GB, Paolisso G, et al. Insulin resistance in cognitive impairment: the InCHIANTI study. Arch Neurol 2005; 62:1067.
  26. Ahtiluoto S, Polvikoski T, Peltonen M, et al. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology 2010; 75:1195.
  27. Dichgans M, Zietemann V. Prevention of vascular cognitive impairment. Stroke 2012; 43:3137.
  28. Kalmijn S, Foley D, White L, et al. Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. The Honolulu-Asia aging study. Arterioscler Thromb Vasc Biol 2000; 20:2255.
  29. Solfrizzi V, Scafato E, Capurso C, et al. Metabolic syndrome and the risk of vascular dementia: the Italian Longitudinal Study on Ageing. J Neurol Neurosurg Psychiatry 2010; 81:433.
  30. Segura B, Jurado MA, Freixenet N, et al. Mental slowness and executive dysfunctions in patients with metabolic syndrome. Neurosci Lett 2009; 462:49.
  31. Ivan CS, Seshadri S, Beiser A, et al. Dementia after stroke: the Framingham Study. Stroke 2004; 35:1264.
  32. Desmond DW, Moroney JT, Sano M, Stern Y. Incidence of dementia after ischemic stroke: results of a longitudinal study. Stroke 2002; 33:2254.
  33. Altieri M, Di Piero V, Pasquini M, et al. Delayed poststroke dementia: a 4-year follow-up study. Neurology 2004; 62:2193.
  34. Lin JH, Lin RT, Tai CT, et al. Prediction of poststroke dementia. Neurology 2003; 61:343.
  35. Censori B, Manara O, Agostinis C, et al. Dementia after first stroke. Stroke 1996; 27:1205.
  36. Inzitari D, Di Carlo A, Pracucci G, et al. Incidence and determinants of poststroke dementia as defined by an informant interview method in a hospital-based stroke registry. Stroke 1998; 29:2087.
  37. Pohjasvaara T, Erkinjuntti T, Ylikoski R, et al. Clinical determinants of poststroke dementia. Stroke 1998; 29:75.
  38. Kokmen E, Whisnant JP, O'Fallon WM, et al. Dementia after ischemic stroke: a population-based study in Rochester, Minnesota (1960-1984). Neurology 1996; 46:154.
  39. Srikanth VK, Quinn SJ, Donnan GA, et al. Long-term cognitive transitions, rates of cognitive change, and predictors of incident dementia in a population-based first-ever stroke cohort. Stroke 2006; 37:2479.
  40. Leys D, Hénon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lancet Neurol 2005; 4:752.
  41. Melkas S, Oksala NK, Jokinen H, et al. Poststroke dementia predicts poor survival in long-term follow-up: influence of prestroke cognitive decline and previous stroke. J Neurol Neurosurg Psychiatry 2009; 80:865.
  42. Gottesman RF, Hillis AE. Predictors and assessment of cognitive dysfunction resulting from ischaemic stroke. Lancet Neurol 2010; 9:895.
  43. Béjot Y, Aboa-Eboulé C, Durier J, et al. Prevalence of early dementia after first-ever stroke: a 24-year population-based study. Stroke 2011; 42:607.
  44. Dong Y, Venketasubramanian N, Chan BP, et al. Brief screening tests during acute admission in patients with mild stroke are predictive of vascular cognitive impairment 3-6 months after stroke. J Neurol Neurosurg Psychiatry 2012; 83:580.
  45. Rist PM, Chalmers J, Arima H, et al. Baseline cognitive function, recurrent stroke, and risk of dementia in patients with stroke. Stroke 2013; 44:1790.
  46. Jacova C, Pearce LA, Costello R, et al. Cognitive impairment in lacunar strokes: the SPS3 trial. Ann Neurol 2012; 72:351.
  47. Snaphaan L, de Leeuw FE. Poststroke memory function in nondemented patients: a systematic review on frequency and neuroimaging correlates. Stroke 2007; 38:198.
  48. Reitz C, Bos MJ, Hofman A, et al. Prestroke cognitive performance, incident stroke, and risk of dementia: the Rotterdam Study. Stroke 2008; 39:36.
  49. Knopman DS, Roberts RO, Geda YE, et al. Association of prior stroke with cognitive function and cognitive impairment: a population-based study. Arch Neurol 2009; 66:614.
  50. Frampton M, Harvey RJ, Kirchner V. Propentofylline for dementia. Cochrane Database Syst Rev 2003; :CD002853.
  51. Gamaldo A, Moghekar A, Kilada S, et al. Effect of a clinical stroke on the risk of dementia in a prospective cohort. Neurology 2006; 67:1363.
  52. Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol 2009; 8:1006.
  53. Narasimhalu K, Ang S, De Silva DA, et al. Severity of CIND and MCI predict incidence of dementia in an ischemic stroke cohort. Neurology 2009; 73:1866.
  54. Savva GM, Stephan BC, Alzheimer's Society Vascular Dementia Systematic Review Group. Epidemiological studies of the effect of stroke on incident dementia: a systematic review. Stroke 2010; 41:e41.
  55. Elkins JS, Yaffe K, Cauley JA, et al. Pre-existing hypertension and the impact of stroke on cognitive function. Ann Neurol 2005; 58:68.
  56. Rowan E, Morris CM, Stephens S, et al. Impact of hypertension and apolipoprotein E4 on poststroke cognition in subjects >75 years of age. Stroke 2005; 36:1864.
  57. Jokinen H, Kalska H, Mäntylä R, et al. White matter hyperintensities as a predictor of neuropsychological deficits post-stroke. J Neurol Neurosurg Psychiatry 2005; 76:1229.
  58. Luchsinger JA, Patel B, Tang MX, et al. Measures of adiposity and dementia risk in elderly persons. Arch Neurol 2007; 64:392.
  59. Newman GC, Bang H, Hussain SI, Toole JF. Association of diabetes, homocysteine, and HDL with cognition and disability after stroke. Neurology 2007; 69:2054.
  60. Kwok CS, Loke YK, Hale R, et al. Atrial fibrillation and incidence of dementia: a systematic review and meta-analysis. Neurology 2011; 76:914.
  61. Firbank MJ, Allan LM, Burton EJ, et al. Neuroimaging predictors of death and dementia in a cohort of older stroke survivors. J Neurol Neurosurg Psychiatry 2012; 83:263.
  62. Gemmell E, Bosomworth H, Allan L, et al. Hippocampal neuronal atrophy and cognitive function in delayed poststroke and aging-related dementias. Stroke 2012; 43:808.
  63. Elkins JS, Longstreth WT Jr, Manolio TA, et al. Education and the cognitive decline associated with MRI-defined brain infarct. Neurology 2006; 67:435.
  64. Ojala-Oksala J, Jokinen H, Kopsi V, et al. Educational history is an independent predictor of cognitive deficits and long-term survival in postacute patients with mild to moderate ischemic stroke. Stroke 2012; 43:2931.
  65. Wang Q, Capistrant BD, Ehntholt A, Glymour MM. Long-term rate of change in memory functioning before and after stroke onset. Stroke 2012; 43:2561.
  66. Hénon H, Durieu I, Guerouaou D, et al. Poststroke dementia: incidence and relationship to prestroke cognitive decline. Neurology 2001; 57:1216.
  67. Levine DA, Galecki AT, Langa KM, et al. Trajectory of Cognitive Decline After Incident Stroke. JAMA 2015; 314:41.
  68. Ukraintseva S, Sloan F, Arbeev K, Yashin A. Increasing rates of dementia at time of declining mortality from stroke. Stroke 2006; 37:1155.
  69. Pasquini M, Leys D, Rousseaux M, et al. Influence of cognitive impairment on the institutionalisation rate 3 years after a stroke. J Neurol Neurosurg Psychiatry 2007; 78:56.
  70. Oksala NK, Jokinen H, Melkas S, et al. Cognitive impairment predicts poststroke death in long-term follow-up. J Neurol Neurosurg Psychiatry 2009; 80:1230.
  71. Narasimhalu K, Ang S, De Silva DA, et al. The prognostic effects of poststroke cognitive impairment no dementia and domain-specific cognitive impairments in nondisabled ischemic stroke patients. Stroke 2011; 42:883.
  72. Blum S, Luchsinger JA, Manly JJ, et al. Memory after silent stroke: hippocampus and infarcts both matter. Neurology 2012; 78:38.
  73. Smith EE, Schneider JA, Wardlaw JM, Greenberg SM. Cerebral microinfarcts: the invisible lesions. Lancet Neurol 2012; 11:272.
  74. Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003; 348:1215.
  75. Gold G, Kövari E, Herrmann FR, et al. Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia. Stroke 2005; 36:1184.
  76. Kalaria RN. Cerebrovascular disease and mechanisms of cognitive impairment: evidence from clinicopathological studies in humans. Stroke 2012; 43:2526.
  77. Arvanitakis Z, Leurgans SE, Barnes LL, et al. Microinfarct pathology, dementia, and cognitive systems. Stroke 2011; 42:722.
  78. Chui H. Vascular dementia, a new beginning: shifting focus from clinical phenotype to ischemic brain injury. Neurol Clin 2000; 18:951.
  79. Rost NS, Rahman RM, Biffi A, et al. White matter hyperintensity volume is increased in small vessel stroke subtypes. Neurology 2010; 75:1670.
  80. Qiu C, Cotch MF, Sigurdsson S, et al. Cerebral microbleeds, retinopathy, and dementia: the AGES-Reykjavik Study. Neurology 2010; 75:2221.
  81. van Es AC, van der Grond J, de Craen AJ, et al. Cerebral microbleeds and cognitive functioning in the PROSPER study. Neurology 2011; 77:1446.
  82. Yakushiji Y, Noguchi T, Hara M, et al. Distributional impact of brain microbleeds on global cognitive function in adults without neurological disorder. Stroke 2012; 43:1800.
  83. Lei C, Lin S, Tao W, et al. Association between cerebral microbleeds and cognitive function: a systematic review. J Neurol Neurosurg Psychiatry 2013; 84:693.
  84. Wardlaw JM, Doubal F, Armitage P, et al. Lacunar stroke is associated with diffuse blood-brain barrier dysfunction. Ann Neurol 2009; 65:194.
  85. Topakian R, Barrick TR, Howe FA, Markus HS. Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis. J Neurol Neurosurg Psychiatry 2010; 81:192.
  86. Swartz RH, Stuss DT, Gao F, Black SE. Independent cognitive effects of atrophy and diffuse subcortical and thalamico-cortical cerebrovascular disease in dementia. Stroke 2008; 39:822.
  87. Neuropathology Group. Medical Research Council Cognitive Function and Aging Study. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet 2001; 357:169.
  88. Wright CB, Festa JR, Paik MC, et al. White matter hyperintensities and subclinical infarction: associations with psychomotor speed and cognitive flexibility. Stroke 2008; 39:800.
  89. Launer LJ, Hughes TM, White LR. Microinfarcts, brain atrophy, and cognitive function: the Honolulu Asia Aging Study Autopsy Study. Ann Neurol 2011; 70:774.
  90. Troncoso JC, Zonderman AB, Resnick SM, et al. Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol 2008; 64:168.
  91. Hulette C, Nochlin D, McKeel D, et al. Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases. Neurology 1997; 48:668.
  92. Erkinjuntti T, Inzitari D, Pantoni L, et al. Research criteria for subcortical vascular dementia in clinical trials. J Neural Transm Suppl 2000; 59:23.
  93. Swartz RH, Black SE. Anterior-medial thalamic lesions in dementia: frequent, and volume dependently associated with sudden cognitive decline. J Neurol Neurosurg Psychiatry 2006; 77:1307.
  94. Gold G, Giannakopoulos P, Herrmann FR, et al. Identification of Alzheimer and vascular lesion thresholds for mixed dementia. Brain 2007; 130:2830.
  95. Benisty S, Gouw AA, Porcher R, et al. Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study. J Neurol Neurosurg Psychiatry 2009; 80:478.
  96. Stebbins GT, Nyenhuis DL, Wang C, et al. Gray matter atrophy in patients with ischemic stroke with cognitive impairment. Stroke 2008; 39:785.
  97. Tatemichi TK, Desmond DW, Prohovnik I, et al. Confusion and memory loss from capsular genu infarction: a thalamocortical disconnection syndrome? Neurology 1992; 42:1966.
  98. Rockwood K, Ebly E, Hachinski V, Hogan D. Presence and treatment of vascular risk factors in patients with vascular cognitive impairment. Arch Neurol 1997; 54:33.
  99. Jick H, Zornberg GL, Jick SS, et al. Statins and the risk of dementia. Lancet 2000; 356:1627.
  100. Greenberg SM, Gurol ME, Rosand J, Smith EE. Amyloid angiopathy-related vascular cognitive impairment. Stroke 2004; 35:2616.
  101. Greenberg SM, Vonsattel JP, Stakes JW, et al. The clinical spectrum of cerebral amyloid angiopathy: presentations without lobar hemorrhage. Neurology 1993; 43:2073.
  102. Gray F, Dubas F, Roullet E, Escourolle R. Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy. Ann Neurol 1985; 18:54.
  103. Cordonnier C, van der Flier WM, Sluimer JD, et al. Prevalence and severity of microbleeds in a memory clinic setting. Neurology 2006; 66:1356.
  104. van Norden AG, van den Berg HA, de Laat KF, et al. Frontal and temporal microbleeds are related to cognitive function: the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) Study. Stroke 2011; 42:3382.
  105. Poels MM, Ikram MA, van der Lugt A, et al. Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology 2012; 78:326.
  106. Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord 1999; 13 Suppl 3:S115.
  107. Staekenborg SS, van der Flier WM, van Straaten EC, et al. Neurological signs in relation to type of cerebrovascular disease in vascular dementia. Stroke 2008; 39:317.
  108. Fischer P, Gatterer G, Marterer A, et al. Course characteristics in the differentiation of dementia of the Alzheimer type and multi-infarct dementia. Acta Psychiatr Scand 1990; 81:551.
  109. de Groot JC, de Leeuw FE, Oudkerk M, et al. Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. Ann Neurol 2000; 47:145.
  110. Mok V, Wong KK, Xiong Y, et al. Cortical and frontal atrophy are associated with cognitive impairment in age-related confluent white-matter lesion. J Neurol Neurosurg Psychiatry 2011; 82:52.
  111. Staekenborg SS, Su T, van Straaten EC, et al. Behavioural and psychological symptoms in vascular dementia; differences between small- and large-vessel disease. J Neurol Neurosurg Psychiatry 2010; 81:547.
  112. Jokinen H, Kalska H, Mäntylä R, et al. Cognitive profile of subcortical ischaemic vascular disease. J Neurol Neurosurg Psychiatry 2006; 77:28.
  113. Ballard CG, Burton EJ, Barber R, et al. NINDS AIREN neuroimaging criteria do not distinguish stroke patients with and without dementia. Neurology 2004; 63:983.
  114. Liao D, Cooper L, Cai J, et al. Presence and severity of cerebral white matter lesions and hypertension, its treatment, and its control. The ARIC Study. Atherosclerosis Risk in Communities Study. Stroke 1996; 27:2262.
  115. Chimowitz MI, Estes ML, Furlan AJ, Awad IA. Further observations on the pathology of subcortical lesions identified on magnetic resonance imaging. Arch Neurol 1992; 49:747.
  116. van Swieten JC, van den Hout JH, van Ketel BA, et al. Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain 1991; 114 ( Pt 2):761.
  117. Gouw AA, Seewann A, Vrenken H, et al. Heterogeneity of white matter hyperintensities in Alzheimer's disease: post-mortem quantitative MRI and neuropathology. Brain 2008; 131:3286.
  118. Fernando MS, Simpson JE, Matthews F, et al. White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke 2006; 37:1391.
  119. Young VG, Halliday GM, Kril JJ. Neuropathologic correlates of white matter hyperintensities. Neurology 2008; 71:804.
  120. Pikula A, Böger RH, Beiser AS, et al. Association of plasma ADMA levels with MRI markers of vascular brain injury: Framingham offspring study. Stroke 2009; 40:2959.
  121. Lo RY, Jagust WJ, Alzheimer's Disease Neuroimaging Initiative. Vascular burden and Alzheimer disease pathologic progression. Neurology 2012; 79:1349.
  122. Longstreth WT Jr, Manolio TA, Arnold A, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke 1996; 27:1274.
  123. de Leeuw FE, de Groot JC, Oudkerk M, et al. A follow-up study of blood pressure and cerebral white matter lesions. Ann Neurol 1999; 46:827.
  124. Dufouil C, de Kersaint-Gilly A, Besançon V, et al. Longitudinal study of blood pressure and white matter hyperintensities: the EVA MRI Cohort. Neurology 2001; 56:921.
  125. van Dijk EJ, Breteler MM, Schmidt R, et al. The association between blood pressure, hypertension, and cerebral white matter lesions: cardiovascular determinants of dementia study. Hypertension 2004; 44:625.
  126. Goldstein IB, Bartzokis G, Guthrie D, Shapiro D. Ambulatory blood pressure and the brain: a 5-year follow-up. Neurology 2005; 64:1846.
  127. Yoshita M, Fletcher E, Harvey D, et al. Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD. Neurology 2006; 67:2192.
  128. Sachdev P, Wen W, Chen X, Brodaty H. Progression of white matter hyperintensities in elderly individuals over 3 years. Neurology 2007; 68:214.
  129. Godin O, Tzourio C, Maillard P, et al. Antihypertensive treatment and change in blood pressure are associated with the progression of white matter lesion volumes: the Three-City (3C)-Dijon Magnetic Resonance Imaging Study. Circulation 2011; 123:266.
  130. White WB, Wolfson L, Wakefield DB, et al. Average daily blood pressure, not office blood pressure, is associated with progression of cerebrovascular disease and cognitive decline in older people. Circulation 2011; 124:2312.
  131. Maillard P, Seshadri S, Beiser A, et al. Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study. Lancet Neurol 2012; 11:1039.
  132. Schmidt R, Petrovic K, Ropele S, et al. Progression of leukoaraiosis and cognition. Stroke 2007; 38:2619.
  133. Gouw AA, van der Flier WM, Fazekas F, et al. Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: the Leukoaraiosis and Disability study. Stroke 2008; 39:1414.
  134. van Dijk EJ, Prins ND, Vrooman HA, et al. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke 2008; 39:2712.
  135. Gottesman RF, Coresh J, Catellier DJ, et al. Blood pressure and white-matter disease progression in a biethnic cohort: Atherosclerosis Risk in Communities (ARIC) study. Stroke 2010; 41:3.
  136. Maillard P, Carmichael O, Fletcher E, et al. Coevolution of white matter hyperintensities and cognition in the elderly. Neurology 2012; 79:442.
  137. Power MC, Deal JA, Sharrett AR, et al. Smoking and white matter hyperintensity progression: the ARIC-MRI Study. Neurology 2015; 84:841.
  138. Wen W, Sachdev PS. Extent and distribution of white matter hyperintensities in stroke patients: the Sydney Stroke Study. Stroke 2004; 35:2813.
  139. Vermeer SE, Hollander M, van Dijk EJ, et al. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003; 34:1126.
  140. Wright CB, Paik MC, Brown TR, et al. Total homocysteine is associated with white matter hyperintensity volume: the Northern Manhattan Study. Stroke 2005; 36:1207.
  141. van Dijk EJ, Prins ND, Vermeer SE, et al. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation 2005; 112:900.
  142. Wong TY, Klein R, Sharrett AR, et al. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002; 288:67.
  143. Khatri M, Wright CB, Nickolas TL, et al. Chronic kidney disease is associated with white matter hyperintensity volume: the Northern Manhattan Study (NOMAS). Stroke 2007; 38:3121.
  144. Park K, Yasuda N, Toyonaga S, et al. Significant association between leukoaraiosis and metabolic syndrome in healthy subjects. Neurology 2007; 69:974.
  145. Barzilay JI, Fitzpatrick AL, Luchsinger J, et al. Albuminuria and dementia in the elderly: a community study. Am J Kidney Dis 2008; 52:216.
  146. de Lau LM, Smith AD, Refsum H, et al. Plasma vitamin B12 status and cerebral white-matter lesions. J Neurol Neurosurg Psychiatry 2009; 80:149.
  147. Pieters B, Staals J, Knottnerus I, et al. Periventricular white matter lucencies relate to low vitamin B12 levels in patients with small vessel stroke. Stroke 2009; 40:1623.
  148. Wright CB, Moon Y, Paik MC, et al. Inflammatory biomarkers of vascular risk as correlates of leukoariosis. Stroke 2009; 40:3466.
  149. Satizabal CL, Zhu YC, Mazoyer B, et al. Circulating IL-6 and CRP are associated with MRI findings in the elderly: the 3C-Dijon Study. Neurology 2012; 78:720.
  150. Kral BG, Nyquist P, Vaidya D, et al. Relation of subclinical coronary artery atherosclerosis to cerebral white matter disease in healthy subjects from families with early-onset coronary artery disease. Am J Cardiol 2013; 112:747.
  151. Gurol ME, Irizarry MC, Smith EE, et al. Plasma beta-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy. Neurology 2006; 66:23.
  152. Gomis M, Sobrino T, Ois A, et al. Plasma beta-amyloid 1-40 is associated with the diffuse small vessel disease subtype. Stroke 2009; 40:3197.
  153. Carmelli D, DeCarli C, Swan GE, et al. Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke 1998; 29:1177.
  154. Turner ST, Jack CR, Fornage M, et al. Heritability of leukoaraiosis in hypertensive sibships. Hypertension 2004; 43:483.
  155. Atwood LD, Wolf PA, Heard-Costa NL, et al. Genetic variation in white matter hyperintensity volume in the Framingham Study. Stroke 2004; 35:1609.
  156. Reed T, Kirkwood SC, DeCarli C, et al. Relationship of family history scores for stroke and hypertension to quantitative measures of white-matter hyperintensities and stroke volume in elderly males. Neuroepidemiology 2000; 19:76.
  157. DeStefano AL, Atwood LD, Massaro JM, et al. Genome-wide scan for white matter hyperintensity: the Framingham Heart Study. Stroke 2006; 37:77.
  158. de Leeuw FE, Richard F, de Groot JC, et al. Interaction between hypertension, apoE, and cerebral white matter lesions. Stroke 2004; 35:1057.
  159. Lemmens R, Görner A, Schrooten M, Thijs V. Association of apolipoprotein E epsilon2 with white matter disease but not with microbleeds. Stroke 2007; 38:1185.
  160. Henskens LH, Kroon AA, van Boxtel MP, et al. Associations of the angiotensin II type 1 receptor A1166C and the endothelial NO synthase G894T gene polymorphisms with silent subcortical white matter lesions in essential hypertension. Stroke 2005; 36:1869.
  161. van Oijen M, Cheung EY, Geluk CE, et al. Haplotypes of the fibrinogen gene and cerebral small vessel disease: the Rotterdam scan study. J Neurol Neurosurg Psychiatry 2008; 79:799.
  162. Turner ST, Fornage M, Jack CR Jr, et al. Genomic susceptibility Loci for brain atrophy, ventricular volume, and leukoaraiosis in hypertensive sibships. Arch Neurol 2009; 66:847.
  163. Kochunov P, Glahn D, Winkler A, et al. Analysis of genetic variability and whole genome linkage of whole-brain, subcortical, and ependymal hyperintense white matter volume. Stroke 2009; 40:3685.
  164. Kochunov P, Glahn D, Lancaster J, et al. Whole brain and regional hyperintense white matter volume and blood pressure: overlap of genetic loci produced by bivariate, whole-genome linkage analyses. Stroke 2010; 41:2137.
  165. Fornage M, Debette S, Bis JC, et al. Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. Ann Neurol 2011; 69:928.
  166. Paternoster L, Chen W, Sudlow CL. Genetic determinants of white matter hyperintensities on brain scans: a systematic assessment of 19 candidate gene polymorphisms in 46 studies in 19,000 subjects. Stroke 2009; 40:2020.
  167. Verdelho A, Madureira S, Ferro JM, et al. Differential impact of cerebral white matter changes, diabetes, hypertension and stroke on cognitive performance among non-disabled elderly. The LADIS study. J Neurol Neurosurg Psychiatry 2007; 78:1325.
  168. Verdelho A, Madureira S, Moleiro C, et al. White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study. Neurology 2010; 75:160.
  169. Libon, DJ, Scheinthal, S, Penney, DL, et al. The neuropsychological differentiaion between Alzheimer's disease and subcortical vascular dementia. In: Current Clinical Neurology, Vascular Dementia: Cerebrovascular Mechanisms and Current Management, Humana Press, Totowa NJ 2005. p.281.
  170. Au R, Massaro JM, Wolf PA, et al. Association of white matter hyperintensity volume with decreased cognitive functioning: the Framingham Heart Study. Arch Neurol 2006; 63:246.
  171. Carey CL, Kramer JH, Josephson SA, et al. Subcortical lacunes are associated with executive dysfunction in cognitively normal elderly. Stroke 2008; 39:397.
  172. Dong C, Nabizadeh N, Caunca M, et al. Cognitive correlates of white matter lesion load and brain atrophy: the Northern Manhattan Study. Neurology 2015; 85:441.
  173. Delano-Wood L, Abeles N, Sacco JM, et al. Regional white matter pathology in mild cognitive impairment: differential influence of lesion type on neuropsychological functioning. Stroke 2008; 39:794.
  174. de Leeuw FE, de Groot JC, Achten E, et al. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry 2001; 70:9.
  175. Schmidt R, Enzinger C, Ropele S, et al. Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. Lancet 2003; 361:2046.
  176. Prins ND, van Dijk EJ, den Heijer T, et al. Cerebral white matter lesions and the risk of dementia. Arch Neurol 2004; 61:1531.
  177. Inzitari D, Simoni M, Pracucci G, et al. Risk of rapid global functional decline in elderly patients with severe cerebral age-related white matter changes: the LADIS study. Arch Intern Med 2007; 167:81.
  178. Smith EE, Egorova S, Blacker D, et al. Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairment and dementia. Arch Neurol 2008; 65:94.
  179. Silbert LC, Nelson C, Howieson DB, et al. Impact of white matter hyperintensity volume progression on rate of cognitive and motor decline. Neurology 2008; 71:108.
  180. van Straaten EC, Fazekas F, Rostrup E, et al. Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study. Stroke 2006; 37:836.
  181. Mosley TH Jr, Knopman DS, Catellier DJ, et al. Cerebral MRI findings and cognitive functioning: the Atherosclerosis Risk in Communities study. Neurology 2005; 64:2056.
  182. Libon DJ, Price CC, Giovannetti T, et al. Linking MRI hyperintensities with patterns of neuropsychological impairment: evidence for a threshold effect. Stroke 2008; 39:806.
  183. Price CC, Mitchell SM, Brumback B, et al. MRI-leukoaraiosis thresholds and the phenotypic expression of dementia. Neurology 2012; 79:734.
  184. Baezner H, Blahak C, Poggesi A, et al. Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology 2008; 70:935.
  185. Soumaré A, Elbaz A, Zhu Y, et al. White matter lesions volume and motor performances in the elderly. Ann Neurol 2009; 65:706.
  186. Blahak C, Baezner H, Pantoni L, et al. Deep frontal and periventricular age related white matter changes but not basal ganglia and infratentorial hyperintensities are associated with falls: cross sectional results from the LADIS study. J Neurol Neurosurg Psychiatry 2009; 80:608.
  187. Behl P, Bocti C, Swartz RH, et al. Strategic subcortical hyperintensities in cholinergic pathways and executive function decline in treated Alzheimer patients. Arch Neurol 2007; 64:266.
  188. Smith EE, Salat DH, Jeng J, et al. Correlations between MRI white matter lesion location and executive function and episodic memory. Neurology 2011; 76:1492.
  189. O'Brien JT, Ames D. White matter lesions in depression and Alzheimer's disease. Br J Psychiatry 1996; 169:671.
  190. Koo BB, Bergethon P, Qiu WQ, et al. Clinical prediction of fall risk and white matter abnormalities: a diffusion tensor imaging study. Arch Neurol 2012; 69:733.
  191. Smith EE, Gurol ME, Eng JA, et al. White matter lesions, cognition, and recurrent hemorrhage in lobar intracerebral hemorrhage. Neurology 2004; 63:1606.
  192. Bohnen NI, Müller ML, Kuwabara H, et al. Age-associated leukoaraiosis and cortical cholinergic deafferentation. Neurology 2009; 72:1411.
  193. DeCarli C, Fletcher E, Ramey V, et al. Anatomical mapping of white matter hyperintensities (WMH): exploring the relationships between periventricular WMH, deep WMH, and total WMH burden. Stroke 2005; 36:50.
  194. Longstreth WT Jr, Arnold AM, Beauchamp NJ Jr, et al. Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 2005; 36:56.
  195. Dufouil C, Godin O, Chalmers J, et al. Severe cerebral white matter hyperintensities predict severe cognitive decline in patients with cerebrovascular disease history. Stroke 2009; 40:2219.
  196. Silbert LC, Howieson DB, Dodge H, Kaye JA. Cognitive impairment risk: white matter hyperintensity progression matters. Neurology 2009; 73:120.
  197. Jokinen H, Gouw AA, Madureira S, et al. Incident lacunes influence cognitive decline: the LADIS study. Neurology 2011; 76:1872.
  198. Moroney JT, Bagiella E, Desmond DW, et al. Meta-analysis of the Hachinski Ischemic Score in pathologically verified dementias. Neurology 1997; 49:1096.
  199. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.
  200. Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2011; 42:2672.
  201. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7:263.
  202. Wetterling T, Kanitz RD, Borgis KJ. Comparison of different diagnostic criteria for vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN). Stroke 1996; 27:30.
  203. Chui HC, Mack W, Jackson JE, et al. Clinical criteria for the diagnosis of vascular dementia: a multicenter study of comparability and interrater reliability. Arch Neurol 2000; 57:191.
  204. Lopez OL, Kuller LH, Becker JT, et al. Classification of vascular dementia in the Cardiovascular Health Study Cognition Study. Neurology 2005; 64:1539.
  205. Pohjasvaara T, Mäntylä R, Ylikoski R, et al. Comparison of different clinical criteria (DSM-III, ADDTC, ICD-10, NINDS-AIREN, DSM-IV) for the diagnosis of vascular dementia. National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences. Stroke 2000; 31:2952.
  206. Gold G, Giannakopoulos P, Montes-Paixao Júnior C, et al. Sensitivity and specificity of newly proposed clinical criteria for possible vascular dementia. Neurology 1997; 49:690.
  207. Holmes C, Cairns N, Lantos P, Mann A. Validity of current clinical criteria for Alzheimer's disease, vascular dementia and dementia with Lewy bodies. Br J Psychiatry 1999; 174:45.
  208. Looi JC, Sachdev PS. Differentiation of vascular dementia from AD on neuropsychological tests. Neurology 1999; 53:670.
  209. O'Sullivan M, Morris RG, Markus HS. Brief cognitive assessment for patients with cerebral small vessel disease. J Neurol Neurosurg Psychiatry 2005; 76:1140.
  210. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal Assessment Battery at bedside. Neurology 2000; 55:1621.
  211. Price CC, Jefferson AL, Merino JG, et al. Subcortical vascular dementia: integrating neuropsychological and neuroradiologic data. Neurology 2005; 65:376.
  212. Reed BR, Mungas DM, Kramer JH, et al. Profiles of neuropsychological impairment in autopsy-defined Alzheimer's disease and cerebrovascular disease. Brain 2007; 130:731.