We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Published Online:https://doi.org/10.2217/nmt.14.37

SUMMARY 

Vascular cognitive impairment (VCI) defines a continuum of disorders ranging from mild cognitive impairment to full-blown dementia, attributable to cerebrovascular causes. Major morphological types – multi-infarct encephalopathy, strategic infarct type, subcortical arteriosclerotic leukoencephalopathy, multilacunar state, postischemic encephalopathy – result from systemic, cardiac and local large or small vessel disease. Cognitive decline is commonly caused by widespread small cerebrovascular lesions (CVLs) affecting regions/networks essential for cognition, memory and behavior. CVLs often coexist with Alzheimer-type and other pathologies, which interact in promoting dementia, but in many nondemented elderly individuals, mixed brain pathologies are also present. Due to the high variability of CVLs, no validated clinical and neuropathological criteria for VCI are available. Cholinesterase inhibitors and memantine produce small cognitive improvement but without essential effect. Antihypertensive treatment, cardiovascular control and lifestyle modifications reducing vascular risk factors are essential. Given its growing health, social and economic burden, prevention and treatment of VCI are a major challenge of neuroscience.

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

  • 1 Prince M, Bryce R, Albanese E et al. The global prevalence of dementia: a systematic review and meta-analysis. Alzheimers Dement. 9, 63–75 (2013).
  • 2 Matthews FE, Arthur A, Barnes LE et al. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet 382, 1405–1412 (2013).
  • 3 James BD, Schneider JA. Increasing incidence of dementia in the oldest old: evidence and implications. Alzheimers Res. Ther. 2, 9 (2010).
  • 4 Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH. Dementia incidence continues to increase with age in the oldest old: the 90+ study. Ann. Neurol. 67, 114–121 (2010).
  • 5 Gardner RC, Valcour V, Yaffe K. Dementia in the oldest old: a multi-factorial and growing public health issue. Alzheimers Res. Ther. 5, 27 (2013).
  • 6 Wimo A, Jonsson L, Bond J, Prince M, Winblad B. The worldwide economic impact of dementia 2010. Alzheimers Dement. 9, 1–11 (2013).
  • 7 Erkinjuntti T, Gauthier S. The concept of vascular cognitive impairment. Front. Neurol. Neurosci. 24, 79–85 (2009).
  • 8 Bowler JV. Vascular cognitive impairment. J. Neurol. Neurosurg. Psychiatry 76(Suppl. 5), v35–v44 (2005).
  • 9 Moorhouse P, Rockwood K. Vascular cognitive impairment: current concepts and clinical developments. Lancet Neurol. 7, 246–255 (2008).
  • 10 Rincon F, Wright CB. Vascular cognitive impairment. Curr. Opin. Neurol. 26, 29–36 (2013).
  • 11 Stephan BC, Matthews FE, Khaw KT, Dufouil C, Brayne C. Beyond mild cognitive impairment: vascular cognitive impairment, no dementia (VCIND). Alzheimers Res. Ther. 1, 4 (2009).
  • 12 Bousser MG, Chabriat H. Vascular dementia. Bull. Acad. Natl Med. 196, 409–428; discussion 428–430 (2012).
  • 13 Korczyn AD, Vakhapova V, Grinberg LT. Vascular dementia. J. Neurol. Sci. 322, 2–10 (2012).
  • 14 Garcia JH, Brown GG. Vascular dementia: neuropathologic alterations and metabolic brain changes. J. Neurol. Sci. 109, 121–131 (1992).
  • 15 Brown MM, Markus HS, Oppenheimer S. Stroke Medicine. Taylor & Francis, London, UK, 81–83 (2006).
  • 16 Román GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol. 1, 426–436 (2002).
  • 17 Tomimoto H. Subcortical vascular dementia. Neurosci. Res. 71, 193–199 (2011).
  • 18 Menon U, Kelley RE. Subcortical ischemic cerebrovascular dementia. Int. Rev. Neurobiol. 84, 21–33 (2009).
  • 19 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. 226, 81–87 (2004).
  • 20 Iadecola C. The pathobiology of vascular dementia. Neuron 80, 844–866 (2013).•• Recent review of pathobiology of vascular dementia.
  • 21 Jellinger KA. Pathology and pathogenesis of vascular cognitive impairment: a critical update. Front. Aging Neurosci. 5, 17 (2013).•• Recent review of vascular dementia.
  • 22 Sicras A, Rejas J, Arco S et al. Prevalence, resource utilization and costs of vascular dementia compared with Alzheimer's dementia in a population setting. Dement. Geriatr. Cogn. Disord. 19, 305–315 (2005).
  • 23 Hill J, Fillit H, Shah SN, del Valle MC, Futterman R. Patterns of healthcare utilization and costs for vascular dementia in a community-dwelling population. J. Alzheimers Dis. 8, 43–50 (2005).
  • 24 Knopman DS, Rocca WA, Cha RH, Edland SD, Kokmen E. Survival study of vascular dementia in Rochester, Minnesota. Arch. Neurol. 60, 85–90 (2003).
  • 25 Fitzpatrick AL, Kuller LH, Lopez OL, Kawas CH, Jagust W. Survival following dementia onset: Alzheimer's disease and vascular dementia. J. Neurol. Sci. 229–230, 43–49 (2005).
  • 26 Levine DA, Langa KM. Vascular cognitive impairment: disease mechanisms and therapeutic implications. Neurotherapeutics 8, 361–373 (2011).
  • 27 Jellinger KA. The enigma of vascular cognitive disorder and vascular dementia. Acta Neuropathol. 113, 349–388 (2007).
  • 28 Murray ME, Knopman DS, Dickson DW. Vascular dementia: clinical, neuroradiologic and neuropathologic aspects. Panminerva Med. 49, 197–207 (2007).
  • 29 Jellinger KA. How should vascular dementia be managed? Neurodegen. Dis. Manag. 3, 109–113 (2013).
  • 30 Román GC, Tatemichi TK, Erkinjuntti T et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43, 250–260 (1993).
  • 31 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. 57, 191–196 (2000).
  • 32 WHO. ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. WHO, Geneva, Switzerland (1993).
  • 33 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th Edition). American Psychiatric Association, VA, USA (2013).
  • 34 Hachinski V, Iadecola C, Petersen RC et al. National Institute of Neurological Disorders and Stroke: Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 37, 2220–2241 (2006).
  • 35 Zhao QL, Zhou Y, Wang YL, Dong KH, Wang YJ. A new diagnostic algorithm for vascular cognitive impairment: the proposed criteria and evaluation of its reliability and validity. Chin. Med. J. (Engl.) 123, 311–319 (2010).
  • 36 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 42, 2672–2713 (2011).
  • 37 Sorbi S, Hort J, Erkinjuntti T et al. EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia. Eur. J. Neurol. 19, 1159–1179 (2012).
  • 38 Sachdev P, Kalaria R, O'Brien J et al. Diagnostic criteria for vascular cognitive disorders: a VASCOG statement. Alzheimer Dis. Assoc. Disord. 28(3), 206–218 (2014).
  • 39 Dubois B, Feldman HH, Jacova C et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 9, 1118–1127 (2010).
  • 40 Reiman EM, McKhann GM, Albert MS et al. Clinical impact of updated diagnostic and research criteria for Alzheimer's disease. J. Clin. Psychiatry 72, e37 (2011).
  • 41 Sarazin M, de Souza LC, Lehericy S, Dubois B. Clinical and research diagnostic criteria for Alzheimer's disease. Neuroimaging Clin. N. Am. 22(1), 23–32 (2012).
  • 42 Sperling RA, Aisen PS, Beckett LA et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 280–292 (2011).
  • 43 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. 7, 263–269 (2011).
  • 44 Karantzoulis S, Galvin JE. Distinguishing Alzheimer's disease from other major forms of dementia. Expert Rev. Neurother. 11, 1579–1591 (2011).
  • 45 Lopez OL, McDade E, Riverol M, Becker JT. Evolution of the diagnostic criteria for degenerative and cognitive disorders. Curr. Opin. Neurol. 24, 532–541 (2011).
  • 46 Consoli A, Pasi M, Pantoni L. Vascular mild cognitive impairment: concept, definition, and directions for future studies. Aging Clin. Exp. Res. 24, 113–116 (2012).
  • 47 Gu J, Fischer CE, Saposnik G, Schweizer TA. Profile of cognitive complaints in vascular mild cognitive impairment and mild cognitive impairment. ISRN Neurol. 2013, 865827 (2013).
  • 48 Vasquez BP, Zakzanis KK. The neuropsychological profile of vascular cognitive impairment not demented: a meta-analysis. J. Neuropsychol. doi: 10.1111/jnp.12039 (2014) (Epub ahead of print).• Review of vascular mild cognitive impairment.
  • 49 Fromm A, Lundervold AJ, Moen G, Skulstad S, Thomassen L. A vascular approach to mild amnestic cognitive impairment: a pilot study. Acta Neurol. Scand. Suppl. 196, 73–76 (2013).
  • 50 Jellinger KA. Challenges in the neuropathological diagnosis of dementias. Int. J. Neuropathol. 1, 8–52 (2013).•• Provides current knowledge of classification and neuropathological diagnosis of dementia disorders.
  • 51 Alafuzoff I, Gelpi E, Al-Sarraj S et al. The need to unify neuropathological assessments of vascular alterations in the ageing brain: multicentre survey by the BrainNet Europe consortium. Exp. Gerontol. 47, 825–833 (2012).
  • 52 Pantoni L, Sarti C, Alafuzoff I et al. Postmortem examination of vascular lesions in cognitive impairment: a survey among neuropathological services. Stroke 37, 1005–1009 (2006).
  • 53 Ferrer I. Cognitive impairment of vascular origin: neuropathology of cognitive impairment of vascular origin. J. Neurol. Sci. 299, 139–149 (2010).
  • 54 Jellinger KA. The enigma of mixed dementia. Alzheimers Dement. 3, 40–53 (2007).
  • 55 Grinberg LT, Thal DR. Vascular pathology in the aged human brain. Acta Neuropathol. 119, 277–290 (2010).
  • 56 Bacchetta JP, Kovari E, Merlo M et al. Validation of clinical criteria for possible vascular dementia in the oldest-old. Neurobiol. Aging 28, 579–585 (2007).
  • 57 Chui HC. Vascular cognitive impairment: today and tomorrow. Alzheimers Dement. 2, 185–194 (2006).
  • 58 Gold G, Bouras C, Canuto A et al. Clinicopathological validation study of four sets of clinical criteria for vascular dementia. Am. J. Psychiatry 159, 82–87 (2002).
  • 59 Knopman DS, Parisi JE, Boeve BF et al. Vascular dementia in a population-based autopsy study. Arch. Neurol. 60, 569–575 (2003).
  • 60 Markesbery WR. Vascular dementia. In: Neuropathology of Dementing Disorders. Markesbery W (Ed.). Arnold Publishers, London, UK, 293–311 (1998).
  • 61 Fernando MS, Ince PG. Vascular pathologies and cognition in a population-based cohort of elderly people. J. Neurol. Sci. 226, 13–17 (2004).
  • 62 White L, Small BJ, Petrovitch H et al. Recent clinical-pathologic research on the causes of dementia in late life: update from the Honolulu-Asia Aging Study. J. Geriatr. Psychiatry Neurol. 18, 224–227 (2005).
  • 63 Sonnen JA, Santa Cruz K, Hemmy LS et al. Ecology of the aging human brain. Arch. Neurol. 68, 1049–1056 (2011).
  • 64 Bokura H, Saika R, Yamaguchi T et al. Microbleeds are associated with subsequent hemorrhagic and ischemic stroke in healthy elderly individuals. Stroke 42, 1867–1871 (2011).
  • 65 Chowdhury MH, Nagai A, Bokura H et al. Age-related changes in white matter lesions, hippocampal atrophy, and cerebral microbleeds in healthy subjects without major cerebrovascular risk factors. J. Stroke Cerebrovasc. Dis. 20, 302–309 (2011).
  • 66 Pasi M, Poggesi A, Salvadori E, Pantoni L. Post-stroke dementia and cognitive impairment. Front. Neurol. Neurosci. 30, 65–69 (2012).
  • 67 Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol. 8, 1006–1018 (2009).
  • 68 Allan LM, Rowan EN, Firbank MJ et al. Long term incidence of dementia, predictors of mortality and pathological diagnosis in older stroke survivors. Brain 134, 3716–3727 (2011).
  • 69 Stewart R. Vascular and mixed dementias. In: Oxford Textbook of Old Age Psychiatry (2nd Edition). Dening T, Thomas A. Eds. Oxford University Press, Oxford, UK, 457–468 (2013).
  • 70 Jellinger KA. Morphologic diagnosis of ‘vascular dementia’: a critical update. J. Neurol. Sci. 270, 1–12 (2008).
  • 71 Jellinger KA. The pathology of ‘vascular dementia’: a critical update. J. Alzheimers Dis. 14, 107–123 (2008).
  • 72 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 54, S10–S15 (2000).
  • 73 Aevarsson O, Skoog I. A population-based study on the incidence of dementia disorders between 85 and 88 years of age. J. Am. Geriatr. Soc. 44, 1455–1460 (1996).
  • 74 Kuller LH, Lopez OL, Jagust WJ et al. Determinants of vascular dementia in the Cardiovascular Health Cognition Study. Neurology 64, 1548–1552 (2005).
  • 75 Kobayashi M, Sato T, Sato A, Imamura T. Oldest-old dementia in a Japanese memory clinic. Brain Nerve 61, 972–978 (2009).
  • 76 Akatsu H, Takahashi M, Matsukawa N et al. Subtype analysis of neuropathologically diagnosed patients in a Japanese geriatric hospital. J. Neurol. Sci. 196, 63–69 (2002).
  • 77 Jellinger KA, Attems J. Prevalence and pathology of vascular dementia in the oldest-old. J. Alzheimers Dis. 21, 1283–1293 (2010).
  • 78 Kovacs GG, Milenkovic I, Wohrer A et al. Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol. 126, 365–384 (2013).• Review of multimorbidity of the aging brain.
  • 79 Kawas CH, Corrada MM. Alzheimer's and dementia in the oldest-old: a century of challenges. Curr. Alzheimer Res. 3, 411–419 (2006).
  • 80 Polvikoski T, Sulkava R, Myllykangas L et al. Prevalence of Alzheimer's disease in very elderly people: a prospective neuropathological study. Neurology 56, 1690–1696 (2001).
  • 81 Xuereb JH, Brayne C, Dufouil C et al. Neuropathological findings in the very old: results from the first 101 brains of a population-based longitudinal study of dementing disorders. Ann. N Y Acad. Sci. 903, 490–496 (2000).
  • 82 Zaccai J, Ince P, Brayne C. Population-based neuropathological studies of dementia: design, methods and areas of investigation: a systematic review. BMC Neurol. 6, 2 (2006).
  • 83 Attems J, Jellinger K. Neuropathological correlates of cerebral multimorbidity. Curr. Alzheimer Res. 10, 569–577 (2013).
  • 84 Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69, 2197–2204 (2007).
  • 85 Schneider JA, Boyle PA, Arvanitakis Z, Bienias JL, Bennett DA. Subcortical infarcts, Alzheimer's disease pathology, and memory function in older persons. Ann. Neurol. 62, 59–66 (2007).
  • 86 Jellinger KA, Attems J. Challenges of multimorbidity of the aging brain: a critical update. J. Neural Transm. PMID:25091618, doi: 10.1007/s00702-014-1288-x (2014) (Epub ahead of print).
  • 87 Thal DR, Grinberg LT, Attems J. Vascular dementia: different forms of vessel disorders contribute to the development of dementia in the elderly brain. Exp. Gerontol. 47, 816–824 (2012).
  • 88 Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 12, 483–497 (2013).
  • 89 Sierra C. Cerebral small vessel disease, cognitive impairment and vascular dementia. Panminerva Med. 54, 179–188 (2012).
  • 90 Brown WR, Thore CR. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol. Appl. Neurobiol. 37, 56–74 (2011).
  • 91 Rincon F, Wright CB. Current pathophysiological concepts in cerebral small vessel disease. Front. Aging Neurosci. 6, 24 (2014).• Recent review on cerebral small vessel disease.
  • 92 Cerebral Small Vessel Disease. Pantoni L, Gorelick PB. Eds. Cambridge University Press, Cambridge, UK (2014).•• Recent facts on cerebral small vessel disease.
  • 93 Attems J, Jellinger K, Thal DR, Van Nostrand W. Review: sporadic cerebral amyloid angiopathy. Neuropathol. Appl. Neurobiol. 37, 75–93 (2011).
  • 94 Tanskanen M, Makela M, Myllykangas L et al. Intracerebral hemorrhage in the oldest old: a population-based study (Vantaa 85+). Front. Neurol. 3, 103 (2012).
  • 95 Jellinger KA, Attems J. Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol. 119, 421–433 (2010).
  • 96 Beason-Held LL, Goh JO, An Y et al. Changes in brain function occur years before the onset of cognitive impairment. J. Neurosci. 33, 18008–18014 (2013).
  • 97 Seo SW, Hwa Lee B, Kim EJ et al. Clinical significance of microbleeds in subcortical vascular dementia. Stroke 38, 1949–1951 (2007).
  • 98 Esiri MM, Joachim C, Sloan C et al. Cerebral subcortical small vessel disease in subjects with pathologically confirmed Alzheimer's disease: a clinicopathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA). Alzheimer Dis. Assoc. Disord. 28, 30–35 (2012).
  • 99 Barker R, Ashby EL, Wellington D et al. Pathophysiology of white matter perfusion in Alzheimer's disease and vascular dementia. Brain 137, 1524–1532 (2014).
  • 100 Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 9, 689–701 (2010).
  • 101 Tikka S, Baumann M, Siitonen M et al. CADASIL and CARASIL. Brain Pathol. 24, 525–544 (2014).
  • 102 Duering M, Csanadi E, Gesierich B et al. Incident lacunes preferentially localize to the edge of white matter hyperintensities: insights into the pathophysiology of cerebral small vessel disease. Brain 136, 2717–2726 (2013).
  • 103 Attems J, Jellinger KA. Hippocampal sclerosis in Alzheimer disease and other dementias. Neurology 66, 775 (2006).
  • 104 Wilson RS, Yu L, Trojanowski JQ et al. TDP-43 pathology, cognitive decline, and dementia in old age. JAMA Neurol. 70, 1418–1424 (2013).
  • 105 Amador-Ortiz C, Ahmed Z, Zehr C, Dickson DW. Hippocampal sclerosis in the elderly differs from hippocampal sclerosis in frontal lobe degeneration. Acta Neuropathol. 113, 245–252 (2007).
  • 106 Kril JJ, Patel S, Harding AJ, Halliday GM. Patients with vascular dementia due to microvascular pathology have significant hippocampal neuronal loss. J. Neurol. Neurosurg. Psychiatry 72, 747–751 (2002).
  • 107 Thom M. Review: hippocampal sclerosis in epilepsy: a neuropathology review. Neuropathol. Appl. Neurobiol. 40, 520–543 (2014).
  • 108 Beach TG, Sue L, Scott S et al. Hippocampal sclerosis dementia with tauopathy. Brain Pathol. 13, 263–278 (2003).
  • 109 Miki Y, Mori F, Hori E, Kaimori M, Wakabayashi K. Hippocampal sclerosis with four-repeat tau-positive round inclusions in the dentate gyrus: a new type of four-repeat tauopathy. Acta Neuropathol. 117, 713–718 (2009).
  • 110 Hatanpaa KJ, Blass DM, Pletnikova O et al. Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia. Neurology 63, 538–542 (2004).
  • 111 Nelson PT, Schmitt FA, Lin Y et al. Hippocampal sclerosis in advanced age: clinical and pathological features. Brain 134, 1506–1518 (2011).
  • 112 Neltner JH, Abner EL, Baker S et al. Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing. Brain 137, 255–267 (2014).
  • 113 Lee JH, Kim SH, Kim GH et al. Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B. Neurology 77, 18–25 (2011).
  • 114 Gold G, Giannakopoulos P, Herrmann FR, Bouras C, Kovari E. Identification of Alzheimer and vascular lesion thresholds for mixed dementia. Brain 130, 2830–2836 (2007).
  • 115 Federico A, Di Donato I, Bianchi S et al. Hereditary cerebral small vessel diseases: a review. J. Neurol. Sci. 322, 25–30 (2012).
  • 116 Clerici F, Caracciolo B, Cova I et al. Does vascular burden contribute to the progression of mild cognitive impairment to dementia? Dement. Geriatr. Cogn. Disord. 34, 235–243 (2012).
  • 117 Ganguli M, Fu B, Snitz BE, Hughes TF, Chang CC. Mild cognitive impairment: incidence and vascular risk factors in a population-based cohort. Neurology 80, 2112–2120 (2013).
  • 118 de Bruijn RF, Ikram MA, Cardiovascular risk factors and future risk of Alzheimer's disease. BMC Med 12, 130 (2014).
  • 119 Peters R. Blood pressure, smoking and alcohol use, association with vascular dementia. Exp. Gerontol. 47, 865–872 (2012).
  • 120 O'Donnell MJ, Xavier D, Liu L et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case–control study. Lancet 376, 112–123 (2010).
  • 121 Wiesmann M, Kiliaan AJ, Claassen JA. Vascular aspects of cognitive impairment and dementia. J. Cereb. Blood Flow Metab. 33, 1696–1706 (2013).• Review of vascular causes of dementia.
  • 122 de la Torre JC. Vascular risk factors: a ticking time bomb to Alzheimer's disease. Am J. Alzheimers Dis. Other Demen. 28, 551–559 (2013).
  • 123 Gasecki D, Kwarciany M, Nyka W, Narkiewicz K. Hypertension, brain damage and cognitive decline. Curr. Hypertens. Rep. 15, 547–558 (2013).
  • 124 Alperovitch A, Blachier M, Soumare A et al. Blood pressure variability and risk of dementia in an elderly cohort, the Three-City Study. Alzheimers Dement. 10((5 Suppl), S330–S337 (2014).
  • 125 Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA. Midlife serum cholesterol and increased risk of Alzheimer's and vascular dementia three decades later. Dement. Geriatr. Cogn. Disord. 28, 75–80 (2009).
  • 126 Loef M, Walach H. Midlife obesity and dementia: meta-analysis and adjusted forecast of dementia prevalence in the United States and China. Obesity (Silver Spring) 21, E51–E55 (2013).
  • 127 Luchsinger JA, Patel B, Tang MX, Schupf N, Mayeux R. Measures of adiposity and dementia risk in elderly persons. Arch. Neurol. 64, 392–398 (2007).
  • 128 Ninomiya T. Diabetes mellitus and dementia. Curr. Diab. Rep. 14, 487 (2014).
  • 129 Qiu C, Sigurdsson S, Zhang Q et al. Diabetes, markers of brain pathology and cognitive function: the Age, Gene/Environment Susceptibility-Reykjavik Study. Ann. Neurol. 75, 138–146 (2014).
  • 130 Ahtiluoto S, Polvikoski T, Peltonen M et al. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology 75, 1195–1202 (2010).
  • 131 Yates KF, Sweat V, Yau PL, Turchiano MM, Convit A. Impact of metabolic syndrome on cognition and brain: a selected review of the literature. Arterioscler. Thromb. Vasc. Biol. 32, 2060–2067 (2012).
  • 132 Panza F, Solfrizzi V, Logroscino G et al. Current epidemiological approaches to the metabolic-cognitive syndrome. J. Alzheimers Dis. 30(Suppl. 2), S31–S75 (2012).
  • 133 Beason-Held LL, Thambisetty M, Deib G et al. Baseline cardiovascular risk predicts subsequent changes in resting brain function. Stroke 43, 1542–1547 (2012).
  • 134 Richard E, Moll van Charante EP, van Gool WA. Vascular risk factors as treatment target to prevent cognitive decline. J. Alzheimers Dis. 32, 733–740 (2012).
  • 135 Hasnain M, Victor RVW. Possible role of vascular risk factors in Alzheimer's disease and vascular dementia. Curr. Pharm. Des. 20(38), 6007–6013 (2014).
  • 136 Staekenborg SS, van Straaten EC, van der Flier WM et al. Small vessel versus large vessel vascular dementia: risk factors and MRI findings. J. Neurol. 255, 1644–1651; discussion 1813–1644 (2008).
  • 137 Moretti R, Torre P, Antonello RM et al. Risk factors for vascular dementia: hypotension as a key point. Vasc. Health Risk Manag. 4, 395–402 (2008).
  • 138 Iadecola C, Park L, Capone C. Threats to the mind: aging, amyloid, and hypertension. Stroke 40, S40–S44 (2009).
  • 139 Gattringer T, Enzinger C, Ropele S et al. Vascular risk factors, white matter hyperintensities and hippocampal volume in normal elderly individuals. Dement. Geriatr. Cogn. Disord. 33, 29–34 (2012).
  • 140 Puccio D, Novo G, Baiamonte V et al. Atrial fibrillation and mild cognitive impairment: what correlation? Minerva Cardioangiol. 57, 143–150 (2009).
  • 141 Purandare N, Voshaar RC, Morris J et al. Asymptomatic spontaneous cerebral emboli predict cognitive and functional decline in dementia. Biol. Psychiatry 62, 339–344 (2007).
  • 142 Sahathevan R, Brodtmann A, Donnan GA. Dementia, stroke, and vascular risk factors: a review. Int. J. Stroke 7, 61–73 (2012).
  • 143 DeCarli C. Clinically asymptomatic vascular brain injury: a potent cause of cognitive impairment among older individuals. J. Alzheimers Dis. 33(Suppl. 1), S417–S426 (2013).
  • 144 Zieren N, Duering M, Peters N et al. Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Neurobiol. Aging 34, 400–407 (2013).
  • 145 Amieva H, Mokri H, Le Goff M et al. Compensatory mechanisms in higher-educated subjects with Alzheimer's disease: a study of 20 years of cognitive decline. Brain 137, 1167–1175 (2014).
  • 146 Stern Y. Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurol. 11, 1006–1012 (2012).
  • 147 Jellinger KA, Attems J. Neuropathological approaches to cerebral aging and neuroplasticity. Dialogues Clin. Neurosci. 15, 29–43 (2013).
  • 148 Dolan H, Crain B, Troncoso J et al. Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of Aging cohort. Ann. Neurol. 68, 231–240 (2010).
  • 149 Yaffe K, Hoang TD, Byers AL, Barnes DE, Friedl KE. Lifestyle and health-related risk factors and risk of cognitive aging among older veterans. Alzheimers Dement. 10, S111–S121 (2014).
  • 150 Bruce DG, Davis WA, Starkstein SE, Davis TM. Mid-life predictors of cognitive impairment and dementia in type 2 diabetes mellitus: the fremantle diabetes study. J. Alzheimers Dis. 42, S63–S70 (2014).
  • 151 Di Marco LY, Marzo A, Munoz-Ruiz M et al. Modifiable lifestyle factors in dementia: a systematic review of longitudinal observational cohort studies. J. Alzheimers Dis. 42(1), 119–135 (2014).
  • 152 Bangen KJ, Nation DA, Delano-Wood L et al. Aggregate effects of vascular risk factors on cerebrovascular changes in autopsy-confirmed Alzheimer's disease. Alzheimers Dement. doi: 10.1016/j.jalz.2013.12.025(2014) (Epub ahead of print).
  • 153 Yip AG, McKee AC, Green RC et al. APOE, vascular pathology, and the AD brain. Neurology 65, 259–265 (2005).
  • 154 Baum L, Lam LC, Kwok T et al. Apolipoprotein E epsilon4 allele is associated with vascular dementia. Dement. Geriatr. Cogn. Disord. 22, 301–305 (2006).
  • 155 Akinyemi RO, Mukaetova-Ladinska EB, Attems J, Ihara M, Kalaria RN. Vascular risk factors and neurodegeneration in ageing related dementias: Alzheimer's disease and vascular dementia. Curr. Alzheimer Res. 10, 642–653 (2013).
  • 156 Schrijvers EM, Schurmann B, Koudstaal PJ et al. Genome-wide association study of vascular dementia. Stroke 43, 315–319 (2012).
  • 157 Schmidt H, Freudenberger P, Seiler S, Schmidt R. Genetics of subcortical vascular dementia. Exp. Gerontol. 47, 873–877 (2012).
  • 158 Yu L, Boyle P, Schneider JA et al. APOE epsilon4, Alzheimer's disease pathology, cerebrovascular disease, and cognitive change over the years prior to death. Psychol. Aging 28, 1015–1023 (2013).
  • 159 Kim Y, Kong M, An J, Ryu J, Lee C. Genetic dissection of susceptibility to vascular dementia. Psychiatr. Genet. 21, 69–76 (2011).
  • 160 Chung SJ, Kim JH, Cho JH et al. Subcortical vascular dementia (SVaD) without hypertension (HTN) may be a unique subtype of vascular dementia (VaD). Arch. Gerontol. Geriatr. 58, 231–235 (2014).
  • 161 Gao YZ, Zhang JJ, Liu H et al. Regional cerebral blood flow and cerebrovascular reactivity in Alzheimer's disease and vascular dementia assessed by arterial spinlabeling magnetic resonance imaging. Curr. Neurovasc. Res. 10, 49–53 (2013).
  • 162 Sabayan B, Jansen S, Oleksik AM et al. Cerebrovascular hemodynamics in Alzheimer's disease and vascular dementia: a meta-analysis of transcranial Doppler studies. Ageing Res. Rev. 11, 271–277 (2012).
  • 163 Ly JV, Rowe CC, Villemagne VL et al. Subacute ischemic stroke is associated with focal 11C PiB positron emission tomography retention but not with global neocortical Abeta deposition. Stroke 43, 1341–1346 (2012).
  • 164 Nagata K, Takano D, Yamazaki T et al. Cerebrovascular lesions in elderly Japanese patients with Alzheimer's disease. J. Neurol. Sci. 322, 87–91 (2012).
  • 165 Attems J, Jellinger KA. The overlap between vascular disease and Alzheimer's disease - lessons from pathology. BMC Med. 12, 206 (2014).
  • 166 Kalback W, Esh C, Castano EM et al. Atherosclerosis, vascular amyloidosis and brain hypoperfusion in the pathogenesis of sporadic Alzheimer's disease. Neurol. Res. 26, 525–539 (2004).
  • 167 Greenberg SM, Gurol ME, Rosand J, Smith EE. Amyloid angiopathy-related vascular cognitive impairment. Stroke 35, 2616–2619 (2004).
  • 168 Bailey TL, Rivara CB, Rocher AB, Hof PR. The nature and effects of cortical microvascular pathology in aging and Alzheimer's disease. Neurol. Res. 26, 573–578 (2004).
  • 169 Zlokovic BV, Deane R, Sallstrom J, Chow N, Miano JM. Neurovascular pathways and Alzheimer amyloid beta-peptide. Brain Pathol. 15, 78–83 (2005).
  • 170 Yarchoan M, Xie SX, Kling MA et al. Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. Brain 135, 3749–3756 (2012).
  • 171 Park L, Zhou J, Zhou P et al. Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 110, 3089–3094 (2013).
  • 172 Lee CW, Shih YH, Kuo YM. Cerebrovascular pathology and amyloid plaque formation in Alzheimer's disease. Curr. Alzheimer Res. 11, 4–10 (2014).
  • 173 Purnell C, Gao S, Callahan CM, Hendrie HC. Cardiovascular risk factors and incident Alzheimer disease: a systematic review of the literature. Alzheimer Dis. Assoc. Disord. 23, 1–10 (2009).
  • 174 Chui HC, Zheng L, Reed BR, Vinters HV, Mack WJ. Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review. Alzheimers Res. Ther. 4, 1 (2012).
  • 175 Stanimirovic DB, Friedman A. Pathophysiology of the neurovascular unit: disease cause or consequence? J. Cereb. Blood Flow Metab. 32, 1207–1221 (2012).
  • 176 de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33, 1152–1162 (2002).
  • 177 Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet 354, 919–920 (1999).
  • 178 Miklossy J. Cerebral hypoperfusion induces cortical watershed microinfarcts which may further aggravate cognitive decline in Alzheimer's disease. Neurol. Res. 25, 605–610 (2003).
  • 179 Chui HC, Zarow C, Mack WJ et al. Cognitive impact of subcortical vascular and Alzheimer's disease pathology. Ann. Neurol. 60, 677–687 (2006).
  • 180 Lee JH, Olichney JM, Hansen LA, Hofstetter CR, Thal LJ. Small concomitant vascular lesions do not influence rates of cognitive decline in patients with Alzheimer disease. Arch. Neurol. 57, 1474–1479 (2000).
  • 181 Zheng L, Vinters HV, Mack WJ et al. Cerebral atherosclerosis is associated with cystic infarcts and microinfarcts but not Alzheimer pathologic changes. Stroke 44, 2835–2841 (2013).
  • 182 Richardson K, Stephan BC, Ince PG et al. The neuropathology of vascular disease in the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Curr. Alzheimer Res. 9, 687–696 (2012).
  • 183 Park JH, Seo SW, Kim C et al. Pathogenesis of cerebral microbleeds: in vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. Ann. Neurol. 73, 584–593 (2013).
  • 184 Lei C, Lin S, Tao W et al. Association between cerebral microbleeds and cognitive function: a systematic review. J. Neurol. Neurosurg. Psychiatry 84, 693–697 (2013).
  • 185 Lo RY, Jagust WJ. Vascular burden and Alzheimer disease pathologic progression. Neurology 79, 1349–1355 (2012).
  • 186 Lewis H, Beher D, Cookson N et al. Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia. Neuropathol. Appl. Neurobiol. 32, 103–118 (2006).
  • 187 Marchant NL, Reed BR, Sanossian N et al. The aging brain and cognition: contribution of vascular injury and abeta to mild cognitive dysfunction. JAMA Neurol. 70, 488–495 (2013).
  • 188 Savva GM, Wharton SB, Ince PG et al. Age, neuropathology, and dementia. N. Engl. J. Med. 360, 2302–2309 (2009).
  • 189 Sinka L, Kovari E, Gold G et al. Small vascular and Alzheimer disease-related pathologic determinants of dementia in the oldest-old. J. Neuropathol. Exp. Neurol 69, 1247–1255 (2010).
  • 190 Zekry D, Duyckaerts C, Moulias R et al. Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol. 103, 481–487 (2002).
  • 191 del Ser T, Hachinski V, Merskey H, Munoz DG. Alzheimer's disease with and without cerebral infarcts. J. Neurol. Sci. 231, 3–11 (2005).
  • 192 Sachdev PS, Chen X, Joscelyne A et al. Hippocampal size and dementia in stroke patients: the Sydney stroke study. J. Neurol. Sci. 260, 71–77 (2007).
  • 193 Toledo JB, Arnold SE, Raible K et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre. Brain 136, 2697–2706 (2013).
  • 194 Haight TJ, Landau SM, Carmichael O et al. Dissociable effects of Alzheimer disease and white matter hyperintensities on brain metabolism. JAMA Neurol. 70, 1039–1045 (2013).
  • 195 Tomimoto H. Vascular cognitive impairment: the relationship between hypertensive small vessel disease and cerebral amyloid angiopathy. Brain Nerve 64, 1377–1386 (2012).
  • 196 Lee MJ, Seo SW, Na DL et al. Synergistic effects of ischemia and beta-amyloid burden on cognitive decline in patients with subcortical vascular mild cognitive impairment. JAMA Psychiatry 71(4), 412–422 (2014).
  • 197 Smallwood A, Oulhaj A, Joachim C et al. Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Neuropathol. Appl. Neurobiol. 38, 337–343 (2012).
  • 198 Launer LJ, Hughes TM, White LR. Microinfarcts, brain atrophy, and cognitive function: the Honolulu Asia Aging Study Autopsy Study. Ann. Neurol. 70, 774–780 (2011).
  • 199 Jokinen H, Lipsanen J, Schmidt R et al. Brain atrophy accelerates cognitive decline in cerebral small vessel disease: the LADIS study. Neurology 78, 1785–1792 (2012).
  • 200 Kövari E, Gold G, Herrmann FR et al. Cortical microinfarcts and demyelination significantly affect cognition in brain aging. Stroke 35, 410–414 (2004).
  • 201 Gold G, Kovari E, Herrmann FR et al. Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia. Stroke 36, 1184–1188 (2005).
  • 202 Giannakopoulos P, Gold G, Kovari E et al. Assessing the cognitive impact of Alzheimer disease pathology and vascular burden in the aging brain: the Geneva experience. Acta Neuropathol. 113, 1–12 (2007).
  • 203 Costanza A, Xekardaki A, Kovari E et al. Microvascular burden and Alzheimer-type lesions across the age spectrum. J. Alzheimers Dis. 32, 643–652 (2012).
  • 204 Ince P. Acquired forms of vascular dementia. In: Cerebrovascular Diseases. Kalimo H (Ed.). ISN Neuropath Press, Basel, Switzerland, 316–323 (2005).
  • 205 Kalaria RN, Kenny RA, Ballard CG et al. Towards defining the neuropathological substrates of vascular dementia. J. Neurol. Sci. 226, 75–80 (2004).
  • 206 Bolandzadeh N, Davis JC, Tam R, Handy TC, Liu-Ambrose T. The association between cognitive function and white matter lesion location in older adults: a systematic review. BMC Neurol. 12, 126 (2012).
  • 207 Drobyshevsky A, Derrick M, Wyrwicz AM et al. White matter injury correlates with hypertonia in an animal model of cerebral palsy. J. Cereb. Blood Flow Metab. 27, 270–281 (2007).
  • 208 Kemper TL, Blatt GJ, Killiany RJ, Moss MB. Neuropathology of progressive cognitive decline in chronically hypertensive rhesus monkeys. Acta Neuropathol. 101, 145–153 (2001).
  • 209 Sabayan B, Westendorp RG, Grond J et al. Markers of endothelial dysfunction and cerebral blood flow in older adults. Neurobiol. Aging 35, 373–377 (2014).
  • 210 Kramer JH, Reed BR, Mungas D, Weiner MW, Chui HC. Executive dysfunction in subcortical ischaemic vascular disease. J. Neurol. Neurosurg. Psychiatry 72, 217–220 (2002).
  • 211 Burton E, Ballard C, Stephens S et al. Hyperintensities and fronto-subcortical atrophy on MRI are substrates of mild cognitive deficits after stroke. Dement. Geriatr. Cogn. Disord. 16, 113–118 (2003).
  • 212 Tullberg M, Fletcher E, DeCarli C et al. White matter lesions impair frontal lobe function regardless of their location. Neurology 63, 246–253 (2004).
  • 213 Nordahl CW, Ranganath C, Yonelinas AP et al. White matter changes compromise prefrontal cortex function in healthy elderly individuals. J. Cogn. Neurosci. 18, 418–429 (2006).
  • 214 Foster V, Oakley AE, Slade JY et al. Pyramidal neurons of the prefrontal cortex in post-stroke, vascular and other ageing-related dementias. Brain 137, 2509–2521 (2014).
  • 215 Regan C, Katona C, Walker Z et al. Relationship of vascular risk to the progression of Alzheimer disease. Neurology 67, 1357–1362 (2006).
  • 216 Wen HM, Mok VC, Fan YH et al. Effect of white matter changes on cognitive impairment in patients with lacunar infarcts. Stroke 35, 1826–1830 (2004).
  • 217 van de Pol L, Gertz HJ, Scheltens P, Wolf H. Hippocampal atrophy in subcortical vascular dementia. Neurodegener. Dis. 8, 465–469 (2011).
  • 218 Wang R, Fratiglioni L, Laveskog A et al. Do cardiovascular risk factors explain the link between white matter hyperintensities and brain volumes in old age? A population-based study. Eur. J. Neurol. 21, 1076–1082 (2014).
  • 219 Wardlaw JM, Allerhand M, Doubal FN et al. Vascular risk factors, large-artery atheroma, and brain white matter hyperintensities. Neurology 82, 1331–1338 (2014).• Vascular risk factors for brain white matter lesions.
  • 220 D'Abreu A, Ott BR. Poststroke dementia. In: Vascular Dementia: Cerebrovascular Mechanisms and Clinical Management. Salloway S (Ed.). Human Press Inc., NJ, USA, 231–241 (2005).
  • 221 Reed BR, Eberling JL, Mungas D, Weiner M, Jagust WJ. Frontal lobe hypometabolism predicts cognitive decline in patients with lacunar infarcts. Arch. Neurol. 58, 493–497 (2001).
  • 222 Naritomi H. Experimental basis of multi-infarct dementia: memory impairments in rodent models of ischemia. Alzheimer Dis. Assoc. Disord. 5, 103–111 (1991).
  • 223 Sarti C, Pantoni L, Bartolini L, Inzitari D. Cognitive impairment and chronic cerebral hypoperfusion: what can be learned from experimental models. J. Neurol. Sci. 203–204, 263–266 (2002).
  • 224 Swartz RH, Sahlas DJ, Black SE. Strategic involvement of cholinergic pathways and executive dysfunction: does location of white matter signal hyperintensities matter? J. Stroke Cerebrovasc. Dis. 12, 29–36 (2003).
  • 225 Hamel E. Cholinergic modulation of the cortical microvascular bed. Prog. Brain Res. 145, 171–178 (2004).
  • 226 Sato A, Sato Y, Uchida S. Activation of the intracerebral cholinergic nerve fibers originating in the basal forebrain increases regional cerebral blood flow in the rat's cortex and hippocampus. Neurosci. Lett. 361, 90–93 (2004).
  • 227 Tomimoto H, Ohtani R, Shibata M, Nakamura N, Ihara M. Loss of cholinergic pathways in vascular dementia of the Binswanger type. Dement. Geriatr. Cogn. Disord. 19, 282–288 (2005).
  • 228 Sharp SI, Francis PT, Elliott MS et al. Choline acetyltransferase activity in vascular dementia and stroke. Dement. Geriatr. Cogn. Disord. 28, 233–238 (2009).
  • 229 Kim SH, Kang HS, Kim HJ et al. The effect of ischemic cholinergic damage on cognition in patients with subcortical vascular cognitive impairment. J. Geriatr. Psychiatry Neurol. 25, 122–127 (2012).
  • 230 Keverne JS, Low WC, Ziabreva I et al. Cholinergic neuronal deficits in CADASIL. Stroke 38, 188–191 (2007).
  • 231 Román GC, Kalaria RN. Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia. Neurobiol. Aging 27, 1769–1785 (2006).
  • 232 Jung S, Zarow C, Mack WJ et al. Preservation of neurons of the nucleus basalis in subcortical ischemic vascular disease. Arch. Neurol. 69, 879–886 (2012).
  • 233 Zhan SS, Beyreuther K, Schmitt HP. Synaptophysin immunoreactivity of the cortical neuropil in vascular dementia of Binswanger type compared with the dementia of Alzheimer type and nondemented controls. Dementia 5, 79–87 (1994).
  • 234 Ishunina TA, Kamphorst W, Swaab DF. Metabolic alterations in the hypothalamus and basal forebrain in vascular dementia. J. Neuropathol. Exp. Neurol 63, 1243–1254 (2004).
  • 235 Montine TJ, Phelps CH, Beach TG et al. National Institute on Aging: Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol. 123, 1–11 (2012).
  • 236 Hyman BT, Phelps CH, Beach TG et al. National Institute on Aging: Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement. 8, 1–13 (2012).
  • 237 Deramecourt V, Slade JY, Oakley AE et al. Staging and natural history of cerebrovascular pathology in dementia. Neurology 78, 1043–1050 (2012).
  • 238 Selnes OA, Vinters HV. Vascular cognitive impairment. Nat. Clin. Pract. Neurol. 2, 538–547 (2006).
  • 239 Hainsworth AH, Brittain JF, Khatun H. Pre-clinical models of human cerebral small vessel disease: utility for clinical application. J. Neurol. Sci. 322, 237–240 (2012).
  • 240 Ihara M, Tomimoto H. Lessons from a mouse model characterizing features of vascular cognitive impairment with white matter changes. J. Aging Res. 2011, 978761 (2011).
  • 241 Lee JH, Bacskai BJ, Ayata C. Genetic animal models of cerebral vasculopathies. Prog. Mol. Biol. Transl. Sci. 105, 25–55 (2012).
  • 242 Tomimoto H, Wakita H. Animal models of vascular dementia: translational potential at the present time and in 2050. Future Neurol. 9, 163–172 (2014).• Current review of animal models of vascular dementia.
  • 243 Maki T, Ihara M, Fujita Y et al. Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice. Stroke 42, 1122–1128 (2011).
  • 244 Butler R, Radhakrishnan R. Dementia. Clin. Evid. (Online) 2012, pii: 1001 (2012).
  • 245 Gorelick PB, Nyenhuis D. Understanding and treating vascular cognitive impairment. Continuum (Minneap. Minn.) 19, 425–437 (2013).
  • 246 Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol. 6, 782–792 (2007).
  • 247 Birks J, McGuinness B, Craig D. Rivastigmine for vascular cognitive impairment. Cochrane Database Syst. Rev. 5, CD004744 (2013).
  • 248 Birks J, Craig D. Galantamine for vascular cognitive impairment. Cochrane Database Syst. Rev. 4, CD004746 (2006).
  • 249 Chen N, Yang M, Guo J et al. Cerebrolysin for vascular dementia. Cochrane Database Syst. Rev. 1, CD008900 (2013).
  • 250 Li F, Cai RL, Zhai L, Gao K, Yang J. Impacts of acupuncture at Jing-well points on the differentiated meridians and temple-three-needle therapy on P300 of patients with early vascular cognitive impairment. Zhongguo Zhen Jiu 33, 784–788 (2013).
  • 251 Peng WN, Zhao H, Liu ZS, Wang S. Acupuncture for vascular dementia. Cochrane Database Syst. Rev. 18(2), CD004987 (2007).
  • 252 Shi GX, Liu CZ, Guan W et al. Effects of acupuncture on Chinese medicine syndromes of vascular dementia. Chin. J. Integr. Med. 20(9), 661–666 (2013).
  • 253 Zhou L, Zhang YL, Cao HJ, Hu H. Treating vascular mild cognitive impairment by acupuncture: a systematic review of randomized controlled trials. Zhongguo Zhong Xi Yi Jie He Za Zhi 33, 1626–1630 (2013).
  • 254 Clinical Trials. www.clinicaltrials.gov.
  • 255 Xing SH, Zhu CX, Zhang R, An L. Huperzine A in the treatment of Alzheimer's disease and vascular dementia: a meta-analysis. Evid Based Complement Alternat. Med. 2014, 363985 (2014).
  • 256 Herrmann N, Lanctot KL, Hogan DB. Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimers Res. Ther. 5, S5 (2013).
  • 257 Soros P, Whitehead S, Spence JD, Hachinski V. Antihypertensive treatment can prevent stroke and cognitive decline. Nat. Rev. Neurol. 9, 174–178 (2013).
  • 258 Gorelick PB. Blood pressure and the prevention of cognitive impairment. JAMA Neurol. 71, 1211–1213 (2014).
  • 259 Valenti R, Pantoni, L, Markus HS. Treatment of vascular risk factors in patients with a diagnosis of Alzheimer's disease: a systematic review. BMC Med. 12, 160 (2014).
  • 260 McGuinness B, O'Hare J, Craig D et al. Cochrane review on ‘Statins for the treatment of dementia’. Int. J. Geriatr. Psychiatry 28, 119–126 (2013).
  • 261 Perez L, Heim L, Sherzai A, Jaceldo-Siegl K. Nutrition and vascular dementia. J. Nutr. Health Aging 16, 319–324 (2012).
  • 262 Caracciolo B, Xu W, Collins S, Fratiglioni L. Cognitive decline, dietary factors and gut-brain interactions. Mech. Ageing Dev. 136–137, 59–61 (2013).
  • 263 Skoog I, Korczyn AD, Guekht A. Neuroprotection in vascular dementia: a future path. J. Neurol. Sci. 322, 232–236 (2012).
  • 264 Barberger-Gateau P, Samieri C, Allès B, Féart C. Could nutrition prevent the onset of dementia? Current evidence from epidemiological and intervention studies. Neurodegen. Dis. Manag. 2, 205–314 (2012).
  • 265 Aarsland D, Sardahaee FS, Anderssen S, Ballard C. Is physical activity a potential preventive factor for vascular dementia? A systematic review. Aging Ment. Health 14, 386–395 (2010).
  • 266 Verdelho A, Madureira S, Ferro JM et al. Physical activity prevents progression for cognitive impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study. Stroke 43, 3331–3335 (2012).
  • 267 Uemura K, Doi T, Shimada H et al. Effects of exercise intervention on vascular risk factors in older adults with mild cognitive impairment: a randomized controlled trial. Dement. Geriatr. Cogn. Dis. Extra 2, 445–455 (2012).
  • 268 Wirth M, Haase CM, Villeneuve S, Vogel J, Jagust WJ. Neuroprotective pathways: lifestyle activity, brain pathology, and cognition in cognitively normal older adults. Neurobiol. Aging 35, 1873–1882 (2014).
  • 269 Debette S. Vascular risk factors and cognitive disorders. Rev. Neurol. (Paris) 169, 757–764 (2013).
  • 270 Rooney RF. Preventing dementia: how lifestyle in midlife affects risk. Curr. Opin. Psychiatry 27, 149–157 (2014).
  • 271 Reis JP, Loria CM, Launer LJ et al. Cardiovascular health through young adulthood and cognitive functioning in midlife. Ann. Neurol. 73, 170–179 (2013).
  • 272 Dichgans M, Zietemann V. Prevention of vascular cognitive impairment. Stroke 43, 3137–3146 (2012).
  • 273 Kaerst L, Kuhlmann A, Wedekind D et al. Cerebrospinal fluid biomarkers in Alzheimer's disease, vascular dementia and ischemic stroke patients: a critical analysis. J. Neurol. 260, 2722–2727 (2013).
  • 274 Olsson B, Hertze J, Lautner R et al. Microglial markers are elevated in the prodromal phase of Alzheimer's disease and vascular dementia. J. Alzheimers Dis. 33, 45–53 (2013).
  • 275 Olsson B, Hertze J, Ohlsson M et al. Cerebrospinal fluid levels of heart fatty acid binding protein are elevated prodromally in Alzheimer's disease and vascular dementia. J. Alzheimers Dis. 34, 673–679 (2013).
  • 276 Chui HC, Ramirez-Gomez L. Clinical and imagingfeatures of mixed Alzheimer and vascular pathologies. Alz. Res. Therapy (2014) (In Press).
  • 277 Kling MA, Trojanowski JQ, Wolk DA, Lee VM, Arnold SE. Vascular disease and dementias: paradigm shifts to drive research in new directions. Alzheimers Dement. 9, 76–92 (2013).
  • 278 Solomon A, Mangialasche F, Richard E et al. Advances in the prevention of Alzheimer's disease and dementia. J. Intern. Med. 275, 229–250 (2014).