Advertisement
Mayo Clinic Proceedings Home

Dementia and Cerebrovascular Disease

  • Author Footnotes
    * Dr Knopman has served as an ad hoc consultant to GE Healthcare, Myriad Pharmaceuticals, and Neurochem Pharmaceuticals in the past 2 years and participated in a clinical trial sponsored by Elan Pharmaceuticals.
    David S. Knopman
    Correspondence
    Address reprint requests and correspondence to David S. Knopman, MD, Department of Neurology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905
    Footnotes
    * Dr Knopman has served as an ad hoc consultant to GE Healthcare, Myriad Pharmaceuticals, and Neurochem Pharmaceuticals in the past 2 years and participated in a clinical trial sponsored by Elan Pharmaceuticals.
    Affiliations
    Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minn
    Search for articles by this author
  • Author Footnotes
    * Dr Knopman has served as an ad hoc consultant to GE Healthcare, Myriad Pharmaceuticals, and Neurochem Pharmaceuticals in the past 2 years and participated in a clinical trial sponsored by Elan Pharmaceuticals.
      Cerebrovascular disease is an important cause of cognitive impairment and dementia in elderly patients. This review highlights the challenges involved in examining the role of cerebrovascular disease in dementia, areas in which consensus is emerging, and an operational framework for clinicians. Two important challenges exist. First, there is no accepted neuropathologic scheme for quantitating cerebrovascular disease in cognitive disturbances. Second, agreement on clinical definitions of vascular dementia is incomplete. Despite the barriers posed by these 2 deficiencies, many consistencies in the clinical, imaging, epidemiological, and neuropathologic aspects of cerebrovascular disease and cognitive impairment have been identified. Different levels of cerebrovascular disease related to cognitive impairment can be suggested on clinical and imaging grounds. The overlap between cerebrovascular disease and Alzheimer disease produces a disorder that might be amenable to therapeutic approaches based on either mechanism.
      AD (Alzheimer disease), NINDS-AIREN (National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences), VaD (vascular dementia), WMH (white matter hyperintensities)
      The link between cerebrovascular disease and dementia has been a controversial topic for decades. At one point, cerebrovascular disease was believed to be the dominant cause of dementia. Then, as recently as a decade ago, it was thought to be exceedingly rare. By 2005, the pendulum has begun to swing back to a larger role for cerebrovascular disease in cognitive disorders. Although recognition of the importance of cerebrovascular disease in dementia is widely accepted, major challenges to the concept remain.
      The terminology for dementia in cerebrovascular disease has long been in question. In the modern era, multi-infarct dementia was preferred for some time; however, this term fails to account for cases with one strategic infarct or with extensive white matter disease. The term vascular dementia (VaD) is currently favored but also has been criticized on several grounds. First, the term obviously focuses on dementia rather than the broader category of cognitive impairment of any level. Second, it implies a certain degree of homogeneity of clinical presentation that does not correspond to reality. Although cerebral infarction may be the common mechanism, the diversity of infarct locations and sizes makes for a clinically heterogeneous disorder. Others, in coming to similar conclusions, have called for fundamental revisions of the concept of cerebrovascular disease and dementia.
      • Hachinski V
      Vascular dementia: a radical redefinition.
      • Bowler JV
      The concept of vascular cognitive impairment.
      This review highlights the challenges involved in examining the role of cerebrovascular disease in dementia, the areas in which consensus is emerging, and an operational framework for clinicians.

      COGNITIVE IMPAIRMENT AND DEMENTIA

      Dementia is a disorder in which individuals lose independence of daily functioning because of cognitive dysfunction. Implicit in the definition of dementia is the loss of ability compared with prior levels of performance. Cognitive dysfunction that does not substantially interfere with daily functioning may also occur. This latter condition is now referred to as mild cognitive impairment. Both mild cognitive impairment and dementia may be caused by cerebrovascular disease.

      CHALLENGES

      Lack of Conceptual Framework for Pathologic VaD Diagnosis

      Criteria for the pathologic diagnosis of cerebrovascular disease sufficient to cause dementia have never been agreed on, and no comprehensive scheme has ever been proposed. There is a pressing need to develop a coherent and comprehensive view of the neuropathologic basis of VaD.
      • Kalaria RN
      • Kenny RA
      • Ballard CG
      • Perry R
      • Ince P
      • Polvikoski T
      Towards defining the neuropathological substrates of vascular dementia.
      In their seminal 1968 article, Blessed et al
      • Blessed G
      • Tomlinson BE
      • Roth M
      The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects.
      hypothesized that infarct volume was the critical feature of VaD, but they did not consider lesion location. The problem that has thus far eluded experts in the field is how to quantify the location and size of infarcts in a way that is logically related to severity of cognitive impairment. There is no conceptual agreement on how to define a threshold for location and size of infarction that equates with a pathologic diagnosis of VaD. This critical deficiency means that no consensus gold standard exists for the pathologic diagnosis. There is no doubt that expert neuropathologists have criteria derived from their own experience, but it is likely that the interobserver reliability of such diagnoses is low.
      An additional contributing problem to the pathologic diagnosis of critical cerebrovascular disease in dementia is the presence of concomitant Alzheimer disease (AD). Alzheimer disease is common in older people, and the burden of AD increases with advancing age.
      • Braak H
      • Braak E
      Frequency of stages of Alzheimer-related lesions in different age categories.
      (Lewy body disease and other less common pathologic changes may also co-occur with AD and cerebrovascular disease in elderly patients, but they are not nearly as common as AD.) In our autopsy series of 89 patients with dementia,
      • Knopman DS
      • Parisi JE
      • Boeve BF
      • et al.
      Vascular dementia in a population-based autopsy study.
      11 (12%) had a combination of cerebrovascular disease with multiple infarcts and AD features, 15 (17%) had 1 infarct with or without rare microscopic infarcts and prominent AD features, and 30 (34%) had pure AD. In 12 cases (13%), there was only cerebrovascular disease and no AD. Although there is general agreement about the neuropathologic diagnosis of AD, the presence of low to moderate levels of AD in many dementia cases with cerebrovascular disease has made it more difficult to determine the independent role of cerebrovascular disease in dementia.
      The role of microvascular disease in cognitive disorders is expanding. Microvascular disease refers to the evidence of infarction that is seen microscopically but cannot be seen on gross inspection of the brain. Despite one provocative clinicopathologic study in Japanese-American patients that observed that microvascular disease accounted for a substantial amount of the variation in cognition,
      • White L
      • Petrovitch H
      • Hardman J
      • et al.
      Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants.
      the contribution of microvascular disease to cognitive dysfunction in other populations is based mainly on inference from imaging studies.
      Diagnosing dementia in postmortem brain is typically performed by a combination of gross and microscopic examinations. In routine neuropathologic practice, sampling of a modest number of brain areas is performed, which may be adequate for neurodegenerative diseases. For the diagnosis of cerebrovascular disease in dementia, a much more exhaustive approach may be needed because of the patchy nature of smaller macroscopic and microscopic infarction. Routine autopsy procedures may be inadequate for estimating the burden of cerebrovascular disease in the setting of a cognitive disorder. To study cerebrovascular disease in dementia adequately, prospective studies specifically designed for detecting cerebrovascular disease must be performed.

      Lack of Clinical Diagnostic Criteria for VaD

      If uncertainty occurs about the pathologic diagnosis of VaD, it should not be surprising that there is poor correspondence between clinical and pathologic diagnoses of VaD. Overall diagnostic accuracy for VaD is low.
      • Knopman DS
      • Parisi JE
      • Boeve BF
      • et al.
      Vascular dementia in a population-based autopsy study.
      • Holmes C
      • Cairns N
      • Lantos P
      • Mann A
      Validity of current clinical criteria for Alzheimer's disease, vascular dementia and dementia with Lewy bodies.
      For example, a population-based clinicopathologic study in the United Kingdom found that the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) diagnostic criteria had a sensitivity of 43%
      • Roman GC
      • Tatemichi TK
      • Erkinjuntti T
      • et al.
      Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop.
      and a specificity of 95%.
      • Holmes C
      • Cairns N
      • Lantos P
      • Mann A
      Validity of current clinical criteria for Alzheimer's disease, vascular dementia and dementia with Lewy bodies.
      The flaws in the neuropathologic gold standard have contributed to a proliferation of definitions of VaD. The different definitions contain common themes but have many unique variations. Many studies, all in agreement, have shown that these various criteria provide diverse estimates of rates of VaD.
      • Wetterling T
      • Kanitz RD
      • Borgis KJ
      Comparison of different diagnostic criteria for vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN).
      • Pohjasvaara T
      • Mantyla R
      • Ylikoski R
      • Kaste M
      • Erkinjuntti T
      • National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche el l'enseignement en Neurosciences
      Comparison of different clinical criteria (DSM-III, ADDTC, ICD-10, NINDS-AIREN, DSM-IV) for the diagnosis of vascular dementia.
      • Gold G
      • Giannakopoulos P
      • Montes-Paixao Junior C
      • et al.
      Sensitivity and specificity of newly proposed clinical criteria for possible vascular dementia.
      Clinical trials, prevalence and incidence studies, and studies of risk factors are rendered incompatible with one another because of the use of different diagnostic criteria across studies. In our experience with a group of patients with clinically diagnosed dementia, application of the NINDS-AIREN criteria gave a proportionate incidence rate for VaD of 4%, whereas application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
      • American Psychiatric Association
      criteria in the same patient population gave a rate of 29%.
      • Knopman DS
      • Rocca WA
      • Cha RH
      • Edland SD
      • Kokmen E
      Incidence of vascular dementia in Rochester, Minn, 1985-1989.
      Neither estimate corresponded closely with neuropathologic diagnoses.
      • Knopman DS
      • Parisi JE
      • Boeve BF
      • et al.
      Vascular dementia in a population-based autopsy study.
      The spectrum of cerebrovascular disease in dementia ranges from a relatively small number of individuals with many features to a larger number with fewer or less specific features of cerebrovascular disease. Categorical diagnostic approaches represent this pattern poorly. A more quantitative approach might better capture this variation. The Ischemic Index, often referred to as the Hachinski Ischemic Scale,
      • Hachinski VC
      • Lassen NA
      • Marshall J
      Multi-infarct dementia: a cause of mental deterioration in the elderly.
      is the only clinical diagnostic tool for cerebrovascular disease and dementia that quantitates clinical features. In contrast to formal diagnostic criteria for VaD, the Ischemic Index has been validated against neuropathologic diagnoses.
      • Rosen WG
      • Terry RD
      • Fuld PA
      • Katzman R
      • Peck A
      Pathological verification of ischemic score in differentiation of dementias.
      • Moroney JT
      • Bagiella E
      • Desmond DW
      • et al.
      Meta-analysis of the Hachinski Ischemic Score in pathologically verified dementias.
      Unfortunately, the Ischemic Index was devised in 1974 before the advent of computed tomography and magnetic resonance imaging. In the final section of this article, an index of cerebrovascular disease in dementia is proposed that represents cerebrovascular disease in cognitive disorders as a spectrum, just as the Hachinski Ischemic Scale sought to do.

      The Spectrum of AD and VaD

      Terms such as AD with cerebrovascular disease, mixed dementia, or possible VaD have been used to reflect the common co-occurrence both clinically and pathologically of the 2 disorders. They appear as afterthoughts to the individual disorders, which has unfortunate effects. Either the overlap condition is ignored in favor of dichotomous diagnostic groupings of AD or VaD or, if a separate category is used for the overlap condition, the subject group may seem too heterogeneous or too arbitrary to work with.

      POINTS OF AGREEMENT

      Yet, in the face of these problems, it is not necessary to accept a nihilistic view of cerebrovascular disease in dementia. In fact, several issues have good and consistent empirical support. By avoiding the constraint of one definition of clinical VaD or its pathologic substrate, it is possible to make some sense of the role of individual features of cerebrovascular disease in cognitive disorders and dementia.

      Clinical Features

      Increased Rate of Dementia After a Stroke. In the first few years after a stroke, the rate of dementia is greatly increased.
      • Henon H
      • Durieu I
      • Guerouaou D
      • et al.
      Poststroke dementia: incidence and relationship to prestroke cognitive decline.
      • Kokmen E
      • Whisnant JP
      • O'Fallon WM
      • Chu CP
      • Beard CM
      Dementia after ischemic stroke: a population-based study in Rochester, Minnesota (1960-1984).
      • Pohjasvaara T
      • Mantyla R
      • Salonen O
      • et al.
      MRI correlates of dementia after first clinical ischemic stroke.
      • Tatemichi TK
      • Desmond DW
      • Stern Y
      • Paik M
      • Sano M
      • Bagiella E
      Cognitive impairment after stroke: frequency, patterns, and relationship to functional abilities.
      As many as 30% of stroke survivors in one study had dementia by 6 months after their stroke.
      • Tatemichi TK
      • Desmond DW
      • Stern Y
      • Paik M
      • Sano M
      • Bagiella E
      Cognitive impairment after stroke: frequency, patterns, and relationship to functional abilities.
      Another study characterized the risk of dementia as 9-fold compared with individuals of the same age and sex without a new stroke.
      • Kokmen E
      • Whisnant JP
      • O'Fallon WM
      • Chu CP
      • Beard CM
      Dementia after ischemic stroke: a population-based study in Rochester, Minnesota (1960-1984).
      Features that further increase that risk are older age, low education, prior cognitive impairment, prior silent infarcts on imaging, diabetes mellitus, left hemisphere stroke location, extensive amount of white matter hyperintensities (WMH), and hippocampal volume loss. Population-based longitudinal studies also show that incident stroke results in accelerated cognitive decline.
      • Knopman D
      • Boland LL
      • Mosley T
      • Atherosclerosis Risk in Communities (ARIC) Study Investigators
      • et al.
      Cardiovascular risk factors and cognitive decline in middle-aged adults.
      • Kuller LH
      • Shemanski L
      • Manolio T
      • et al.
      Relationship between ApoE, MRI findings, and cognitive function in the Cardiovascular Health Study.
      The consistent and powerful link between an acute stroke and subsequent cognitive decline defines one type of vascular cognitive disorder. From a clinician's perspective, the possibility of poststroke dementia should be factored into planning for medical care during the first year after a stroke, especially if 1 or more of the higher-risk features were present.
      Several of the existing clinical criteria for VaD have incorporated the link between stroke and subsequent dementia. With the caveats about neuropathologic diagnoses in mind, our studies support this feature as specific for VaD, but it had only modest sensitivity. In an autopsy series, we found that 15 of 89 patients developed dementia after a stroke. Ten (67%) had substantial infarction at autopsy.
      • Knopman DS
      • Parisi JE
      • Boeve BF
      • et al.
      Vascular dementia in a population-based autopsy study.
      None of the pathologically pure AD cases exhibited this feature.
      Lack of Cognitive Profile Diagnostic of Pure Cerebrovascular Disease. From a conceptual perspective, a wide variety of cognitive deficits from stroke should be possible because any brain region could be involved in a zone of infarction. Prominent amnesic disturbances, aphasia, visuospatial deficits, and executive deficits are all possible in patients with pure cerebrovascular disease.
      Few studies based on pathologic confirmation of diagnosis have compared cognitive profiles of VaD vs other dementias.
      • Reed BR
      • Mungas DM
      • Kramer JH
      • et al.
      Clinical and neuropsychological features in autopsy-defined vascular dementia.
      Some group differences exist between patients with clinically diagnosed VaD vs AD, such as a greater likelihood of attentional and executive deficits and a lower likelihood of anterograde amnesia.
      • Looi JC
      • Sachdev PS
      Differentiation of vascular dementia from AD on neuropsychological tests.
      In population-based longitudinal studies of cardiovascular risk factors and cognition, hypertension and diabetes have been associated with increased rates of decline in tests of psychomotor speed rather than in tests of memory.
      • Knopman D
      • Boland LL
      • Mosley T
      • Atherosclerosis Risk in Communities (ARIC) Study Investigators
      • et al.
      Cardiovascular risk factors and cognitive decline in middle-aged adults.
      • Haan MN
      • Shemanski L
      • Jagust WJ
      • Manolio TA
      • Kuller L
      The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons.
      The tendency for cerebrovascular disease to preferentially affect psychomotor slowing, attention, and executive function does not translate into a set of diagnostic features that distinguish cerebrovascular disease from AD. In practice, the cognitive deficits that occur with cerebrovascular disease are simply too heterogeneous to be characterized by 1 pattern of cognitive deficits.
      • Reed BR
      • Mungas DM
      • Kramer JH
      • et al.
      Clinical and neuropsychological features in autopsy-defined vascular dementia.
      Therefore, although a careful assessment of cognitive function has merit for characterizing the degree of cognitive impairment, the cognitive profile of someone with dementia or mild cognitive impairment by itself is not useful for establishing whether cerebrovascular disease contributes to the cognitive disorder.
      Modest Value of Focal Neurologic Signs. The presence of focal neurologic signs, such as hemiparesis, hemianopia, or hemisensory loss, strongly suggests a cerebral localization. If these signs are due to stroke, they should be accompanied by a history of stroke or imaging evidence of infarcts. Other causes of these signs must be excluded. When the only focal neurologic sign is a reflex asymmetry or an isolated extensor toe sign, there is less support for a cerebrovascular origin because of the lower specificity of isolated neurologic signs. In contrast, focal neurologic signs, such as hemiparesis, hemisensory loss, or hemianopia, are not necessary to diagnose a cerebrovascular cause of a cognitive disorder. There are many brain locations where cognition can be compromised that do not result in the more typical neurologic signs of stroke.
      Ruling Out AD in Elderly Patients. In cognitively impaired elderly patients, AD can never be ruled out, even in the presence of several convincing features of cerebrovascular disease. No biomarker or imaging evidence of AD exists that has sufficient specificity to enable a clinician to rule out the disorder. For patients with cerebrovascular disease and cognitive impairment who are younger than approximately 65 to 70 years, AD probably plays a minor role. For patients older than 70 years, who constitute most patients with cerebrovascular disease and cognitive impairment, AD should almost always be considered present.
      Use of AD Therapies for Clinically Defined VaD. Several studies with cholinesterase inhibitors have been performed in patients with VaD defined by the NINDS-AIREN criteria.
      • Roman GC
      • Tatemichi TK
      • Erkinjuntti T
      • et al.
      Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop.
      Both patients with probable VaD and those with possible VaD achieved modest benefits with either galantamine
      • Erkinjuntti T
      • Kurz A
      • Gauthier S
      • Bullock R
      • Lilienfeld S
      • Damaraju CV
      Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial.
      or donepezil
      • Black S
      • Roman GC
      • Geldmacher DS
      • Donepezil 307 Vascular Dementia Study Group
      • et al.
      Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial.
      • Wilkinson D
      • Doody R
      • Helme R
      • Donepezil 308 Study Group
      • et al.
      Donepezil in vascular dementia: a randomized, placebo-controlled study.
      compared with placebo-treated patients. Although the patients with VaD in these trials who received placebo appeared to decline more slowly than AD patients in similarly constructed trials, the magnitude of treatment effects in VaD patients was nearly identical to that seen in patients with AD. Memantine, approved for the treatment of moderate to severe AD, has also been studied in patients with VaD using the same diagnostic criteria.
      • Wilcock G
      • Mobius HJ
      • Stoffler A
      • MMM 500 Group
      A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM 500).
      • Orgogozo JM
      • Rigaud AS
      • Stoffler A
      • Mobius HJ
      • Forette F
      Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300).
      The results of these studies have shown modest benefits as well. None of these drugs have gained regulatory approval specifically for VaD.
      The positive results for these 3 agents could reflect their nonspecific nature. In contrast, especially for the cholinesterase inhibitors, the patients with VaD in these studies might have had substantial concomitant AD findings. The therapeutic effects of the cholinesterase inhibitors in clinically diagnosed VaD support that claim.

      Epidemiology

      Dementia With Cerebrovascular Disease Increases With Advancing Age. Even though estimates of the incidence and prevalence of dementia vary from study to study, all population-based epidemiological investigations have shown that VaD increases with advancing age.
      • Knopman DS
      • Rocca WA
      • Cha RH
      • Edland SD
      • Kokmen E
      Incidence of vascular dementia in Rochester, Minn, 1985-1989.
      • Lobo A
      • Launer LJ
      • Fratiglioni L
      • Neurologic Diseases in the Elderly Research Group
      • et al.
      Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts.
      By whatever criteria are being used to define key vascular features, those features become proportionately more common with advancing age. In addition, AD increases with advancing age,
      • Lobo A
      • Launer LJ
      • Fratiglioni L
      • Neurologic Diseases in the Elderly Research Group
      • et al.
      Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts.
      so no age-related variations exist in the incidence of the 2 disorders that can be exploited for diagnostic reasons.
      Because clinical stroke is common and increases with advancing age, cerebrovascular disease and dementia should be commonly encountered in clinical practice. However, in dementia or memory clinics, VaD is often uncommon.
      • Hulette C
      • Nochlin D
      • McKeel D
      • et al.
      Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases.
      There are several reasons why dementia after stroke is underrecognized and underrepresented in dementia clinics. Recovery from stroke is a dynamic process, and as one set of problems resolve, other latent ones such as cognitive impairment then appear. Cognitive impairment in stroke survivors is underrecognized because of the overwhelming nature of other stroke-related deficits such as hemiparesis, hemianopia, or aphasia. In addition, the diagnostic label of “stroke” is probably less threatening to patients and families than “dementia,” so a formal diagnostic linkage of cerebrovascular disease and cognitive impairment is left implicit in many patients. Therefore, although VaD may be uncommon in patients presenting with memory complaints, VaD is common among stroke survivors who do not seek diagnostic evaluations. Dementia with a contribution from cerebrovascular disease should be commonly considered when treating elderly patients in the primary care setting.
      Prognosis of Dementia With Cerebrovascular Disease Compared With AD. Patients with dementia and cerebrovascular disease have worse survival rates compared to those with no evidence of cerebrovascular disease. The higher the grade of cerebrovascular disease burden, the worse the survival rate. One study asserted that patients with clinically defined VaD had survival rates similar to those with AD,
      • Wolfson C
      • Wolfson DB
      • Asgharian M
      • Clinical Progression of Dementia Study Group
      • et al.
      A reevaluation of the duration of survival after the onset of dementia.
      but that study used clinical diagnostic criteria that lacked specificity for important cerebrovascular disease. In our studies, in which we examined survival as a function of individual cerebrovascular features, those with both dementia temporally related to stroke and bilateral infarcts had a worse prognosis than those with only 1 of these features. Having 1 of the features was still worse than having neither feature.
      • Knopman DS
      • Rocca WA
      • Cha RH
      • Edland SD
      • Kokmen E
      Survival study of vascular dementia in Rochester, Minnesota.
      Other features of cerebrovascular disease, such as simply having a history of stroke unrelated in time to the dementia, carried less risk of mortality.
      Cardiovascular Risk Factors and Dementia. Many links exist between vascular disease and AD. Cerebral atherosclerosis is associated with a higher risk of AD.
      • Honig LS
      • Kukull W
      • Mayeux R
      Atherosclerosis and AD: analysis of data from the US National Alzheimer's Coordinating Center.
      Cardiovascular risk factors are associated with clinically diagnosed AD
      • Breteler MM
      • Bots ML
      • Ott A
      • Hofman A
      Risk factors for vascular disease and dementia.
      • Kuller LH
      • Lopez OL
      • Newman A
      • et al.
      Risk factors for dementia in the Cardiovascular Health Cognition Study.
      • Luchsinger JA
      • Reitz C
      • Honig LS
      • Tang MX
      • Shea S
      • Mayeux R
      Aggregation of vascular risk factors and risk of incident Alzheimer disease.
      and VaD.
      • Ross GW
      • Petrovitch H
      • White LR
      • et al.
      Characterization of risk factors for vascular dementia: the Honolulu-Asia Aging Study.
      • Hebert R
      • Lindsay J
      • Verreault R
      • Rockwood K
      • Hill G
      • Dubois MF
      Vascular dementia: incidence and risk factors in the Canadian study of health and aging.
      The commonalities in associations between cardiovascular risk factors and dementia labeled as AD or VaD underline the relevance of vascular disease to dementia and the flaws in simplistic diagnostic categories. The mechanisms by which vascular disease affects dementia could involve both AD and cerebrovascular disease. Vascular risk factors may have a direct effect on AD not mediated through infarction. For example, patients with diabetes might have abnormalities in the processing of the β-amyloid peptide.
      • Craft S
      • Watson GS
      Insulin and neurodegenerative disease: shared and specific mechanisms.
      Vascular risk factors are possibly associated with cognitive impairment through concomitant clinical or subclinical cerebrovascular disease.
      From a clinical perspective, many cardiovascular risk factors are modifiable. Several large prospective studies of hypertension have shown that treatment of hypertension reduces the rate of incident dementia.
      • Hanon O
      • Forette F
      Treatment of hypertension and prevention of dementia.
      In the most recently reported trial of more than 6000 elderly individuals followed up for nearly 4 years, perindopril or indapamide reduced the incidence of dementia from 7.1% to 6.3% (relative risk reduction of 12% compared with controls).
      • Tzourio C
      • Anderson C
      • Chapman N
      • PROGRESS Collaborative Group
      • et al.
      Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease.
      The APOE ε4 genotype is a modest risk factor for cardiovascular disease.
      • Eichner JE
      • Dunn ST
      • Perveen G
      • et al.
      Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review.
      However, the APOE genotype may not have much impact on risk of incident stroke.
      • Slooter AJ
      • Cruts M
      • Hofman A
      • et al.
      The impact of APOE on myocardial infarction, stroke, and dementia: the Rotterdam Study.
      In contrast, it is a powerful risk factor for AD.
      • Farrer LA
      • Cupples LA
      • Haines JL
      • APOE and Alzheimer Disease Meta Analysis Consortium
      • et al.
      Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis.
      Although it has been claimed to be a risk factor for clinically defined VaD,
      • Slooter AJ
      • Tang MX
      • van Duijn CM
      • et al.
      Apolipoprotein E epsilon4 and the risk of dementia with stroke: a population-based investigation.
      the poor specificity of the clinical diagnosis of VaD raises the possibility that the association was driven by the presence of underlying AD. Such a view is supported by the findings that APOE genotype modulated the effects of vascular risk factors on AD.
      • Haan MN
      • Shemanski L
      • Jagust WJ
      • Manolio TA
      • Kuller L
      The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons.
      • Peila R
      • White LR
      • Petrovich H
      • et al.
      Joint effect of the APOE gene and midlife systolic blood pressure on late-life cognitive impairment: the Honolulu-Asia Aging Study.
      • Kalmijn S
      • Feskens EJ
      • Launer LJ
      • Kromhout D
      Cerebrovascular disease, the apolipoprotein e4 allele, and cognitive decline in a community-based study of elderly men.
      The allelic variation in APOE and its relationship to cardiovascular disease and dementia, but not stroke, are an intriguing conundrum that highlights the importance of understanding better the overlap between AD and cerebrovascular disease.

      Imaging

      Lack of Neuroimaging Profile Diagnostic of Pure Cerebrovascular Disease. No neuroimaging profile exists that is diagnostic of pure cerebrovascular disease in a patient with dementia. According to neuropathologic observations, there is no simple way to describe burden of infarction as it relates to dementia. Similar observations have been made in longitudinal studies of stroke survivors.
      • Pohjasvaara T
      • Mantyla R
      • Salonen O
      • et al.
      MRI correlates of dementia after first clinical ischemic stroke.
      • Ballard CG
      • Burton EJ
      • Barber R
      • et al.
      NINDS AIREN neuroimaging criteria do not distinguish stroke patients with and without dementia.
      No consistent pattern of infarction exists in those who developed dementia and those who did not.
      In contrast, if infarcts are apparent on imaging, especially ones larger than lacunes, indisputable evidence exists for cerebrovascular disease. Although there is no guarantee that the cerebrovascular disease is etiologically related to the dementia, it seems reasonable to hypothesize that a greater burden of visible infarcts by imaging implies a greater likelihood that cerebrovascular disease affects cognition.
      Association of Silent Infarcts With Cognitive Impairment. Several population-based studies that included imaging in their subject evaluation protocols have found a remarkably high rate of silent infarcts on imaging, some as high as 20%.
      • Longstreth Jr, WT
      • Bernick C
      • Manolio TA
      • Bryan N
      • Jurgreis CA
      • Price TR
      Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study.
      These infarcts are referred to as silent because there was no clinical history of a stroke. Importantly, these studies have also included cognitive assessments. Patients with silent infarcts on imaging had greater cognitive decline compared with those with no silent infarcts.
      • Longstreth Jr, WT
      • Dulberg C
      • Manolio TA
      • et al.
      Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.
      Silent infarcts were also associated with a greater risk of subsequent dementia. In a study from the Netherlands, the hazard ratio for the risk of dementia with any silent infarcts, in which they were characterized simply as present or absent, was 2.26 (95% confidence interval, 1.1-4.7).
      • Vermeer SE
      • Prins ND
      • den Heijer T
      • et al.
      Silent brain infarcts and the risk of dementia and cognitive decline.
      Therefore, even in the absence of overt strokes, cerebrovascular disease on magnetic resonance imaging is associated with subsequent risk of cognitive decline and dementia. Infarcts on imaging have validity as evidence of cerebrovascular disease.
      WMH and Cognitive Impairment. White matter hyperintensities, sometimes referred to as leukoariosis, are often seen on magnetic resonance images in elderly individuals. White matter hyperintensities represent areas of demyelination, enlarged perivascular spaces, and occasionally infarctions. A large body of work has revealed several consistent observations about WMH, their relationship to vascular disease, and their relationship to cognition. White matter hyperintensities are common in elderly patients and increase in intensity with advancing age.
      • Longstreth Jr, WT
      • 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.
      They are clearly associated with several conditions, the most notable of which is hypertension.
      • Longstreth Jr, WT
      • 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.
      • Breteler MM
      • van Swieten JC
      • Bots ML
      • et al.
      Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study.
      Other cardiovascular risk factors, such as diabetes, cigarette smoking, or elevated homocysteine level, are also often associated with WMH. The presence of increasing burdens of WMH is associated with a greater risk of stroke. In addition, WMH are associated with cognitive impairment
      • de Groot JC
      • de Leeuw FE
      • Oudkerk M
      • et al.
      Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study.
      and greater risk of cognitive decline.
      • De Groot JC
      • De Leeuw FE
      • Oudkerk M
      • et al.
      Periventricular cerebral white matter lesions predict rate of cognitive decline.
      One study showed that the rate of subsequent cognitive decline in individuals without dementia but with severe WMH was 3 times that of people without dementia overall.
      • De Groot JC
      • De Leeuw FE
      • Oudkerk M
      • et al.
      Periventricular cerebral white matter lesions predict rate of cognitive decline.
      In studies that included patients with cognitive impairment and controls, WMH were an independent predictor of cognitive decline, even more powerfully than the presence of lacunar infarcts.
      • Mungas D
      • Jagust WJ
      • Reed BR
      • et al.
      MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer's disease.
      Not surprisingly, severe WMH in individuals without dementia are also a risk factor for the subsequent development of dementia
      • Prins ND
      • van Dijk EJ
      • den Heijer T
      • et al.
      Cerebral white matter lesions and the risk of dementia.
      and cerebrovascular disease. Progressively lesser grades of WMH have less linkage to cerebrovascular disease.
      Hippocampal Atrophy in AD. Hippocampal atrophy on magnetic resonance imaging has been studied intensely in AD and mild cognitive impairment. Although there is no doubt that hippocampal atrophy is a common finding in AD, the presence of hippocampal atrophy cannot be taken as proof that AD is the cause of the cognitive disorder to the exclusion of cerebrovascular disease. Infarcts may involve the hippocampus directly, and subcortical ischemic vascular disease can also affect hippocampal volume.
      • Zarow C
      • Vinters HV
      • Ellis WG
      • et al.
      Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia.

      Pathologic Findings

      Cerebrovascular Disease and Clinical Expression of AD. Alzheimer disease and cerebrovascular disease have a complementary relationship. Even without specifying infarct location and size, a relationship between the presence of any infarction and AD exists. If cerebrovascular disease is present, it takes fewer AD pathologic features to produce the same degree of dementia.
      • Heyman A
      • Fillenbaum GG
      • Welsh-Bohmer KA
      • Consortium to Establish a Registry for Alzheimer's Disease
      • et al.
      Cerebral infarcts in patients with autopsy-proven Alzheimer's disease: CERAD, part XVIII [published correction appears in Neurology. 1998;51:1809].
      • Snowdon DA
      • Greiner LH
      • Mortimer JA
      • Riley KP
      • Greiner PA
      • Markesbery WR
      Brain infarction and the clinical expression of Alzheimer disease: the Nun Study.
      • Schneider JA
      • Wilson RS
      • Bienias JL
      • Evans DA
      • Bennett DA
      Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology.
      • Petrovitch H
      • Ross GW
      • Steinhorn SC
      • et al.
      AD lesions and infarcts in demented and non-demented Japanese-American men.
      • Riekse RG
      • Leverenz JB
      • McCormick W
      • et al.
      Effect of vascular lesions on cognition in Alzheimer's disease: a community-based study.
      The presence of cerebrovascular disease in patients with dementia and concomitant AD will tend to produce a more severe dementia (Figure 1). It is clear that there are no easy categorical distinctions between the 2 diseases. Instead, they exist in tandem.
      Figure thumbnail gr1
      FIGURE 1Balance between Alzheimer disease (AD) and cerebrovascular disease and the mapping of clinical diagnoses on the pathologic findings. Diagnostic labels at the bottom of the graph depict current common use. Shaded area covers the broad region that represents the overlap of the 2 diseases, encroaching on regions that might currently be labeled as AD and especially on regions that are currently called vascular dementia (VaD). Diagnostic areas are not drawn to the scale of the relative prevalence of the disorders.
      Predictable Cognitive Deficits After Stroke. On the basis of clinical experience, moderate-sized infarcts (larger than lacunar infarcts) in the caudate, thalamus, hippocampus, dominant perisylvian region, or nondominant posterior perisylvian region invariably produce acute stroke syndromes with obvious cognitive dysfunction. Clinically, covert large infarcts in these regions are probably uncommon. The cognitive dysfunction may improve substantially in the weeks and months after the stroke, but deficits may be permanent. Some of these deficits could reach the threshold for dementia. Infarcts in these regions in the setting of a cognitive disorder represent strong evidence of relevant cerebrovascular disease.

      OPERATIONAL FRAMEWORK FOR CEREBROVASCULAR DISEASE IN DEMENTIA

      Alzheimer disease and cerebrovascular disease occur together in elderly patients. Clinically defined VaD and AD both are highly likely to have pathologic contributions from both cerebrovascular disease and AD. Imposing arbitrary boundaries between the 2 is misleading. Important contributions of cerebrovascular disease in patients who might be labeled as having pure AD might go unrecognized, as might the contributions of AD to many cases labeled as pure VaD. Both AD and cerebrovascular disease must be considered together clinically, epidemiologically, and neuropathologically.
      Cerebrovascular disease is clinically heterogeneous. It can involve any cerebral region, produce any pattern of cognitive deficits, and evolve in complex ways. However, amidst this heterogeneity are 3 features—imaging, history of stroke, and neurologic signs—that have obvious specificity for cerebrovascular disease. The clinical and imaging features relevant to cerebrovascular disease in dementia are given in Table 1. Some features can be viewed in terms of their impact. For example, a stroke that was temporally related to the subsequent development of dementia is a stronger cerebrovascular feature than a stroke with no cognitive sequelae. Two infarcts on imaging should have more impact than 1 infarct.
      TABLE 1Index of Cerebrovascular Disease (CVD) in Cognitive Impairment
      Probability of CVD
      Not supportive (low)Supportive (moderate)Strongly supportive (high)
      No history of strokeAny stroke above midbrain by history, without subsequent impact on cognitionStroke temporally related to onset of dementia or worsening of cognition
      One focal sign (eg, an unexplained extensor toe sign or a reflex asymmetry)2 or 3 neurologic signs suggestive of cerebrovascular originMultiple neurologic signs strongly suggestive of cerebrovascular origin
      White matter hyperintensities, none or minimalWhite matter hyperintensities, mild to moderateWhite matter hyperintensities, severe
      0 or 1 lacune2 to 3 lacunes≥4 lacunes
      No cortical infarcts or only 1 small oneCortical infarct, singleCortical infarcts, large, multiple
      No infarcts in critical regionsLacune or small infarct only in critical regionsHippocampal, caudate, thalamic infarct larger than lacune
      The analysis of the data on cerebrovascular disease and cognitive impairment can be summarized by the following statements.
      • 1.
        A history of stroke, imaging evidence of stroke, and neurologic signs typical of stroke are the best clinical indicators of cerebrovascular disease.
      • 2.
        The more clinical evidence for cerebrovascular disease implies greater cerebrovascular disease.
      • 3.
        Alzheimer disease commonly accompanies cerebrovascular disease in dementia.
      • 4.
        Alzheimer disease can never be ruled out on clinical or imaging grounds.
      • 5.
        More cerebrovascular disease implies less AD and vice versa, for a particular level of cognitive impairment.
      Although it would be possible to assign scores and then define certain score ranges for the ratings in Table 1 in order to define low, moderate, or high probabilities of cerebrovascular disease, or by inference high, moderate, or low probabilities of AD, there is an inadequate or no empirical basis for doing so. Perhaps the only categorical boundary that is defensible is for AD with negligible cerebrovascular disease. The term pure AD has been regularly and successfully used in AD clinical trials. In contrast, elderly patientswith high burdens of cerebrovascular disease may still have some AD, making it truly difficult to identify pure VaD. In younger patients, the possibility of pure VaD is perhaps more likely.
      The evidence presented in this review shows that cerebrovascular disease is an important pathophysiologic mechanism in dementia. Cerebrovascular disease burden does not lend itself to categorical diagnostic labels. A better approach is to acknowledge that there is a continuum of brain vascular disease and AD.
      Much more work remains. Defining the cerebrovascular pathologic substrate of cognitive impairment is a huge undertaking that will require large prospective clinical and pathologic investigations. Then, developing consensus clinical criteria should be attempted. Ultimately, the greater clinical and pathologic precision will lead to new therapeutic and management insights into cerebrovascular disease and cognitive impairment.
      The limitations of this review should be acknowledged. This was not a formal evidence-based review but one that was driven by an attempt to identify points of agreement that were supported by evidence or, if not available, by accepted clinical logic. Unfortunately, this review cannot provide clinicians with simple diagnostic criteria. Instead, this review sought to highlight some important clinical features that support a diagnosis of cerebrovascular disease that is etiologically related to cognitive disorders.

      Acknowledgments

      I thank my colleagues Walter A. Rocca, MD, and Joseph E. Parisi, MD, for their collaborations on vascular dementia projects.

      REFERENCES

        • Hachinski V
        Vascular dementia: a radical redefinition.
        Dementia. 1994; 5: 130-132
        • Bowler JV
        The concept of vascular cognitive impairment.
        J Neurol Sci. 2002; 203–204: 11-15
        • Kalaria RN
        • Kenny RA
        • Ballard CG
        • Perry R
        • Ince P
        • Polvikoski T
        Towards defining the neuropathological substrates of vascular dementia.
        J Neurol Sci. 2004; 226: 75-80
        • Blessed G
        • Tomlinson BE
        • Roth M
        The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects.
        Br J Psychiatry. 1968; 114: 797-811
        • Braak H
        • Braak E
        Frequency of stages of Alzheimer-related lesions in different age categories.
        Neurobiol Aging. 1997; 18: 351-357
        • Knopman DS
        • Parisi JE
        • Boeve BF
        • et al.
        Vascular dementia in a population-based autopsy study.
        Arch Neurol. 2003; 60: 569-575
        • White L
        • Petrovitch H
        • Hardman J
        • et al.
        Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants.
        Ann N Y Acad Sci. 2002; 977: 9-23
        • 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: 45-50
        • Roman GC
        • Tatemichi TK
        • Erkinjuntti T
        • et al.
        Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop.
        Neurology. 1993; 43: 250-260
        • Wetterling T
        • Kanitz RD
        • Borgis KJ
        Comparison of different diagnostic criteria for vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN).
        Stroke. 1996; 27: 30-36
        • Pohjasvaara T
        • Mantyla R
        • Ylikoski R
        • Kaste M
        • Erkinjuntti T
        • National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche el l'enseignement en Neurosciences
        Comparison of different clinical criteria (DSM-III, ADDTC, ICD-10, NINDS-AIREN, DSM-IV) for the diagnosis of vascular dementia.
        Stroke. 2000; 31: 2952-2957
        • Gold G
        • Giannakopoulos P
        • Montes-Paixao Junior C
        • et al.
        Sensitivity and specificity of newly proposed clinical criteria for possible vascular dementia.
        Neurology. 1997; 49: 690-694
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 4th ed. American Psychiatric Association, Washington, DC1994
        • Knopman DS
        • Rocca WA
        • Cha RH
        • Edland SD
        • Kokmen E
        Incidence of vascular dementia in Rochester, Minn, 1985-1989.
        Arch Neurol. 2002; 59: 1605-1610
        • Hachinski VC
        • Lassen NA
        • Marshall J
        Multi-infarct dementia: a cause of mental deterioration in the elderly.
        Lancet. 1974; 2: 207-210
        • Rosen WG
        • Terry RD
        • Fuld PA
        • Katzman R
        • Peck A
        Pathological verification of ischemic score in differentiation of dementias.
        Ann Neurol. 1980; 7: 486-488
        • Moroney JT
        • Bagiella E
        • Desmond DW
        • et al.
        Meta-analysis of the Hachinski Ischemic Score in pathologically verified dementias.
        Neurology. 1997; 49: 1096-1105
        • Henon H
        • Durieu I
        • Guerouaou D
        • et al.
        Poststroke dementia: incidence and relationship to prestroke cognitive decline.
        Neurology. 2001; 57: 1216-1222
        • Kokmen E
        • Whisnant JP
        • O'Fallon WM
        • Chu CP
        • Beard CM
        Dementia after ischemic stroke: a population-based study in Rochester, Minnesota (1960-1984).
        Neurology. 1996; 46: 154-159
        • Pohjasvaara T
        • Mantyla R
        • Salonen O
        • et al.
        MRI correlates of dementia after first clinical ischemic stroke.
        J Neurol Sci. 2000; 181: 111-117
        • Tatemichi TK
        • Desmond DW
        • Stern Y
        • Paik M
        • Sano M
        • Bagiella E
        Cognitive impairment after stroke: frequency, patterns, and relationship to functional abilities.
        J Neurol Neurosurg Psychiatry. 1994; 57: 202-207
        • Knopman D
        • Boland LL
        • Mosley T
        • Atherosclerosis Risk in Communities (ARIC) Study Investigators
        • et al.
        Cardiovascular risk factors and cognitive decline in middle-aged adults.
        Neurology. 2001; 56: 42-48
        • Kuller LH
        • Shemanski L
        • Manolio T
        • et al.
        Relationship between ApoE, MRI findings, and cognitive function in the Cardiovascular Health Study.
        Stroke. 1998; 29: 388-398
        • Reed BR
        • Mungas DM
        • Kramer JH
        • et al.
        Clinical and neuropsychological features in autopsy-defined vascular dementia.
        Clin Neuropsychol. 2004; 18: 63-74
        • Looi JC
        • Sachdev PS
        Differentiation of vascular dementia from AD on neuropsychological tests.
        Neurology. 1999; 53: 670-678
        • Haan MN
        • Shemanski L
        • Jagust WJ
        • Manolio TA
        • Kuller L
        The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons.
        JAMA. 1999; 282: 40-46
        • Erkinjuntti T
        • Kurz A
        • Gauthier S
        • Bullock R
        • Lilienfeld S
        • Damaraju CV
        Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial.
        Lancet. 2002; 359: 1283-1290
        • Black S
        • Roman GC
        • Geldmacher DS
        • Donepezil 307 Vascular Dementia Study Group
        • et al.
        Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial.
        Stroke. 2003; 34: 2323-2330
        • Wilkinson D
        • Doody R
        • Helme R
        • Donepezil 308 Study Group
        • et al.
        Donepezil in vascular dementia: a randomized, placebo-controlled study.
        Neurology. 2003; 61: 479-486
        • Wilcock G
        • Mobius HJ
        • Stoffler A
        • MMM 500 Group
        A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM 500).
        Int Clin Psychopharmacol. 2002; 17: 297-305
        • Orgogozo JM
        • Rigaud AS
        • Stoffler A
        • Mobius HJ
        • Forette F
        Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300).
        Stroke. 2002; 33: 1834-1839
        • Lobo A
        • Launer LJ
        • Fratiglioni L
        • Neurologic Diseases in the Elderly Research Group
        • et al.
        Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts.
        Neurology. 2000; 54: S4-S9
        • Hulette C
        • Nochlin D
        • McKeel D
        • et al.
        Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases.
        Neurology. 1997; 48: 668-672
        • Wolfson C
        • Wolfson DB
        • Asgharian M
        • Clinical Progression of Dementia Study Group
        • et al.
        A reevaluation of the duration of survival after the onset of dementia.
        N Engl J Med. 2001; 344: 1111-1116
        • Knopman DS
        • Rocca WA
        • Cha RH
        • Edland SD
        • Kokmen E
        Survival study of vascular dementia in Rochester, Minnesota.
        Arch Neurol. 2003; 60: 85-90
        • Honig LS
        • Kukull W
        • Mayeux R
        Atherosclerosis and AD: analysis of data from the US National Alzheimer's Coordinating Center.
        Neurology. 2005; 64: 494-500
        • Breteler MM
        • Bots ML
        • Ott A
        • Hofman A
        Risk factors for vascular disease and dementia.
        Haemostasis. 1998; 28: 167-173
        • Kuller LH
        • Lopez OL
        • Newman A
        • et al.
        Risk factors for dementia in the Cardiovascular Health Cognition Study.
        Neuroepidemiology. 2003; 22: 13-22
        • Luchsinger JA
        • Reitz C
        • Honig LS
        • Tang MX
        • Shea S
        • Mayeux R
        Aggregation of vascular risk factors and risk of incident Alzheimer disease.
        Neurology. 2005; 65: 545-551
        • Ross GW
        • Petrovitch H
        • White LR
        • et al.
        Characterization of risk factors for vascular dementia: the Honolulu-Asia Aging Study.
        Neurology. 1999; 53: 337-343
        • Hebert R
        • Lindsay J
        • Verreault R
        • Rockwood K
        • Hill G
        • Dubois MF
        Vascular dementia: incidence and risk factors in the Canadian study of health and aging.
        Stroke. 2000; 31: 1487-1493
        • Craft S
        • Watson GS
        Insulin and neurodegenerative disease: shared and specific mechanisms.
        Lancet Neurol. 2004; 3: 169-178
        • Hanon O
        • Forette F
        Treatment of hypertension and prevention of dementia.
        Alzheimer's Dementia. 2005; 1: 30-37
        • Tzourio C
        • Anderson C
        • Chapman N
        • PROGRESS Collaborative Group
        • et al.
        Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease.
        Arch Intern Med. 2003; 163: 1069-1075
        • Eichner JE
        • Dunn ST
        • Perveen G
        • et al.
        Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review.
        Am J Epidemiol. 2002; 155: 487-495
        • Slooter AJ
        • Cruts M
        • Hofman A
        • et al.
        The impact of APOE on myocardial infarction, stroke, and dementia: the Rotterdam Study.
        Neurology. 2004; 62: 1196-1198
        • Farrer LA
        • Cupples LA
        • Haines JL
        • APOE and Alzheimer Disease Meta Analysis Consortium
        • et al.
        Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis.
        JAMA. 1997; 278: 1349-1356
        • Slooter AJ
        • Tang MX
        • van Duijn CM
        • et al.
        Apolipoprotein E epsilon4 and the risk of dementia with stroke: a population-based investigation.
        JAMA. 1997; 277: 818-821
        • Peila R
        • White LR
        • Petrovich H
        • et al.
        Joint effect of the APOE gene and midlife systolic blood pressure on late-life cognitive impairment: the Honolulu-Asia Aging Study.
        Stroke. 2001; 32: 2882-2889
        • Kalmijn S
        • Feskens EJ
        • Launer LJ
        • Kromhout D
        Cerebrovascular disease, the apolipoprotein e4 allele, and cognitive decline in a community-based study of elderly men.
        Stroke. 1996; 27: 2230-2235
        • Ballard CG
        • Burton EJ
        • Barber R
        • et al.
        NINDS AIREN neuroimaging criteria do not distinguish stroke patients with and without dementia.
        Neurology. 2004; 63: 983-988
        • Longstreth Jr, WT
        • Bernick C
        • Manolio TA
        • Bryan N
        • Jurgreis CA
        • Price TR
        Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study.
        Arch Neurol. 1998; 55: 1217-1225
        • Longstreth Jr, WT
        • Dulberg C
        • Manolio TA
        • et al.
        Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.
        Stroke. 2002; 33: 2376-2382
        • 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: 1215-1222
        • Longstreth Jr, WT
        • 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: 1274-1282
        • Breteler MM
        • van Swieten JC
        • Bots ML
        • et al.
        Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study.
        Neurology. 1994; 44: 1246-1252
        • 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: 145-151
        • De Groot JC
        • De Leeuw FE
        • Oudkerk M
        • et al.
        Periventricular cerebral white matter lesions predict rate of cognitive decline.
        Ann Neurol. 2002; 52: 335-341
        • Mungas D
        • Jagust WJ
        • Reed BR
        • et al.
        MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer's disease.
        Neurology. 2001; 57: 2229-2235
        • Prins ND
        • van Dijk EJ
        • den Heijer T
        • et al.
        Cerebral white matter lesions and the risk of dementia.
        Arch Neurol. 2004; 61: 1531-1534
        • Zarow C
        • Vinters HV
        • Ellis WG
        • et al.
        Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia.
        Ann Neurol. 2005; 57: 896-903
        • Heyman A
        • Fillenbaum GG
        • Welsh-Bohmer KA
        • Consortium to Establish a Registry for Alzheimer's Disease
        • et al.
        Cerebral infarcts in patients with autopsy-proven Alzheimer's disease: CERAD, part XVIII [published correction appears in Neurology. 1998;51:1809].
        Neurology. 1998; 51: 159-162
        • Snowdon DA
        • Greiner LH
        • Mortimer JA
        • Riley KP
        • Greiner PA
        • Markesbery WR
        Brain infarction and the clinical expression of Alzheimer disease: the Nun Study.
        JAMA. 1997; 277: 813-817
        • Schneider JA
        • Wilson RS
        • Bienias JL
        • Evans DA
        • Bennett DA
        Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology.
        Neurology. 2004; 62: 1148-1155
        • Petrovitch H
        • Ross GW
        • Steinhorn SC
        • et al.
        AD lesions and infarcts in demented and non-demented Japanese-American men.
        Ann Neurol. 2005; 57: 98-103
        • Riekse RG
        • Leverenz JB
        • McCormick W
        • et al.
        Effect of vascular lesions on cognition in Alzheimer's disease: a community-based study.
        J Am Geriatr Soc. 2004; 52: 1442-1448