Understanding the pathology of vascular cognitive impairment

doi:10.1016/j.jns.2004.11.029

Journal of the Neurological Sciences

Volumes 229–230, 15 March 2005, Pages 57-63

https://doi.org/10.1016/j.jns.2004.11.029 Get rights and content

Abstract

The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive impairment (VCI), and of mixed dementia (Alzheimer disease+vascular encephalopathy) are a matter of discussion and no validated neuropathologic criteria for these disorders are currently available. In Western memory clinic-based series, VaD/CVI is suggested in 8–10% of cognitively impaired elderly; its prevalence in autopsy series ranges from 0.03% to 58% (mean 5–15%). Fairly unusual as an isolated nosological entity, CVI appears to correlate with focal, multifocal or diffuse cortical and/or subcortical microinfarcts and lacunes often affecting strategically important brain areas (thalamus, frontobasal, limbic system), hemispheric white matter and, less often, large brain areas. They result from systemic, cardiac or local large or small vessel disease. The lesion pattern in “pure” VCI with predominant multiple small (subcortical) lesions related to microangiopathies differs from that in “mixed dementia” (AD+VaD), more often associated with large infarcts, suggesting different pathogenesis. In very old subjects, selective hippocampal sclerosis may be accompanied by multiple other vascular pathologies. Minor cerebrovascular lesions (CVL), except for severe amyloid angiopathy, appear not essential for cognitive decline in full-blown AD, while both mild AD-type pathology and small vessel disease may interact synergistically in “unmasking” or promoting dementia. AD pathology is significantly less severe in the presence of cerebrovascular lesions. Further studies are needed to validate diagnostic criteria for VCI and to clarify the impact of vascular lesions on cognitive impairment.

Introduction

The role of cerebrovascular disease (CVD) and ischemic brain damage for cognitive decline remains controversial. Dementia related to vascular disorders was first described as “arteriosclerotic dementia” [1] and was later replaced by other terms (Table 1).

While not all patients with vascular cognitive impairment (VCI) develop dementia according to standard diagnostic criteria, such patients are at risk of dementia and at least half of them progress to dementia [3]. Morphologic substrates of cognitive impairment resulting from cerebrovascular lesions (CVL) remain confusing, since they constitute a multifactorial disorder related to a wide variety of lesions and causes. Even when cerebrovascular pathology (CVP) appears to be the main underlying process, the effect of damaged brain parenchyma is variable and, therefore, the clinical, radiological and pathological appearances may be heterogeneous. Complicating the diagnosis of VCI are other coexisting pathologic entities in the aging brain.

In contrast to recently refined morphological criteria for Alzheimer disease (AD) and other degenerative dementias [11], [12], no generally accepted and validated neuropathological criteria for VCI have been established up to date, and no definite morphological substrates have been included in the currently used clinical diagnostic criteria for VCI, e.g. DSM-IV, SCADDTC [13] and NINDS-AIREN [14].

Section snippets

Prevalence and incidence patterns

Given the difficulty in diagnosing VCI, considerable methodological and geographical differences, it remains difficult to draw conclusions about its frequency and distribution. Evaluation of 11 pooled European population-based studies of subjects of over age 65 revealed an age-standardized prevalence of 6.4% for all dementias, 4.4% for AD and 2.6% for vascular dementia (VaD) [15]. The incidence varies between 6 and 15/year/1000 persons aged 70 years and older and increases with advancing age

Major morphological substrates

Pathologic changes in the brain related to VCI are multiple; they include arterial territory infarcts, distal field (watershed/borderzone) infarcts, small and medium sized lesions mainly in functionally important brain areas, lacunar infarcts and scars, white matter lesions (WMLs), incomplete ischemic injury, hippocampal lesions and sclerosis. They have been categorized as multifocal and/or diffuse disease and focal, strategically placed lesions. They are caused by many vascular and ischemic

Pathogenesis

The pathogenic factors involved in VCI include the volume of brain destruction, its location, and the numbers of CVLs, but Pantoni [27] emphasized the overlap between vascular and degenerative mechanisms and a lack of correlation between clinical and pathology findings.

Importance of small cerebrovascular lesions

Comparing the neuropathology findings in elderly demented subjects without considerable AD pathology and non-demented controls, Esiri et al. [4] saw correlations of microvascular brain damage with dementia. Severe lacunar state, microinfarcts and cerebral amyloid angiopathy (CAA) had a greater prevalence in the dementia groups, which had less frequent macroscopic infarcts than non-demented. Without differences in severity of extracerebral atheroma, the dementia group more often revealed

Pathophysiology

VaD is thought to be caused by focal or multifocal lesions involving strategic brain areas with deafferentation of frontal and limbic cortical structures with interruption of thalamo-cortical and striato-cortical pathways caused by lesions in basal ganglia, thalamus or connecting white matter. The pattern of cognitive impairment is consistent with models of disturbed cortical and subcortical neuronal pathways [36]. Complex interactions between subcortical lesions and radiologically detected

The enigma of mixed dementia

Mixed type dementia (MD) is characterized by combined pathologies of both AD and VaD, but the distinction between these diseases is controversial. The CERAD classification does not consider MD [45], while in the ADDTC criteria [13], a second CVD in addition to AD must be shown to be causally related to dementia. In the NINDS-AIREN criteria [14], the term AD with CVD is reserved to patients fulfilling the clinical criteria of possible AD who have also clinical and imaging signs of relevant CVD,

Concluding remarks

CVI is a non-frequent heterogenous group of disorders in the course of which multiple ischemic and/or vascular brain lesions of variable etiology result in progressive cognitive impairment. The major subgroups and their causes are summarized in Table 6. The concept that VaD is determined primarily by the volume of infarcted brain has not been confirmed. Cognitive involvement appears to correlate with widespread ischemic and/or vascular lesions throughout the brain with particular involvement of

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Understanding the pathology of vascular cognitive impairment

Abstract

Introduction

Section snippets

Prevalence and incidence patterns

Major morphological substrates

Pathogenesis

Importance of small cerebrovascular lesions

Pathophysiology

The enigma of mixed dementia

Concluding remarks

J. Neurol. Sci.

J. Neurol. Sci.

Prog. Neurobiol.

J. Neurol. Sci.

J. Neurol. Sci.

Toxicology

Neurobiol. Aging

The dementias and progressive diseases of the basal ganglia

Multi-infarct dementia. A cause of mental deterioration in the elderly

Lancet

Progression of impairment in patients with vascular cognitive impairment without dementia

Neurology

Neuropathological assessment of the lesions of significance in vascular dementia

J. Neurol. Neurosurg. Psychiatry

Vascular dementia

Cerebrovascular dementia: pathophysiology, diagnosis and treatment

CNS Drugs

Neuropathologic substrates of ischemic vascular dementia

J. Neuropathol. Exp. Neurol.

The neuropathological substrate of vascular-ischemic dementia

Vascular cognitive impairment. Preventable dementia

New neuropathological criteria for Alzheimer disease

Arch. Neurol.

Alzheimer disease and cerebrovascular pathology: an update

J. Neural Transm.

Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer's Disease Diagnostic and Treatment Centers

Neurology

Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop

Neurology

Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic diseases in the elderly research group

Neurology

Vascular dementia: incidence and risk factors in the Canadian study of health and aging

Stroke

Dementia with Lewy bodies according to the consensus criteria in a general population aged 75 years or older

J. Neurol. Neurosurg. Psychiatry

Prevention

Relation of cerebral infarctions to dementia and cognitive function in older persons

Neurology

Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases

Neurology

Brain infarction and the clinical expression of Alzheimer disease. The Nun Study

JAMA

A neuropathological study of dementia in nursing homes over a 17-year period, in Shimane Prefecture, Japan

Gerontology