Vascular Cognitive Impairment Introduction

Vascular cognitive impairment refers to the broad spectrum of cognitive deficits associated with cerebrovascular diseases. Although multiple or strategically placed infarcts are well-established causes of cognitive decline, lesions of the periventricular white matter, the neuroimaging correlate of which is termed leukoaraiosis, are most often associated with vascular cognitive impairment. The periventricular white matter is highly susceptible to cerebrovascular damage, but the underlying pathogenic mechanisms are not well understood. Leukoaraiosis is a prominent feature of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by mutations of the vascular smooth muscle gene Notch 3 and of familial forms of cerebral amyloid angiopathy linked to mutations in the amyloid precursor protein gene. Elucidating how these genetic conditions lead to white matter damage may provide insight into the pathogenesis of sporadic cases of leukoaraiosis typically associated with stroke risk factors like hypertension and diabetes. Despite the great disease burden imposed by leukoaraiosis, little is known about the relationship between different microvascular pathologies and spatial pattern of white matter damage and how they affect stroke incidence and outcome. Furthermore, the relative contribution of coexisting vascular and neurogenerative pathologies on cognitive deficits needs to be better defined. These issues were addressed in the session on vascular cognitive impairment of this year’s Princeton Conference. We provide a brief overview of the key findings of the articles presented in this section.

The article by Ayata¹ examines the pathogenic substrates of the increased susceptibility to ischemia associated with CADASIL. Investigations in mouse models have demonstrated that deletion or mutations of Notch 3 produce profound alterations in the fundamental mechanisms regulating the cerebral circulation. These alterations impair the blood flow delivery to the brain and increase the susceptibility of the tissue to ischemic injury. The findings suggest that CADASIL mutations increase the vulnerability of the brain to ischemic injury by producing a marked reduction in cerebrovascular reserves. These vascular changes are likely to have an impact on the extensive white matter lesions associated with this condition.

Van Nostrand et al² address the microvascular abnormalities observed in a mouse model of familial cerebral amyloid angiopathy of the Dutch-Iowa type. These mice exhibited microvascular amyloid accumulation and widespread astrocytic and microglia activation as well as decreased cognitive function. Remarkably, deletion of the proinflammatory gene inducible nitric oxide synthase in Dutch-Iowa type mice worsened cognitive function, an effect linked to increased tau phosphorylation and degeneration of the affected neurons. Therefore, Dutch-Iowa type mice lacking inducible nitric oxide synthase more completely recapitulate the phenotype of capillary cerebral amyloid angiopathy in humans. These findings challenge the notion that inducible nitric oxide synthase-derived nitric oxide is always deleterious and provides a potential link among vascular pathology, neurofibrillary tangles, and neurodegeneration.

The article by Smith³ summarizes the evidence linking leukoaraiosis to increased stroke risk and worse stroke outcome and presents new data on the distribution of leukoaraiosis in different vascular pathologies. It was found that the spatial distribution of white matter lesions due to hypertensive vascular changes, which affect predominantly penetrating arteries, was comparable to that of patients with possible or probable cerebral amyloid angiopathy, a pathology dominant in pial arteries. The data suggest that the response of the periventricular white matter to differing vascular pathologies is stereotyped and support the notion that hypoperfusion in watershed areas may be a critical factor in the pathogenesis of leukoaraiosis.

Schneider and Bennett’s paper⁴ addresses the overlap between vascular and neurodegenerative factors in the pathogenesis of dementia. Clinical–pathological studies provide evidence that the presence of vascular lesions (eg, cerebral infarctions, amyloid angiopathy) aggravates the damaging effects on cognition of neurodegenerative pathology (amyloid plaques, neurofibrillary tangles, Lewy bodies). Discrete additive effects on the cognitive function were observed for each of the pathologies studied. These observations, collectively, demonstrate that the pathological substrates of dementias in the community are heterogeneous and include large contributions from both neurodegenerative and vascular components suggesting that the prevention of cerebrovascular disease could have a large impact on the prevention of cognitive decline in the elderly.

Despite the diversity of models, methods, and approaches, a common thread emerges from the wealth of data presented in these articles. That is, the structural and functional integrity of cerebral blood vessels is vital for the preservation of cognitive function. To a great extent, cognitive health depends on cerebrovascular health, and a deeper understanding of the subtle interactions between cerebrovascular function and cognition is needed to protect mankind from one of its most devastating afflictions.