Vascular Cognitive Impairment and Dementia: JACC Scientific Expert Panel

Abstract

Cognitive impairment associated with aging has emerged as one of the major public health challenges of our time. Although Alzheimer's disease is the leading cause of clinically diagnosed dementia in Western countries, cognitive impairment of vascular etiology is the second most common cause and may be the predominant one in East Asia. Furthermore, alterations of the large and small cerebral vasculature, including those affecting the microcirculation of the subcortical white matter, are key contributors to the clinical expression of cognitive dysfunction caused by other pathologies, including Alzheimer's disease. This scientific expert panel provides a critical appraisal of the epidemiology, pathobiology, neuropathology, and neuroimaging of vascular cognitive impairment and dementia, and of current diagnostic and therapeutic approaches. Unresolved issues are also examined to shed light on new basic and clinical research avenues that may lead to mitigating one of the most devastating human conditions.

Keywords: Alzheimer’s disease; cerebral blood flow; cognitive dysfunction; small vessel disease; stroke.

CENTRAL ILLUSTRATION. Vascular Cognitive Impairment and Dementia

Risk factors and lifestyle, as well as genetic variants, can either promote (+) or stave off (−) damage to large and small cerebral blood vessels, which, in turn, leads to neuropathological changes that result in vascular cognitive impairment.

FIGURE 1. Classification of VCI

Diagnostic classification for major vascular cognitive impairment (VCI) (major VCI = vascular dementia [VaD]). The 6-month temporal basis for cognitive decline after stroke (dashed box) differentiates post-stroke dementia (PSD) from other forms of VaD. *Patients who also have evidence for comorbid pathology representing an established nonvascular cause of dementia such as Alzheimer’s disease (AD) or dementia with Lewy bodies (DLB) are classified as mixed dementia. Mild VCI refers to impairment in at least 1 cognitive domain and mild to no impairment in instrumental activities of daily living or activities of daily living (independent of the motor/sensory sequelae of the vascular event). Data from Skrobot et al. (12).

FIGURE 2. Risk Factors for Dementia

Risk factors for vascular dementia, post-stroke dementia, dementia of unspecified etiology (unspecified dementia), and Alzheimer’s dementia. Data derived from Dichgans and Leys (23) and Pendlebury et al. (134). Note that recent genetic and epidemiological evidence implicates AD as a risk factor for stroke (135).

FIGURE 3. Pathobiology of Neurovascular Dysfunction in Vascular Cognitive Impairment

Modifiable risk factors (hypertension, lifestyle factors, and so on), genetic factors (ApoE, and so on), and aging impair key functions of the neurovascular unit leading to the alterations in brain function underlying cognitive impairment. Notice that the neurovascular unit is involved not only in flow regulation, but also in other vital functions that are essential for maintaining brain health. BBB = blood-brain barrier; CBF = cerebral blood flow; EC = endothelial cell; PVM = perivascular macrophage; SMC = smooth muscle cell.

FIGURE 4. Neuropathology of VCI

Small-vessel disease pathologies: (A) chronic microscopic infarct in the anterior caudate nucleus on hematoxylin & eosin stain; (B) microbleed surrounding damaged cortical blood vessel in the temporal lobe on hematoxylin & eosin stain; (C) arteriolosclerosis in the basal ganglia on hematoxylin & eosin; (D) enlarged perivascular spaces on hematoxylin & eosin stain; (E) white matter pallor in the posterior watershed region on Luxol fast blue and hematoxylin stain; and (F) amyloid angiopathy and Alzheimer’s disease pathology in the midfrontal cortex (immunohistochemistry with the anti-β-amyloid antibody 4G8).

FIGURE 5. Neuroimaging of Vascular Cognitive Impairment

(A) Signal alterations on conventional magnetic resonance imaging (visible lesions) in small vessel disease (SVD). The arrowheads indicate the pathology mentioned at the top of each brain scan. (B) Diffusion tensor imaging shows increased water diffusivity in the brain of an SVD patient. (C) Diffusion imaging can be analyzed using different strategies, including regional and global approaches.