Neuropathology Lessons in Vascular Dementia

Unlike Alzheimer disease (AD), no consensus has been reached regarding the pathologic diagnosis of vascular dementia (VaD). Conceptually, VaD may be regarded as severe cognitive impairment resulting from cerebrovascular-related brain injury (CVBI), which in turn is attributed to cerebroor cardio-vascular disease (CVD) (Fig. 1). Unfortunately, this concept has defied simple translation into practice. While there is good correlation between the severity of cognitive impairment and the density of neurofibrillary tangles or neuritic plaques in AD, no simple metric has been discovered for VaD. Large infarct volume (eg, .50 mL) is associated with dementia, but a small strategically placed 1-cm lacune may do the same. The level of heterogeneity in the size, location, and number of CVBI and the variability in behavioral manifestations are not well suited to simple phenotypic or categorical classification. Nonetheless, this is the state of art that is reviewed here. As the database grows, new continuous and quantitative brain-behavior models will evolve. Meanwhile, we may consider the lessons that neuropathology has to offer here and now. First, neuropathology is the best method to ascertain the severity and type of underlying CVD. Second, neuropathology is still needed to validate the use of MRI as a surrogate marker for CVBI. Finally, neuropathology is still the best way to assess the presence and severity of Alzheimer pathology and to address the relative contributions of AD and CVBI to cognitive impairment. This review is organized as follows: Common types of cerebrovascular disease (CVD) Common types of cerebrovascular brain injury (CVBI) Detection of CVBI by MRI Categorical diagnosis of VaD Contributions of CVBI to cognitive impairment along a continuum COMMON TYPES OF CEREBROVASCULAR DISEASE Atherosclerosis affects the intimal and subintimal lining of blood vessels. Cholesterol deposits and associated inflammatory changes are noted in large arteries. These pathologies are associated with artery-to-artery thromboembolism and large cortical-subcortical infarcts. Smaller vessels may also be involved. Subintimal accumulations of foam cells may be observed in the proximal portions of small perforating arteries (200–800 mm in diameter). These are associated with small, deep infarcts in basal ganglia, thalamus, and pons. Risk factors include hyperlipidemia, diabetes mellitus, smoking, hyperhomocysteinemia, and elevated C-reactive protein. Thickness of the carotid artery intima, brachial-foot ratio, and pulsatility index provide clinical measures of atherosclerosis. Arteriolosclerosis affects the media of small arterioles. One observes onion-skin concentric proliferation of smooth muscle cells, degeneration of the tunica media and internal elastic lamina, and replacement of smooth muscle cell replacement by fibroblasts, collagen, and laminin. The vessel becomes an elongated, tortuous, narrow, and paucicellular hyaline tube. Arteriolosclerosis is associated with lacunar infarcts in deep white and gray matter structures. Fibrinoid necrosis refers to focal segmental necrosis of small arterioles (40–300 mm diameter). The media is replaced with collagenous sclerosis and mural foam cells (lipohyalinosis). Fibrinoid necrosis is associated with hemorrhages and lacunar infarcts in the basal ganglia, thalamus, pons, and cerebellum. Major risk factors include hypertension and diabetes mellitus. Assessment of the retinal arterioles on funduscopic examination offers a clinical measure of arteriolosclerosis. Cerebral amyloid angiopathies (CAA) comprise a group of disorders characterized by the deposition of amyloidogenic proteins in the walls of cerebral blood vessels. The proteins deposited may differ widely in amino acid sequence, but share the common propensity to form beta-pleated sheets. The 40 to 42 amino acid a-beta protein is deposited in the CAA associated with Alzheimer disease and the Dutch form of hereditary cerebral hemorrhage with amyloid (HCHWA-Dutch). At least 8 hereditary forms of CAA have been identified, including Familial AD, HCHWA-Dutch, HCHWA-Icelandic, familial amyloid polyneuropathy/meningo-vascular amyloidoses, familial amyloidoses Finnish type, familial prion disease, familial British dementia, and Familial Danish dementia. CAA is associated with lobar hemorrhages, microinfarcts, and leukoencephalopathy. Genetic forms may be diagnosed by DNA sequencing. The sporadic forms often go unsuspected until there is a clinical event and often unconfirmed until neuropathological examination. Received for publication August 23, 2004; accepted September 6, 2004. From the Department of Neurology, University of Southern California, Los Angeles, California. Supported by the National Institute on Aging: P01 AG12435. Reprints: Helena Chui, Department of Neurology, University of Southern California, 1510 San Pablo Street, Room 643, Los Angeles, CA 90033 (e-mail: chui@usc.edu). Copyright 2005 by Lippincott Williams & Wilkins