The risk factors for VaD are shown in Table 19.1. Several recent reviews of the subject are available (Gorelick, 1997; Skoog, 1998). As expected, many of the risk factors for VaD are the same as for stroke. Age is an extremely important risk factor for VaD. The prevalence of VaD doubled every five to ten years after age 65 (Hofman et al., 1991). Other non-modifiable risk factors include genetic predisposition and Asian background. However, modifiable risk factors for VaD include hypertension, diabetes mellitus, atrial fibrillation, elevated cholesterol, alcohol abuse, and cigarette smoking.
Table 19.1. Risk factors for vascular dementia
Advancing age Hypertension Diabetes mellitus Myocardial infarction
Cardiac disease (especially atrial fibrillation) Elevated LDL cholesterol Prior strokes
Cerebral atrophy Alcohol abuse
Low educational attainment
Familial cerebral amyloidosis
A few examples of VaD are transmitted on an inherited basis. Small numbers of patients with familial amyloid angiopathies develop dementia after multiple cerebral hemorrhages or infarcts. Patients with cerebral hemorrhage with amyloidosis have been described in Iceland (HCHWA-I) and the Netherlands (Dutch form) (HCHWA-D). Both are dominantly inherited disorders and have amyloid deposited in cerebral arteries and arterioles. HCHWA-I causes intracerebral hemorrhages in younger individuals (20-30 years old). Cystatin C, a cysteine protease inhibitor, is present in blood vessel walls in HCHWA-I. A single mutation on the cystatin C gene on chromosome 20 has been demonstrated in this disorder (Abrahamson et al., 1992). HCHWA-D affects normotensive patients in the age range of 40-60 years. The amyloid fibrils are similar to those found in AD. A mutation in the amyloid precursor protein gene at codon 618 has been described in this disorder (Levy et al., 1990).
In 1993, Tournier-Lasserve et al. described an autosomal dominant disorder linked to chromosome 19, termed 'cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy' (CADASIL), which is increasingly recognized as a cause of stroke and cognitive alterations in mid-adult life. The major clinical features are migraine headaches, subcortical strokes, psychiatric symptoms, and cognitive decline. Pathologically, there is a widespread arteriopathy in medium and small arteries that contain a granular osmiophilic material (GOM). Identification of GOM in skin, muscle, or nerve by electron microscopy allows a specific diagnosis of CADASIL. CADASIL is due to a mutation in the Notch-3 gene, which encodes a transmembrane receptor protein (Joutel et al., 1996). Notch-3 is expressed in vascular smooth muscle cells. A 210-kDa Notch-3 cleavage product is present at the cytoplasmic membrane of vascular smooth muscle cells (Joutel, 2000).
Numerous studies have shown that the e4 allele of apolipoprotein E (apoE) is a major risk factor for AD; however, studies of apoE in VaD have yielded variable results. Although several recent studies have described an increased frequency of apoE-e4 in patients with dementia with stroke (Slooter et al., 1997; Hofman et al., 1997; Hebert et al., 2000), other studies from different countries have not confirmed this (Traykov et al., 1999; Alafuzoff et al., 2000; Barba et al., 2000). Again, varying definitions and criteria and the potential overlap with AD in clinical studies make interpretation of these data difficult.
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