The findings of many investigators suggest that cerebral vascular pathology may synergize with Alzheimer disease (AD) pathology, leading to earlier onset of clinical dementia symptoms and more severe dementia than would have been produced by the AD pathology alone. For example, [1
] found that among 61 prospectively followed persons with autopsy confirmed AD, individuals with brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts. In a comparison of 72 subjects with autopsy proven AD with 32 subjects who evidenced AD pathology and cerebral infarcts or lacunes, the subjects with vascular lesions had more severe dementia despite essentially no difference in semiquantitative measures of plaques and tangles [2
] found that persons diagnosed clinically with AD who also met NINDS-AIREN neuroimaging criteria for vascular dementia [4
] had more rapid clinical progression than did subjects diagnosed with AD alone.
There is also evidence that lesser degrees of vascular pathology may also be important. In a histological examination of 7 brains following postmortem MRI, subcortical WMH were associated with arteriosclerosis, dilated perivascular spaces and vascular ectasia with occasional gliosis and small areas of infarction [5
]. A pathological study of WMH in 11 elderly subjects suggested that punctate, early confluent and confluent WMH reflected ischemic damage ranging from mild perivascular alterations to large areas with variable loss of fibers, multiple small cavitations and marked arteriolosclerosis and that irregular periventricular WMH were characterized by microcystic infarcts and patchy myelin rarefication. Hyperintense periventricular caps and a smooth halo were areas of demyelination with subependymal gliosis and breaks in the ependymal lining [6
]. Other pathological studies confirm the association of WMH with cerebrovascular disease but also find WMH attributable to non-vascular causes [7
Clinical evidence for a vascular origin of WMH includes a population-based study of 111 subjects ranging in age from 65–84 years in which the prevalence and severity of lesions increased with age and were associated independently with a history of stroke or myocardial infarction, factor VIIc activity and fibrinogen level. There was an association with hypertension and high cholesterol only in subjects from 65–74 years of age [9
]. In a random sample of 1077 community-dwelling persons between 60–90 years of age, the prevalence and degree of WMH increased with age, and to a higher degree in women than in men [10
] found that age-adjusted WMH load in subjects 55–72 years of age was significantly higher in persons diagnosed clinically as vascular dementia than in persons diagnosed clinically as cognitively normal, mild cognitive impairment, or AD. In another study showing an association between hypertension and WMH, there was reduced risk of progression following successful reduction of blood pressure [12
]. There is also evidence that elevated plasma homocysteine levels may be related to vascular disease [13
], cognitive impairment [14
], and volume of WMH [15
In sum, the evidence from pathological and clinical studies suggests that WMH are at least partially due to the effects of cerebrovascular disease and aging [15
], and may be increased by elevated homocysteine level, as indicated in .
Possible Relationship of Risk Factors to White Matter Hyperintensities, Neuronal Vulnerability, and Dementia.
In a small study of American Indians, we found an association between diabetes and hypertension and the clinical diagnosis of probable AD [17
]. The present report compares findings in American Indians with a diagnosis of probable AD with age-matched, cognitively intact American Indians and assesses the relationship of plasma homocysteine to WMH volume (WMHV), whole brain volume (WBV), and WMHV/WBV and the frequency of the apolipoprotein E4 allele in both groups.