Plasma amyloid β, apolipoprotein E, lacunar infarcts, and white matter lesions

Abstract

Lacunar brain infarcts and cerebral white matter lesions are frequently observed on magnetic resonance imaging scans in elderly subjects. These lesions are also frequent in patient with cerebral amyloid angiopathy. We examined whether plasma amyloid beta peptide (Abeta) levels are associated with lacunar infarcts and white matter lesions in the general population, and whether the apolipoprotein E (APOE) genotype modifies these associations. We studied 1,077 participants within the population-based Rotterdam Scan Study, who were 60 to 90 years of age and free of dementia. Cross-sectional associations were analyzed by regression models with adjustments for age, sex, creatinine levels, and hypertension. In APOE epsilon4 carriers, plasma Abeta levels were positively associated with lacunar infarcts and white matter lesions, whereas in noncarriers no associations were observed. Per standard deviation increase in Abeta(1-40) and Abeta(1-42) levels the odds ratios for lacunar infarcts were 1.72 (95% confidence interval [CI] = 1.22-2.43) and 1.93 (95% CI = 1.31-2.85), the periventricular white matter lesion grade increased by 0.32 (95% CI = 0.08-0.57) and 0.29 (95% CI = 0.00-0.57), and the subcortical white matter lesion volume increased by 0.48 ml (95% CI = 0.04-0.91) and 0.24 ml (95% CI = -0.27-0.75). Higher Abeta levels are associated with more lacunar infarcts and white matter lesions in elderly subjects who carry an APOE epsilon4 allele.

NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid β Peptide

“…Another deleterious vascular effect of A␤ 1-40 is a disruption of cerebrovascular autoregulation (Niwa et al, 2002b), a mechanism in part mediated by vasoactive factors produced in endothelial cells, which prevents fall of CBF during hypotension Jones et al, 1999;Chillon and Baumbach, 2002). Failure of autoregulation leads to ischemic damage of cortical white matter (Matsushita et al, 1994), a finding that may be responsible for the white matter lesions observed in patients with AD (Brun and Englund, 1986;Van Dijk et al, 2004). These observations, collectively, suggest that A␤ peptides, in addition to their well known deleterious effects on neurons (Selkoe and Schenk, 2003), can also disrupt the function of cerebral blood vessels.…”

“…AD and cerebrovascular diseases share common risk factors (Stewart et al, 1998;Breteler, 2000;Casserly and Topol, 2004), suggesting similarities in their pathogenic mechanisms. Furthermore, AD patients have increased cerebrovascular atherosclerosis and exhibit white matter abnormalities resembling ischemic lesions (Brun and Englund, 1986;Roher et al, 2003Roher et al, , 2004Van Dijk et al, 2004). These observations have been complemented by studies in mouse models of AD demonstrating that A␤ disrupts the regulation of the cerebral circulation, rendering the brain more susceptible to injury (Zhang et al, 1997).…”

Heterogeneity in age-related white matter changes

“…These data and the estimated heritability index of white matter lesions in the range of 55-73% [1,12] led to the conduct of genetic association studies to determine the role of genetic factors in the etiology of agerelated white matter changes. Previous epidemiologic studies reported positive associations between the presence of the apolipoprotein E (ApoE) e4 allele, and the extent and progression of MRI lesions in the deep/subcortical white matter [27,88]. Our own group conducted a pilot study in which we performed postmortem MRIs of unfixed brains in 13 patients who had died of various causes and used immunohistochemistry to assess the presence of apoE immunoreactivity in brain areas including white matter lesions.…”

Carotid dissection causing occipital lobe infarction

“…3,4,[45][46][47] Elevated tHcy and elevated plasma A␤ levels are both implicated as premorbid risk factors for the development of AD 11,40,41 and for associated microangiopathic changes on MRI. 25,48 Both tHcy and A␤40 could be markers of vascular damage in the brain; tHcy and A␤40 were associated with white matter ischemic changes in APOE ε4 carriers in the Rotterdam study. 25,48 The more general association of tHcy with plasma A␤ is independent of diagnosis (both neurodegenerative and cerebrovascular) and APOE genotype in our sample.…”

“…22 Plasma amyloid-␤ protein (A␤) has been examined as a potential risk factor for Alzheimer disease (AD) and the related process of cerebral amyloid angiopathy (CAA) but was not consistently elevated in these conditions. 23,24 Recent data from the populationbased Rotterdam study, however, demonstrated an association between plasma A␤ and microvascular disease in the brain in APOE ε4 carriers, 25 suggesting that A␤ might be a cause or marker of cerebrovascular dysfunction.…”