Showing papers by "B. T. Hyman published in 1998"
TL;DR: Analysis of a clinical series of patients with CAA-related hemorrhage confirmed an overrepresentation of APOE ϵ2 as well as an association between this allele and earlier age of first hemorrhage, suggesting that APOEϵ2 and ϵ4 might promote CAA’s hemorrhage through separate mechanisms.
Abstract: Objective: Hemorrhage related to cerebral amyloid angiopathy (CAA) appears to occur through a multistep pathway that includes deposition of β-amyloid in cerebral vessels and specific vasculopathic changes in the amyloid-laden vessels, such as cracking of the vessel wall. Recent reports suggest a positive association between CAA-related hemorrhage and both the apolipoprotein E (APOE) ϵ4 allele and, unexpectedly, the APOE ϵ2 allele. Unlike APOE ϵ4, APOE ϵ2 does not appear to act through increased β-amyloid deposition. We therefore sought to determine whether it might specifically accelerate the second step in this pathway, that is, development of the vasculopathic changes that lead to hemorrhage. Methods: To determine the role of APOE in development of vasculopathic changes, we compared APOE genotypes in two groups of postmortem brains: 52 brains with complete amyloid replacement of vessel walls but without vasculopathic changes, and 23 brains with complete amyloid replacement of vessels with the accompanying changes of cracking of the vessel wall and paravascular leaking of blood. Results: Frequency of APOE ϵ2 was significantly greater in the group with vasculopathy (0.09) than the group without (0.01, p = 0.03). The groups did not differ in mean age or extent of neuritic plaques. Analysis of a clinical series of patients with CAA-related hemorrhage confirmed an overrepresentation of APOE ϵ2 as well as an association between this allele and earlier age of first hemorrhage. Conclusions: These data suggest that APOE ϵ2 and ϵ4 might promote CAA-related hemorrhage through separate mechanisms: ϵ4 by enhancing amyloid deposition and ϵ2 by causing amyloid-laden vessels to undergo the vasculopathic changes that lead to rupture.
228 citations
TL;DR: Findings suggest that progression from asymptomatic to advanced CAA reflects progressive accumulation of amyloid in vessels previously seeded with amyloids, and that this process is selectively enhanced by apoliporprotein E ϵ4.
Abstract: Cerebrovascular deposits of amyloid (cerebral amyloid angiopathy, or CAA) are generally asymptomatic, but in advanced cases, they can lead to vessel rupture and hemorrhage. The process of progression in CAA was studied by comparison of postmortem brains with asymptomatic ("mild") CAA to brains with the form of the disease associated with hemorrhage ("severe CAA"). Cortical and meningeal vessels were immunostained for beta-amyloid and examined by confocal microscopy and by systematic quantitative sampling. We focused on 2 quantitative parameters: the proportion of vessels affected by amyloid (a measure of amyloid seeding of vessels) and the amount of amyloid per affected vessel (a measure of growth of existing lesions). Surprisingly, there was no difference between the proportion of affected cortical vessels in mild and severe CAA (0.29 vs 0.32, p = 0.65), but rather an increase in the area of the 40 amino acid form of beta-amyloid per affected cortical vessel (198.5 +/- 38.7 vs 455.8 +/- 100.9 microm2/vessel, p < 0.007). Increasing doses (from 0 to 1 to 2 copies) of the apolipoprotein E epsilon4 allele were also associated with greater amyloid per vessel without change in the proportion of affected vessels within each class of CAA severity. These findings suggest that progression from asymptomatic to advanced CAA reflects progressive accumulation of amyloid in vessels previously seeded with amyloid, and that this process is selectively enhanced by apolipoprotein E epsilon4.
186 citations
TL;DR: The hypothesis that the G/G genotype is over-represented in Alzheimer’s disease in an additional independent data set and the presence of the G allele was associated with an increase in Aβ burden in a small series is tested.
Abstract: alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.
161 citations
TL;DR: The findings further implicate apolipoproteins in the response of the brain to injury in vivo and suggest that transcriptional up-regulation of the Apolipoprotein receptors studied is not a prominent feature in theresponse.
54 citations
TL;DR: It is unusual that a single biomarker fulfills all three roles, and certainly none of the available biomarkers proposed for use in Alzheimer’s disease (AD) are able to do so, and in evaluating the utility of current biomarkers, the prospects for developing future biomarkers must be considered independently.
6 citations
2 citations