AMYLOID ANGIOPATHY, EARLY PLAQUES, AND AGING

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Amyloidosis comprises a heterogeneous group of diseases that vary in clinical expression and the composition and distribution of insoluble amyloid fibrils. It is believed that all types of amyloidosis involve overproduction of a soluble precursor, and that deposition occurs in patients who are genetically or otherwise defective in degrading these molecules. We put forward a tripartite division of the elements central to the issue of pathogenesis: the inherent chemical amyliodogenic potential of the precursor protein; the possibility of aberrant protein metabolism, and the existence of disease microenviromental tissue factors that may facilitate the conversion of precursor proteins into their insoluble amyloid products. Recently we have shown that the amyloid fibrils of sporadic cerebral amyloid angiopathy and an autosomal dominant form of familial amyloid angiopathy in patients of Dutch origin (also designated Hereditary Cerebral Hemorrhage with Amyloidosis of Dutch Type) are similar to Alzheimer Disease amyloid B-protein. These findings indicate that B-amyloid deposition disorders form a spectrum of overlapping clinicopathological conditions which range from patients with predominant vascular involvement to patients having a combination of vascular and parenchyma involvement in varying proportions, manifested clinically by stroke and dementia, respectively. We have also found that these disorders exhibit varying neuritic plaque-like structures, or "preamyloidotic lesions," suggesting that they represent an early stage of B- protein deposition. Similar amyloid deposits are often encountered in a significant percent of neurologically asymptomatic aged individuals; hence it is important to clarify their relationship. We propose the following: 1) Biochemical and immunohistochemical studies of early amyloid deposits in asymptomatic elders and patients with cerebral amyloid angiopathy. 2) Identification of the amyloid protein precursor in aged humans. 3) Study of cellular origin and synthesis of the amyloid protein precursor in cells grown in culture. This study is relevant for understanding the basic etiopathogenetic mechanisms associated with amyloid deposition in aging, amyloid angiopathy, and Alzheimer's Disease; it may be useful for diagnostic purposes at a pathological and clinical level.