Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common adult-onset degenerative disorders of the nervous system. Patients with AD and a substantial number of patients with PD develop dementia during the course of their illness. Although recent studies indicate that these disorders involve several neuronal populations, the cellular substrate for the memory deficits and abnormalities in cognitive processes, language, visual-spatial skills, and mood are not well understood. In both diseases, certain cell groups show neurofibrillary pathology, i.e., neurofibrillary tangles, Lewy bodies, and argentophilic neurites in senile plaques. Our work with experimental disorders of cytoskeletal pathology suggest that affected neurons in AD and PD exhibit abnormalities in the function of the cytoskeleton. Our research specifically addresses issues concerning the distribution and character of these pathological processes in relation to clinical disease. At The Johns Hopkins Medical Institutions, we have substantial numbers of patients with AD and PD who are well characterized by clinical examinations, neuropsychological tests, and in vitro imaging methods. Affected individuals provide an unusual opportunity to investigate the biology of brain pathology in carefully studied individuals with AD or PD. Using a variety of approaches (immunohistochemistry/histochemistry, neurochemical assays, and computer-assisted imaging methods), we will investigate specific pathologies, including: the number and size of neurons in specific cell groups thought to be at risk in AD or PD; the distribution and density of plaques and tangles; and the distribution of transmitter markers and specific cytoskeletal elements within plaques and tangles. Using statistical approaches, our findings in the brain will be correlated with clinical findings in individual patients. The long-range goal of these investigations is to understand the mechanisms and consequences of specific cellular pathologies in AD and PD. Understanding these processes should lead to insights into the dynamics of disease, raise questions about etiological factors, and suggest rational approaches to therapy.