Our project attempts to define the natural history of Alzheimer's disease (AD) with a prospective clinico-pathologic study and uses these data to evaluate potential biological and clinical markers of this illness. We have been studying a chort of 160 demented subjects and 100 controls for up to 3 years. We collect extensive core data, and perform yearly neurological and neuropsychological exams on these subjects. Our preliminary data have suggested that 1) several subjects who met pathological criteria of AD were not demented when evaluated just prior to death, and 2) several demented subjects had numerous senile plaques, but no cortical neurofibrillary tangles, and may represent a subgroup of """"""""plaque- only"""""""" AD. Our preliminary biological marker studies found Alz 68 (a protein which may be unique to AD) in the CSF of 3 out of 3 AD patients, but in none of 3 controls. We also measure concentrations of neurofibrillary tangles proteins in CSF. Our fibroblast studies have identified differences in cholinergic differentiating activity and calcium metabolism in fibroblasts from AD patients. We are also measuring the frequency of the rare complement C4 allele, C42B, in our AD patients to try and confirm whether than allele is frequently associated with AD. We are studying the rate of progression of cognitive decline in AD and analyzing which factors are associated with differences in rate or pattern of decline. We will continue our studies using experimental and traditional neuropsychological tests aimed at identifying the cognitive subprocesses impaired in AD. We have found the elderly subjects with """"""""apparent"""""""" memory disorders may have deficits in processing and retrieval, but truly demented subjects have impaired storage as well. Our neuroimaging studies have found that a unique measure called the hippocampal index correlates better than more traditional measures with cognitive performance. By studying both the course of AD and potential markers of this illness, we will try to improve diagnostic accuracy and may uncover fundamental clues about this illness.
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