Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), and Parkinson's disease with dementia (PDD) are neurodegenerative disorders that lead to a global dementia syndrome. Despite differences in the prominence and order of appearance of various clinical characteristics (e.g., dementia, movement disorder, visual hallucinations), the disorders can be quite similar in clinical presentation once dementia is present, making them difficult to clinically differentiate (particularly AD vs. DLB and DLB vs. PDD). Recent evidence suggests that differences in the patterns of cognitive deficits associated with the disorders might aid in distinguishing between them and have some utility in predicting rate of global cognitive decline. Thus, the goal of the proposed project is to determine whether mildly demented DLB, PDD, and AD patients differ in the relative severity of deficits they exhibit on experimental and clinical neuropsychological tests (Study I). Based upon the different distributions of pathological changes associated with the three disorders it is anticipated that semantic knowledge and episodic memory deficits will be most salient in AD, visuospatial processing deficits will be most salient in DLB, and implicit category learning deficits will be most salient in PDD. Furthermore, we will determine whether or not unique patterns of deficits on these tests are maintained over a one-year period (Study II). Previous evidence suggests that the degree of impairment in the most salient cognitive deficit in each disorder predicts the rate of subsequent global cognitive decline. We will address this question by directly comparing the cognitive predictors of decline in three disorders (Studies Illa-c). We anticipate that degree of semantic memory loss (and not the lack of integrity in other cognitive functions) will uniquely predict decline in AD, severity of visuospatial processing deficits will uniquely predict decline in DLB, and degree of category learning impairment will uniquely predict decline in PDD. In exploratory studies (Studies IV-VI), we will examine the relationship between the degree of impairment on the cognitive tests from each domain and the severity of neuropathologic changes in the presumed underlying brain substrate. We anticipate that posterior cortical pathology (e.g., a-synuclein pathology, (3-amyloid and tau pathology, synapse loss) will be associatedwith visuospatial dysfunction and decline (DLB

Public Health Relevance

(Seeinstructions): Identification of differences in the neuropsychological deficits in AD, DLB, and PDD will allow us to better differentiate among the three disorders and facilitate early diagnosis. Validation of cognitive markers that predict subsequent rate of global cognitive decline will improve the accuracy of prognosis and may provide a method to enhance cohorts with rapid decliners for clinical trials of potential disease modifying therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Special Emphasis Panel (ZAG1-ZIJ-4)
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University of California San Diego
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