Alzheimer's disease (AD) is the most common form of geriatric dementia; however, there are other, partially overlapping, pathogenic processes that also contribute to cognitive impairment late in life, most frequently Lewy body disease and vascular disease. Surrogate measures such as biomarkers, in concert with neurological examination and neuroimaging, will aid in the diagnosis of geriatric dementias and serve as objective measures of disease progression and response to therapeutics. Here we propose to test the hypothesis that unbiased identification and quantification of the cerebrospinal fluid (CSF) proteome can be used to assemble a roster of proteins that objectively characterizes the different facets of geriatric dementia. We will test this hypothesis by accomplishing the following Specific Aims: (1) Discovery: Using Isotope Coated Affinity Tagging coupled with 2-dimensional liquid chromatography/electrospray ionization-mass spectrometry we will determine relative quantitative differences in the CSF proteome of controls vs. patients with different types of geriatric dementia, (2) Confirmation: Using a combination of immunochemical methods we will confirm the major discoveries of Aim 1 and develop a multianalyte profile (MAP) for geriatric dementias, (3) Validation: While blinded to diagnosis, we will validate our findings in a separate set of controls and patients with mild cognitive impairment (MCI) and different forms of geriatric dementia, and (4) Data and Sample Exchange: databases and resources resulting from these analyses will be made available to other investigators using alternative methods in the investigation of biomarkers for geriatric dementias. Once completed, these studies will have discovered, confirmed, and validated a MAP for objectively assessing different facets of geriatric dementia.
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