The goal of this project is to evaluate novel candidate protein biomarkers for Alzheimer's disease that we have previously identified in CSF using a non-biased proteomics approach (two-dimensional difference in gel electrophoresis [2D-DIGE] coupled with liquid chromatography and tandem mass spectrometry [LCMS/MS]) that compared the CSF proteomes of samples derived from two groups of well-characterized subjects: one with mild dementia of the Alzheimer's type (DAT) and evidence of amyloid deposition in the brain (low CSF Ab42 levels) (N=24);and another without demenia and no evidence of amyloid deposition in the brain (high CSF Ab42 levels) (N=24). To evaluate these candidate biomarkers, in Aim 1 we will develop specific quantitative assays (e.g. ELISA) and validate them assays using CSF from the original 'discovery'cohort of subject samples.
In Aim 2, we will apply these validated assays to a Iarger, independent set of CSF samples obtained from well-characterized volunteer subjects followed longitudinally at the WU ADRC, in order to evaluate each assay's diagnostic and prognostic utility.
In Aim 3, we propose to perform 'top down'proteomics on a small number of these candidate biomarkers that exhibited aberrant patterns of migration on 2D-DIGE suggestive of unusual post-translational modifications characterizing such distinguishing modifications will enable the development of additional biomarker assays in the future, and may yield insights into the pathophysiology of AD.
This study is intended to discover novel CSF AD biomarkers and evaluate their diagnostic and prognostic utility. These biomarkers are expected to: 1) facilitate the diagnosis of AD prior to dementia onset;2) aid in identification of cognitively normal individuals most likely to progress to dementia, 3) aid in identification of very mildly demented patients whose dementia is most likely to worsen, and 4) yield new insights into the pathophysiology of AD. These findings will directly impact future clinical trial enrollment and patient care.
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