It has become increasingly clear that Parkinson's disease (PD) is often associated with cognitive impairment. Pathological evaluations have repeatedly demonstrated that dementia in PD patients (PD-D) is associated with either formation of Lewy bodies (LBs) or Alzheimer's changes (presence of neurofibrillary tangles (NfTs) and senile plaques (SPs)) in the cortex. It is well known that formation of LBs, NfTs and SPs are related to deposition of 1-synuclein (SNCA), tau and A?, respectively. However, the changes in these key proteins are not known in relationship to the development of PD-D. We have hypothesized that development of cognitive impairment in PD is associated with unique post-translational modifications (PTMs) of SNCA, tau and A?, and that the PTMs are isoform/species specific, as well as disease stage specific. Thus, one of the major goals of the proposal is to characterize the PTMs of various isoforms/species of SNCA, tau and A? as a function of PD- D development using various state-of-the-art proteomics techniques. Additionally, as development of PD-D likely involves cellular processes beyond just SNCA, tau and A?, for the purpose of discovering biomarkers that are clinically accessible, we will also use a high throughput proteomic technique to characterize a sub- proteome with a unique PTM (glycosylation) that is highly enriched in body fluids, i.e. proteins carrying great potentials to be biomarkers for PD-D. Both analyses (targeted and unbiased profiling) will be applied to pathologically confirmed brain tissues initially, followed by confirmation and validation in the cerebrospinal fluid (CSF) and plasma, respectively. The confirmed and validated markers, whether in CSF or plasma, can then serve as the basis of highly sensitive and specific multiplex immunoassays (xMAP) used to identify PD patients at risk for developing cognitive deficits. Four Specific Aims have been designed to accomplish these goals: 1) Identify proteins unique to the development of PD-D in pathologically involved brain regions in confirmed PD cases with and without dementia clinically. 2) Confirm and validate unique proteins, revealed in brain tissue, in lumbar CSF obtained from living subjects at different stages with and without dementia clinically. 3) Confirm and validate unique proteins, revealed in brain tissue, in plasma obtained from living subjects at different stages with and without dementia clinically. 4) Establish xMAP assays for detecting cognitive impairment in PD 7. PUBLIC HEALTH RELEVANCE: This project investigates the potential biomarkers correlating with the development of cognitive impairment in Parkinson's patients. Identification of these makers can increase therapeutic window for Parkinson's patients at risk for developing dementia that is associated with mortality, caregiver burden and risk for nursing home admission.