Parkinson's disease (PD) is a disabling neurodegenerative disorder which includes various manifestations of cognitive compromise and behavioral abnormalities at all stages of the disease. Knowledge of the natural history and temporal progression of cognitive decline in PD is essential to provide the predictors for dementia in PD and for the design of clinical trials aimed at evaluating promising therapeutic interventions. There has been a great of interest in evaluating the potential of advanced noninvasive neuroimaging techniques, such as positron emission computed tomography (PET) and magnetic resonance imaging (MRI). Improved understanding of how cognitive function is altered in vivo in brain tissue would be an invaluable step in developing potential PD biomarkers. In this proposal, we will use multiple imaging modalities including PET, MR spectroscopy (MRS) and MR diffusion tensor imaging (MRDTI), in parallel with plasma metabolomic profiles to obtain complementary measures of potential metabolic, physiologic, and structural changes, and evaluate their relationship with cognitive decline in PD at different stages of disease severity. We will examine 30 early sporadic PD without dementia (PDND), 30 sporadic PD with early dementia (PD-D), and 30 controls matched with respect to age, ethnicity, gender and education. All subjects will undergo complete clinical and neurological examination, neuropsychological and behavioral testing, as well as imaging measurements including [18F]-fluorodeoxyglucose (FDG) PET, structural MRI, 1H and 31P MRS imaging (MRSI), and MRDTI, and metabolomic profiling from blood samples. Cognitive function and behavior status will be tested in the domains of overall mental status, memory, learning, language, executive and visual spatial function as well as depression, anxiety, and apathy. All subjects will be re-evaluated at 2 year interval. Between-subjects and within-subjects differences in neurological examinations, neuropsychological and behavioral status, neuroimaging measurements, and serum metabolomic levels will be evaluated. Correlation between cognitive function and imaging assessments and serum metabolomics for different degrees of disease severity will be examined. We will also evaluate the sensitivity and specificity of utilizing the combined neuroimaging and metabolomic markers in facilitating the diagnosis of cognitive impairment and dementia in PD, and monitor the progression of the disease. In summary, the long-term and overall goal of this study will be to investigate the natural history of cognitive decline in PD, and evaluate the potential of advanced functional neuroimaging techniques and serum metabolomic profiling in providing objective markers of cognitive impairment in PD. These markers can predict dementia at preclinical stage, and serve as surrogate markers of response to promising therapeutic interventions. PUBLIC HEALTH RELEVANCE: This study aimed to evaluate the potential of utilizing the neuroimaging techniques, such as positron emission computed tomography (PET) and magnetic resonance imaging (MRI), and plasma metabolomic profiling in providing objective markers for cognitive decline in PD. These markers can predict dementia in PD, and serve as diagnostic or surrogate markers of response to promising therapeutic interventions aimed at delaying or even preventing the onset and progression of the disease.