Research Project 2

Principal investigator: Kathleen L. Poston, MD, MS

Working memory in Parkinson disease: a cognitive & systems neuroscience approach

Cognitive impairment and dementia are among the most devastating symptoms of Parkinson’s disease (PD). Early PD patients exhibit subtle cognitive dysfunction that is often already present by the time motor symptoms develop, and over 15% of PD patients will fulfill criteria for Mild Cognitive Impairment (PD-MCI) at the time of the initial PD diagnosis. Among the cognitive deficits seen in PD, many patients have specific impairment of working memory (WM), which plays an important role in virtually all higher-order cognitive functions. Here, we propose to initiate a systematic study of WM dysfunction in PD patients. The overarching goals of this study are to determine changes in brain activation, network connectivity, and causal neural dynamics associated with WM deficits in patients with PD, contrast these changes with WM deficits in amnestic-MCI (aMCI) patients, and determine the changes in activation, connectivity, and causal dynamics associated with dopaminergic medications. In Aim 1 we will use a WM task during functional Magnetic Resonance Imaging (fMRI) to determine the differential patterns of brain activation during WM in PD-MCI and aMCI. In Aim 2, we will generalize our findings from Aim 1 using task-free fMRI to determine the intrinsic connectivity differences in brain regions associated with WM in the two groups. Finally, in Aim 3 we will investigate changes in patterns of activation and intrinsic connectivity in PD associated with cortical dopamine metabolism and oral dopamine replacement. We will test the hypothesis that weak cortico-striatal network interactions are prominent features of WM deficits in PD, and that the strength of these interactions is related to individual differences in deficits. Our proposed studies will lead to new and improved understanding of the mechanisms underlying cognitive impairment in PD and Alzheimer’s disease, the two most common neurodegenerative disorders in the aging population.

The long-term goal of our research is to better understand the working memory and executive cognitive deficits, and their neurobiological bases, in people with Parkinson’s disease. Our proposed studies will provide a systematic and detailed analysis of working memory deficits in Parkinson’s disease patients. Characterizing these deficits is profoundly important to reducing the substantial human and financial costs associated with cognitive dysfunction in PD, and ultimately promoting better treatments for patients.