This is an application for a K23 Mentored Patient-Oriented Research Career Development Award titled Basal ganglia modulation of cognitive systems in Parkinson's disease. The primary goal of the proposed research is to investigate regional and brain network abnormalities associated with mild cognitive impairment (MCI) in Parkinson's disease (PD) patients using event-related and resting state functional MRI (fMRI). The rigorous education and training plan will increase the candidate's expertise in fMRI methodology, statistical analysis, behavioral neuroscience, and clinical research methods, thus providing the candidate the necessary skills to ensure success of the proposed research and to become an independent investigator. The candidate's long term career goal is to use fMRI to elucidate the pathophysiology of cognitive dysfunction in PD and to develop an fMRI based imaging tool that is a sensitive marker of cognitive impairment in PD and an objective biomarker of treatment response. This proposal investigates in vivo functional changes associated with cognitive dysfunction in early PD patients without (PD-noMCI) and with (PD-MCI) mild cognitive impairment, compared to normal controls.
Aim 1 uses fMRI tasks targeting executive control processes that require activation of basal ganglia nuclei in normal controls to determine changes in basal ganglia and cortical activation associated with PD cognitive impairment. In addition to changes in regional brain activation, cognitive impairment in PD likely also stems from alterations in connectivity between critical brain regions; therefore in Aim 2 we will investigate functional connectivity between basal ganglia nuclei and the cortex using resting state fMRI. Finally, dopaminergic medications can lead to both cognitive enhancement and further impairment, depending on the cognitive function. Therefore, Aim 3 will investigate changes in basal ganglia and cortical activation, striato- cortical connectivity, and intrinsic networks in the PD-noMCI and PD-MCI groups while ON medications compared to the previously performed OFF medication studies. Changes in basal ganglia activation and functional connectivity associated with PD-MCI identified in this proposed research will help clarify the role of basal ganglia nuclei in early PD cognitive impairment and, thus, have implications on the development of therapies for this currently untreatable symptom.

Public Health Relevance

Cognitive dysfunction in PD patients causes substantial human and financial costs and constitutes a growing public health challenge for the aging American population. The proposed research seeks to clarify the function of the basal ganglia in modulation of PD-associated cognitive impairment, ultimately promoting better treatments for PD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS075097-05
Application #
8874314
Study Section
NST-2 Subcommittee (NST)
Program Officer
Babcock, Debra J
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Kim, Jeehyun; Zhang, Kai; Cai, Weidong et al. (2018) Dopamine-related dissociation of cortical and subcortical brain activations in cognitively unimpaired Parkinson's disease patients OFF and ON medications. Neuropsychologia 119:24-33
Milchenko, Mikhail; Norris, Scott A; Poston, Kathleen et al. (2018) 7T MRI subthalamic nucleus atlas for use with 3T MRI. J Med Imaging (Bellingham) 5:015002
Hendershott, Taylor R; Zhu, Delphine; Llanes, Seoni et al. (2017) Domain-specific accuracy of the Montreal Cognitive Assessment subsections in Parkinson's disease. Parkinsonism Relat Disord 38:31-34
Ng, Bernard; Varoquaux, Gael; Poline, Jean Baptiste et al. (2017) Distinct alterations in Parkinson's medication-state and disease-state connectivity. Neuroimage Clin 16:575-585
Warden, Clara; Hwang, Jaclyn; Marshall, Anisa et al. (2016) The effects of dopamine on digit span in Parkinson's disease. J Clin Mov Disord 3:5
Poston, Kathleen L; YorkWilliams, Sophie; Zhang, Kai et al. (2016) Compensatory neural mechanisms in cognitively unimpaired Parkinson disease. Ann Neurol 79:448-63
Leaver, Katherine; Poston, Kathleen L (2015) Do CSF Biomarkers Predict Progression to Cognitive Impairment in Parkinson's disease patients? A Systematic Review. Neuropsychol Rev 25:411-23
Müller-Oehring, Eva M; Sullivan, Edith V; Pfefferbaum, Adolf et al. (2015) Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson's disease. Brain Imaging Behav 9:619-38
Niethammer, Martin; Tang, Chris C; Feigin, Andrew et al. (2014) A disease-specific metabolic brain network associated with corticobasal degeneration. Brain 137:3036-46
YorkWilliams, Sophie; Poston, Kathleen L (2014) What light have resting state fMRI studies shed on cognition and mood in Parkinson's disease? J Clin Mov Disord 1:4

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