Parkinson disease (PD) is a neurodegenerative disease affecting at least 1 million people in the U.S. Each year, 9,000 PD patients undergo deep brain stimulator (DBS) placement into the subthalamic nucleus (STN- DBS), the most commonly used basal ganglia target. Despite motor improvement, up to 50% of patients have cognitive impairment after DBS. Cognitive impairment is associated with a 2-3 fold increase in mortality, progression to dementia, and nursing home placement. At present, subjects with cognitive impairment after DBS cannot be identified pre-operatively and the effects of DBS on cognitive function are not fully understood. A specific group of PD patients, carriers of mutations in the glucocerebrosidase (GBA) gene, are at particularly high risk for cognitive impairment. PD-GBA mutation carriers have dysfunction of the glucocerebrosidase (GCase) enzyme, resulting in more rapid accumulation and spread of Lewy bodies compared with non- mutation carriers. Clinically, PD-GBA mutation carriers have: (1) deficits in visual memory due to higher Lewy body burden in hippocampal and medial temporal regions, and (2) faster progression to dementia secondary to diffuse cortical Lewy body pathology. Approximately 12-17% of PD subjects with DBS carry GBA mutations, indicating that a substantial portion of the DBS population may be susceptible to cognitive problems. Importantly, STN-DBS itself can impair cognition through modulation of the striato-anterior cingulate cortex circuit, resulting in impulsivity and more errors when faced with tasks that rely on executive functions. Therefore, my central hypothesis is that PD-GBA mutation carriers have greater global cognitive decline after STN-DBS compared with PD-GBA mutation carriers without STN-DBS, and compared with non-mutation carriers with and without STN-DBS. This is a critical area of research because if an association between GBA and STN-DBS is detected, clinicians will be able to identify subjects at risk for worsened cognitive dysfunction through genetic testing and prevent harm by: (1) recommending that PD-GBA mutation carriers avoid STN- DBS, or (2) considering an alternative DBS target such as the globus pallidus interna (GPi) that may have less cognitive side effects. This training grant will provide skills in PD cognition, PD genetics, longitudinal data analysis, clinical trial design, manuscript publication and grantsmanship. The following aims are proposed:
Aim 1 : Determine the longitudinal changes in global cognitive function in PD-GBA mutation carriers and non- mutation carriers with and without STN-DBS;
Aim 2 : Determine the specific pattern of cognitive dysfunction in PD-GBA mutation carriers and non-mutation carriers with and without STN-DBS;
Aim 3 : Determine the differential effects of DBS on cognitive function in the ON-stimulation state vs. OFF-stimulation state, comparing PD-GBA mutation and non-mutation carriers. The PI is fellowship trained in movement disorders, completed a Masters in clinical research, and has a growing number of original first-author publications, demonstrating his commitment to a career in clinical research. Rush University Medical Center is the ideal environment for this proposed research since this program, established in 1980, is one of the oldest movement disorders training programs in the United States and has a long track record of training clinician-researchers. The primary mentor for this proposal, Deborah Hall, MD, PhD, is an internationally recognized clinician-scientist with expertise in neurogenetics and epidemiology. The co-mentors include Robert Wilson, PhD an expert in studies that determine longitudinal cognitive trajectories in aging and repeated measures analysis; Glenn Stebbins, PhD an expert in biostatistics who has served as the chief statistician to numerous clinical studies in PD and other movement disorders; and Christopher Goetz, MD, an internationally recognized expert in PD and clinical trial design. Successful funding and implementation of this proposal will allow the PI to pursue the following career goals: 1) Acquire further knowledge in PD cognition with a focus on neurobiology, systems neurophysiology of DBS, and methods of neuropsychological assessment. 2) Master methods in analysis of longitudinal data, repeated measures analysis, and clinical trial design. 3) Learn basic techniques in interpretation of genetic data and ethical issues related to genetic testing. The candidate's background and goals, the research and mentoring environment, and the design of the proposed study, positions the PI as an ideal candidate for the K23 mechanism.

Public Health Relevance

Every year, approximately 9,000 Parkinson disease (PD) patients undergo deep brain stimulator (DBS) placement into the subthalamic nucleus (STN-DBS). Studies suggest that PD patients with mutations in the glucocerebrosidase (GBA) gene are at high risk for cognitive impairment and approximately 10-18% of subjects undergoing DBS carry GBA mutations. There may be an interaction between STN-DBS, which also impairs cognitive function, and GBA, resulting in worsened cognitive function. This project will 1) determine the relationship between GBA mutation status and post-operative STN-DBS cognitive function, 2) broaden genotype-phenotype relationships of GBA mutation carriers and 3) provide scientific knowledge regarding the longitudinal cognitive effects of DBS in GBA mutation carriers through repeated neuropsychological testing.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neurological Sciences Training Initial Review Group (NST)
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Babcock, Debra J
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Rush University Medical Center
Schools of Medicine
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Pal, Gian; Ouyang, Bichun; Verhagen, Leo et al. (2018) Probing the striatal dopamine system for a putative neuroprotective effect of deep brain stimulation in Parkinson's disease. Mov Disord 33:652-654
Weiss, Daniel; Pal, Gian D (2018) Validating the targets for neurostimulation in essential tremor. Neurology 91:247-248