Parkinson Disease and DBS: Cognitive Effects in GBA Mutation Carriers

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 10-17% 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.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease; Cognitive Decline; Parkinson; Genetic Predisposition; GBA Gene Mutation
• Intervention / Treatment: Other: cognitive assessments

Detailed Description

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 10-17% 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, the 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. 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.

• Study Type: Observational
• Enrollment (Estimated): 262

Contacts and Locations

• Study Contact: Name: Gian D Pal, MD, MS; Phone Number: 7322357733; Email: gian.pal@rutgers.edu

Study Locations

• United States
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Recruiting
      • Rutgers-Robert Wood Johnson Medical School
      • Contact: Gian Pal, MD; Phone Number: 732-235-7733; Email: gian.pal@rutgers.edu
      • Principal Investigator: Gian D Pal, MD, MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Parkinson's disease subjects with onset of symptoms under age 60 with moderate to advanced disease. Subjects can be with OR without deep brain stimulation.

Description

Inclusion Criteria:

• Parkinson's disease
• onset of symptoms under age 60
• at least 5 years of disease
• with OR without deep brain stimulation

Exclusion Criteria:

• dementia

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
GBA mutation carriers without DBS; Parkinson's disease patients who have moderate to advanced disease but have not undergone deep brain stimulation. Subjects will be tested for GBA mutation status as part of this study.	Other: cognitive assessments; Cognitive assessments will be performed at baseline, 1 year, and 2 years, depending on subject cohort placement
non-mutation carriers without DBS; Parkinson's disease patients who have moderate to advanced disease but have not undergone deep brain stimulation. Subjects will be tested for GBA mutation status as part of this study.	Other: cognitive assessments; Cognitive assessments will be performed at baseline, 1 year, and 2 years, depending on subject cohort placement
GBA mutation carriers with DBS; Parkinson's disease patients who have moderate to advanced disease and have undergone deep brain stimulation. Subjects will be tested for GBA mutation status as part of this study.	Other: cognitive assessments; Cognitive assessments will be performed at baseline, 1 year, and 2 years, depending on subject cohort placement
non-mutation carriers with DBS; Parkinson's disease patients who have moderate to advanced disease and have undergone deep brain stimulation. Subjects will be tested for GBA mutation status as part of this study.	Other: cognitive assessments; Cognitive assessments will be performed at baseline, 1 year, and 2 years, depending on subject cohort placement

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mattis Dementia Rating Scale	scale to assess global cognition	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NIH toolbox cognition battery	iPAD based cognitive battery	1 year
Neuro-QoL	scale to assess quality of life	2 years
PROMIS	scale to assess quality of life	2 years

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Gian Pal, Rutgers University

Publications and helpful links

General Publications

• Pal GD, Hall D, Ouyang B, Phelps J, Alcalay R, Pauciulo MW, Nichols WC, Clark L, Mejia-Santana H, Blasucci L, Goetz CG, Comella C, Colcher A, Gan-Or Z, Rouleau GA, Marder K; Consortium on Risk for Early Onset Parkinson's Disease (CORE-PD) Investigators. Genetic and Clinical Predictors of Deep Brain Stimulation in Young-Onset Parkinson's Disease. Mov Disord Clin Pract. 2016 Sep-Oct;3(5):465-471. doi: 10.1002/mdc3.12309. Epub 2016 Jan 18.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2017
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: July 25, 2017
• First Submitted That Met QC Criteria: July 28, 2017
• First Posted (Actual): July 31, 2017

Study Record Updates

• Last Update Posted (Actual): June 2, 2023
• Last Update Submitted That Met QC Criteria: June 1, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: deep brain stimulation; cognition; young onset Parkinson disease
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Disease Attributes; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Cognition Disorders; Disease Susceptibility; Parkinson Disease; Cognitive Dysfunction; Genetic Predisposition to Disease
• Other Study ID Numbers: Pro2020000729; 1K23NS097625-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No