Parkinson Disease and DBS: Cognitive Effects in GBA Mutation Carriers

NCT ID: NCT03234478

Last Updated: 2024-11-21

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 150 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-07-01
• Study Completion Date: 2024-06-30

Brief Summary

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.

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.

Conditions

Parkinson; Parkinson Disease; Genetic Predisposition; GBA Gene Mutation; Cognitive Decline

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

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.

cognitive assessments

Intervention Type: OTHER

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.

cognitive assessments

Intervention Type: OTHER

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.

cognitive assessments

Intervention Type: OTHER

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.

cognitive assessments

Intervention Type: OTHER

Cognitive assessments will be performed at baseline, 1 year, and 2 years, depending on subject cohort placement

Interventions

cognitive assessments

Cognitive assessments will be performed at baseline, 1 year, and 2 years, depending on subject cohort placement

Intervention Type: OTHER

Eligibility Criteria

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

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

Rutgers, The State University of New Jersey

OTHER

Sponsor Role: lead

Responsible Party

Gian Dev Pal, MD, MS

Assistant Professor of Neurological Sciences

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Gian Pal

Role: PRINCIPAL_INVESTIGATOR

Rutgers University

Locations

Rutgers-Robert Wood Johnson Medical School

New Brunswick, New Jersey, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 27709117 (View on PubMed)

Other Identifiers

1K23NS097625-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Pro2020000729

Identifier Type: -

Identifier Source: org_study_id