Parkinson Disease and DBS: Cognitive Effects in GBA Mutation Carriers

• ClinicalTrials.gov Identifier: NCT03234478
• Recruitment Status: Recruiting
• First Posted: July 31, 2017
• Last Update Posted: December 9, 2022
• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Gian Dev Pal, MD, MS, Rutgers, The State University of New Jersey

Study Description

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.

Condition or disease	Intervention/treatment
Parkinson; Parkinson Disease; Genetic Predisposition; GBA Gene Mutation; Cognitive Decline	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 Design

• Study Type: Observational
• Estimated Enrollment: 262 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Parkinson Disease and DBS: Cognitive Effects in GBA Mutation Carriers
• Actual Study Start Date: July 1, 2017
• Estimated Primary Completion Date: June 30, 2023
• Estimated Study Completion Date: June 30, 2023

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures :

1. Mattis Dementia Rating Scale [ Time Frame: 2 years ]
   scale to assess global cognition

Secondary Outcome Measures :

1. NIH toolbox cognition battery [ Time Frame: 1 year ]
   iPAD based cognitive battery
2. Neuro-QoL [ Time Frame: 2 years ]
   scale to assess quality of life
3. PROMIS [ Time Frame: 2 years ]
   scale to assess quality of life

Biospecimen Retention:   Samples With DNA

blood will be retained for analysis of GBA metabolites.

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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.

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

Contacts and Locations

Contacts

Contact: Gian D Pal, MD, MS; 7322357733; gian.pal@rutgers.edu

Locations

United States, New Jersey

Rutgers-Robert Wood Johnson Medical School; Recruiting

New Brunswick, New Jersey, United States, 08901

Contact: Gian Pal, MD 732-235-7733 gian.pal@rutgers.edu

Principal Investigator: Gian D Pal, MD, MS

Sponsors and Collaborators

Rutgers, The State University of New Jersey

National Institutes of Health (NIH)

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Gian Pal; Rutgers University

More Information

Publications of Results:

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.

• Responsible Party: Gian Dev Pal, MD, MS, Assistant Professor of Neurological Sciences, Rutgers, The State University of New Jersey
• ClinicalTrials.gov Identifier: NCT03234478
• Other Study ID Numbers: Pro2020000729; 1K23NS097625-01A1 ( U.S. NIH Grant/Contract )
• First Posted: July 31, 2017
• Last Update Posted: December 9, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Gian Dev Pal, MD, MS, Rutgers, The State University of New Jersey:

deep brain stimulation; cognition; young onset Parkinson disease

Additional relevant MeSH terms:

Parkinson Disease; Disease Susceptibility; Genetic Predisposition to Disease; Cognitive Dysfunction; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Disease Attributes; Pathologic Processes