Parkinson Disease and DBS: Cognitive Effects in GBA Mutation Carriers

Parkinson Disease Clinical Trial

Official title:

Parkinson Disease and DBS: Cognitive Effects in GBA Mutation Carriers

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03234478
• Other study ID #: Pro2020000729
• Secondary ID: 1K23NS097625-01A
• Status: Recruiting
• Start date: July 1, 2017
• Est. completion date: June 30, 2024

Study information

• Verified date: June 2023
• Source: Rutgers, The State University of New Jersey
• Contact: Gian D Pal, MD, MS
• Phone: 7322357733
• Email: gian.pal[@]rutgers.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 262
• Est. completion date: June 30, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Cognitive Decline
• Cognitive Dysfunction
• GBA Gene Mutation
• Genetic Predisposition
• Genetic Predisposition to Disease
• Parkinson
• Parkinson Disease

Intervention

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

Locations

Country	Name	City	State
United States	Rutgers-Robert Wood Johnson Medical School	New Brunswick	New Jersey

Sponsors (3)

Lead Sponsor	Collaborator
Rutgers, The State University of New Jersey	National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. G — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mattis Dementia Rating Scale	scale to assess global cognition	2 years
Secondary	NIH toolbox cognition battery	iPAD based cognitive battery	1 year
Secondary	Neuro-QoL	scale to assess quality of life	2 years
Secondary	PROMIS	scale to assess quality of life	2 years