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Parkinson Disease and DBS: Cognitive Effects in GBA Mutation Carriers

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ClinicalTrials.gov Identifier: NCT03234478
Recruitment Status : Recruiting
First Posted : July 31, 2017
Last Update Posted : August 28, 2018
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Gian Pal, Rush University Medical Center

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 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, 2020
Estimated Study Completion Date : June 30, 2022


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




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.


Information from the National Library of Medicine

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03234478


Contacts
Contact: Gian D Pal, MD, MS 3125632900 gian_d_pal@rush.edu

Locations
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Gian D Pal, MD    312-563-2900    gian_d_pal@rush.edu   
Principal Investigator: Gian D Pal, MD, MS         
Sponsors and Collaborators
Rush University Medical Center
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)

Publications of Results:
Responsible Party: Gian Pal, Assistant Professor of Neurological Sciences, Rush University Medical Center
ClinicalTrials.gov Identifier: NCT03234478     History of Changes
Other Study ID Numbers: 15092406-IRB01
1K23NS097625-01A1 ( U.S. NIH Grant/Contract )
First Posted: July 31, 2017    Key Record Dates
Last Update Posted: August 28, 2018
Last Verified: August 2018
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 Pal, Rush University Medical Center:
deep brain stimulation
cognition
young onset Parkinson disease

Additional relevant MeSH terms:
Parkinson Disease
Cognitive Dysfunction
Disease Susceptibility
Genetic Predisposition to Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Disease Attributes
Pathologic Processes