# Parkinson disease and DBS: cognitive effects in GBA mutation carriers

> **NIH NIH K23** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2021 · $182,410

## Abstract

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 12-17% 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, my 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. This training grant will provide skills in PD cognition, PD genetics, longitudinal data
analysis, clinical trial design, manuscript publication and grantsmanship. 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. The PI is fellowship trained in movement disorders,
completed a Maste...

## Key facts

- **NIH application ID:** 10234214
- **Project number:** 5K23NS097625-05
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** Gian D Pal
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $182,410
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10234214

## Citation

> US National Institutes of Health, RePORTER application 10234214, Parkinson disease and DBS: cognitive effects in GBA mutation carriers (5K23NS097625-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10234214. Licensed CC0.

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