Parkinson Disease and DBS: Cognitive Effects in GBA Mutation Carriers

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.

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