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GBA Variations, Cholinergic Degeneration, and Cognitive Decline in Parkinson’s Disease

Study Rationale:
Mutations in the GBA gene are the most common genetic risk factors for Parkinson’s disease. People with GBA mutations (GBA-PD) may develop the disease at a younger age and may have more severe cognitive impairment, postural instability and gait disorders. The cholinergic system, a collection of nerve cells that communicate via the neurotransmitter acetylcholine, plays an important role in these symptoms. Our goal is to gain a better understanding of the cholinergic system in GBA-PD and the related clinical symptoms, using cholinergic PET imaging.

We hypothesize that GBA-PD will have a distinct pattern, with more degeneration of the cholinergic system related to the severity of their symptoms, in particular cognitive impairment and specific motor symptoms.

Study Design:
We will compare the cholinergic system and clinical characteristics of 80 GBA-PD and 125 PD participants without GBA mutations. Participants will be sourced from the Dutch Parkinson Cohort (DUPARC) study and a nationwide screening of Dutch Parkinson’s volunteers. All participants will receive a cholinergic PET scan and extensive clinical examinations, including a complete cognitive and motor-symptom assessment.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
The current study will improve our understanding of the cholinergic pathology underlying the clinical characteristics of Parkinson’s and GBA-PD in particular. Our results will provide future leads for personalized treatment approaches, including current cholinergic treatment regimens. Moreover, our results will improve the selection of subjects for future research, including disease-modification trials.

Next Steps for Development:
To move towards personal treatment approaches,  future research in pre-clinical and clinical trials can be informed by the results of this study. In addition, the selection of subjects for future research can be improved after validating our findings in other cohort studies.


  • Teus van Laar, MD, PhD

    Groningen Netherlands

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