Objective: The objective of this study was to assess cholinergic activity changes in patients with Parkinson’s disease carrying GBA1 variants(GBA-PD) and in non-manifesting carriers(GBA-NMC) using PET.

Background: Heterozygous carriers of pathogenic GBA1 variants have an increased risk of developing Parkinson’s disease(PD). The clinical phenotype of GBA-PD is largely indistinguishable from idiopathic PD(iPD), except for a slightly younger age of onset and a greater cognitive impairment. Reduction of cortical cholinergic activity is linked to cognitive dysfunction in PD. Previous studies have shown reduced cortical cholinergic innervation in GBA-PD, similar to iPD, but with potentially greater regional involvement. Given the high risk of dementia in GBA-PD carriers, characterization of cholinergic dysfunction in this population is particularly relevant.

In other genetic forms of PD, e.g. LRRK2-related, cholinergic alterations have been observed even in NMCs, but data for GBA1 are lacking. We hypothesized that GBA-PD would show significant cholinergic changes, potentially even at a premotor stage.

Method: We conducted a PET imaging study using [11C]PMP, a tracer of acetylcholinesterase activity, in GBA-PD(n=7), GBA-NMC(n=4), and healthy controls(HC, n=5). The AChE hydrolysis rate (k3) was quantified in 48 cortical regions. Intergroup comparisons were performed using nonparametric tests.

Results: Age and sex did not differ significantly between groups. Median disease duration in GBA-PD was 36 months, and MoCA scores were similar between GBA-PD and GBA-NMC. GBA-PD showed lower PMP k3 in 38 of 48 cortical regions compared to HC, though differences were not statistically significant. In contrast, GBA-NMC exhibited higher PMP k3 in multiple cortical regions compared to HC, with significant increases in the left precuneus, dorsolateral prefrontal, and occipital cortices, as well as right posterior inferior temporal gyrus and medial orbital cortex. Trend-level increases were observed in the right precuneus and anterior cingulate, and in the left posterior cingulate, medial orbital, anterior frontal, and temporal cortice.

Conclusion: GBA-NMC showed increased cortical cholinergic activity, resembling findings in LRRK2-NMC. This may represent an early compensatory mechanism aimed at preserving cortical cholinergic function before neurodegeneration occurs. Further data collection is underway and results will be presented.

11C-PMP K3 in cortical regions

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MDS Abstracts - https://www.mdsabstracts.org/abstract/asymptomatic-gba1-mutation-carriers-have-increased-cortical-cholinergic-activity/