Objective: To investigate 2-yr interval change in cholinergic transporters in biology-based cholinergic subgroups using serial VAChT [¹⁸F]FEOBV brain PET in Parkinson’s disease (PD).

Background: Current subtyping approaches in PD are mainly based on clinical data that may bias biologically accurate definition of sub-groups. This is because clinical effects of biological compensatory mechanisms are difficult to capture clinically yet may be driving progression in PD.

Method: 96 PD subjects & 31 NC underwent [¹⁸F]FEOBV PET. Principal component analysis (PCA) using VOIs from PET data comparing PD to control subjects was applied.

Results: PCA revealed 5 factors. Based on cholinergic innervation status (<P5 of >P95 in normal) four different subgroups were defined: A) hypercholinergic (mainly driven by PC5 posterior cortex) and normal status in the other factors; B) normocholinergic activity in all factors; C) decompensated hypocholinergic status (low PC1 and at least one other low factor) and D) compensated hypocholinergic status (at least hypocholinergic status in PC1 with at least hypercholinergic activity). All subgroups had posterior cortical denervation but increasing in extent from groups A->B->C->D. A reverse hypercholinergic gradient (esp. cerebellum, cholinergic forebrain, subcortical gray matter) was also present in groups A->B->C but not in D. The 2-yr interval data showed prominent cortical losses in B, mild predominant anterior cortical losses in C and mild posterior cingulum, fimbriae and pallidal losses in group D. Despite these losses 2-yr interval increases were still present in these groups (esp. cerebellum, cholinergic forebrain, caudate) but with very limited increases in group D.

Conclusion: There is a progressive pattern of cortical cholinergic denervation in all subgroups in the setting of cholinergic compensation (esp. cerebellum, cholinergic forebrain & caudate) where compensatory activity in these subgroups continues to persist (but decreases in extent) over a 2-yr follow-up in PD. Cholinergic compensation may play an important role in PD progression.

Funding: Study funded by National Institutes of Health (P01 NS015655, RO1 NS070856, P50 NS091856, P50 NS123067), Department of Veterans Affairs grant (I01 RX001631), the Michael J. Fox Foundation, and the Parkinson’s Foundation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cholinergic-subtyping-in-parkinson-disease-differential-2-year-interval-changes/