Objective: Assess presynaptic cholinergic integrity and associated functional connectivity differences in Parkinson disease (PD)-related dystonia.

Background: Dystonia is observed in 30-60% of individuals with PD. [1] Striatal cholinergic dysfunction and abnormal sensorimotor network connectivity are implicated in other dystonia phenotypes, [2-3] but their role in PD-related dystonia is unknown.

Method: Participants with PD were selected from a longitudinal study including clinical dystonia assessment, [¹⁸F]VAT PET scans and 3T resting-state functional MRI (rs-fMRI). Individuals were classified as PD with dystonia (PD+DYS) or without dystonia (PDnoDYS). Group differences in demographics and clinical variables were assessed using chi-square or independent t-tests. Whole-brain voxel-wise cluster analysis of [¹⁸F]VAT PET binding potential (BP) used a ≥ 15% between group threshold (Bonferroni corrected p<0.01). Regions showing significant BP differences were used as seeds for whole-brain seed-based functional connectivity (FC) rs-fMRI. FC significance was set at t ≥2.2 and cluster size ≥25 voxels after Monte Carlo simulation (1000 permutations, FDR corrected).

Results: 83 participants (57% female) with [¹⁸F]VAT PET and rs-fMRI within the same study year were included (58 PD+DYS, 25 PDnoDYS). PD+DYS participants were younger (p=0.04), with no differences in sex, disease duration, levodopa equivalent daily dose (LEDD), or levodopa-related dyskinesias. After PET quality control, 43 participants (30 PD+DYS, 13 PDnoDYS)​ were analyzed. PD+DYS showed reduced [¹⁸F]VAT BP in bilateral striatum. [figure1] These clusters served as FC seeds in 56 participants (39 PD+DY, 17 PDnoDYS)​, revealing decreased FC in PD+DYS involving the right putamen and left occipital cortex. [figure2]

Conclusion: PD-related dystonia is associated with reduced presynaptic cholinergic integrity and disrupted FC.  These findings implicate cholinergic dysfunction within basal ganglia-cortical networks as a potential substrate of PD dystonia. The absence of associations with disease duration, LEDD, or dyskinesias support PD dystonia as a distinct pathophysiologic phenotype rather than a treatment complication.

Figure 1

Figure 2

References: 1. Jankovic, J. & Tintner, R. Dystonia and parkinsonism. Parkinsonism Relat Disord 8, 109–121. (2001).
2. Eskow Jaunarajs KL, Bonsi P, Chesselet MF, Standaert DG, Pisani A. Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia. Prog Neurobiol. 2015;127-128:91-107.
3. Vo A, Nguyen N, Fujita K, Schindlbeck KA, Rommal A, Bressman SB, Niethammer M, Eidelberg D. Disordered network structure and function in dystonia: pathological connectivity vs. adaptive responses. Cereb Cortex. 2023;33(11):6943-58. Epub 2023/02/08. doi: 10.1093/cercor/bhad012. PubMed PMID: 36749014; PMCID: PMC10233302

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cholinergic-dysfunction-associated-to-aberrant-functional-connectivity-in-parkinson-disease-related-dystonia/