Objective: To characterize individual-level topographical patterns of cholinergic upregulation and downregulation in Multiple System Atrophy (MSA) using a whole brain voxel-wise approach.

Background: MSA is a neurodegenerative disorder with α-synuclein pathology causing neuronal degeneration. Limited dopaminergic therapy response suggests additional neurochemical changes to dopamine neurons loss. Our prior work identified cholinergic alterations in MSA (1), and our recent preliminary [¹⁸F]FEOBV PET data revealed cholinergic downregulation in the brainstem and medial temporal lobe at a group level. Individual-level variations remain unexplored. Mapping subject-specific patterns may clarify clinical heterogeneity and inform novel therapeutic strategies.

Method: Five MSA patients and 31 healthy controls underwent [¹⁸F]FEOBV PET and MRI. Voxel-wise W-maps were generated (La Joie et al., 2012; PMID: 23152610) to quantify individual deviations (W-scores) from normal controls, correcting for age and sex. Significant cholinergic downregulation was defined as W-scores < -1.65, while upregulation as W-scores > 1.65.

Results: Single-subject W-maps revealed significant variability in cholinergic system status across the 5 MSA cases. Two MSA-parkinsonian (MSA-p) patients (Case 1 and Case 2, Figure 1) showed widespread cortical upregulation in the frontal (esp. orbitofrontal regions) and parietal cortices, with shared posterior putamen downregulation. Case 1 had more extensive cortical downregulation, lower Montreal Cognitive Assessment (MoCA) (23 vs. 25), and was younger (69 vs. 75). Case 3 (MSA-p) showed right-lateralized fronto-parietal downregulation, minimal upregulation, the highest fall frequency (1/day), but intact cognition (MoCA 30). Case 4 (MSA-p) had limited frontal downregulation but extensive upregulation in frontal, sensorimotor, and cerebellar regions, corresponding to low Postural Instability and Gait Disorder scores (7), no falls, and MoCA 24. The only MSA-cerebellar case had localized cerebellar downregulation and upregulation in the posterior and prefrontal cortices.

Conclusion: Cholinergic dysregulation in MSA exhibits significant intersubject variability, with distinct patterns of upregulation and downregulation potentially linked to clinical phenotypic differences.

Figure 1

References: (1) Gilman S, Koeppe RA, Nan B, Wang CN, Wang X, Junck L, Chervin RD, Consens F, Bhaumik A. Cerebral cortical and subcortical cholinergic deficits in parkinsonian syndromes. Neurology. 2010 May 4;74(18):1416-23. doi: 10.1212/WNL.0b013e3181dc1a55. PMID: 20439843; PMCID: PMC2871002.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/topographical-heterogeneity-of-cholinergic-system-status-in-multiple-system-atrophy-a-series-report/