Objective: To characterize individual-level topographical patterns of cholinergic changes compared to controls in Progressive Supranuclear Palsy (PSP) using a voxel-wise approach.

Background: The cholinergic system is notably affected in PSP, with our previous research showing vulnerability in selective brain regions such as the prefrontal cortex, anterior insulae, temporal pole, striatal subregions, brainstem, and cerebellum, using [¹⁸F]-FEOBV PET(1). Our preliminary data also suggested that PSP-Richardson syndrome (PSP-RS) exhibits more severe cholinergic denervation compared to parkinsonian (PSP-P) variants. Subject-specific data are lacking, limiting the clinical utility of [¹⁸F]-FEOBV PET for differential diagnosis and treatment.

Method: 13 PSP patients and 31 healthy controls (HC) underwent [¹⁸F]-FEOBV PET and MRI. 10 patients were classified as PSP-RS (9 probable, 1 possible), 2 as PSP-P (1 probable, 1 suggested), and 1 as PSP with Progressive Gait Freezing (PGF)(2). Voxel-wise W-maps were generated(3) to quantify individual deviations from HC, adjusting for age and sex. Significant cholinergic downregulation was defined as W-scores<-1.65, and upregulation as W-scores>1.65.

Results: Single-subject W-maps revealed more frequent severe cholinergic denervation in PSP-RS patients compared to PSP-P and PSP-PGF subtypes. In PSP-RS, 70% of patients (7/10) showed widespread cholinergic downregulation in the prefrontal cortex, bilateral basal ganglia, thalamus, and temporal pole, with variable involvement of the cerebellum (3 patients) (Figure 1). Three PSP-RS patients exhibited more localized downregulation in the bilateral putamen and insula (Cases 10 and 13), and one in the right-lateralized temporal lobe. Three PSP-RS patients showed upregulation in sensory-motor cortex and thalamus. The two PSP-P patients exhibited limited downregulation in the prefrontal cortex (Case 2) and more widespread downregulation, including the cerebellum (Case 8). The PSP-PGF subtype showed downregulation in the right putamen, bilateral temporal poles, bilateral thalamus, brainstem, and cerebellum.

Conclusion: A single subject imaging analysis based on not only hypo- but also hypercholinergic binding may help to better understand the high intrinsic heterogeneity of the disease, even within clinical subtypes, and may have potential as a novel biomarker for diagnosis and personalized treatment strategies.

Figure 1

References: (1) Kanel P, Spears CC, Roytman S, Koeppe RA, Frey KA, Scott PJH, Albin RL, Bohnen NI. Differential cholinergic systems’ changes in progressive supranuclear palsy versus Parkinson’s disease: an exploratory analysis. J Neural Transm (Vienna). 2022 Dec;129(12):1469-1479. doi: 10.1007/s00702-022-02547-9. Epub 2022 Oct 12. PMID: 36222971; PMCID: PMC10017092.
(2) Höglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, Mollenhauer B, Müller U, Nilsson C, Whitwell JL, Arzberger T, Englund E, Gelpi E, Giese A, Irwin DJ, Meissner WG, Pantelyat A, Rajput A, van Swieten JC, Troakes C, Antonini A, Bhatia KP, Bordelon Y, Compta Y, Corvol JC, Colosimo C, Dickson DW, Dodel R, Ferguson L, Grossman M, Kassubek J, Krismer F, Levin J, Lorenzl S, Morris HR, Nestor P, Oertel WH, Poewe W, Rabinovici G, Rowe JB, Schellenberg GD, Seppi K, van Eimeren T, Wenning GK, Boxer AL, Golbe LI, Litvan I; Movement Disorder Society-endorsed PSP Study Group. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Mov Disord. 2017 Jun;32(6):853-864. doi: 10.1002/mds.26987. Epub 2017 May 3. PMID: 28467028; PMCID: PMC5516529.
(3) La Joie R, Perrotin A, Barré L, Hommet C, Mézenge F, Ibazizene M, Camus V, Abbas A, Landeau B, Guilloteau D, de La Sayette V, Eustache F, Desgranges B, Chételat G. Region-specific hierarchy between atrophy, hypometabolism, and β-amyloid (Aβ) load in Alzheimer’s disease dementia. J Neurosci. 2012 Nov 14;32(46):16265-73. doi: 10.1523/JNEUROSCI.2170-12.2012. PMID: 23152610; PMCID: PMC6794030.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/brain-cholinergic-changes-in-progressive-supranuclear-palsy-a-single-subject-voxel-wise-approach-to-understanding-heterogeneity/