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Spatial Covariance of Cholinergic Muscarinic M 1 / M 4 Receptors in Parkinson's Disease

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Colloby, Sean J. 
Nathan, Pradeep J. 
Bakker, Geor 
Lawson, Rachael A. 
Yarnall, Alison J. 


ABSTRACT: Background: Parkinson's disease (PD) is associated with cholinergic dysfunction, although the role of M1 and M4 receptors remains unclear. Objective: To investigate spatial covariance patterns of cholinergic muscarinic M1/M4 receptors in PD and their relationship with cognition and motor symptoms. Methods: Some 19 PD and 24 older adult controls underwent 123I‐iodo‐quinuclidinyl‐benzilate (QNB) (M1/M4 receptor) and 99mTc‐exametazime (perfusion) single‐photon emission computed tomography (SPECT) scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of intercorrelated voxels across individuals. Linear regression analyses derived specific M1/M4 spatial covariance patterns associated with PD. Results: A cholinergic M1/M4 pattern that converged onto key hubs of the default, auditory–visual, salience, and sensorimotor networks fully discriminated PD patients from controls (F1,41 = 135.4, P < 0.001). In PD, we derived M1/M4 patterns that correlated with global cognition (r = −0.62, P = 0.008) and motor severity (r = 0.53, P = 0.02). Both patterns emerged with a shared topography implicating the basal forebrain as well as visual, frontal executive, and salience circuits. Further, we found a M1/M4 pattern that predicted global cognitive decline (r = 0.46, P = 0.04) comprising relative decreased binding within default and frontal executive networks. Conclusions: Cholinergic muscarinic M1/M4 modulation within key brain networks were apparent in PD. Cognition and motor severity were associated with a similar topography, inferring both phenotypes possibly rely on related cholinergic mechanisms. Relative decreased M1/M4 binding within default and frontal executive networks could be an indicator of future cognitive decline. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society


Funder: National Institute for Health Research Biomedical Research Centre in Ageing and Chronic Disease and Biomedical Research Unit in Lewy Body Dementia at Newcastle

Funder: National Institute for Health Research Dementia Biomedical Research Unit at Cambridge


RESEARCH ARTICLE, RESEARCH ARTICLES, Parkinson's disease, muscarinic receptors, SPECT, spatial covariance, cholinergic M1/M4 receptors, networks

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Movement Disorders

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John Wiley & Sons, Inc.
Medical Research Council (G9817682)
Sosei Heptares (Industry grant)