Spatial covariance of cholinergic muscarinic M1/M4 receptors in Parkinson’s disease

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 123 I-iodo-quinuclidinyl-benzilate (QNB) (M1 /M4 receptor) and 99m Tc-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.