Spatial Covariance of Cholinergic Muscarinic M₁ /M₄ Receptors in Parkinson's Disease

Parkinson's disease (PD) is associated with cholinergic dysfunction, although the role of M1 and M4 receptors remains unclear.

To investigate spatial covariance patterns of cholinergic muscarinic M₁ /M₄ receptors in PD and their relationship with cognition and motor symptoms.

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.

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 (F_1,41  = 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.

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.