Abstract
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 (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. 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.
Highlights
Groups were matched for gender and age, while for global cognition Parkinson’s disease (PD) was slightly worse than controls (P ≤ 0.003)
We identified baseline M1/M4 patterns that separately correlated with global cognition, motor severity, and cognitive progression, which could represent signatures of M1/M4 expressions for cognitive and motor dysfunction as well as cognitive decline in PD
In independent cohorts, there was shared topography between the current M1/M4 pattern and our previously reported M1/M4 pattern in PD dementia (PDD),[12] that is relative decreased binding in fusiform, striatal, and lateral temporal with lateral preserved/increased binding in lateral orbitofrontal and occipitoparietal regions
Summary
The pattern (Fig. 2a) consisted of relative preserved/increased M1/M4 binding (warm colors) in fusiform, insula, occipital lobe, inferior parietal, and precuneus with relative decreased binding (cold colors) in superior/middle frontal gyri, dorsomedial prefrontal cortex, medial frontal gyrus, superior parietal, superior temporal gyrus, anterior cingulate, parahippocampus, caudate, and basal forebrain. There were variations that were likely attributed to differences in disease/cognitive severity, namely a more extensive decreased M1/M4 pattern within anterior cingulate, insula, basal forebrain, and medial temporal areas, inferring, as dementia develops, that deficits in relative M1/M4 expression extend into basal forebrain, salience, and memory circuits.
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