Cholinergic muscarinic M1/M4 receptor networks in dementia with Lewy bodies.

Sean J Colloby,Ian G Mckeith,John-Paul Taylor,John T O’Brien,Pradeep J Nathan,Geor Bakker

doi:10.1093/braincomms/fcaa098

Abstract

Cholinergic dysfunction is central in dementia with Lewy bodies, possibly contributing to the cognitive and psychiatric phenotypes of this condition. We investigated baseline muscarinic M1/M4 receptor spatial covariance patterns in dementia with Lewy bodies and their association with changes in cognition and neuropsychiatric symptoms after 12 weeks of treatment with the cholinesterase inhibitor donepezil. Thirty-eight participants (14 cholinesterase inhibitor naive patients, 24 healthy older individuals) underwent 123I-iodo-quinuclidinyl-benzilate (M1/M4 receptor assessment) and 99mTc-exametazime (perfusion) single-photon emission computed tomography scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of inter-correlated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns associated with patients. A discreet M1/M4 pattern that distinguished patients from controls (W1,19.7 = 16.7, P = 0.001), showed relative decreased binding in right lateral temporal and insula, as well as relative preserved/increased binding in frontal, precuneus, lingual and cuneal regions, implicating nodes within attention and dorsal visual networks. We then derived from patients an M1/M4 pattern that correlated with a positive change in mini-mental state examination (r = 0.52, P = 0.05), showing relative preserved/increased uptake in prefrontal, temporal pole and anterior cingulate, elements of attention-related networks. We also generated from patients an M1/M4 pattern that correlated with a positive change in neuropsychiatric inventory score (r = 0.77, P = 0.002), revealing relative preserved/increased uptake within a bilateral temporal-precuneal-striatal system. Although in a small sample and therefore tentative, we posit that optimal response of donepezil on cognitive and neuropsychiatric signs in patients with dementia with Lewy bodies were associated with a maintenance of muscarinic M1/M4 receptor expression within attentional/executive and ventral visual network hubs, respectively.

Highlights

Dementia with Lewy bodies (DLB) is a common form of dementia in older age, where marked cholinergic dysfunction including reduced choline acetyltransferase is a key neurochemical feature and major contributor to the cognitive, sleep and psychiatric symptoms (Aarsland et al, 2003)
Thirty-seven QNB PC images were initially generated from which PC1, PC3 and PC6 formed the baseline SCPQNB that distinguished DLB from controls (Fig. 2A and B)
The covariance pattern involved bilateral concomitant preserved/increased M1/M4 binding in fusiform, inferior temporal, precuneus, caudate and left cuneus with bilateral concomitant decreased uptake in anterior and mid-cingulate, medial frontal and superior postcentral gyri (Supplementary Table 5). This was the first study examining the association between muscarinic M1/M4 patterns of spatial covariance and improvements in cognitive and neuropsychiatric symptoms with cholinergic therapy in DLB

Summary

Introduction

Dementia with Lewy bodies (DLB) is a common form of dementia in older age, where marked cholinergic dysfunction including reduced choline acetyltransferase is a key neurochemical feature and major contributor to the cognitive, sleep and psychiatric symptoms (Aarsland et al, 2003). In Parkinson’s disease dementia which overlaps with DLB in aspects of clinical phenotype, neuropathology and neurochemistry (Outeiro et al, 2019), several dysfunctional cholinergic networks have been proposed to affect the attention, visuoperceptual and memory domains (Gratwicke et al, 2015). Acetylcholine neurotransmission is facilitated by both muscarinic and nicotinic receptors. Of the former, there are five muscarinic subtypes (M1–M5), which are widely distributed throughout the central nervous system and brain and are considered to play an important role in learning and memory with M1 implicated, in particular, in regulating cognition (Anagnostaras et al, 2003; Erskine et al, 2019). Elevation of M2 in anterior cingulate (Teaktong et al, 2005) and M3 in frontal structures (Shiozaki et al, 1999) as well as decreased M4 in temporal cortex (Shiozaki et al, 1999)

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