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

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 intercorrelated 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 a 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 a 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.

(Dis‐)Connected Dots in Dementia with Lewy Bodies—A Systematic Review of Connectivity Studies

“…76,77 Despite the described associations between connectivity disruptions and DLB core clinical features, these associations did not consistently materialize in all studies. 27,29,35,39,59 This may be attributable to the diverse range of symptoms in patients with DLB, since the presence of two core clinical features or the combination of one core clinical feature and one indicative biomarker…”

PET Imaging of Cholinergic Neurotransmission in Neurodegenerative Disorders

“…The nonselective SPECT ligand 123 I-iodoquinuclidinylbenzilate targeting M1 and M4 mAChRs has been successfully used for novel important network analyses of mAChR modulatory contributions to large-scale alterations in brain-network function in AD and DLB (99,100).…”

“…The first-in-humans application of the nonselective mAChR PET ligand 4-18 F-fluorodexetimide showed promising findings, including high brain uptake, high image quality, unspecific binding in the cerebellum (making it valid to be used as a reference region), low interindividual variability in healthy subjects, and irreversible kinetics of tracer distribution in brain regions high in mAChRs (98). The nonselective M1 and M4 SPECT ligand 123 I-iodoquinuclidinylbenzilate, in combined use with 99m Tc-exametazime SPECT to account for cerebral blood flow, is successfully used for cholinergic receptor network investigations on neurodegenerative disorders (99).…”

Chemistry and Toxicology of Major Bioactive Substances in Inocybe Mushrooms

“…The M2 and M3 subtypes mediate the muscarinic response of peripheral autonomic tissues. The M1 and M4 subtypes are more abundant in the brain and autonomic ganglia [ 27 ]. M1, M3 and M5 interact with Gq protein to stimulate the hydrolysis of phosphoinositide and release intracellular calcium [ 28 ].…”