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

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 (W_1,19.7 = 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.