Colloby_2020_Brain.Commun_2_fcaa098

Cholinergic dysfunction is central in dementia with Lewy bodies, possibly contributing to the cognitive and psychiatric phenotypes of this condition. We investigated baseline muscarinic M(1)/M(4) 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 (123)I-iodo-quinuclidinyl-benzilate (M(1)/M(4) receptor assessment) and (99m)Tc-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 M(1)/M(4) and perfusion spatial covariance patterns associated with patients. A discreet M(1)/M(4) 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 M(1)/M(4) 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 M(1)/M(4) 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 M(1)/M(4) receptor expression within attentional/executive and ventral visual network hubs, respectively.