Basal Forebrain Volume Mediates the Relationship Between Cortical Cholinergic Level and Cognition in Parkinson’s Disease

Abstract

AbstractBackgroundCholinergic denervation is associated with cognitive decline in Parkinson’s disease (PD). This is likely due to atrophy of the basal forebrain, which is affected by α‐synuclein early in PD. Studies show associations between basal forebrain volume and cognition and between cortical cholinergic levels and cognition, but no study has determined if basal forebrain volume mediates the relationship between cholinergic levels and cognition.MethodParticipants included 103 non‐demented individuals with idiopathic PD (M:F = 76:27; Age = 67.3±7.6 yrs) who underwent structural MRI and [18F] fluoroethoxybenzovesamicol (FEOBV) cholinergic PET imaging. We averaged cholinergic PET values in 7 ROIs derived from FreeSurfer in a prior publication (van der Zee, 2022): 1) bilateral temporoparietal regions (PC1); 2) subcortical and limbic regions (PC2); 3) bilateral cingulate regions (PC3); 4) left frontal regions (PC4); 5) right frontal and temporal regions (PC5); 6) cerebellum (PC6); and 7) bilateral entorhinal and left temporal regions (PC7). We used an executive function composite (Stroop Color‐Word Inhibition/Switching, Trail Making Switching, Letter Fluency, WASI‐IV Matrix Reasoning) and a verbal recall measure (CVLT‐II Long Delay Free Recall) as outcome variables.ResultAfter controlling for age, basal forebrain volume fully mediated the associations between PC3 (indirect effect:β = 0.075, 95% CI = 0.002‐0.166; total effect:β = 0.235, p = .02; direct effect:β = 0.161, p = .13) and PC7 (indirect effect:β = 0.069, 95% CI = 0.007‐0.141; total effect:β = 0.212, p = .02; direct effect: β = 0.142, p = .15) and executive function. Basal forebrain volume fully mediated the association between PC1 and verbal recall (indirect effect:β = 0.079, 95% CI = 0.014‐0.163; total effect:β = 0.222, p = .02; direct effect:β = 0.141, p = .14) and partially mediated the association between PC3 (indirect effect:β = 0.076, 95% CI = 0.003‐0.156; total effect:β = 0.345, p<.001; direct effect:β = 0.269, p = .01), PC5 (indirect effect:β = 0.070, 95% CI = 0.003‐0.150; total effect:β = 0.341, p<.001; direct effect:β = 0.271, p<.01), and PC7 (indirect effect:β = 0.072, 95% CI = 0.005‐0.150; total effect:β = 0.298, p<.01; direct effect:β = 0.226, p = .02) and verbal recall.ConclusionThis is the first study to demonstrate that basal forebrain volume mediates the relationship between cholinergic level and cognitive function. Future studies will investigate additional cognitive domains and measure structural integrity of individual nuclei in the basal forebrain.