Association of dopamine depletion and cholinergic basal forebrain atrophy with brain metabolism and cognition in Parkinson's disease

Abstract

Background: Cognitive dysfunction is one of the most debilitating non-motor symptoms of Parkinson's disease (PD). This study aimed to explore the interplay between altered neurotransmitter activities, including dopamine and acetylcholine, and brain metabolism in cognitive decline in PD. Methods: We enrolled 172 PD patients (mean +/- SD age 69.8 +/- 8.6 years; 93 females) who underwent brain magnetic resonance imaging, N-(3-[F-18]fluoropropyl)-2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane (F-18-FP-CIT) positron emission tomography (PET), F-18-fluorodeoxyglucose (FDG) PET, and neuropsychological testing. General linear models and mediation analyses were used to investigate the association between striatal dopamine transporter (DAT) availability or basal forebrain (BF) volume, brain metabolism, and domain-specific cognitive scores. Results: A significant relationship between caudate dopamine depletion and posterior BF atrophy was found in PD patients. Caudate and putaminal dopamine depletion were associated with altered brain metabolism in regions where PD patients showed decreased metabolism compared with healthy controls, whereas atrophy in the posterior BF was associated with hypometabolism in the lateral prefrontal, orbitofrontal, inferior parietal, and lateral temporal cortices as well as in the precuneus, with a significant interaction between caudate DAT availability and posterior BF volume. Caudate dopamine depletion was associated with visuospatial, memory, and executive dysfunction, whereas posterior BF atrophy was additionally associated with attention. Mediation analyses revealed that visuospatial dysfunction was associated with caudate dopamine depletion or posterior BF atrophy via altered brain metabolism, while executive dysfunction was linked to both directly and through metabolism changes. Conclusions: Caudate dopaminergic and posterior BF cholinergic deficits are interrelated and affect cognition in a domain-specific manner, either directly or through the mediation of altered brain metabolism.