Abstract
OBJECTIVE: Apathy is a common nonmotor symptom in Parkinson's disease (PD) affecting 40% of patients. The aim of the study was to investigate brain changes and correlates of frontal, striatal, and limbic pathways related to subclinical symptoms of apathy in PD patients. METHODS: Thirty-two PD patients divided into low-subclinical symptoms of apathy (LSA) (n = 18) and high-subclinical symptoms of apathy (HSA) (n = 14) and 25 healthy controls (HC) underwent a T1-weighted, diffusion-weighted, and resting-state functional MRI. Apathy was evaluated with the Lille Apathy Rating Scale. Voxel-based morphometry, tract-based spatial statistics, and resting-state functional connectivity (FC) analyses were performed with a region-of-interest approach. RESULTS: HSA-PD showed increased white matter axial and mean diffusivity compared with HC and increased white matter axial diffusivity compared with LSA-PD. HSA-PD showed decreased fronto-striatal and fronto-limbic FC compared with HC and decreased fronto-striatal FC compared with LSA-PD. LSA-PD showed decreased fronto-limbic but increased fronto-striatal FC (hyperconnectivity) compared with HC. No significant differences in grey matter were found. Fronto-striatal FC and white matter axial and mean diffusivity were associated with symptoms of apathy in HSA-PD. The fronto-striatal hyperconnectivity was associated with lower symptoms of apathy in LSA-PD. INTERPRETATION: Findings suggest distinct brain alterations in PD groups with subclinical symptoms of apathy. The increased pattern of activation in LSA-PD, accompanied with lower apathetic symptomatology, might be the initial manifestation of compensatory mechanisms for dysfunctional limbic pathway. The same pattern of hyperconnectivity has been found in other pathologies and the implication of these abnormalities as a cross-disease model for initial apathy symptomatology is further discussed.