Distribution of amyloid beta and its influence in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is traditionally categorized as a subcortical disorder originating from alpha-synuclein accumulation along the dopaminergic pathway, resulting in prominent motor symptoms. However, broadening this viewpoint, individuals with PD exhibit not only motor symptoms but also neuropsychiatric and cognitive symptoms. These motor and non-motor manifestations suggest potential alterations in cortical involvement with subcortical connections. A new approach to improve the ability to explain Parkinson's Disease (PD) has emerged, which entails considering different pathological aspects instead of solely concentrating on alpha-synuclein as the primary pathological molecule. Consequently, this study adopts a novel approach by investigating the role of amyloid beta in the aggravation of clinical symptoms of PD. This research aims to elucidate the amyloid burden associated with PD in relation to both motor and non-motor, especially neuropsychiatric symptoms. Firstly, the study demonstrates the pattern of amyloid accumulation in PD patients using F-18 Florbetaben (FBB) PET imaging. This study also explores white matter microstructural network changes in the amyloid-positive PD using diffusion tensor imaging (DTI). We acquired FBB PET and T1-weighted MR images from 166 idiopathic Parkinson’s disease patients, propensity-matched into 48 amyloid beta-negative (PD Ab-) and 48 amyloid beta-positive (PD Ab+) cases. Each patient underwent FBB PET, T1-weighted MR, and diffusion tensor imaging. Additionally, they went through cognitive assessments, including the Korean Mini-Mental State Examination (K-MMSE) and Seoul Neuropsychological Screening Battery (SNSB). At the same time, behavioral and psychiatric features were evaluated with the Neuropsychiatric Inventory (NPI) and Mild Behavioral Impairment (MBI) score. Fourty-two PD Ab- and thirty-seven PD Ab+ patients underwent the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) motor test during the off-medication state. Utilizing Desikan-Killiany-Tourville (DKT) cortical labeling and Freesurfer subcortical segmentation protocols, we assessed the regional standardized uptake value ratios (SUVr) across 62 cortical and 14 subcortical regions. Regions exhibiting distinct regional amyloid beta accumulation were selected based on age, sex, and disease duration-adjusted SUVr values and subsequently subjected to linear regression models with cognitive and neuropsychiatric measures. White matter deterministic tractography was conducted using MRTrix3 software. To depict differences in structural connectivity related to amyloid status, we employed threshold-free network-based statistics (TFNBS) to identify distinctive edges between the amyloid-positive and negative groups. Widespread amyloid accumulation was observed across the entire brain, including the subcortex, in PD Ab+. Regional SUVr values could explain motor symptom severity. The amyloid SUVr values revealed that the most significant non-motor feature association with amyloid was the burden of neuropsychiatric symptoms based on amyloid status but not with cognitive performance. Specifically, the amyloid accumulation was correlated with reduced motivation, affective dysregulation, and abnormal perception. When examining structural connectivity through DTI, PD Ab+ showed lower network strength involving the anterior cingulate, orbitofrontal, and subcortical structures. In summary, this study highlights the explanatory role of amyloid beta in the manifestation of decreased motivation, affective dysregulation, and abnormal perception features of neuropsychiatric burden in PD. The widespread distribution of amyloid throughout the brain, including the subcortex, emphasizes its extensive involvement in PD pathology. Moreover, structural network differences were observed, particularly in the anterior cingulate and other regions, highlighting the complex neural implications of amyloid beta. These findings focus on the need for targeted therapeutic strategies addressing motor and neuropsychiatric aspects in the comprehensive management of PD.