Association of amyloid copathology and white matter network in Parkinson’ disease

2023-2025

The primary underlying factor in Parkinson’s disease (PD) is the buildup of ɑ-synuclein, affecting dopaminergic pathways. Recent research has shifted toward understanding non-motor deficits in PD, given its shared cognitive and neuropsychiatric characteristics with Alzheimer’s disease. However, the relationship between alpha-synuclein and non-motor symptoms has shown inconsistent results, prompting a focus on a mixed-pathology perspective, particularly amyloid beta (Aβ) accumulation. Previous studies suggest associations between alpha-synuclein and Aβ, with over 30% of late-stage PD cases exhibiting Aβ prevalence.

Traditionally, motor symptoms like resting tremors and bradykinesia are primary indicators of PD, but non-motor symptoms, especially neuropsychiatric ones, often precede classic motor symptoms, common in early stages, and significantly impact the quality of life. However, an association between white matter (WM) abnormalities in PD and Aβ deposition has not been established. This study aims to identify where Aβ accumulates and investigate WM as an additional target influenced by Aβ. The role of white matter in signal relay suggests that the neocortical burden emerges as a potential stressor in PD due to retrograde nigrostriatal degeneration. The observed heterogeneity in PD indicates widespread microstructural changes across the brain, extending beyond the nigrostriatal pathway5, even in the absence of obvious brain atrophy.

Despite the growing recognition of concurrent Alzheimer pathology as one of the major factors that aggravates cognitive and neuropsychiatric symptoms (NPS) in Parkinson’s disease (PD), the mechanistic link between these symptoms and amyloid-β (Aβ) deposition remain poorly understood. Herein, we investigated whether Aβ elicit white matter (WM) network disruption and further explored the potential clinical consequences.

This retrospective study included patients with PD who underwent 18 F-florbetaben PET, DTI, and neuropsychological assessments. After extracting Aβ-susceptible structural WM networks by comparing DTI-metrics (Fractional anisotropy [FA] and mean diffusivity [MD]) according to Aβ status, multivariate linear regression analyses were performed to explore the potential associations between Aβ burden, integrity of identified WM networks, and clinical measures (cognitive performance and NPS). We then performed mediation analyses to determine whether the network integrity mediated the effect of Aβ on clinical measures.

Our findings suggest that coexistent Aβ may elicit additive vulnerability in WM microstructures in patients with PD. Considering the mediating role of WM network integrity in the effect of Aβ on clinical measures, WM network degeneration may serve as a potential intermediate pathway through which Aβ copathology contributes to cognitive and neuropsychiatric manifestation in PD. Together, these findings suggest that Aβ-related WM network vulnerability represents a key intermediate mechanism linking molecular pathology to behavioral phenotypes, offering a network-based perspective on PD heterogeneity.

Presentations:

  • OHBM 2024, Organization for Human Brain Mapping Conference Seoul, Korea (2024, June 24-25)
  • KHBM 2023 Fall Conference, Korean Society of Human Brain Mapping Conference, Suwon, Korea (2023, October 27-28)
  • This project is nearly ready for manuscript submission!!

Presentation Material: