Relationships between neuropsychiatric symptoms, subtypes of astrocyte activities, and brain pathologies in Alzheimer's disease and Parkinson's disease
Oceanna Yueran Li, Steven S. Shin, Shi‐Sheng Zhou, Adam Turnbull, Feng Lin, for the Alzheimer's Disease Neuroimaging Initiative
Abstract
INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative diseases (NDs). This study examined astrocytic contributions to neuropsychiatric symptoms (NPS), focusing on astrocytic protein activity and its relationship with NPS severity, accounting for clinical and pathological features of NDs. METHODS: Cerebrospinal astrocytic proteins (glial fibrillary acidic protein [GFAP], chitinase-3-like protein 1 [YKL-40], and aquaporin-4 [AQP4]) from Alzheimer's Disease Neuroimaging Initiative (ADNI) (AD) and Parkinson's Progression Markers Initiative (PPMI) (PD) were analyzed using K-means clustering. Six NPS domains, ND-specific pathologies (amyloid-beta/Aβ for AD, alpha-synuclein/αSyn for PD), and nonspecific pathology (phosphorylated tau/ptau) were assessed. RESULTS: In both samples, three astrocytic clusters were identified, and the "highYKL|lowOthers" cluster (high YKL-40, low GFAP/AQP4) consistently showed lower ptau and NPS severity compared to the "highAll" cluster (high GFAP, YKL-40, AQP4). In PPMI, the "highYKL|lowOthers" cluster also attenuated the relationship between αSyn and NPS compared to the "highAll" cluster. DISCUSSION: Astrocytic activity relates to NPS, highlighting astrocytic proteins as potential therapeutic targets for NPS in NDs. HIGHLIGHTS: Astrocytic protein clusters were linked to NPS severity in AD and PD cohorts. The "highYKL|lowOthers" cluster showed lower ptau and NPS severity than "allhigh" cluster in AD and PD cohorts. Astrocytic proteins may serve as therapeutic targets for managing NPS in NDs.