Relationships between neuropsychiatric symptoms, subtypes of astrocyte activities, and brain pathologies in Alzheimer's disease and Parkinson's disease

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.

Keywords: Alzheimer's disease; Parkinson's disease; astrocyte; neuropsychiatric symptoms; tauopathy.

FIGURE 1

Sample selection flowchart across ADNI and PPMI. ADNI, Alzheimer's Disease Neuroimaging Initiative; Aβ, amyloid‐beta; AQP4, aquaporin‐4; αSyn, alpha‐synuclein; AD, Alzheimer's disease; CSF, cerebrospinal fluid; Dx, diagnosis; GDS, Geriatric Depression Scale; GFAP, glial fibrillary acidic protein; MCI, mild cognitive impairment; MDS‐UPDRS, Movement Disorder Society Unified Parkinson's Disease Rating Scale; NPI, Neuropsychiatric Inventory; PD, Parkinson's disease; PPMI, Parkinson's Progression Markers Initiative; ptau, phosphorylated tau; QUIP, Questionnaire for Impulsive‐Compulsive Disorders in Parkinson's Disease; STAI, State‐Trait Anxiety Inventory; YKL‐40, chitinase‐3‐like protein 1.

FIGURE 2

K‐means clustering analysis for astrocyte biomarkers across ADNI and PPMI. The K‐means clustering of distinct astrocyte biomarker patterns in (A) ADNI and (E) PPMI. Sum of squared distances across candidate cluster solutions in (B) ADNI and (F) PPMI. Astrocyte protein levels across clusters in (C) ADNI and (G) PPMI, in which red was for GFAP, purple for YKL‐40, dark gray for AQP4. Distribution of preclinical and clinical ND in each cluster in (D) ADNI and (H) PPMI. ADNI, Alzheimer's Disease Neuroimaging Initiative; AQP4, aquaporin‐4; GFAP, glial fibrillary acidic protein; ND, neurodegenerative disease; PPMI, Parkinson's Progression Markers Initiative; YKL‐40, chitinase‐3‐like protein 1.

FIGURE 3

Comparisons of ND pathologies and NPS between astrocyte clusters in ADNI (A–D) and PPMI (E–H) with Cluster 3 considered as the reference. ADNI, Alzheimer's Disease Neuroimaging Initiative; Aβ, amyloid‐beta; αSyn, alpha‐synuclein; ND, neurodegenerative disease; NPS, neuropsychiatric symptoms; PPMI, Parkinson's Progression Markers Initiative; ptau, phosphorylated tau; *p < 0.05;**p < 0.01;***p < 0.001.

FIGURE 4

Comparison of NPS subdomains between astrocyte clusters in ADNI (A) and PPMI (B) with Cluster 3 considered as the reference. Note: Underline font: uncorrected significant difference between Cluster 1 and Cluster 3; Bolden font: uncorrected significant difference between Cluster 2 and Cluster 3; Bolden underline font: uncorrected significant difference between both Cluster 1 and Cluster 3, and Cluster 2 and Cluster 3. *FDR corrected significant difference. ADNI, Alzheimer's Disease Neuroimaging Initiative; FDR, false discovery rate; NPS, neuropsychiatric symptoms; PPMI, Parkinson's Progression Markers Initiative.

FIGURE 5

Relationship between ND Pathologies and NPS moderated by astrocyte clusters in ADNI (A–C) and PPMI (D–F) with Cluster 3 as the reference. Note: The shaded area represents the 95% confidence interval. There was a significant interaction between Cluster 2 and Cluster 3 for αSyn and NPS in PPMI (F). ADNI, Alzheimer's Disease Neuroimaging Initiative; Aβ, amyloid‐beta; αSyn, alpha‐synuclein; ND, neurodegenerative disease; NPS, neuropsychiatric symptoms; PPMI, Parkinson's Progression Markers Initiative; ptau, phosphorylated tau.