Objective: To investigate associations between CSF biomarkers and cognitive decline in Parkinson’s Disease-Subjective Cognitive Decline (PD-SCD).

Background: The presence of cognitive complaints without objective cognitive impairment in Parkinson’s Disease (PD), known as PD-SCD, has been linked to cognitive decline. PD-SCD is regarded as a prodromal stage of cognitive impairment and represents a promising target for clinical trials. However, progression among patients with this clinical marker is highly variable, highlighting the need for further research to better identify those patients at greatest risk of cognitive decline.

Method: We included patients from the Parkinson’s Progression Markers Initiative (PPMI) cohort with PD-SCD, available baseline CSF beta-amyloid_1-42 (Aβ₄₂) and phosphorylated-tau₁₈₁ (p-tau₁₈₁), and longitudinal Montreal Cognitive Assessment (MoCA). Linear mixed-effects models (LMEMs) were used to test how CSF biomarkers predicted cognitive decline. Based on the AT(N) system, Aβ₄₂ and p-tau₁₈₁ were used to identify patients with low Aβ₄₂ or with biological Alzheimer’s Disease (AD) diagnosis.

Results: We included a total of 80 patients. At baseline, the mean age was 62.1 years and the median disease duration was 5.6 months. Among the five patients with biological AD (as per CSF biomarkers), MoCA scores showed a greater decline compared to patients without biological AD (year 7: β=-4.15, p=0.009). After excluding AD patients from the analysis, LMEMs still demonstrated an association between baseline log-transformed Aβ₄₂ and MoCA progression (β=2, p=0.004). Based on these findings, we categorized patients into three CSF-based subgroups: Normal Aβ₄₂ (n=50), Low Aβ₄₂ (n=25), and Biological AD (n=5). LMEMs predicted faster cognitive decline for Low Aβ₄₂ vs Normal Aβ₄₂ (β=-0.161 points-per-year, p=0.007), and for Biological AD vs Normal Aβ₄₂ (β=-0.390 points-per-year, p<0.001) (Figure). Additionally, the risk of developing dementia was higher in the Low Aβ₄₂ (HR=5.2, p=0.029) and the Biological AD subgroups (HR=7.7, p=0.013) (Table).

Conclusion: Baseline CSF Aβ₄₂ is associated with cognitive decline in PD-SCD. Additionally, we identified three CSF biomarker-based cognitive trajectories (normal Aβ₄₂, low Aβ₄₂, and biological AD), each characterized by progressively worse cognitive outcomes. These results could help guide enrichment strategies in future clinical trials targeting cognitive decline in PD.

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Table

References: 1. Siciliano M, Tessitore A, Morgante F, et al. Subjective Cognitive Complaints in Parkinson’s Disease: A Systematic Review and Meta-Analysis. Movement Disorders 2024;39(1):17–28.
2. Cousins KAQ, Irwin DJ, Tropea TF, et al. Evaluation of ATNPD Framework and Biofluid Markers to Predict Cognitive Decline in Early Parkinson Disease. Neurology 2024;102(4):e208033.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/csf-biomarker-based-cognitive-trajectories-in-parkinsons-disease-subjective-cognitive-decline/