Evaluation of ATNPD Framework and Biofluid Markers to Predict Cognitive Decline in Early Parkinson Disease

Abstract

Background and objectives: In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-β-amyloid 1-42 (Aβ₄₂), phosphorylated tau 181 (p-tau₁₈₁), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau₁₈₁ and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ₄₂. First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD β-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATN_PD) using CSF Aβ₄₂ (A), p-tau₁₈₁ (T), and serum NfL (N) and tested ATN_PD prediction of longitudinal cognitive decline in PD.

Methods: Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate [FDR] corrected). In patients with PD, LMEMs tested how baseline ATN_PD status (AD [A+T+N±] vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected).

Results: Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years]; Mann-Whitney Wilcoxon: p = 0.4) and sex distribution (patients with PD = 231 male individuals [63%]; controls = 107 male individuals [64%]; χ²: p = 1). Patients with PD had overall lower CSF p-tau₁₈₁ (β = -0.16, 95% CI -0.23 to -0.092, p = 2.2e-05) and t-tau than controls (β = -0.13, 95% CI -0.19 to -0.065, p = 4e-04), but not Aβ₄₂ (p = 0.061) or NfL (p = 0.32). Over time, patients with PD had greater increases in serum NfL than controls (β = 0.035, 95% CI 0.022 to 0.048, p = 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Aβ₄₂ (p = 0.18), p-tau₁₈₁ (p = 1), or t-tau (p = 0.96). Using ATN_PD, PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (β = -73, 95% CI -110 to -37, p = 0.00077) than all other ATN_PD statuses including A+ alone (A+T-N-; n = 75; 21%).

Discussion: In patients with early PD, CSF p-tau₁₈₁ and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATN_PD (incorporating CSF Aβ₄₂, CSF p-tau₁₈₁, and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.