Evaluation of ATN_PDframework and biofluid markers to predict cognitive decline in early Parkinson’s disease

Background and Objectives In Parkinson’s disease (PD), Alzheimer’s disease (AD) co-pathology is common and clinically relevant. However, the longitudinal progression of AD cerebrospinal fluid (CSF) biomarkers – β-amyloid 1-42 (Aβ 42 ), phosphorylated tau 181 (p-tau 181 ) and total tau (t-tau) – in PD is poorly understood, and may be distinct from clinical AD. Moreover, it is unclear if CSF p-tau 181 and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ 42 . 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 Aβ 42 (A), p-tau 181 (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 (PPMI) cohort, clinically-diagnosed with sporadic PD or as normal Controls, and followed annually for 5 years. Linear mixed effects models (LMEM) tested the interaction of diagnosis with longitudinal trajectories of analytes (log-transformed, FDR-corrected). In 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 PD and 168 Controls, with comparable baseline mean (±SD) age (PD=62±10; Control=61±11]; Mann-Whitney-Wilcoxon: p =0.40) and gender distribution (PD=231 males [63%]; Control=107 males [64%]; chi-square: p =1.0). PD had overall lower CSF p-tau 181 (β=-0.16, 95%CI=-0.23 – -0.092, p =2.2e-05) and t-tau than Controls (β=-0.13, 95%CI=-0.19 – -0.065, p =4.0e-04), but not Aβ 42 ( p =0.061) or NfL ( p =0.32). Over time, PD had greater increases in serum NfL than Controls (β=0.035, 95%CI=0.022 – 0.048, p =9.8e-07); PD slopes did not differ from controls for CSF Aβ 42 ( p =0.18), p-tau 181 ( p =1.0) or t-tau ( p =0.96). Using ATN PD , PD classified as A+T+N± (n=32; 9%) had consistently worse cognitive decline, including on global MoCA (β=-73, 95%CI=-110 – -37, p =0.00077), than all other ATN PD statuses including A+ alone (A+T-N-; n=75; 21%). Discussion In early PD, CSF p-tau 181 and t-tau were low compared to Controls and did not increase over 5 year follow-up. Even so, classification using modified ATN PD (incorporating CSF p-tau 181 with CSF Aβ 42 and serum NfL) may identify biologically-relevant subgroups of PD to improve prediction of cognitive decline in early PD.