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

Abstract

AbstractBackground and ObjectivesIn 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 (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 if CSF p-tau181and 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 (ATNPD) using CSF Aβ42(A), p-tau181(T), and serum NfL (N), and tested ATNPDprediction of longitudinal cognitive decline in PD.MethodsParticipants 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 ATNPDstatus (AD [A+T+N±]vs. not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank-transformed, FDR-corrected).ResultsParticipants 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-tau181(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 Aβ42(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 Aβ42(p=0.18), p-tau181(p=1.0) or t-tau (p=0.96). Using ATNPD, 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 ATNPDstatuses including A+ alone (A+T-N-; n=75; 21%).DiscussionIn early PD, CSF p-tau181and t-tau were low compared to Controls and did not increase over 5 year follow-up. Even so, classification using modified ATNPD(incorporating CSF p-tau181with CSF Aβ42and serum NfL) may identify biologically-relevant subgroups of PD to improve prediction of cognitive decline in early PD.