Neurofilament light chain and \u03b1-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes

Corinne Quadalti,Marcello Rossi,Andrea Mastrangelo,Barbara Polischi,Piero Parchi,Giovanna Calandra-Buonaura,Giuseppe Plazzi,Niccolò Candelise,Luisa Sambati,Pietro Cortelli,Corrado Zenesini,Giulia Giannini,Sabina Capellari,Simone Baiardi

doi:10.1038/s41531-021-00232-4

Abstract

Neurofilament light chain (NfL) and α-synuclein oligomeric seeds (α-syn-s) are promising biomarkers for patients with parkinsonism. We assessed their performance in discriminating Parkinson disease (PD) from atypical parkinsonisms (APDs) and evaluated the association between NfL levels and clinical measures of disease severity. We measured NfL in cerebrospinal fluid (CSF) and/or plasma by immunoassays and α-syn-s in CSF by real-time quaking-induced conversion (RT-QuIC) in patients with PD (n = 153), multiple system atrophy (MSA) (n = 80), progressive supranuclear palsy/cortico-basal syndrome (PSP/CBS) (n = 58), dementia with Lewy bodies (n = 64), isolated REM-sleep behaviour disorder (n = 19), and isolated autonomic failure (n = 30). Measures of disease severity included disease duration, UPDRS-III score, Hoehn and Yahr stage, orthostatic hypotension, MMSE score, and CSF amyloid-beta profile. Both CSF NfL (cNfL) and plasma NfL (pNfL) levels were markedly elevated in APDs, and allowed differentiation with PD (vs. APDs, cNfL AUC 0.96; pNfL AUC 0.95; vs. MSA cNfL AUC 0.99; pNfL AUC 0.97; vs. PSP/CBS cNfL AUC 0.94; pNfL AUC 0.94). RT-QuIC detected α-syn-s in 91.4% of PD, but only 2.5% of APDs (all MSA). In PD/PDD, motor scales significantly correlated with cNfL levels. Although pNfL and both cNfL and α-syn-s accurately distinguished PD from APDs, the combined assessment of CSF markers provided a higher diagnostic value (PD vs. APDs AUC 0.97; vs. MSA AUC 0.97; vs. PSP/CBS AUC 0.99) than RT-QuIC alone (p = 0.047 vs. APDs; p = 0.002 vs MSA; p = 0.007 vs PSP/CBS), or cNfL alone (p = 0.011 vs. APDs; p = 0.751 vs MSA; p = 0.0001 vs. PSP/CBS). The results support the use of these assays in specialised clinics.

Highlights

Parkinson disease (PD) is clinically difficult to discriminate from atypical parkinsonism disorders (APDs), namely multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and cortical basal syndrome (CBS), especially during the early disease stages.Current diagnostic criteria for both PD and APDs have some limitations because they require a combination of clinical findings, multiple diagnostic investigations, and an adequate follow-up of several years to reach an accurate disease identification[1,2]
Demographic variables and comparison of the diagnostic value of plasma and cerebrospinal fluid (CSF) Neurofilament light chain (NfL) levels in the differential diagnosis of patients with parkinsonism. Those from the PD and MSA groups were significantly younger than patients with progressive supranuclear palsy/cortico-basal syndrome (PSP/CBS), PD dementia (PDD), and dementia with Lewy bodies (DLB), and sex distribution was characterised by a higher prevalence of males in all patient groups, except for MSA (Table 1)
We reported the results of a comprehensive evaluation of the diagnostic and prognostic value of NfL and α-syn seeding activity, including the comparison between CSF NfL (cNfL) and plasma NfL (pNfL) performance, and the analysis of the added value of a combined CSF analysis of NfL and α-syn seeding activity, in a large cohort of patients with parkinsonism and related prodromal syndromes

Summary

Introduction

Current diagnostic criteria for both PD and APDs have some limitations because they require a combination of clinical findings, multiple diagnostic investigations, and an adequate follow-up of several years to reach an accurate disease identification[1,2]. The growing interest towards early and accurate identification of neurodegenerative diseases makes the search for in vivo molecular markers of diagnostic and prognostic value for PD and APDs of fundamental importance[3]. Given their specificity, has been raised by novel ultrasensitive in vitro assays exploiting the template prion-like capacities of the pathogenic protein as an amplification strategy to detect a minute amount of disease-specific misfolded, aggregated forms of α-synuclein (α-syn) in CSF11. We and others have recently shown that abnormal α-syn aggregates can be reliably detected in the CSF of patients with PD by real-time quaking-induced conversion (RT-QuIC), allowing a differentiation between APDs and PD due to Lewy body disease (LBD)[12,13,14,15,16]

Methods

Results

Conclusion