RT Journal Article
SR Electronic
T1 Cross-Sectional and Longitudinal Validation of Serum Neurofilament Light Chain (NfL) as a Biomarker of Parkinson’s Disease Progression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 762237
DO 10.1101/762237
A1 Brit Mollenhauer
A1 Mohammed Dakna
A1 Tzu-Ying Liu
A1 Douglas Galasko
A1 Tatiana Foroud
A1 Henrik Zetterberg
A1 Sebastian Schade
A1 Roland Gera
A1 Wenting Wang
A1 Feng Gao
A1 Niels Kruse
A1 Mark Frasier
A1 Lana M. Chahine
A1 Christopher S. Coffey
A1 Andrew B. Singleton
A1 Tanya Simuni
A1 Daniel Weintraub
A1 John Seibyl
A1 Arthur W. Toga
A1 Caroline M. Tanner
A1 Karl Kieburtz
A1 Kenneth Marek
A1 Andrew Siderowf
A1 Jesse M. Cedarbaum
A1 Samantha J. Hutten
A1 Claudia Trenkwalder
A1 Danielle Graham
YR 2019
UL http://biorxiv.org/content/early/2019/09/11/762237.abstract
AB Background Alterations in neurofilament light chain (NfL), reflecting axonal damage, have been proposed as a biomarker for neurological disorders including Parkinson’s disease (PD).Methods We measured NfL concentrations by immunoassay in (1) a set of longitudinal CSF samples from 82 PD, 14 other neurodegenerative disorders (OND), and 53 healthy controls (HC); (2) A cross-sectional cohort with paired CSF and serum samples from subjects with 151 PD, 344 OND, and 20 HC, and (3a) a large longitudinal validation cohort with serum samples from 375 PD, 178 HC, and 57 prodromal Lewy Body disorder with hyposmia or isolated REM sleep behaviour disorder (iRBD), (3b) 216 symptomatic and 298 asymptomatic LRRK2, GBA, and SNCA mutation carriers in the Parkinson’s Progression Markers Initiative (PPMI). Mean differences in serum NfL levels between diagnostic groups, and correlation with motor signs, cognitive measures and dopamine transporter imaging, were assessed. Linear mixed effects models were used to assess longitudinal changes in log10 (NfL) in relation to demographic, clinical, and imaging variables.Findings In the longitudinal cohort (1) NfL in CSF increased over time and was significantly positively correlated with MDS-UPDRS III motor and total scores in the PD group (p=0·0231 and 0·0081). In the cross-sectional cohort (2) the paired CSF and serum NfL samples were highly correlated (Spearman’s rank . In the large validation cohort (3a) mean baseline serum NfL was higher in PD (13 ±7·2pg/ml), hyposmics (15±15·1pg/ml), and iRBD (17±8pg/ml) compared with HC (12±6·7pg/ml) but was highest in the seven OND cases (18±7pg/ml). In the genetic cohort (3b), serum NfL levels were lower in asymptomatic than in symptomatic mutation carriers. There was a significant (age-adjusted) longitudinal increase in serum NfL in PD compared with HC. Serum NfL values were significantly positively associated with longitudinal MDS-UPDRS motor and total scores, as well as age.Interpretation We identified NfL as the first blood-based PD progression biomarker. NfL levels in serum samples are increased in PD compared to HC, increase significantly over time in PD, and correlate with a clinical measure of disease severity. Although the specificity of NfL in PD is low and additional, more specific biomarkers are needed, serum NfL is the first blood-based biomarker candidate that could support disease stratification (PD vs. OND), track clinical progression, and might be used to assess responsiveness to neuroprotective treatments.