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bioRxiv · 10.1101/762237

Cross-Sectional and Longitudinal Validation of Serum Neurofilament Light Chain (NfL) as a Biomarker of Parkinson’s Disease Progression

Mollenhauer, B.·Dakna, D.·Liu, T.-Y.·Galasko, D.·Foroud, T.·Zetterberg, H.·Schade, S.·Gera, R.·Wang, W.·Gao, F.·Kruse, N.·Frasier, M.·Chahine, L.·Coffey, C. S.·Singleton, A. B.·Simuni, T.·Weintraub, D.·Seibyl, J.·Toga, A. W.·Tanner, C. M.·Kieburtz, K.·Marek, K.·Siderowf, A.·Cedarbaum, J. M.·Hutten, S. J.·Trenkwalder, C.·Graham, D.
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Abstract

ObjectiveTo assess neurofilament light chain (NfL), as a biomarker for Parkinsons disease (PD). MethodsWe quantified NfL in (1) longitudinal CSF samples from PD, other cognate/neurodegenerative disorders (OND), and healthy controls (HC); (2) a cross-sectional cohort with paired CSF and serum samples from participants with PD, OND, and HC, and (3) a large longitudinal validation cohort with serum samples from PD, OND, HC, prodromal conditions, and mutation carriers. ResultsIn the longitudinal discovery cohort (1) NfL in CSF was highest in OND and higher in PD vs. HC across all visits (p<0.05) but did not change longitudinally. In the cross-sectional cohort (2) paired CSF and serum NfL samples were highly correlated (Spearmans rank [Formula]; p<10^-6). In the large validation cohort (3) mean baseline serum NfL was higher in PD (13{+/-}7.2pg/ml) vs. HC (12{+/-}6.7pg/ml; p=0.0336) and was highest in OND (18{+/-}7pg/ml; p=0.0351). Serum NfL increased longitudinally in PD vs. HC (p<0.01). Longitudinal motor scores were positively longitudinally associated with NfL, whereas some cognitive scores showed a negative longitudinal association with NfL. ConclusionsNfL levels in serum samples are increased in PD vs. HC, increase significantly over time, and correlate with clinical measures of PD severity. Although the specificity of NfL in PD is low and 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 possibly assess responsiveness to neuroprotective treatments. NfL as a biomarker of response to neuroprotective interventions remains to be determined. Funding sources for studyPPMI is sponsored by the Michael J. Fox Foundation for Parkinsons Research (MJFF) and is co-funded by MJFF, Abbvie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Eli Lilly & Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer and UCB. The funders had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript or in the decision to submit the manuscript for publication. Financial Disclosure/Conflict of Interest concerning the research related to the manuscriptBrit Mollenhauer, Douglas Galasko, Tatiana Foroud, Lana M. Chahine, Christopher S. Coffey, Andrew B. Singleton, Tanya Simuni, Daniel Weintraub, John Seibyl, Arthur W. Toga, and Caroline M. Tanner received funding from The Michael J. Fox Foundation for Parkinsons Research. Mohammed Dakna, Tzu-Ying Liu, Henrik Zetterberg, Sebastian Schade, Roland G. Gera, Wenting Wang, Feng Gao, Niels Kruse, Mark Frasier, Jesse M. Cedarbaum, Samantha J. Hutten, Claudia Trenkwalder, and Danielle Graham report no disclosures.

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Mollenhauer, B., Dakna, D., Liu, T.-Y., Galasko, D., Foroud, T., Zetterberg, H., Schade, S., Gera, R., Wang, W., Gao, F., Kruse, N., Frasier, M., Chahine, L., Coffey, C. S., Singleton, A. B., Simuni, T., Weintraub, D., Seibyl, J., Toga, A. W., Tanner, C. M., Kieburtz, K., Marek, K., Siderowf, A., Cedarbaum, J. M., Hutten, S. J., Trenkwalder, C., Graham, D.. 2019-09-11. Cross-Sectional and Longitudinal Validation of Serum Neurofilament Light Chain (NfL) as a Biomarker of Parkinson’s Disease Progression. https://doi.org/10.1101/762237

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