Neurofilament light (NfL) concentration in cerebrospinal fluid (CSF) and blood serves as an important biomarker in neurology drug development. Changes in NfL are generally assumed to reflect changes in neuronal damage, while little is known about the clearance of NfL from biofluids. We observed an NfL increase of 3.5-fold in plasma and 5.7-fold in CSF in an asymptomatic individual at risk for genetic prion disease following 6 weeks treatment with oral minocycline for a dermatologic indication. Other biomarkers remained normal, and proteomic analysis of CSF revealed that the spike was exquisitely specific to neurofilaments. NfL dropped nearly to normal levels 5 weeks after minocycline cessation, and the individual remained free of disease 2 years later. Plasma NfL in dermatology patients was not elevated above normal controls. Dramatically high plasma NfL (>500 pg/mL) was variably observed in some hospitalized individuals receiving minocycline. In mice, treatment with minocycline resulted in variable increases of 1.3- to 4.0-fold in plasma NfL, with complete washout 2 weeks after cessation. In neuron-microglia co-cultures, minocycline increased NfL concentration in conditioned media by 3.0-fold without any visually obvious impact on neuronal health. We hypothesize that minocycline does not cause or exacerbate neuronal damage, but instead impacts the clearance of NfL from biofluids, a potential confounder for interpretation of this biomarker.

BE, RK, AE, CB are employees of IQ Proteomics. KTH is an employee of Charles River Laboratories. SEA acknowledges speaking fees from Abbvie, Biogen, EIP Pharma, Roche, and Sironax; consulting fees from Athira, Biogen, Cassava, Cognito, Cortexyme, Sironax, and vTv; research support from Abbvie, Amylyx, EIP Pharma, and Merck. EVM acknowledges speaking fees from Eli Lilly; consulting fees from Deerfield and Alnylam; research support from Ionis, Gate, Sangamo, Eli Lilly. HZ is co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg.SMV acknowledges speaking fees from Ultragenyx, Illumina, Biogen, Eli Lilly; consulting fees from Invitae and Alnylam; research support from Ionis, Gate, Sangamo, Eli Lilly.

We thank all research participants for their contributions to this study. This work was funded by Prion Alliance, the Broad Institute (BroadIgnite Accelerator), donations to the Prions@Broad fund, and the National Institutes of Health (R21 TR003040, R01 NS125255, R01 NS132022).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Human samples were collected through Mass General Brigham (MGB) Institutional Review Board (IRB) protocols 2015P000221, 2017P000214, and 2021P002185. Our prion cohort research participant provided written informed consent. Discarded plasma samples were collected under a waiver of consent approved by the MGB IRB.

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Source code and an analytical dataset sufficient to reproduce all figures and statistics in this manuscript will be made publicly available at https://github.com/ericminikel/mino

https://github.com/ericminikel/mino