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PreprintCited by 11Prion Diseases and Protein MisfoldingAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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Evidence that minocycline treatment confounds the interpretation of neurofilament as a biomarker

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Gentile, Juliana E, Heiss, Christina, Corridon, Taylor L, Mortberg, Meredith A, Fruhwürth, Stefanie, Guzman, Kenia, Grötschel, Lana, Chan, Kwan, Herring, Neil C, Janicki, Timothy, Nhass, Rajaa, Sarathy, Janani Manavala, Erickson, Brian, Kunz, Ryan, Erickson, Alison, Braun, Craig, Henry, Katherine T, Bry, Lynn, Arnold, Steven E, Minikel, Eric Vallabh, Zetterberg, Henrik, Vallabh, Sonia M·2024·Brain Communications
DOI 10.1101/2024.05.01.24306384PMC PMC12100619

Preprint — published as 10.1093/braincomms/fcaf175

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Abstract

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.

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  • The analysis did not account for the varied medications or supplements taken by participants; however, findings from a recent study suggest that microglia play a role in clearing NfL and that certain drugs, like minocycline, inhibit this clearance and consequently may increase NfL concentrations in the absence of neurodegeneration.

    “Our analysis also did not account for the varied medications or supplements taken by participants; however, findings from a recent study suggest that microglia play a role in clearing NfL and that certain drugs, like minocycline, inhibit this clearance and consequently may increase NfL concentrations in the absence of neurodegeneration [73].”

    From Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders (2025) · cites this paper as [73]

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Metadata

Authors
Gentile, J. E., Heiss, C., Corridon, T. L., Mortberg, M. A., Fruhwürth, S., Guzman, K., Grötschel, L., Chan, K., Herring, N. C., Janicki, T., Nhass, R., Sarathy, J. M., Erickson, B., Kunz, R., Erickson, A., Braun, C., Henry, K. T., Bry, L., Arnold, S. E., Minikel, E. V., Zetterberg, H., & Vallabh, S. M.
Affiliations
  • Broad Institute (US)
  • University of Gothenburg (SE)
  • Brigham and Women's Hospital (US)
  • Charles River Laboratories (United States) (US)
  • Harvard University (US)
  • Sahlgrenska University Hospital (SE)
Corresponding author
  • Zetterberg, Henrik
  • Vallabh, Sonia M
ORCID
Venue
Brain Communications
Publisher
openRxiv
Published
2024-05-02
Volume
7
Issue
3
Pages
fcaf175-fcaf175
ISSN
2632-1297 (ISSN-L)
DOI
10.1101/2024.05.01.24306384
PMC
PMC12100619
OpenAlex
W4410686831
Cited by
11
References
0
Citations by year
2026: 2 · 2025: 7 · 2024: 2
FWCI
2.71
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Brain Communications (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Massachusetts General Hospital
  • Broad Institute
  • National Institutes of Health (1r01ns132022-01a1, R21TR003040)
  • National Institute of Neurological Disorders and Stroke (R01 NS132022, R01NS125255)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
minocycline, neurofilament light chain, cerebrospinal fluid biomarkers, blood biomarkers, prion disease, neuroinflammation

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