The role of neurofilament light in genetic frontotemporal lobar degeneration
Open accessAbstract
Genetic frontotemporal lobar degeneration caused by autosomal dominant gene mutations provides an opportunity for targeted drug development in a highly complex and clinically heterogeneous dementia. These neurodegenerative disorders can affect adults in their middle years, progress quickly relative to other dementias, are uniformly fatal and have no approved disease-modifying treatments. Frontotemporal dementia, caused by mutations in the GRN gene which encodes the protein progranulin, is an active area of interventional drug trials that are testing multiple strategies to restore progranulin protein deficiency. These and other trials are also examining neurofilament light as a potential biomarker of disease activity and disease progression and as a therapeutic endpoint based on the assumption that cerebrospinal fluid and blood neurofilament light levels are a surrogate for neuroaxonal damage. Reports from genetic frontotemporal dementia longitudinal studies indicate that elevated concentrations of blood neurofilament light reflect disease severity and are associated with faster brain atrophy. To better inform patient stratification and treatment response in current and upcoming clinical trials, a more nuanced interpretation of neurofilament light as a biomarker of neurodegeneration is now required, one that takes into account its relationship to other pathophysiological and topographic biomarkers of disease progression from early presymptomatic to later clinically symptomatic stages.
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Due to its prognostic utility, NfL measures may additionally improve clinical trial design by enabling the well-balanced stratification of slow and fast progressors across treatment arms, thereby decreasing treatment outcome variability.
“Due to its prognostic utility, NfL measures may additionally improve clinical trial design by enabling the well-balanced stratification of slow and fast progressors across treatment arms, thereby decreasing treatment outcome variability [65, 66].”
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 [65]
The sections on NfL as a pharmacodynamic marker and on summary recommendations (pages not provided) describe NfL as potentially useful for distinguishing fast from slow progressors and for patient stratification in trials. They do not say that stratification would balance progressors across treatment arms or decrease treatment-outcome variability. (LLM, conf=0.85)
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Self-citationWeston, P. S. J., Poole, T., Nicholas, J. M., Toussaint, N., Simpson, I., Marc Modat, A., Ryan, N. S., Liang, Y., Rossor, M. N., Schott, J. M., et al. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00679-2 · Cited by 41 · see citing works
Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia
Panman, J. L., Venkatraghavan, V., van der Ende, E. L., Steketee, R. M. E., Jiskoot, L. C., Poos, J. M., Dopper, E. G. P., Meeter, L. H. H., Kaat, L. D., Rombouts, S. A. R. B., et al. (2021) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-323541 · Cited by 38 · see citing works
Self-citationParbo, P., Madsen, L. S., Ismail, R., Zetterberg, H., Blennow, K., Eskildsen, S. F., Vorup‐Jensen, T., & Brooks, D. J. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-019-0574-0 · Cited by 35 · see citing works
Self-citationAltered neuronal architecture and plasticity in the visual cortex of adult MMP-3-deficient mice
Aerts, J., Nys, J., Moons, L., Hu, T., & Arckens, L. (2014) · Brain Structure and Function · doi:10.1007/s00429-014-0819-4 · Cited by 32 · see citing works
Blanc, G. L., Pomerleau, V. J., McCarthy, J., Borroni, B., Swieten, J. C. V., Galimberti, D., Sánchez‐Valle, R., Laforce, R. J., Moreno, F., Synofzik, M., et al. (2020) · Annals of Neurology · doi:10.1002/ana.25748 · Cited by 32 · see citing works
Self-citationTrageser, K. J., Smith, C., Herman, F. J., Ono, K., & Pasinetti, G. M. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01298 · Cited by 31 · see citing works
Bridel, C., Verberk, I. M. W., Heijst, J. A., Killestein, J., & Teunissen, C. E. (2020) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2020.102666 · Cited by 31 · see citing works
Self-citationSpotorno, N., Lindberg, O. E., Nilsson, C., Waldö, M. L., van Westen, D., Nilsson, K., Vestberg, S., Englund, E. M., Zetterberg, H., Blennow, K., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0236384 · Cited by 31 · see citing works
Self-citationBorrego‐Écija, S., Turón‐Sans, J., Ximelis, T., Aldecoa, I., Molina‐Porcel, L., Povedano, M., Rubio, M. Á., Gámez, J., Cano, A., Paré, M., et al. (2021) · Brain Pathology · doi:10.1111/bpa.12942 · Cited by 28 · see citing works
Chen, Q., & Kantarci, K. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00080 · Cited by 27 · see citing works
Willemse, E. A. J., Scheltens, P., Teunissen, C. E., & Vijverberg, E. G. B. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00841-4 · Cited by 26 · see citing works
Self-citationCortical microstructure in primary progressive aphasia: a multicenter study
Illán‐Gala, I., Montal, V., Borrego‐Écija, S., Mandelli, M. L., Falgàs, N., Welch, A. E., Pegueroles, J., Santos‐Santos, M., Bejanin, A., Alcolea, D. A., et al. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-00974-0 · Cited by 25 · see citing works
Intra-axonal protein synthesis - a new target for neural repair?
Twiss, J., Kalinski, A. L., Sachdeva, R., & Houlé, J. D. (2016) · Neural Regeneration Research · doi:10.4103/1673-5374.191193 · Cited by 23 · see citing works
Nowacki, P., Koziarska, D., & Masztalewicz, M. (2019) · Folia Neuropathologica · doi:10.5114/fn.2019.88453 · Cited by 20 · see citing works
Neurofilament‐light in former athletes: a potential biomarker of neurodegeneration and progression
Taghdiri, F., Multani, N., Ozzoude, M., Tarazi, A., Khodadadi, M., Wennberg, R. A., Mikulis, D. J., Green, R., Colella, B., Davis, K. D., et al. (2020) · European Journal of Neurology · doi:10.1111/ene.14251 · Cited by 19 · see citing works
Self-citationDistinctive age-related temporal cortical thinning in asymptomatic granulin gene mutation carriers
Moreno, F., Sala‐Llonch, R., Barandiarán, M., Sánchez‐Valle, R., Estanga, A., David Bartrés-faz, A., Sistiaga, A., Alzualde, A., Fernández, E., Martí-Massó, J. F., et al. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.005 · Cited by 19 · see citing works
Disease-related cortical thinning in presymptomatic granulin mutation carriers
Borrego‐Écija, S., Sala‐Llonch, R., Swieten, J. C. V., Borroni, B., Moreno, F., Masellis, M., Tartaglia, M. C., Graff, C., Galimberti, D., Laforce, R. J., et al. (2020) · NeuroImage Clinical · doi:10.1016/j.nicl.2020.102540 · Cited by 14 · see citing works
Self-citationNeurofilament Light Chain Related to Longitudinal Decline in Frontotemporal Lobar Degeneration
Zhang, J. V., Irwin, D. J., Blennow, K., Zetterberg, H., Lee, E. B., Shaw, L. M. J., Rascovsky, K., Massimo, L. M., McMillan, C. T., Chen‐Plotkin, A. S., et al. (2020) · Neurology Clinical Practice · doi:10.1212/cpj.0000000000000959 · Cited by 7 · see citing works
Self-citation
Flagged first, then by citations
3 of the 97 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
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Biomarker-guided decision making in clinical drug development for neurodegenerative disorders
Cummings, J. L., Teunissen, C. E., Fiske, B. K., Ber, I. L., Wildsmith, K. R., Schöll, M., Dunn, B., & Scheltens, P. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01165-w · Cited by 68 · see citing works
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Neurofilaments Light Chain in Neurodegenerative Dementias: A Review of Imaging Correlates
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A framework for translating tauopathy therapeutics: Drug discovery to clinical trials
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Self-citationSheth, U., Öijerstedt, L., Heckman, M. G., White, L. J., Heuer, H. W., Lario Lago, A., Forsberg, L. K., Faber, K. M., Foroud, T. M., Rademakers, R., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00821-4 · Cited by 20 · see citing works
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Self-citationPlasma proteomic signatures of cellular aging predict human disease
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Self-citationNeurofilament heavy phosphorylated epitopes as biomarkers in ageing and neurodegenerative disease
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Self-citationEpigenetic dysregulation of transposable elements in cognitive impairment and Alzheimer’s disease
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Fluid and Imaging Markers of Frontotemporal Lobar Degeneration
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- Authors
- Zetterberg, H., Teunissen, C., van Swieten, J., Kuhle, J., Boxer, A., Rohrer, J. D., Mitic, L., Nicholson, A. M., Pearlman, R., McCaughey, S. M., & Tatton, N.
- Affiliations
- Sahlgrenska University Hospital (SE)
- Amsterdam University Medical Centers (NL)
- Department of Neurology, Erasmus Medical Center , Rotterdam , the Netherlands
- Department of Clinical Research, Department of Neurology, Department of Biomedicine, Multiple Sclerosis Centre, University Hospital Basel, University of Basel , Basel , Switzerland
- University of California, San Francisco (US)
- UK Dementia Research Institute (GB)
- Mayo Clinic in Florida (US)
- The Bluefield Project to Cure FTD , San Francisco, CA , USA
- Alector (United States) (US)
- Corresponding author
- Tatton, Nadine
- ORCID
- Venue
- Brain Communications
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-11-26
- Volume
- 5
- Issue
- 1
- Pages
- fcac310-fcac310
- ISSN
- 2632-1297 (ISSN-L)
- PMC
- PMC9866262
- OpenAlex
- W4309975195
- Cited by
- 19
- References
- 97
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 7 · 2023: 1
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Brain Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Alector, Inc
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- neurofilament light chain, frontotemporal dementia, progranulin, cerebrospinal fluid biomarkers, disease progression, brain atrophy, presymptomatic disease, patient stratification, clinical trial endpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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