Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis
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Abstract
Background With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used. Methods A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75 ECD , plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated. Findings Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40 pg/mL and >100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75 ECD , and plasma miR-181ab is more limited. Interpretation Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency. Funding NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).
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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 [66]
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- Authors
- Benatar, M., Macklin, E. A., Malaspina, A., Rogers, M.-L., Hornstein, E., Lombardi, V., Renfrey, D., Shepheard, S., Magen, I., Cohen, Y., Granit, V., Statland, J. M., Heckmann, J. M., Rademakers, R., McHutchison, C. A., Petrucelli, L., McMillan, C. T., Wuu, J., Benatar, M., Granit, V., Statland, J. M., Heckmann, J. M., McMillan, C. T., Elman, L., Ravits, J., Katz, J., Trivedi, J., Swenson, A., Burns, T. M., Caress, J., Jackson, C., Maiser, S., Pioro, E. P., & So, Y.
- Affiliations
- Harvard University (US)
- National Hospital for Neurology and Neurosurgery (GB)
- Flinders University (AU)
- Weizmann Institute of Science (IL)
- University of Antwerp (BE)
- Euan MacDonald Centre for Motor Neuron Disease Research (GB)
- Mayo Clinic in Florida (US)
- University of Miami (US)
- Corresponding author
- Wuu, Joanne
- ORCID
- Venue
- eBioMedicine
- Publisher
- Elsevier BV
- Published
- 2024-10
- Volume
- 108
- Pages
- 105323
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC11415817
- OpenAlex
- W4402467226
- Cited by
- 61
- References
- 51
- Citations by year
- 2026: 30 · 2025: 26 · 2024: 5
- FWCI
- 16.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Stirling Online Research Repository (University of Stirling) (submittedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- ALS Association (16-TACL-242, NS092091)
- University of Miami
- National Institutes of Health (NS092091)
- National Institute on Aging (R01AG066152, P01AG066597, U19AG063911, T32AG076411, P30AG062677, P30AG072979)
- National Institute of Neurological Disorders and Stroke (P01NS084974, R01NS109260, U01NS107027, R35NS097273, U54NS123743, U54NS092091)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- amyotrophic lateral sclerosis, prognostic factors, neurofilament light chain, survival prediction, sample size determination, trial design, disease progression
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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.
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