Abstract
Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum — from clinically silent, to prodromal, to clinically manifest — and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes — motor neuron, frontotemporal and extrapyramidal — rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.
Key points
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Amyotrophic lateral sclerosis, frontotemporal dementia and a group of extrapyramidal movement disorders are related across a phenotypic spectrum and have shared biological substrates such as TDP43 or tau pathology.
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Disease evolves along a phenotypic continuum from clinically silent, to prodromal, to clinically manifest disease. Existing diagnostic criteria might require updates given new knowledge of prodromal and early manifest disease.
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Biomarkers reflecting the underlying biology of these diseases and the resulting neurodegenerative changes have begun to emerge, but the temporal relationship of the biomarkers to clinical phenotypes is unclear.
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The Miami Framework offers a unified approach to specifying both the pleotropic clinical manifestations of these diseases and, in parallel, the temporal course of emergent biomarkers.
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Informed by data and experience from multiple genetic forms of amyotrophic lateral sclerosis and frontotemporal dementia, the Miami Framework probably has relevance to all forms of these diseases.
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Communicating the emergence of prodromal disease to the affected individual is complex and requires great caution but can be informed by experience and insights from genetic and biomarker counselling.
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Change history
29 May 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41582-024-00978-4
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Acknowledgements
We are indebted to participants in the Pre-Symptomatic Familial ALS (Pre-fALS) and ARTFL LEFFTDS Longitudinal FTD (ALLFTD) studies for their contribution to research. Data and insights from these studies provided a foundation for discussions at the Second International Pre-Symptomatic ALS Workshop. The Second International Pre-Symptomatic ALS Workshop was made possible through the generous support of the ALS Association, the Association for Frontotemporal Degeneration, the Muscular Dystrophy Association, the Motor Neurone Disease Association of England, Wales and Northern Ireland, Biogen, Eli Lilly, Novartis, Regeneron, uniQure and the National Institutes of Health (U54-NS092091).
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M.B. prepared the initial draft of the manuscript. J.W., M.R.T., A.A.-C., E.D.H., C.T.M., R.C.P., and R.P. substantively edited the initial draft. All authors contributed to discussion of the content, and reviewed or edited the manuscript. M.B. and J.W. prepared the figures and finalized the manuscript for submission.
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M.B. receives consulting fees for Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB and UniQure. The University of Miami has licensed intellectual property to Biogen to support design of the ATLAS study. R.C.P. reports consulting for Roche, Genentech, Eli Lilly and Co., Eisai, and Nestle. R.P. reports grants and personal fees from Fonds de la Recherche en Sante, grants from the Canadian Institute of Health Research, the Michael J. Fox Foundation, the National Institute of Health, Roche and the Webster Foundation, and personal fees from Takeda, Abbvie, Biogen, Bristol Myers Squibb, Curasen, Eisai, the International Parkinson and Movement Disorders Society, Korro, Lilly, Merck, Novartis, Paladin, Parkinson Canada, and Vaxxinity outside the submitted work. L.D. reports consulting for Biogen, MJH Life Sciences, Passage Bio and Sano Genetics. N.T. is an employee of the ALS Association. A.B. has served as a paid consultant to AGTC, Alector, Alzprotect, Amylyx, Arkuda, Arrowhead, Arvinas, Aviado, Boehringer Ingelheim, Denali, Eli Lilly, GSK, Humana, Life Edit, Merck, Modalis, Oligomerix, Oscotec, Roche, Transposon and Wave. B.F.B. reports honoraria for scientific advisory board activities for the Tau Consortium, funded by the Rainwater Charitable Foundation, and institutional research grant support for clinical trials from Alector, Biogen, Cognition Therapeutics, EIP Pharma, GE Healthcare and Transposon. P.D. is an employee of Association for Frontotemporal Degeneration. P.L. reports honoraria for advisory boards, consultancies or speaker remuneration from Abbvie, Alexion, Bial, Desitin, ITF Pharma, Novartis Pharma, Stada Pharm, Woolsey Pharma and Zambon. He is a co-inventor on patents EP 2825175 B1, US 9.980,972 B2 for the treatment of ALS. His work on ALS is funded by the Bundesministerium für Bildung und Forschung (01ED2204A, 01GM1917A, 01GM1704A/B), the Deutsche Forschungsgemeinschaft (SyNergy project-ID 390857198) and the Deutsche Gesellschaft für Muskelkranke (DGM). P.M.A. reports paid consultancies and serves/has served on advisory boards for Arrowhead, Avrion, Biogen, Orphazyme, Regeneron, Roche, and uniQure and as clinical trial site investigator for AB Science, Alexion Pharmaceuticals, AL-S Pharma and Lilly, Amylyx, Biogen Idec, IONIS Pharmaceuticals, Orion Pharma, Rhône-Poulenc and Sanofi. Since 1993, he has been Director of the ALS-genetic laboratory at Umeå University Hospital, which performs not-for-profit research genetic testing. He is a member of the ClinGen ALS Gene variant Curation Expert panel. A.A.-C. reports consultancies or advisory boards for Amylyx, Apellis, Biogen, Brainstorm, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, Orion Pharma, Quralis, Sano, Sanofi and Wave Pharmaceuticals, and the following patent: “Use of CSF-Neurofilament determinations and CSF-Neurofilament thresholds of prognostic and stratification value with regards to response to therapy in neuromuscular and neurodegenerative diseases”. The other authors report no conflicts of interest.
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ALLFTD: https://www.allftd.org/
Spectrum Disorders Gene Curation: https://clinicalgenome.org/affiliation/40096/
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Benatar, M., Wuu, J., Huey, E.D. et al. The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology. Nat Rev Neurol (2024). https://doi.org/10.1038/s41582-024-00961-z
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DOI: https://doi.org/10.1038/s41582-024-00961-z
