The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology

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.

Figure 1.. The Miami Framework for amyotrophic lateral sclerosis and related neurodegenerative disorders

The Miami Framework recognizes the clinical syndromes and the underlying biology of disease in parallel. The three phenotypic axes include motor neuron (Axis I, orange), frontotemporal (Axis II, blue) and extrapyramidal (Axis III, green). Within each axis, disease can progress from clinically silent, to prodromal, to clinically manifest, with independent timelines for each axis; for example, being prodromal in one axis does not mean being prodromal in the other axes. Moreover, people might have disease in any (or all) of the three axes. Distinct from the clinical phenotypes are the underlying biology of these disorders, including TDP43, tau, neurodegeneration and others such as SOD1 pathology. Insights into this pathobiology might be gleaned from biomarkers, for example, cryptic peptides for functional loss of TDP43 (ref. ) or extracellular vesicle TDP43 (ref. ); cerebrospinal fluid (CSF) phosphorylated (p)-tau for tau neuropathology; CSF endogenous SOD1 peptide for SOD1 pathology; and neurofilament, plasma p-tau or urinary p75 (ref. ) for neurodegeneration. As the temporal patterns of the biomarkers are different and still incompletely understood, these are not depicted in the figure.

Figure 2.. Illustrative examples of the Miami Framework

Two hypothetical patients are presented. Patient A, representing a patient with a SOD1 A4V mutation, had mild motor impairment (MMI) followed by clinically manifest amyotrophic lateral sclerosis (ALS); a frontotemporal prodrome then developed and no extrapyramidal phenotype, such as tremor, was present. An increase in serum neurofilament light chain (NfL) would be expected prior to the emergence of MMI. Patient B, representing a patient with a C9orf72 repeat expansion, first developed mild behavioural impairment (MBI), followed by MMI, and then clinically manifest behavioural variant frontotemporal dementia (bvFTD); after the subsequent emergence of a tremor indicative of mild extrapyramidal impairment (MEPI), clinically manifest ALS also became apparent, yielding a phenotype of bvFTD–ALS with MEPI. Serum NfL might increase during the prodromal period but might also only increase following phenoconversion to bvFTD. MCI, mild cognitive impairment.