TY - JOUR
T1 - Cortical Excitability as a Prognostic and Phenotypic Stratification Biomarker in Amyotrophic Lateral Sclerosis
AU - the MND Study Group of the Italian Neurological Society (SIN) and the Neurostimulation-Neuromodulation Study Group of the Italian Society of Clinical Neurophysiology (SINC)
AU - Ranieri, Federico
AU - Senerchia, Gianmaria
AU - Bonan, Luigi
AU - Casali, Stefania
AU - Cabona, Corrado
AU - Cantone, Mariagiovanna
AU - De Marchi, Fabiola
AU - Diamanti, Luca
AU - Doretti, Alberto
AU - Fini, Nicola
AU - Filosto, Massimiliano
AU - Fortuna, Andrea
AU - Iovino, Aniello
AU - Iuzzolino, Valentina Virginia
AU - Lanza, Giuseppe
AU - Lunetta, Christian
AU - Maderna, Luca
AU - Mandrioli, Jessica
AU - Mazzini, Letizia
AU - Musumeci, Gabriella
AU - Nuredini, Andi
AU - Sorarù, Gianni
AU - Toriello, Antonella
AU - Ticozzi, Nicola
AU - Todisco, Massimiliano
AU - Vacchiano, Veria
AU - Zinno, Lucia
AU - Silani, Vincenzo
AU - Rossi, Simone
AU - Di Lazzaro, Vincenzo
AU - Dubbioso, Raffaele
AU - Calvi, Francesca
AU - Caputo, Maria
AU - Gazzina, Stefano
AU - Filippi, Laura
AU - Piras, Rachele
AU - Boscarino, Marilisa
AU - Bella, Rita
AU - Pennisi, Manuela
AU - Pilato, Fabio
AU - Iodice, Rosa
N1 - Publisher Copyright:
© 2025 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2025/10
Y1 - 2025/10
N2 - Objective: Despite its clinical heterogeneity, amyotrophic lateral sclerosis is unified by early and prominent alterations in cortical excitability, increasingly recognized as contributors to disease progression. This study assessed whether the ratio between motor evoked potential (MEP) amplitude, reflecting upper motor neuron integrity, and compound muscle action potential (CMAP) amplitude, indexing lower motor neuron function, could provide an accessible marker of corticospinal excitability to stratify patients by phenotype, stage, and survival. Methods: In this multicenter retrospective study, 743 amyotrophic lateral sclerosis patients from 16 tertiary centers in Italy were analyzed. The MEP:CMAP ratio, recorded from upper limb muscles, was categorized as hyperexcitable, normal, or hypoexcitable. Phenotypes included progressive muscular atrophy (or lower motor neuron), flail arm/leg, classic, bulbar, patient with predominant upper motor neuron signs (or pyramidal), and primary lateral sclerosis. Disease stage was assessed using King's staging. Survival was analyzed using Kaplan–Meier curves and Cox regression models. Results: The MEP:CMAP ratio differed significantly across phenotypes (p < 0.0001), with hyperexcitability predominating in lower motor neuron, flail, classic, and bulbar forms, and hypoexcitability in pyramidal and primary lateral sclerosis. Hypoexcitability increased in advanced King's stages (p < 0.0001). Hyperexcitable patients had shorter survival (p = 0.004), including when tested within 1 year of onset (p = 0.006). Cox regression identified the MEP:CMAP ratio as an independent survival predictor (HR 1.84, 95% CI 1.12–3.03, p = 0.016). Interpretation: This real-world study supports the clinical value of the MEP:CMAP ratio as a scalable biomarker of cortical excitability in amyotrophic lateral sclerosis, with prognostic relevance across phenotypes and disease stages. ANN NEUROL 2025;98:801–813.
AB - Objective: Despite its clinical heterogeneity, amyotrophic lateral sclerosis is unified by early and prominent alterations in cortical excitability, increasingly recognized as contributors to disease progression. This study assessed whether the ratio between motor evoked potential (MEP) amplitude, reflecting upper motor neuron integrity, and compound muscle action potential (CMAP) amplitude, indexing lower motor neuron function, could provide an accessible marker of corticospinal excitability to stratify patients by phenotype, stage, and survival. Methods: In this multicenter retrospective study, 743 amyotrophic lateral sclerosis patients from 16 tertiary centers in Italy were analyzed. The MEP:CMAP ratio, recorded from upper limb muscles, was categorized as hyperexcitable, normal, or hypoexcitable. Phenotypes included progressive muscular atrophy (or lower motor neuron), flail arm/leg, classic, bulbar, patient with predominant upper motor neuron signs (or pyramidal), and primary lateral sclerosis. Disease stage was assessed using King's staging. Survival was analyzed using Kaplan–Meier curves and Cox regression models. Results: The MEP:CMAP ratio differed significantly across phenotypes (p < 0.0001), with hyperexcitability predominating in lower motor neuron, flail, classic, and bulbar forms, and hypoexcitability in pyramidal and primary lateral sclerosis. Hypoexcitability increased in advanced King's stages (p < 0.0001). Hyperexcitable patients had shorter survival (p = 0.004), including when tested within 1 year of onset (p = 0.006). Cox regression identified the MEP:CMAP ratio as an independent survival predictor (HR 1.84, 95% CI 1.12–3.03, p = 0.016). Interpretation: This real-world study supports the clinical value of the MEP:CMAP ratio as a scalable biomarker of cortical excitability in amyotrophic lateral sclerosis, with prognostic relevance across phenotypes and disease stages. ANN NEUROL 2025;98:801–813.
UR - https://www.scopus.com/pages/publications/105011144618
U2 - 10.1002/ana.27305
DO - 10.1002/ana.27305
M3 - Article
SN - 0364-5134
VL - 98
SP - 801
EP - 813
JO - Annals of Neurology
JF - Annals of Neurology
IS - 4
ER -