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. 2025 Jun 25.
doi: 10.1002/ana.27305. Online ahead of print.

Cortical Excitability as a Prognostic and Phenotypic Stratification Biomarker in Amyotrophic Lateral Sclerosis

Federico Ranieri #  1 , Gianmaria Senerchia #  2 , Luigi Bonan  3 , Stefania Casali  4 , Corrado Cabona  5 , Mariagiovanna Cantone  6 , Fabiola De Marchi  7 , Luca Diamanti  8 , Alberto Doretti  9 , Nicola Fini  10 , Massimiliano Filosto  11   12 , Andrea Fortuna  13 , Aniello Iovino  14 , Valentina Virginia Iuzzolino  2 , Giuseppe Lanza  15   16 , Christian Lunetta  17 , Luca Maderna  9 , Jessica Mandrioli  10   18 , Letizia Mazzini  7 , Gabriella Musumeci  19 , Andi Nuredini  20 , Gianni Sorarù  13 , Antonella Toriello  14 , Nicola Ticozzi  9   21 , Massimiliano Todisco  22 , Veria Vacchiano  3 , Lucia Zinno  20 , Vincenzo Silani  9   21 , Simone Rossi  23 , Vincenzo Di Lazzaro  19   24 , Raffaele Dubbioso  2 ; MND Study Group of the Italian Neurological Society (SIN) and the Neurostimulation‐Neuromodulation Study Group of the Italian Society of Clinical Neurophysiology (SINC)
Collaborators, Affiliations

Cortical Excitability as a Prognostic and Phenotypic Stratification Biomarker in Amyotrophic Lateral Sclerosis

Federico Ranieri et al. Ann Neurol. .

Abstract

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.

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