Federico Ranieri, Gianmaria Senerchia, Luigi Bonan, Stefania Casali, Corrado Cabona, Mariagiovanna Cantone, Fabiola De Marchi, Luca Diamanti, Alberto Doretti, Nicola Fini, Massimiliano Filosto, Andrea Fortuna, Aniello Iovino, Valentina Virginia Iuzzolino, Giuseppe Lanza, Christian Lunetta, Luca Maderna, Jessica Mandrioli, Letizia Mazzini, Gabriella Musumeci, Andi Nuredini, Gianni Sorarù, Antonella Toriello, Nicola Ticozzi, Massimiliano Todisco, Veria Vacchiano, Lucia Zinno, Vincenzo Silani, Simone Rossi, Vincenzo Di Lazzaro, Raffaele Dubbioso
{"title":"皮质兴奋性作为肌萎缩性侧索硬化症的预后和表型分层生物标志物。","authors":"Federico Ranieri, Gianmaria Senerchia, Luigi Bonan, Stefania Casali, Corrado Cabona, Mariagiovanna Cantone, Fabiola De Marchi, Luca Diamanti, Alberto Doretti, Nicola Fini, Massimiliano Filosto, Andrea Fortuna, Aniello Iovino, Valentina Virginia Iuzzolino, Giuseppe Lanza, Christian Lunetta, Luca Maderna, Jessica Mandrioli, Letizia Mazzini, Gabriella Musumeci, Andi Nuredini, Gianni Sorarù, Antonella Toriello, Nicola Ticozzi, Massimiliano Todisco, Veria Vacchiano, Lucia Zinno, Vincenzo Silani, Simone Rossi, Vincenzo Di Lazzaro, Raffaele Dubbioso","doi":"10.1002/ana.27305","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Interpretation: </strong>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.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1000,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cortical Excitability as a Prognostic and Phenotypic Stratification Biomarker in Amyotrophic Lateral Sclerosis.\",\"authors\":\"Federico Ranieri, Gianmaria Senerchia, Luigi Bonan, Stefania Casali, Corrado Cabona, Mariagiovanna Cantone, Fabiola De Marchi, Luca Diamanti, Alberto Doretti, Nicola Fini, Massimiliano Filosto, Andrea Fortuna, Aniello Iovino, Valentina Virginia Iuzzolino, Giuseppe Lanza, Christian Lunetta, Luca Maderna, Jessica Mandrioli, Letizia Mazzini, Gabriella Musumeci, Andi Nuredini, Gianni Sorarù, Antonella Toriello, Nicola Ticozzi, Massimiliano Todisco, Veria Vacchiano, Lucia Zinno, Vincenzo Silani, Simone Rossi, Vincenzo Di Lazzaro, Raffaele Dubbioso\",\"doi\":\"10.1002/ana.27305\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Interpretation: </strong>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.</p>\",\"PeriodicalId\":127,\"journal\":{\"name\":\"Annals of Neurology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":8.1000,\"publicationDate\":\"2025-06-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/ana.27305\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/ana.27305","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Cortical Excitability as a Prognostic and Phenotypic Stratification Biomarker in Amyotrophic Lateral Sclerosis.
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.
期刊介绍：
Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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