Interaction of sex and onset site on the disease trajectory of amyotrophic lateral sclerosis

Ortholand, Juliette; Pradat, Pierre-François; Tezenas du Montcel, Sophie; Durrleman, Stanley

doi:10.1007/s00415-023-11932-7

Cited by 4 publications

(3 citation statements)

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“…34 Our longitudinal analysis, however, was only meant to capture the general ALSFRS-R decline trend, and the different progression rates between men and women. Our findings theoretically harmonize with those from models describing patient-specific clinical trajectories 7 ; the decrease in FVC % and BMI occurred earlier in women, but was overall more severe in men. Second, we validated our results in two cohorts that vary significantly in terms of participant recruitment, thus prompting caution in the generalizability of these results.…”

Section: Discussionsupporting

confidence: 85%

“…4,6 The influence of sexual dimorphism on disease progression has recently been investigated, albeit not within a population-based context. 7 In the present study, we investigated how the interplay between sex, age, and type of disease onset might influence disease course by examining survival and several clinical outcomes in two well-characterized ALS populations, one from a population-based cohort and one from a large multicentric cohort, both at the time of diagnosis and through the longitudinal analyses of prospectively collected data.…”

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confidence: 99%

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Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis

Grassano,

Moglia,

Palumbo

et al. 2024

Annals of Neurology

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ObjectiveTo investigate sex‐related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors.MethodsOur primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching.ResultsThe PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00–1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09–1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS‐R points/month, 95% CI 0.07–0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (−4.2 forced vital capacity%/month, 95% CI −6.3 to −2.2, p < 0.0001) and faster weight loss (−0.15 kg/month, 95% CI −0.25 to −0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex‐related survival differences. Analysis of patients from PRO‐ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends.InterpretationThe shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex‐specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024

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Section: Discussionsupporting

confidence: 85%

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confidence: 99%

Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis

Grassano,

Moglia,

Palumbo

et al. 2024

Annals of Neurology

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“…Symptoms may vary according to the disease onset site that is an important driver of the disease progression [ 4 ]. Symptoms of spinal ALS appear initially in the upper or lower limbs in the form of muscle weakness, fatigue, or pain.…”

Section: Introductionmentioning

confidence: 99%

Physical therapy for muscle strengthening in individuals with amyotrophic lateral sclerosis: A protocol for a systematic review and meta-analysis

Souza,

da Silva,

Macedo

et al. 2024

PLoS ONE

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Introduction People with Amyotrophic Lateral Sclerosis (ALS) can present initially muscle weakness, which is a debilitating symptom that may be improved by engaging in muscle strengthening activities. Currently, the effects of motor interventions for muscle strengthening in people with ALS are unclear. This review intends to analyze the effects of motor interventions for muscle strengthening in individuals with ALS Methods and analysis Randomized, non-randomized, and quasi-experimental clinical trials assessing individuals with ALS of both sexes, aged 18 years or older, who have received motor interventions for muscle strengthening considering all practices that can lead to increased strength, endurance, power and muscular hypertrophy will be included. No restriction on language, location, or publication date will be applied. MEDLINE, EMBASE, Cochrane Library (CENTRAL), SPORTDiscus, and Physiotherapy Evidence Database (PEDro) databases will be searched. The US National Institutes of Health Ongoing, ClinicalTrials.gov, and the reference lists of included studies will also be searched. Two reviewers will independently screen titles and abstracts and extract data from included studies. The methodological quality of the included studies will be assessed by the PEDro scale and the certainty of the evidence by the GRADE approach. Disagreements will be resolved by a third researcher. Findings will be presented in text and table formats. A meta-analysis will compare the effects of motor interventions for muscle strengthening versus placebo or other interventions.

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Delineating sex-dependent and anatomic decline of motor functions in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Shelest,

Tindel,

Lauzon

et al. 2024

Preprint

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The transgenic SOD1G93A mouse model is the most widely used animal model of amyotrophic lateral sclerosis (ALS), a fatal disease of motor neuron degeneration. While genetic background influences onset and progression variability of motor dysfunction, the C57BL/6 background most reliably exhibits robust ALS phenotypes; thus, it is the most widely used strain in mechanistic studies. In this model, paresis begins in the hindlimbs and spreads rostrally to the forelimbs. Males experience earlier onset, greater disease severity, and shorter survival than females. However, the influence of sex on patterns of declining motor function between forelimbs and hindlimbs as well as among distinct, spinal-innervated muscle groups within each limb are not fully understood. To provide a higher resolution framework of degenerating motor function across the body, we conducted more comprehensive, limb-dependent and independent measures of motor decline over the course of disease. Subsequently, we compared the timing and intensity of these features across sex, and we consider to what extent these patterns are conserved in clinical observations from human ALS patients. We found male mice experienced earlier and less localized onset than females. We also report distinct motor features decline at different rates between sexes. Finally, mice showed differences in correlation between the decline of left- and right-side measures of the hindlimb. Consequently, our findings reinforce and refine the utility of the SOD1 mouse in modeling more highly resolved, sex-specific differences in ALS patient motor behavior. This may better guide preclinical studies in stratifying patients by sex and anatomical site of onset.

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Interaction of sex and onset site on the disease trajectory of amyotrophic lateral sclerosis

Cited by 4 publications

References 50 publications

Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis

Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis

Physical therapy for muscle strengthening in individuals with amyotrophic lateral sclerosis: A protocol for a systematic review and meta-analysis

Delineating sex-dependent and anatomic decline of motor functions in the SOD1G93A mouse model of amyotrophic lateral sclerosis

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