The research team followed 42 adults diagnosed with ALS according to the El Escorial criteria, all attending a nutrition consultation within the hospital’s multidisciplinary ALS unit between March 2023 and May 2025. The cohort, 36 percent of whom were women, had a mean age of 66.1 years, and slightly more than half had bulbar onset disease. Over the follow-up period, 19 of the 42 patients died, corresponding to a mean survival of about 21 months from the baseline nutritional assessment. The researchers deliberately set out to test whether a practical, integrated assessment of muscle health, combining body composition measured by bioelectrical impedance, handgrip dynamometry, ultrasound imaging, and a formal sarcopenia diagnosis, could add prognostic information that conventional clinical markers miss.

The technical backbone of the study was a 50-kilohertz phase-sensitive impedance analyzer, used to derive a panel of body composition parameters including body cell mass, body cell mass index, fat mass, total body water, and the appendicular skeletal muscle mass index, or ASMI, which expresses the muscle mass of the arms and legs divided by height squared. Following the Global Leadership Initiative on Malnutrition criteria, low muscle mass was defined as an ASMI below 7.0 kilograms per square meter in men and below 6.0 in women. Sarcopenia was diagnosed according to the EWGSOP2 framework, requiring the coexistence of low muscle strength, assessed by handgrip thresholds of less than 27 kilograms in men and 16 kilograms in women, and low muscle mass. Each patient also underwent ultrasound imaging of the quadriceps rectus femoris and abdominal adiposity measurements, and completed the Short Physical Performance Battery.

At baseline, the differences between patients who would survive the follow-up period and those who would not were striking, and they were not the differences clinicians might expect. Body mass index did not differ significantly between the two groups, nor did the prevalence of malnutrition reach statistical significance, although it trended higher among nonsurvivors. What separated the groups was muscle. Survivors had significantly higher body cell mass, higher body cell mass index, and a markedly higher ASMI, averaging 6.94 kilograms per square meter compared with 5.80 in nonsurvivors. Survivors also retained substantially stronger grips, averaging 25.45 kilograms versus 17.67 kilograms, and had lost far less weight in the preceding months. Sarcopenia was present in nearly 28 percent of nonsurvivors but only about 5 percent of survivors, a fivefold difference that immediately flagged the condition as a candidate marker of lethal trajectory.

When the team ran univariate logistic regression models, every BIVA-derived muscle mass parameter emerged as a protective factor against mortality. Each additional kilogram of body cell mass reduced the odds of death by roughly 16 percent, and the effect of ASMI was even more pronounced: an odds ratio of 0.29, meaning higher appendicular muscle mass was associated with a 71 percent reduction in the odds of dying during follow-up. Handgrip strength also predicted survival in unadjusted models, while ultrasound-derived measures of quadriceps morphology, phase angle, hydration status, and most regional fat depots did not. Interestingly, greater leg subcutaneous fat thickness was associated with lower mortality odds, hinting at the still-debated protective role of energy reserves in this hypermetabolic disease.

The critical question, of course, was whether ASMI simply echoed information already captured by age, functional status, disease duration, and site of onset. To test this, the investigators built a series of adjusted multivariable models. The result was remarkably consistent: lower ASMI remained independently associated with mortality after adjustment for the ALSFRS-R score, for age, for disease duration, and for onset type, with odds ratios ranging from 0.28 to 0.37 across individual models and remaining significant at 0.33 when age, functional score, and onset type were combined. Only in the fully saturated model including all covariates simultaneously, where the small number of 19 deaths stretched the statistical limits, did the association narrow to a borderline, nonsignificant result, a caveat the authors themselves emphasize in framing their conclusions as exploratory.

The time-to-event analyses sharpened the picture considerably. Receiver operating characteristic analysis identified an optimal ASMI cut-off of 6.74 kilograms per square meter, achieving 88 percent sensitivity and 65 percent specificity for predicting mortality, with an area under the curve of 0.81, the highest discriminative performance of any muscle-related parameter tested. In Cox proportional hazards models adjusted for age and ALSFRS-R, patients falling below the ASMI cut-off faced nearly a fivefold increase in the risk of death, while those below the body cell mass index threshold of 7.20 carried more than a threefold elevated risk. But the most dramatic finding belonged to sarcopenia itself: patients meeting the combined criteria faced a hazard ratio of 17.19 for mortality, the single strongest predictor identified in the entire study.

Why would muscle mass outperform both BMI and, after adjustment, even grip strength as a prognostic signal? The authors argue that ASMI captures something fundamental about the neurogenic and metabolic burden of ALS. Progressive motor neuron loss triggers denervation, muscle fiber atrophy, mitochondrial dysfunction, oxidative stress, and chronic low-grade inflammation, all amplified by the hypermetabolism and reduced intake that characterize the disease. A shrinking muscle reservoir thus integrates, in a single measurable quantity, the downstream consequences of neurodegeneration, metabolic derangement, and nutritional decline. This may explain why several patients in the cohort displayed normal BMI alongside depressed body cell mass, a body composition pattern invisible to scales and tape measures. Muscle depletion, the study suggests, can run well ahead of overt weight loss and before malnutrition criteria are formally met.

The divergence between grip strength and muscle mass carries its own mechanistic interest. When handgrip strength was evaluated in a domain-based model that accounted for ASMI, it lost its independent association with mortality, suggesting that its prognostic power is largely mediated by the amount of muscle available to generate force. In ALS, strength is further complicated by denervation patterns, motor unit dysfunction, and compensatory reinnervation, so a patient can transiently preserve force even as muscle is wasting away. A single handgrip measurement probes one upper-limb muscle group; ASMI reflects the whole-body appendicular reserve. The authors interpret this hierarchy as a call for comprehensive morphofunctional assessment rather than reliance on any isolated strength metric.

The clinical implications could be immediate. Unlike computed tomography or dual-energy X-ray absorptiometry, which have previously linked low muscle mass to shorter ALS survival but carry cost, radiation, and accessibility barriers, bioelectrical impedance and handgrip dynamometry are inexpensive, safe, and easily repeatable at the bedside. The findings support incorporating muscle mass screening into routine ALS care from the moment of diagnosis, potentially triggering earlier nutritional surveillance, optimized protein and energy intake, and individualized rehabilitation. They also open the door to using ASMI and sarcopenia status as stratification or enrichment tools in clinical trials, matching patients with distinct prognostic profiles to appropriate study arms. The authors caution that their single-center cohort of 42 patients with 19 deaths cannot confirm causality, that impedance equations were not specifically validated in ALS, and that larger multicenter cohorts are needed. But if the findings hold, the humble measurement of limb muscle mass may become one of the most quietly powerful numbers in the care of people facing this devastating disease.

Subject of Research: The prognostic value of appendicular skeletal muscle mass and sarcopenia for survival in patients with amyotrophic lateral sclerosis

Article Title: Appendicular Skeletal Muscle Mass and Sarcopenia as Prognostic Markers in Amyotrophic Lateral Sclerosis

Article References: Zarco‐Martín, M. T., Andreo‐López, M. C., Yagui‐Beltrán, M. S., & Fernández‐Soto, M. L. (2026). Appendicular Skeletal Muscle Mass and Sarcopenia as Prognostic Markers in Amyotrophic Lateral Sclerosis. Journal of Cachexia, Sarcopenia and Muscle, 17(5), Article e70378. https://doi.org/10.1002/jcsm.70378

Image Credits: AI Generated

DOI: 10.1002/jcsm.70378

Keywords: amyotrophic lateral sclerosis, sarcopenia, appendicular skeletal muscle mass, bioelectrical impedance vector analysis, handgrip strength, prognosis, survival, body composition, malnutrition, EWGSOP2, motor neuron disease, muscle wasting