Association between creatinine-to-cystatin C ratio and ALSFRS-R across clinical phenotypes

Background Reliable and accessible biomarkers for amyotrophic lateral sclerosis (ALS) are scarce. Creatinine (Cre) reflects muscle mass, whereas cystatin C (CysC) reflects neurodegeneration without affecting muscle mass; however, both have limitations. We aimed to investigate whether the creatinine-to-cystatin C ratio (Cre/CysC) could serve as a robust indicator of functional status in patients with ALS experiencing muscle mass reduction. Methods We retrospectively analyzed 30 patients diagnosed with ALS at the National Organization Hospital Okinawa Hospital between 2021 and 2024. Baseline ALS Functional Rating Scale–Revised (ALSFRS-R) scores and serum Cre and CysC levels were recorded. Associations with the ALSFRS-R were assessed using Spearman’s correlation, with subgroup analyses by sex, site of onset, age, body mass index (BMI), and diagnostic delay. Results Cre/CysC correlated strongly with ALSFRS-R ( r _s =0.648, p = 0.0001), outperforming Cre ( r _s =0.427) and CysC ( r _s =–0.119). This association was consistent across most subgroups, particularly in females and limb-onset patients, but was absent in patients with bulbar-onset ALS. In multivariable analysis adjusted for age and BMI, Cre/CysC remained independently associated with ALSFRS-R (β = 21.5, 95% CI 9.58–33.4, p = 0.001). Conclusions Cre/CysC showed a stronger cross-sectional association with the functional status than either marker alone. Because it is derived from routine laboratory tests, Cre/CysC may serve as a potential clinical marker of ALS. Prospective longitudinal studies are warranted to determine the prognostic value of these markers.