Aziza Shavkatovna Kadirova, Gulnora Kutpitdinovna Rakhmatullaeva, Javlon Jasur Ugli Salimjonov
Age, BMI, and renal function should be considered when interpreting circulating NfL and GFAP, particularly in studies of progression. The available evidence does not support universal biomarker cut-offs or uniform interpretation of PIRA-associated concentrations. Prospective studies with harmonised PIRA definitions, sufficiently long follow-up, and consistent confounder adjustment are needed.
BACKGROUND: Despite achieving NEDA‑3, a substantial proportion of patients with multiple sclerosis (MS) accumulate disability through progression independent of relapse activity (PIRA). This scoping review evaluates serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in relation to disease activity and progression, with particular focus on the effects of age, BMI, and renal function on biomarker interpretation.
METHODS: The review followed PRISMA‑ScR guidelines (PubMed, Scopus, Web of Science, January 2016 - February 2026). Longitudinal studies (≥ 12 months) with multivariable adjustment were prioritised. Of 467 screened records, 367 were excluded; 100 full‑text articles were assessed. Of these, 36 were excluded. Sixty‑four publications were included; 34 original analytical studies formed the basis of the structured synthesis.
RESULTS: sNfL was consistently associated with acute inflammatory activity, whereas associations with progression were less consistent after adjustment for age and other covariates. sGFAP showed stronger associations with PIRA and disability progression in several longitudinal studies, although findings were heterogeneous. PIRA definitions and follow-up durations varied substantially, limiting direct comparability. Evidence regarding renal-function adjustment was limited and heterogeneous: adjustment attenuated the association between sGFAP and progression in one study, whereas associations remained evident in other studies accounting for renal function.
CONCLUSIONS: Age, BMI, and renal function should be considered when interpreting circulating NfL and GFAP, particularly in studies of progression. The available evidence does not support universal biomarker cut-offs or uniform interpretation of PIRA-associated concentrations. Prospective studies with harmonised PIRA definitions, sufficiently long follow-up, and consistent confounder adjustment are needed.