Exploring the role of interleukin 18 and neuroinflammation in amyotrophic lateral sclerosis

Introduction Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder marked by the degeneration of upper and lower motor neurons. Despite increasing understanding of its pathogenesis, there is still no curative treatment. The identification of reliable biomarkers for diagnosis, prognosis, and treatment monitoring remains a critical unmet clinical need. Among the potential candidates, Interleukin-18 (IL-18), a pro-inflammatory cytokine involved in neuroinflammatory processes, has shown relevance in other neurodegenerative diseases including ALS. Purpose of the Study This study aimed to evaluate the role of IL-18 as a potential biomarker in ALS. Specifically, the study sought to: (1) compare IL-18 concentrations in serum and cerebrospinal fluid (CSF) between ALS patients and healthy controls (HC); (2) assess correlations with clinical phenotypes, genetic variants, and disease severity; (3) investigate associations with progression indicators and survival; and (4) analyze IL-18 longitudinal dynamics in a subgroup of patients. Materials and Methods We conducted a mixed retrospective and prospective cohort study including 49 ALS patients and 24 matched HC. IL-18 concentrations were measured in serum and CSF via Ella Simple Plex automated ELISA technology. Clinical data from the Emilia-Romagna ALS Registry included phenotype classification, ALSFRS-R, disease staging (King’s and MiToS), respiratory function, cognitive status, and genetic profiles. A subset of ALS patients enrolled in the RAP-ALS trial contributed longitudinal IL-18 measurements. Results Notably, CSF IL-18 levels were significantly associated with the ALS-FTD phenotype (p = 0.0340). Furthermore, serum IL-18 showed a statistically significant positive correlation with forced vital capacity (FVC) at sampling (p = 0.0074), suggesting a possible link between IL-18 and preserved respiratory function in early disease stages. However, no significant differences were observed in IL-18 concentrations between ALS patients and controls: mean serum IL-18 levels were 215.1 ± 78.9 pg/mL in ALS and 398.9 ± 856.8 pg/mL in HC (p = 0.3627); mean CSF IL-18 levels were 4.00 ± 1.49 pg/mL in ALS and 3.94 ± 3.28 pg/mL in HC (p = 0.9337). IL-18 values were not associated with age, diagnostic delay, disease duration, BMI, ALSFRS-R score, or progression rate. ROC curve analysis showed limited discriminative power (AUC = 0.5156 for serum, 0.6008 for CSF). Longitudinal evaluation of IL-18 in RAP-ALS trial participants (n=18) over five time points revealed no consistent temporal trends. Discussion Despite IL-18’s known role in immune signaling and its expression in CNS-resident cells such as microglia and astrocytes, our findings do not support its utility as a standalone biomarker for ALS diagnosis or prognosis. Our results are consistent with prior evidence that systemic inflammatory cytokines, although mechanistically relevant, may not serve as reliable surrogate markers of disease burden due to the multifactorial nature and clinical heterogeneity of ALS. Nonetheless, some notable findings emerge from the analysis. First, the positive correlation between serum IL-18 and initial respiratory function, that could point to a protective or compensatory inflammatory response during early disease stages. Additionally, the statistically significant associations of CSF IL-18 with ALS-FTD phenotype, suggesting that IL-18 might be involved in distinct ALS subtypes, even if its quantitative levels do not predict progression in the general ALS population. Longitudinal analysis of IL-18 levels in a subgroup of patients enrolled in the RAP-ALS trial further confirmed the lack of significant fluctuation across disease stages, limiting its potential as a dynamic biomarker for disease monitoring. Taken together, these findings do not support the use of IL-18 as a diagnostic or prognostic biomarker in isolation.