BACKGROUND AND OBJECTIVE: Aicardi-Goutières syndrome (AGS) is a prototypical type I interferon-driven neuroimmunological disorder in which immune-mediated inflammation causes progressive brain injury. Targeted immunosuppression with Janus kinase (JAK) inhibitors has shown clinical benefit, yet neurological outcomes remain difficult to quantify, and the interferon (IFN) score poorly reflects neuroaxonal damage. We investigated whether plasma neurofilament light chain (pNfL) and glial fibrillary acidic protein (pGFAP) serve as sensitive biomarkers of neurological involvement and response to immunosuppressive therapy.

METHODS: Plasma samples from 55 patients with genetically confirmed AGS and 55 age- and sex-matched healthy controls were analyzed using single molecule array assays. pNfL and pGFAP levels were assessed in relation to age, clinical disease severity, IFN score, and treatment with JAK inhibitors. Longitudinal samples before and during therapy were available from 11 patients.

RESULTS: Treatment-naïve AGS patients exhibited significantly elevated pNfL and pGFAP levels compared with controls, and biomarker concentrations correlated with clinical disease severity. pNfL and pGFAP were strongly correlated with each other but showed only weak to moderate associations with the IFN score. Longitudinal within-patient analyses demonstrated significant declines in pNfL and pGFAP following initiation of JAK inhibitor therapy, whereas the IFN score remained unchanged.

DISCUSSION: pNfL and pGFAP are sensitive indicators of neuroaxonal and astroglial injury in AGS, capturing neurological disease burden and treatment-associated changes more accurately than the IFN score. These findings support their use as objective biomarkers for monitoring immune-mediated brain injury and therapeutic response, and warrant validation in larger longitudinal studies.