Elevated CSF 14-3-3 Protein Levels: A Potential Biomarker for NMOSD

In a groundbreaking study published in the journal *Neurology* on July 22, 2025, researchers have identified elevated levels of cerebrospinal fluid (CSF) 14-3-3 protein as a potential biomarker for neuroaxonal damage in patients with aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD). This multicentric retrospective cohort study, led by Dr. Manuel Comabella, MD, PhD, head of the Neuroimmunology Laboratory at the Fundació Institut de Recerca del HUVH, involved a comparative analysis of 29 AQP4-NMOSD patients, 43 with myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and 62 with multiple sclerosis (MS).

The study's findings reveal that patients with AQP4-NMOSD exhibited significantly higher levels of CSF 14-3-3 protein (median 4471 AU/mL, interquartile range [IQR] 3323-12,303) compared to those with MS (3170 AU/mL, IQR 2523-3749; P-adjusted = 0.001) and MOGAD (3112 AU/mL, IQR 2358-3875; P-adjusted = 0.004). Notably, there were no significant differences in CSF 14-3-3 levels between MS and MOGAD patients (P-adjusted = 0.989), indicating the specificity of this biomarker for AQP4-NMOSD.

The implications of elevated CSF 14-3-3 protein levels extend beyond mere diagnosis; they correlate with disease severity and predict poor clinical recovery outcomes. Specifically, patients with a final Expanded Disability Status Scale (EDSS) score of 6 or greater had higher baseline levels of 14-3-3 protein compared to those with lower scores (median 12,303 AU/mL vs. 3391 AU/mL; P-adjusted = 0.003). This suggests that CSF 14-3-3 protein could serve as a prognostic tool, particularly for those experiencing myelitis attacks.

Dr. Comabella noted, "While serum glial fibrillary acidic protein (GFAP) is a well-established astroglial biomarker for diagnosing and predicting relapses in AQP4-NMOSD, CSF 14-3-3 may complement this diagnostic approach, particularly in ambiguous clinical cases. Its association with long-term disability underscores its potential utility in guiding treatment strategies."

Despite these promising findings, the study's retrospective design and lack of longitudinal assessment present limitations that warrant further investigation. The authors underscore the need for additional studies encompassing diverse myelitis etiologies to clarify the specificity and utility of CSF 14-3-3 protein levels in clinical practice.

The research indicates a growing understanding of neuroaxonal biomarkers in demyelinating disorders, suggesting a potential shift towards personalized treatment strategies that leverage multiple biomarkers in tandem. As researchers continue to explore the nuances of these biomarkers, patients and healthcare providers may gain new insights into managing complex conditions like AQP4-NMOSD more effectively.

In summary, the elevated CSF 14-3-3 protein levels present a promising avenue for future research and clinical application, potentially leading to improved diagnostic accuracy and treatment outcomes for patients suffering from AQP4-NMOSD. As this field evolves, the integration of biomarkers could play a crucial role in enhancing personalized medicine in neurology.