To examine the contribution of glial cell and neuroinflammation-related molecules to the spinal muscular atrophy (SMA) process and to identify biomarkers related to diagnosis and/or nusinersen response.

Twenty-four adult SMA patients receiving nusinersen therapy and twelve healthy controls were included in the study. The level of molecules associated with glial cells [Glial Fibrillary Acidic Protein (GFAP) and Glial Cell-derived Neurotrophic Factor (GDNF)] and neuroinflammatory activity [Chitinase-3 Like-protein1 (CHI3L1 or YKL-40) and interleukin-6 (IL-6)] were evaluated in cerebrospinal fluid (CSF) samples of SMA patients before nusinersen and after 15 months of the treatment. In addition, their contribution to the pathogenesis were evaluated with comparison of their CSF levels in healthy subjects.

SMA patients had higher GFAP and IL-6 levels (p<0.05) and lower GDNF levels (p<0.05) compared to controls. In ROC curve analyses, the diagnostic determinacy of GFAP had 87.5% sensitivity and 100% specificity when cutoff is set at ≥6.12 ng/ml. In logistic regression model created by combining different molecules (GFAP, GDNF, YKL-40), the area under the curve reached 1.0 (p<0.001). IL-6 and YKL-40 levels decreased under treatment; on the contrary, GDNF levels increased (p<0.05). Lastly, higher GFAP levels were associated with better clinical outcome (OR= 0.624, p<0.05).

Our study supports the contribution glial cells and neuroinflammation contribute in SMA pathogenesis. GFAP is a biomarker of SMA with both diagnostic and prognostic significance, and its higher levels are associated with better clinical outcome. New therapy strategies against glial pathways and anti-inflammatory agents may have positive impact on existing therapies.