Evaluation of inflammatory and glial cell-related biomarkers in adults with Spinal Muscular Atrophy (SMA) under nusinersen treatment

Spinal muscular atrophy (SMA) is an inherited disease characterized by progressive loss of motor neurons affecting anterior horn cells of the spinal cord and brainstem motor nuclei. It is thought that the pathogenesis of SMA is not limited to motor neuron degeneration, but many different cell and tissue types, especially glial cells, and neuroinflammation contribute to the process as well. In this study, it was aimed to examine the contribution of glial cell and neuroinflammation-related molecules to the process and to identify biomarkers related to diagnosis and/or treatment response. Accordingly, 24 adult SMA patients receiving nusinersen therapy and 12 controls were included in the study. Four molecules associated with glial cells (GFAP and GDNF) and neuroinflammatory activity (YKL-40 and IL-6) were selected, and levels of these molecules in cerebrospinal fluid (CSF) samples were evaluated in SMA patients before nusinersen and 15 months after nusinersen treatment. In addition, their contribution to the pathogenesis were evaluated with control group comparisons. 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 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). Higher CSF GFAP levels were associated with better clinical outcome (OR= 0.624, p<0.05). To sum up, these findings support the hypothesis of glial cells and neuroinflammation contribute to 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 additional positive impact on existing therapies.