Cerebrospinal fluid biomarkers of efficacy in patients affected by Spinal Muscular Atrophy type 1 treated with nusinersen.

Background/aim. The advent of new therapies, such as the antisense oligonucleotide nusinersen, has significantly improved the natural course of spinal muscular atrophy (SMA). Tau proteins and neurofilaments are well known markers of axonal degeneration. The neurofilament light protein (NfL) has been proposed as a possible biomarker in SMA. This study aimed to investigate the role of total-tau (ttau), phosphorylated tau (ptau), NfL, and phosphorylated neurofilament heavy chain (pNfH) proteins as potential cerebrospinal fluid (CSF) biomarkers of axonal degeneration and response to nusinersen treatment in 14 SMA type 1 patients with a wide age range (2-156 months). Methods and results Motor functions was assessed using the “Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders” (CHOP-INTEND) scale at baseline, six months, and ten months after treatment. Eight out 14 patients showed motor improvement. At baseline CSF ttau and ptau concentration showed a significant negative correlation with age (p = 0.0002 and p = 0.0054 respectively) and a positive correlation with the CHOP-INTEND score (p = 0.0075 and p = 0.0342, respectively). After treatment the tau biomarkers did not show any change, whereas NfL and pNfH concentration significantly decreased (p = 0.0001). The NfL concentration decline related to age at baseline (p < 0.05). There was also a significant correlation between the decrease of NfL and the improvement of the CHOP-INTEND motor score, but only in the subgroup of patients with a functional improvement above 3 points (p < 0.05). Conclusions CSF NfL may be a powerful biomarker for monitoring treatment response to nusinersen both in younger and older patients with severe SMA.