Cerebrospinal fluid biomarkers of efficacy in patients affected by spinal muscular atrophy type 1 treated with nusinersen

Background: 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 neuro-axonal damages. The neurofilament light protein (NfL) has been proposed as a possible biomarker in SMA. This study aimed to investigate the role of total-tau (t-tau), phosphorylated tau at 181 sites (p-tau 181), NfL, and phosphorylated neurofilament heavy chain (pNfH) proteins as potential cerebrospinal fluid (CSF) biomarkers of disease severity and/or nusinersen treatment response in 14 SMA type 1 patients with a wide age range (2–156 months). Methods and results: Motor functions were 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 of 14 patients showed motor improvement. At baseline CSF t-tau and p-tau181 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 correlated to age at baseline (p < 0.05) and to the improvement of the CHOP-INTEND motor score, in the subgroup of patients with a functional improvement above 3 points (p < 0.05). Conclusions: CSF neurofilaments and particularly NfL may bepromising biomarkers for monitoring treatment response to nusinersen, both in younger and older patients with severe SMA.