Neurofilament Heavy Chain and Tau Protein Are Not Elevated in Cerebrospinal Fluid of Adult Patients with Spinal Muscular Atrophy during Loading with Nusinersen

Abstract

Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

“…In SMA children, the baseline level of Tau in the CSF was significantly higher than in controls and it decreased with Nusinersen treatment [ 140 ]. On the contrary, the eleven SMA type 3 patients also analyzed for the NF content, described above by Totzeck et al [ 136 ], did not exhibit alteration in the amount of tau protein. The analyses of tau protein and the discordant outcomes highlight once again the importance of defining bigger cohorts of patients, in particular adults, to study putative molecular biomarkers for SMA.…”

“…Although NFs seem to be reliable biomarkers for SMA infants, as their level is reduced upon Nusinersen treatment and this is generally correlated with an improved motor function [ 134 ], few recent publications have described contradicting results for the use of NFs as biomarkers for adult SMA patients’ response to therapy [ 29 , 135 ]. Eleven SMA type 3 patients (all adults—38.5 years mean age) analyzed for their pNF-H content in blood and CSF showed no change after administration of the Nusinersen loading doses [ 136 ]. In agreement with this effect, no significant difference was observed in the amount of NfL and pNF-H in another group of SMA patients (types 2 and 3) after the fourth injection of Nusinersen [ 135 ].…”

New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges

“…Similar results were confirmed in plasma in the ENDEAR study in symptomatic SMA type I patients [ 85 ]. In older patients with less severe forms of SMA, the role of NFs has not yet been confirmed probably as consequence of a slower disease progression [ 86 , 87 ]. SMN protein regulates RNA metabolism and biogenesis of microRNA (miRNA), which are gene expression modulators, and their dysregulation is implicated in a variety of neuromuscular diseases.…”

Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review

“…Clinical trials which could address this issue require long durations and robust clinical outcome measures, drawing attention to the need for biomarkers which are sensitive to changes in disease progression and/or response to disease modifying agents [120]. Unlike studies in infants and children with SMA, in which circulating neurofilaments are emerging as potential measures to assess disease progression and response to nusinersen treatment [121], no studies in adults with SMA have yielded a robust, reliable measurement [86,88,[122][123][124][125][126]. A potential complexity in trying to detect elevated markers of axonal degradation in adults with SMA is again the slow rate of progression.…”