Neurofilament as a potential biomarker for spinal muscular atrophy

Abstract

Objective To evaluate plasma phosphorylated neurofilament heavy chain ( pNF ‐H) as a biomarker in spinal muscular atrophy ( SMA ). Methods Levels of pNF ‐H were measured using the ProteinSimple ® platform in plasma samples from infants with SMA enrolled in ENDEAR ( NCT 02193074) and infants/children without neurological disease. Results Median pNF ‐H plasma level was 167.0 pg/mL (7.46–7,030; n = 34) in children without SMA (aged 7 weeks–18 years) and was higher in those aged < 1 versus 1–18 years ( P = 0.0002). In ENDEAR participants with infantile‐onset SMA , median baseline pNF ‐H level (15,400 pg/mL; 2390–50,100; n = 117) was ~10‐fold higher than that of age‐matched infants without SMA ( P < 0.0001) and ~90‐fold higher than children without SMA ( P < 0.0001). Higher pretreatment pNF ‐H levels in infants with SMA were associated with younger age at symptom onset, diagnosis, and first dose; lower baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders score; and lower peroneal compound muscle potential amplitude. Nusinersen treatment was associated with a rapid and greater decline in pNF ‐H levels: nusinersen‐treated infants experienced a steep 71.9% decline at 2 months to 90.1% decline at 10 months; sham control–treated infants declined steadily by 16.2% at 2 months and 60.3% at 10 months. Interpretation Plasma pNF ‐H levels are elevated in infants with SMA . Levels inversely correlate with age at first dose and several markers of disease severity. Nusinersen treatment is associated with a significant decline in pNF ‐H levels followed by relative stabilization. Together these data suggest plasma pNF ‐H is a promising marker of disease activity/treatment response in infants with SMA.

Advances in Treatment of Spinal Muscular Atrophy – New Phenotypes, New Challenges, New Implications for Care

“…Under treatment with nusinersen, these levels decreased faster in the verum group than in sham control group. This decrease was more pronounced the earlier the therapy was started [63]. In CSF of an adult SMA cohort, levels of pNF-H in CSF were below detection limit, but levels of NSE and pTAUprotein showed a significant decrease under treatment [64].…”

Cerebrospinal fluid proteomic profiling in nusinersen‐treated patients with spinal muscular atrophy

“…Plasma pNfH was recently described as a potential marker of disease activity and treatment response in infants with SMA 1 (Darras, Crawford, et al, ). In contrast, another recent study provided evidence that CSF concentrations of neurofilament light chain (NfL) and pNfH are neither elevated in adolescent or adult SMA 2 and SMA 3 patients compared with controls nor influenced by the loading dosing of nusinersen (treatment day 63) (Wurster, Günther, et al, ).…”

“…As plasma phosphorylated neurofilament heavy chain (pNfH) is emerging as a potential marker of disease activity and treatment response in infants with SMA 1 (Darras, Crawford, et al, ), biomarkers indicating a potential early therapeutic response in adolescent and adult patients are lacking to date. For biomarker screenings in SMA, cerebrospinal fluid (CSF) is a promising bioanalyte because (1) it is in direct contact with the diseased spinal cord and lower brain stem and (2) nusinersen is directly administered to the CSF compartment.…”

The light at the end of the tunnel gets vivid for spinal muscular atrophy

“…Long‐term treatment of nusinersen is found to alleviate SMA disease symptoms and improve lifestyle in patients suffering from SMA1 and SMA2. However, in terms of biomarker availability such as phospho‐neurofilament heavy chain or light chain in SMA1 (Darras et al, ), adolescent and adult SMA differ significantly from the infantile SMA cases (Wurster, Steinacker, et al, ). It indicates that adolescent and adult forms of the disease might be different pathologically from the infantile SMA.…”