Total tau in cerebrospinal fluid detects treatment responders among spinal muscular atrophy types 1–3 patients treated with nusinersen

Abstract

AimsConsidering the substantial variability in treatment response across patients with spinal muscular atrophy (SMA), reliable markers for monitoring response to therapy and predicting treatment responders need to be identified. The study aimed to determine if measured concentrations of disease biomarkers (total tau protein, neurofilament light chain, and S100B protein) correlate with the duration of nusinersen treatment and with scores obtained using functional scales for the assessment of motor abilities.MethodsA total of 30 subjects with SMA treated with nusinersen between 2017 and 2021 at the Department of Pediatrics, University Hospital Centre Zagreb, Croatia, were included in this study. Cerebrospinal fluid (CSF) samples were collected by lumbar puncture prior to intrathecal application of nusinersen. Protein concentrations in CSF samples were determined by enzyme‐linked immunosorbent assay in 26 subjects. The motor functions were assessed using functional motor scales.ResultsThe main finding was significantly decreased total tau correlating with the number of nusinersen doses and motor improvement in the first 18–24 months of treatment (in all SMA patients and SMA type 1 patients). Neurofilament light chain and S100B were not significantly changed after administration of nusinersen.ConclusionsThe measurement of total tau concentration in CSF is a reliable index for monitoring the biomarker and clinical response to nusinersen therapy in patients with SMA.

Molecular Biomarkers for the Diagnosis, Prognosis, and Pharmacodynamics of Spinal Muscular Atrophy

“…This could contribute significantly to the disparities among the studies. Moreover, a recent study has convincingly shown that t-tau levels decrease significantly in patients with SMA 1 (but not SMA 2 and 3) when treated with nusinersen [82]. More research is needed to discover which biomarker (or combination of biomarkers) is best for predicting disease severity, evaluating therapeutic response and separating treatment responders from nonresponders.…”

“…Table 2 demonstrates that NfL and pNfH were used as potential pharmacodynamic (response) biomarkers in the majority of studies that examined the utility of molecular biomarkers for monitoring therapeutic response in SMA. In the majority of studies, a decrease in NfL and pNfH levels was observed following treatment with nusinersen [39,[61][62][63][76][77][78][79][80][81], whereas others observed no change in the levels of these biomarkers [45,56,60,[82][83][84] (Table 2).…”

“…Tau proteins stabilize microtubules, and an increase in t-tau levels in CSF is observed when neuronal death occurs [85]. Most studies observed a decrease in t-tau levels in response to nusinersen treatment [62,79,82], whereas others observe no change in the levels of this biomarker [45,84,86] (Table 2). Studies that analyzed phosphorylated tau isoforms after nusinersen treatment observed no change [45] or decrease [84] in phosphorylated tau levels.…”

“…An increase in S100B levels was observed in many diseases of the central nervous system. Only two studies analyzed S100B as a pharmacodynamic biomarker, and both of these studies observed no change in S100B levels upon nusinersen treatment [82,86].…”

Identifying Biomarkers of Spinal Muscular Atrophy for Further Development

“…Other recent candidate biomarkers include genetic factors such as SMN2 copy number [ 10 , 13 – 15 , 81 , 82 ], SMN2 polymorphisms [ 10 , 13 – 16 , 81 – 83 ], and modifier genes [ 73 , 84 – 89 ]; transcription and splicing regulators, such as microRNAs [ 90 – 94 ], methylation factors [ 95 – 99 ], and long non-coding RNAs [ 100 – 103 ]; biomolecular factors such as SMN protein [ 18 , 39 , 48 , 57 , 81 , 104 – 106 ], neurofilament (NF) [ 78 , 107 – 118 ], tau protein [ 112 , 119 – 121 ], and muscle damage indicators [ 122 – 124 ]; muscle imaging parameters including magnetic resonance imaging (MRI) [ 122 – 124 ] and electrical impedance myography (EIM) [ 75 , 125 – 127 ]; and electrophysiological parameters including compound muscle action potential (CMAP) [ 128 – 133 ], motor unit number estimation (MUNE) [ 75 , 125 – 127 ], and repetitive nerve stimulation [ 45 , 75 , 134 – 138 ].…”