Table_1_Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma as a Nusinersen treatment response marker in childhood-onset SMA individuals from Serbia.XLS

IntroductionBiomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise.
MethodsWe conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls (n = 22), patients with Duchenne muscular dystrophy (n = 17), myotonic dystrophy type 1 (n = 11), untreated SMA individuals with chronic type 3 disease (n = 8), and children with presymptomatic SMA (n = 3).
ResultsSMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment.
ConclusionOur findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration.

引言 能够反映脊髓性肌萎缩症（spinal muscular atrophy, SMA）患者疾病发作及短期、长期治疗效果的生物标志物仍存在未被满足的临床需求，而磷酸化神经丝重链（phosphorylated neurofilament heavy chain, pNF-H）展现出显著的应用前景。
方法 本研究开展了一项纵向前瞻性队列研究，旨在评估29例接受诺西那生钠（Nusinersen）治疗的儿童起病型脊髓性肌萎缩症患者脑脊液（cerebrospinal fluid, CSF）与血浆中的pNF-H水平，其中1型SMA患者6例、2型17例、3型6例。将治疗前及治疗过程中的pNF-H水平与对照组（22例）、杜氏肌营养不良症（Duchenne muscular dystrophy）患者（17例）、1型强直性肌营养不良症（myotonic dystrophy type 1）患者（11例）、未接受治疗的慢性3型SMA患者（8例）以及症状前SMA儿童患者（3例）的对应水平进行对比。
结果 治疗启动前，1型SMA患者的脑脊液pNF-H平均水平最高。所有接受诺西那生钠治疗的1、2、3型SMA患者，其基线脑脊液pNF-H平均水平均显著高于对照组，且该水平与疾病起病年龄、首次给药年龄、病程及初始CHOP INTEND评分（仅1型和2型SMA）呈负相关。在22个月的治疗期间，所有患者的脑脊液pNF-H水平在负荷给药阶段均出现下降，并在初始维持给药阶段后稳定于较低水平。与其他队列相比，1型和2型SMA患者的基线血浆pNF-H水平显著升高；其中1型患者在治疗2个月后、2型患者在治疗14个月后，血浆pNF-H水平均出现明显下降。与之相反，基线pNF-H水平较低的3型SMA患者，在接受14个月治疗后，其血浆pNF-H水平未出现显著波动。
结论 本研究结果表明，未接受治疗的SMA患者脑脊液pNF-H水平显著高于对照组，提示监测脑脊液pNF-H水平可作为儿童起病型SMA患者短期快速治疗反应的评估指标，且不受疾病亚型影响，同时其或可用于评估神经退行性变的长期抑制效果。血浆pNF-H可作为1型和2型SMA患者疾病进展及/或治疗反应的合适结局指标，但不适用于3型SMA患者。症状前SMA婴儿的pNF-H水平可出现升高，这证实了疾病早期即存在神经元退行性变。