Neurology Unit, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124, Bari, Italy.
Neurophysiopathology Unit, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Italy.
Clin Drug Investig. 2021 Sep;41(9):775-784. doi: 10.1007/s40261-021-01071-0. Epub 2021 Aug 13.
Nusinersen was approved as the first disease-modifying therapy in spinal muscular atrophy (SMA). Our aim was to analyse therapy-related changes in cerebrospinal fluid (CSF) and serum parameters of adult type 2-3 SMA and to correlate biochemical data with motor functional status.
Nine adult SMA type 2-3 patients and ten control subjects without neurodegenerative diseases were included in our single-centre study. Cross-sectional analysis of CSF routine parameters, CSF neurofilament light chain, CSF Tau, CSF phospho-Tau and serum creatinine was performed between SMA patients at baseline (T0) and control subjects. The above-mentioned fluid parameters were longitudinally analysed in the SMA cohort after loading dose (T1) and after four maintenance doses (T2, T3, T4, T5). Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and the 6-minute walking test (6MWT) were used to evaluate motor outcomes.
Improvements in HFMSE, RULM and 6MWT were observed only after the loading dose of nusinersen. No significant differences in routine CSF parameters and CSF markers of neurodegeneration were found between SMA patients and control subjects. Serum creatinine levels were significantly lower in SMA patients than in control subjects. CSF/serum albumin ratio (Qalb) significantly increased from T0 to each time point, without any further increase after the maintenance doses. Persistent systemic oligoclonal bands (OCBs) were found in five patients from baseline. Three more patients developed persistent systemic OCBs from T1; one patient showed intrathecal OCBSs from baseline to T5. Markers of neurodegeneration did not change during the follow-up and did not correlate with motor scores at baseline and at each timepoint. Serum creatinine levels significantly correlated with HFMSE and RULM at each time point.
The increase of the Qalb values and the development of systemic OCBs in some SMA patients could be due to repeated lumbar puncture and to the immunogenic effect of nusinersen. On the other hand, the presence of OCBs in serum and/or CSF at baseline should be further investigated. Furthermore, biomarkers of neurodegeneration did not play a prognostic role in our cohort of adult SMA patients.
依那西普被批准为脊髓性肌萎缩症（SMA）的首个治疗疾病的药物。我们的目的是分析成人 2-3 型 SMA 的脑脊液（CSF）和血清参数的治疗相关性变化，并将生化数据与运动功能状态相关联。
我们进行了一项单中心研究，纳入了 9 名成人 2-3 型 SMA 患者和 10 名无神经退行性疾病的对照组。在 SMA 患者的基线（T0）和对照组之间进行了 CSF 常规参数、CSF 神经丝轻链、CSF Tau、CSF 磷酸化 Tau 和血清肌酐的横断面分析。在 SMA 队列中，在负荷剂量（T1）后和四个维持剂量（T2、T3、T4、T5）后进行了上述液体参数的纵向分析。使用哈默史密斯功能性运动量表扩展版（HFMSE）、修订后的上肢模块（RULM）和 6 分钟步行测试（6MWT）评估运动结果。
仅在接受依那西普负荷剂量后，HFMSE、RULM 和 6MWT 才得到改善。SMA 患者与对照组之间的 CSF 常规参数和神经退行性 CSF 标志物无显著差异。SMA 患者的血清肌酐水平明显低于对照组。CSF/血清白蛋白比值（Qalb）从 T0 到每个时间点均显著增加，维持剂量后无进一步增加。基线时 5 名患者持续存在系统性寡克隆带（OCBs）。从 T1 开始，又有 3 名患者出现持续性系统性 OCBs；1 名患者从基线到 T5 出现了鞘内 OCBs。在随访期间，神经退行性标志物没有变化，与基线和每个时间点的运动评分无关。血清肌酐水平与每个时间点的 HFMSE 和 RULM 显著相关。
在一些 SMA 患者中，Qalb 值的增加和系统性 OCBs 的发展可能是由于反复腰椎穿刺和依那西普的免疫原性所致。另一方面，在基线时血清和/或 CSF 中存在 OCBs 应进一步研究。此外，神经退行性标志物在我们的成人 SMA 患者队列中没有发挥预后作用。
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