Cerebrospinal Fluid and Clinical Profiles in Adult Type 2-3 Spinal Muscular Atrophy Patients Treated with Nusinersen: An 18-Month Single-Centre Experience.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Is cerebrospinal fluid amyloid-ß42 a promising biomarker of response to nusinersen in adult spinal muscular atrophy patients?

INTRODUCTION: Nusinersen was approved as the first treatment for all types of spinal muscular atrophy (SMA), including adults with SMA types 2 and 3. Robust biomarkers of treatment response in SMA adults are lacking. Our aim was to examine cerebrospinal fluid (CSF) amyloid-ß40 (Aß40) and amyloid-ß42 (Aß42) peptides as biomarkers of treatment response. METHODS: Eight patients with SMA types 2 and 3 were recruited consecutively in a single-center study. CSF was sampled at baseline, after a loading dose, and after three maintenance doses. Levels of Aß42 and Aß40 were evaluated for each CSF sampling. Wilcoxon matched-pairs signed-rank test was used to detect longitudinal changes. RESULTS: CSF levels of Aß42 increased from baseline to day 420 (95% confidence interval, P = .018), with a significant increase at days 180 and 420 compared with days 0 and 300, respectively (95% confidence interval, P = .012 and P = .018). DISCUSSION: The maintenance and promotion of wellness of residual motor neurons mediated by the restored level of SMN protein due to nusinersen could result in an increased level of amyloid peptides.

Motor-evoked potentials in amyotrophic lateral sclerosis: potential implications in detecting subclinical UMN involvement in lower motor neuron phenotype.

BACKGROUND: In amyotrophic lateral sclerosis (ALS), the involvement of lower motor neuron is well defined by electromyography, whereas a reliable marker of upper motor neuron (UMN) damage still lacks. Aim of the study was to estimate the role of transcranial magnetic stimulation (TMS)-induced motor-evoked potentials (MEPs) as marker of subclinical UMN involvement. METHODS: Clinical evidence of UMN damage was prospectively compared to MEPs in 176 ALS patients diagnosed between 2011 and 2014, and classified according to existing diagnostic criteria. Finally, we evaluated the appearance of clinical UMN signs and the level of diagnostic certainty in ALS after 1 year of follow-up. RESULTS: At presentation, abnormal MEPs were found in 80% of patients with clinical evidence of UMN damage and in 72% of patients without clinical involvement of UMN. Among these latter, 61% showed appearance of UMN clinical signs after 1 year. Approximately 70% of patients with clinical lower motor neuron (LMN) phenotype showed MEP abnormalities, while they were considered not classifiable ALS according to Airlie house or Awaji criteria. Furthermore, abnormal MEPs in absence of clinical UMN signs at baseline were found in 80% of spinal ALS that after 1-year developed UMN signs at limbs, compared to 50% of bulbar ALS. CONCLUSIONS: TMS is a reliable marker of subclinical UMN damage particularly among LMN phenotype and ensure an early ALS diagnosis in ~ 70% of such cases.