Background: Functional scores (CHOP-INTEND) and motor compound muscle action potential (CMAP) are commonly used to assess disease severity and interval change in Spinal Muscular Atrophy (SMA). However, there is paucity of laboratory biomarkers.
Objectives: To study the cerebrospinal fluid (CSF) biomarkers in SMA.
Methods: We prospectively collected CSF from SMA patients receiving intrathecal nusinersen at our institution. The CSF samples were randomized across two 96-well plates for each of the three assays: neurofilament light chain (NfL), monocyte chemoactive protein 1 (MCP-1), interleukin-8 (IL-8), fractalkine, interferon gamma induced protein 10 (IP-10), and amyloid precursor protein beta weighted (APPβw). All samples were run in duplicate and were normalized across plates using CSF standard values. Baseline and follow-up weight, CHOP-INTEND, abductor pollicis brevis (APB) and adductor digiti mini motor (ADM) CMAP were recorded. Descriptive and nonparametric tests were performed using SPSS software.
Results: Fifteen SMA children (8 boys, 7 girls), mean age 3.6 ± 3.48 years (range 1-12 years) included. Mean ± S.D. for weight 13.92 ± 11.3 Kg (range 5.6-26.5 Kg), CHOP-INTEND 29.78 ± 14.69 (range 7-54, maximum 64), CMAP APB 1.38 ± 0.92 mV (range 0.1-3.5) and ADM 0.52 ± 0.36 mV (range 0.1-1.7). Fifty-eight CSF samples collected (average 3.8/ subject, range 1-5) between May 2017 to January 2020. Mean ± S.D. for NfL 3168.40 ± 601.68 (range 137.28-80608), IP-10 219.17 ±114.21 (range 76.73-644), IL-8 20.04 ± 25.04 (range 6.50-195.79), fractalkine 50.08 ± 24.60 (range 11.18-150.99), MCP-1 571.58 ± 258.99 (range 155.33-1436.6), APPβw 139.84 ± 94.18 (range 1-500). Logarithmic transformation of CSF values and correlation with clinical-electrophysiological parameters were performed before and after treatment. Statistically significant (p<0.001) correlation between IL-8 and CHOP-INTEND, APB CMAP during treatment phase was recorded.
Conclusions: Cross-sectionally, there were only modest trends of association between CSF biomarkers and clinical measures before treatment. Cross-sectionally, IL-8 correlated strongly with weight, APB CMAP, and CHOP-INTEND during treatment. Longitudinally, within each individual, following clinical measures correlated with specific CSF biomarkers from the corresponding time point: APB CMAP inversely with IL-8, weight inversely with APPβw. Longitudinally, within each individual, CHOP intend over time was associated with baseline IL-8, MCP-1, and APPβw. CSF NfL poorly tracked with longitudinal clinical measures, potentially because it reflects both neuronal loss as well normal development.