Impact of stem cell therapy on brain metabolic profile in cerebral palsy assessed by magnetic resonance spectroscopy in a randomized clinical trial

Stem cell therapies have shown promise in cerebral palsy (CP). However, their effects on brain metabolites, measured by proton magnetic resonance spectroscopy (1HMRS), remain unexplored. In this randomized clinical trial, we evaluated 1HMRS measures (N-acetyl aspartate [NAA], choline [Cho], creatine [Cr], myo-inositol [mI], NAA/Cho, and NAA/Cr) within periventricular white matter (PVWM) in children with CP at baseline and 12 months after a single intrathecal injection of umbilical cord-mesenchymal stem cells (UC-MSCs:20 × 106) or umbilical cord blood-mononuclear cells (UCB-MNCs:5 × 106/kg). Generalized Estimating Equations (GEEs) were employed to assess treatment efficacy, the adjusted effects of sex, CP type, and gestational age (GA) on post-treatment findings, and the association between metabolites and gross motor function measure (GMFM-66). Seventy-three participants were included: UCB-MNC (n = 27), UC-MSC (n = 26), and sham (n = 20). Primary analyses indicated no significant time*treatment interaction effects for any of the metabolites. In exploratory analyses, a significant CP type*treatment interaction was found for the post-intervention NAA/Cho (UC-MSC vs. sham; P-value = 0.02). Significant GA status*treatment interactions were also observed for post-intervention Cho (UC-MSC vs. sham; P-value = 0.009) and post-intervention mI (UCB-MNC vs. sham; P-value = 0.03). Additionally, longitudinal increases in NAA/Cr and NAA/Cho were positively associated with GMFM-66 improvement during the follow-up in UCB-MNC and UC-MSC groups, respectively, whereas Cho*time interaction was linked to smaller functional gains in the UCB-MNC group over time. Neither UC-MSC nor UCB-MNC had a significant overall effect on measured metabolite concentrations/ratios within the PVWM at 12 months following a single injection. Exploratory findings should be interpreted cautiously. Trial registration: The trial was registered in both the Iranian Registry of Clinical Trials (IRCT201706176907N13; registered on 12/07/2017) and ClinicalTrials.gov (NCT03795974; registered on 08/01/2019).