Neurobiological Correlates Associated with Clinical Improvement in an Open Label Trial Assessing Autologous Umbilical Cord Blood for Treatment of Young Children with Autism

Background: While the exact mechanism underlying neural differences in autism (ASD) remains unknown, a number of studies have linked altered immune responses to brain overgrowth and altered white matter connectivity. As such, immune modulating therapeutic interventions have the potential of impacting neurodevelopment and clinical outcomes in ASD. In support of this, we have previously reported significant improvement following treatment with a single infusion of autologous cord blood

Objectives: The current study explored whether behavioral improvements were associated with differences in total cerebral volume (TCV) at baseline and changes in brain white-matter connectivity following treatment.

Methods: Twenty-five children participated in a phase I, open-label trial to assess the feasibility and safety of a single infusion of autologous cord blood in 2-6 year old children with ASD. Clinical improvement was measured through change in scores from baseline to 6 months on the Vineland Adaptive Behavior Scales‐II Socialization subscale (VABS‐SS) and the Expressive One‐Word Picture Vocabulary Test‐4 (EOW), as well as the Clinical Global Impression-Improvement Scale (CGI-I) score at 6 months. Brain volume and white-matter connectivity were measured at baseline and 6-months in a subset of 19 children. TCV was calculated from the baseline MRI using an automated template-based method to mask out brainstem and cerebellum. Changes in white-matter connectivity from baseline to 6 months were calculated from 25-direction Diffusion Tensor Imaging (DTI). DTI data were analyzed using deterministic tractography, the Connectome Mapping ToolKit (CMTK), and a priori defined nodes from a pediatric gray matter atlas. The relationships between TCV or white-matter connectivity and behavioral improvement were assessed with Spearmen correlations to account for non-normal distribution of clinical variables.

Results: Correcting for age, higher baseline TCV was associated with greater improvement on the EOW (r=0.52, p=0.02) and CGI-I (r=-0.44, p=0.04), and trend level improvement on the VABS-SS (r=0.4, p=0.07). Improvement across all 3 behavioral outcome measures was correlated with increased connectivity between the right frontal pole and the globus pallidus (GP; all p≤0.04) and between the left fusiform and superior temporal cortex (STC; all p=0.04). Improvement on the VABS-SS and the EOW was associated with increased connectivity between the left STC and putamen (both p=0.03). Improvement on the VABS-SS and the CGI-I was associated with increased connectivity between the left inferior temporal cortex and STC, the thalamus and the hippocampus, and the temporal pole and the GP (all p≤0.04). Finally, improvement on the EOW and the CGI-I, was associated with increased connectivity between the right frontal and temporal pole, the STC and GP, and the rostral middle frontal cortex and GP, as well as between the left fusiform and middle temporal cortex (all p≤0.04).

Conclusions: Significant improvements in behavior in children with ASD were seen in a phase I, open label study after autologous cord blood infusion. The current results suggest that children with larger TCV at baseline showed the greatest levels of improvement. Furthermore, behavioral improvements were associated with increased white-matter connectivity in brain regions previously linked to social, communication, and language abilities.