Evaluating Immunopathogenic Biomarkers During Severe Malaria Illness as Modifiers of the Neuropsychologic Benefits of Computer Cognitive Games Rehabilitation in Ugandan Children

Background.

We explored three immunopathogenic biomarkers collected during acute malaria illness as potential moderators of gains from a computerized cognitive rehabilitation training (CCRT) intervention.

Method. Von Willebrand Factor (vWF), tumor necrosis factor (TNF), and Regulated on Activation, Normal T Expressed and Secreted (RANTES) were assayed from plasma and cerebral spinal fluid (CSF) of children during acute severe malaria anemia or cerebral malaria. Two years after acute malaria illness, 150 surviving children and 150 non-malaria community controls (CC) from their households 6 to 12 years old entered a three-arm randomized controlled trial of titrating and non-titrating CCRT against no CCRT. Tests of cognition (Kaufman Assessment Battery for Children; KABC), Tests of Variables of Attention (TOVA), and Achenbach Child Behavior Checklist (CBCL) were administered before and after 24 CCRT sessions over a 3-month period, and at one-year follow-up. Differences in outcomes by trial arms and biomarker levels were evaluated using linear mixed effects models.

Results.

Severe malaria survivors with lower levels of vWF, lower CSF levels of TNF, and higher levels of plasma and CSF RANTES had better KABC cognitive performance after both titrating and non-titrating CCRT compared to no CCRT. For the CBCL, high plasma RANTES was associated with no benefit from either the titrating and non-titrating CCRT, while high TNF plasma was predictive of the benefit for both interventions. These biomarker moderating effects were not evident for CC children.

Conclusion.

Severe malaria immunopathogenic biomarkers may be related to poorer long-term brain/behavior function as evidenced by diminished benefit from a computerized cognitive rehabilitation intervention.