# Severe Malaria And Risk to The Brain (SMART Brain)

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $83,213

## Abstract

PROJECT SUMMARY/ABSTRACT
Cerebral malaria (CM) and severe malarial anemia (SMA), which together affect >1 million children annually,
are associated with long-term neurodevelopmental impairment (NDI). Our data show that some systemic
factors are associated with NDI in CM and SMA (e.g., endothelial dysregulation, acute kidney injury), but
others are associated with NDI CM alone (e.g., inflammatory cytokines). Our findings suggest that both shared
and unique systemic pathways contribute to NDI in CM vs. SMA. While our studies to date have advanced
understanding of systemic pathways that may lead to NDI in children with CM or SMA, the central nervous
system (CNS) pathways that contribute to NDI in children after CM or SMA remain unknown. In children with
CM, the relationship of CNS findings to NDI has rarely been assessed, while in children with SMA, there is a
paucity of CNS testing. Without data on how CNS pathways relate to NDI after CM or SMA, optimal
interventions to prevent or mitigate NDI cannot be developed. The central hypotheses of this study are that the
contribution of systemic factors to NDI in CM or SMA is mediated by CNS factors, and that the specific factors
and relative contributions of factors differ in CM and SMA. The proposed study will leverage investment by
Indiana University (IU) in an IU-Global Health Uganda Center for Child Neurodevelopment in Jinja, Uganda. IU
will donate a Hyperfine mobile MRI and BrainAmp EEG to the Center, and provide training in MRI, EEG and
TCD testing. The specific aims of this study are to: 1) identify CNS risk factors for neurodevelopment
impairment (NDI) after CM vs. SMA; 2) establish systemic risk factors for NDI after CM vs. SMA; and 3) define
the pathways by which systemic and CNS factors contribute to NDI after CM vs. SMA. We will conduct the
study in a cohort of 620 children 6 months to 4 years of age (120 children with CM, 300 with SMA, 100 with
uncomplicated malaria and 100 community children) who will be followed for 12 months after disease/
enrollment and have neurodevelopmental testing at 12-month follow-up. CNS pathways will be evaluated
through bedside MRI testing with the Hyperfine Swoop MRI, quantitative EEG and evoked response potential
testing, and transcranial Doppler ultrasound evaluation of cerebral blood flow patterns. Systemic pathways
identified in prior studies as associated with brain injury, long-term neurodevelopment or both will be tested for
reproducibility. Finally, established and novel statistical models will be used to identify systemic and CNS risk
factors and mediation pathways for long-term NDI. We expect that unique systemic and CNS pathways will
lead to NDI in CM compared to SMA. Identification of these pathways will allow for targeted interventions to
prevent NDI in the millions of children with CM or SMA. The study will constitute a major advance in the
understanding of the pathophysiology of brain injury and recovery in severe malaria, and provide critical new...

## Key facts

- **NIH application ID:** 11090071
- **Project number:** 3R01NS055349-16S1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Chandy C. John
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $83,213
- **Award type:** 3
- **Project period:** 2024-07-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11090071

## Citation

> US National Institutes of Health, RePORTER application 11090071, Severe Malaria And Risk to The Brain (SMART Brain) (3R01NS055349-16S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11090071. Licensed CC0.

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