TITLE: Malarial Impact on Neurobehavioral Development (MIND) Study

 Principal Investigators:  Chandy C John, MD, MS, Indiana University and Paul Bangirana, PhD, Makerere University

Co-Investigators: Andrea Conroy, PhD, Indiana University, Dibyadyuti Datta, MS, PhD, Indiana University, Wanzhu Tu, MS, PhD, Indiana University, Robert O. Opoka, MBChB, M.Med, MPH, MHPE, Makerere University, Richard Idro, MBChB, M.Med, PhD, Makerere University, Ruth Namazzi, MBChB, MMED, Makerere University, Bjarne Robberstad, Msc, PhD, University of Bergen, Margaret Semrud-Clikeman, PhD University of Minnesota, USA, Noeline Nakasujja, MBChB, M.Med, PhD, Makerere University

Brief description of the study

This will be a longitudinal  cohort study  with a 5 year follow up where caregivers and children with the five most common forms of severe malaria that is cerebral malaria(CM), severe malarial anemia(SMA), malaria with repeated seizures(M/S), respiratory distress(RD), prostration(PR) and healthy community children(CC) from the same neighborhood or household as the children with malaria will be assessed for;

1) To establish the duration and age specific manifestations of neurobehavioral sequelae of severe malaria from childhood to adulthood;

2) Determine the functional and economic costs of neurobehavioral sequelae of severe malaria; and

3) Identify the metabolic, immunologic and parasitic factors predictive of long-term neurobehavioral and functional impairment after severe malaria.

The US National Institutes of Health.
Organizational affiliation of the researchers
1. Indiana University
2. Makerere University
3. University of Bergen
4. University of Minnesota

Study design
Longitudinal cohort analysis


Research Training in Infection and Neurodevelopment in Uganda.

Aim 1. Expand research expertise in Uganda in the areas of:

1.Neurodevelopmental and cognitive assessment,through training of a doctoral student and post-doctoral fellow in neuropsychology at Makerere University.

2. Nutrition-related risk of infection and neurocognitive impairment, through training of a post-doctoral fellow in nutritional epidemiology at Makerere University.

3. Epidemiology and pathogenesis of infection-related brain injury, through training of a doctoral student and post-doctoral fellow in infectious disease epidemiology at Makerere University, and training of a doctoral student in immunology at Indiana University.

Students will conduct their research within ongoing malaria, HIV and micronutrient deficiency research projects and will participate in integrated core training designed to foster interdisciplinary collaboration. Epidemiology trainees will complement their on-site training with Masters of Infectious Disease Epidemiology online training from the London School of Tropical Medicine and Hygiene. At completion of training, graduates will be ready for positions as university faculty or in the Ministry of Health, working on research and/or interventions to understand, prevent and treat infection-related neurocognitive impairment.

Aim 2. Build research capacity in Uganda through development of a core laboratory and data management center, and workshop and short-term training of clinical and laboratory personnel.

The core lab and data management centers established in the prior period will be enhanced, with additional lab capacity for molecular biology studies, and additional data center database and statistical capability. Focused workshop and short-term training will be provided to medical, neuropsychology, and laboratory personnel involved in research studies at Makerere University, to build on-site research capacity in the areas of infectious disease, nutrition and neurodevelopment research. At the project completion, quantifiable improvement in research capacity will lead to an improved research environment that supports further independent work in infectious disease, nutrition and neurodevelopment.

Aim 3. Advance research capacity in Uganda through research administration training.

 Independent research capacity requires expertise in research administration. The renewal application will build on the strengths of administration training provided by the original grant by providing training for Masters Degrees in Management Studies and in Business Administration, with a focus on research study administration

Principal Investigator: Dr. Idro Richard

Renewed for another 5 years till 2023

Neurodevelopmental outcomes in children with severe malaria.

The research proposed in this study is innovative in several aspects, including the choice of study population, the multi-factorial assessment of potential risk factors, and the methods proposed to test for risk factors. This study will be, to our knowledge, the first prospective study to assess NDI in the five most common types of severe malaria and also the first prospective study of NDI in children with severe malaria treated with artesunate. All prior studies of NDI in severe malaria in African children to date, including our studies, have assessed these sequelae in children treated with quinine or chloroquine. Comparison of AS to quinine treatment will give insight into the ways in which AS may increase or decrease NDI, and inform consideration on adjunctive therapy to prevent NDI in children receiving AS.

The goal of this proposal is to determine the risk factors for and the pathogenesis of neurodevelopmental impairment in children with the five types of severe malaria treated with artesunate.

1. Objective AIM 1
To establish the functional areas and degree of neurodevelopmental function affected by the five major forms of severe malaria in children treated with artesunate.
The working hypotheses for this objective are that: 1) children with all forms of severe malaria will have developmental impairment; 2) areas and degree of impairment will differ according to form of malaria; 3) artesunate therapy will be associated with lower levels of developmental impairment than quinine.
We will test these hypotheses by comparing areas and age-adjusted levels of neurologic, developmental, and behavioral impairment in children with 5 types of severe malaria (CM, RD, M/S, SMA, and prostration) treated with artesunate compared to healthy children 12 months after enrollment. The level of impairment in children with CM or SMA will be compared in children in the present (artesunate) and past (quinine) studies.

Primary outcome measures:
1) Mullen Early Learning Scales Composite (measure of overall cognition)
2) Early Childhood Vigilance Test (measure of attention)
3) Color Object Association Test (measure of declarative memory) at 12 months after enrollment/discharge
Secondary outcome measures:
1) Behavioral Rating Inventory of Executive Functions (BRIEF)
2) Z-scores on individual Mullen Early Learning Scales
3) Presence of neurologic deficits at discharge or 12 months follow-up

2. Objective AIM 2
To identify the immunologic, metabolic, and nutritional risk factors associated with neurodevelopmental impairment in children with severe malaria treated with artesunate.
The working hypotheses for this objective are that: 1) specific factors are associated with developmental impairment in severe malaria, and 2) these factors differ according to the type of severe malaria. We will test these hypotheses by comparing the presence/level of risk factors in children with severe malaria to level of neurologic, developmental, and behavioral impairment in these children 12 months after enrollment.

Risk factors assessed:
1) Markers of endovascular inflammation (NO and ADMA, specific cytokines, endothelial activation markers, oxidative stress markers)
2) Markers of central nervous system inflammation or injury (cerebrospinal fluid NO and ADMA, cytokines, oxidative stress markers)
3) Metabolic changes (carboxyhemoglobin, hypoglycemia, lactic acidosis)
4) Micronutrients affected by inflammation and associated with developmental impairment (iron, vitamin A, vitamin E).

Principal Investigator: Dr. Opoka Robert.

Ended Dec 2018, Renewed as MIND


Principal Investigator:  Dr. Opoka Robert

Zinc for Infection Prevention in Sickle Cell Disease.


Principal Investigator:  Dr. Opoka Robert

R25 Global Health Fellowships


1. Dr. Damalie Nalwanga

2. Dr. Theresa Piloya

3. Dr. Ahmed Ddungu

4. Mr. Tom Ngabirano

Ongoing (NCE)

Sickle Cell Disease in a Low Resource Area: Benefits of Hydroxyurea in Mitigating Early Onset Lung Disease.

Principal Investigator: Dr. Aanyu Hellen.


Children’s Oxygen Administration Strategies Trial” (COAST Study).


Children’s Oxygen Administration Strategies Trial- Nutrition.


Implementing a digital Child mental Health screening, literacy and Management Tool in Faith based settings.

Principal Investigator: Dr. Janet Nakigudde.


Optimising Iron Status while minimizing morbidity in HIV- infected Ugandan Children.

Principal Investigator: Dr. Musiime Victor.


Optimizing Benefits While Reducing Risks of Iron in Malaria Endemic Areas.

Principal Investigator: Dr. Mupere.

Program based for Promotion of prevention of Violence against children.  

Principal Investigators:

1. Dr. Opoka Robert

2. Dr. Mpyangu Christine.

Project is winding up.

Oral Antihyoertensive Therapy: Apathway to efficient reduction of Maternal Complications from Severe Hypertension in Low Resource Environments.

Principal Investigator: Dr. Ononge.

Project is winding up.

The aim of the project is to establish a Center Of Excellence For Patient-Centered Care And Non-Communicable Disease Management In Uganda.

Principal Investigators:

1. Dr. Robert Kalyesubula

2. Dr. Kayongo Alex

Project wrapping up.

Burden and Risk of Neurological and Cognitive Impairment in Pediatric Sickle Cell Anemia in Uganda; (BRAIN SAFE).

Principal Investigator: Dr. Idro Richard

Project is concluding.

Solar-Powered Oxygen System (SPO2).

Principal Investigator: Dr. Robert Opoka.

Status: Enrolling.

PI: Dr. Paul Bangirana