This page describes Andre's collaboration with investigators in South Africa studying the effects of HIV on neural development in children.

Data Location

/cluster/gerenuk/user/andre_hiv/HIV_UCT_longitudinalstudy

People Involved

From Cape Town:

Ernesta Meintjes- (joint-PI on the project) physicist in the Department of Biomedical Engineering at the University of Cape Town (UCT)

Barbara Laughton- (also joint-PI) pediatrician at Stellenbosch University (sometimes abbreviated SUN) and Tygerberg Hospital (east of the city), where the children come for study.

Ken Mbugua- graduate student in biomedical engineering. He visited the Martinos Center for a couple of weeks two or three years ago and now he's analyzing the spectroscopy data and the 5 year old morphometry data.

Frances Robertson- Admins in Ernesta’s lab? set up data copying for us

Keri Woods- Admins in Ernesta’s lab?

Martha Holmes- demographics person (American. post-doc? did lot of analyses for spectroscopy. neuroscience person. well organized)

Emmanuel Nwosu - graduate student using HIV data for thesis/dissertation.

From MGH:

Andre van der Kouwe- developed technical acquistion methods for un-sedated children, oversees MGH work for grant

Allison Moreau- RA working on the project. processed structural MRI data through FreeSurfer longitudinal stream pipeline and calcuated parameter maps from multi-echo FLASH data.

History

Our study is part of a larger study that was an international drug trial (CIPRA- Comprehensive International Program of Research on AIDS). South African piece and then Cape Town subset of that. CHER (Children w/ HIV early antiretroviral therapy)- local study name. piggybacked on for imaging. now can get demographics.

R21

Dates of funding: ?

The project was originally an R21 titled "Neuroimaging Technology for Pediatric Development Disorders in South Africa". Ernesta and Andre developed a set of techniques for imaging young children without sedation:

use custom-designed motion-corrected MR pulse sequences
can get statistical significance w/ fewer subjects, long analysis will increase power to see subtle differences between groups
post-processing of DTI data for motion correction
consistent on-line positioning on the scanner
offline post-processing for distortion correction

This grant funded the study of the 5-year-old children for the HIV Project.

R01

Dates of funding: 7/1/2011 - 6/40/2017

This grant continued the work of the HIV project by providing funding to continue scanning the same (and new) children at 7 and 9 years old, using the techniques developed during the R21.

BACKGROUND AND SIGNIFICANCE

Since the advent of highly active ART (HAART), HIV has transitioned from a fatal disease to a chronic condition in which there may be ongoing damage to the central nervous system (CNS) especially in the developing brain of the young child. Because CNS penetration by ART is limited, the brain becomes a reservoir for the virus, and few drugs are available that impact these reservoirs. NeuroAIDS affects children differently and more dramatically than adults. Few studies of school-age HIV positive children exist and even fewer include neuroimaging. These studies are practically non- existent in the developing world. In this project we have the unique opportunity to study the effects of HIV and ART on the developing brain over a period of 4 years in a well-characterized cohort of young children using neuropsychological and behavioural assessments combined with advanced neuroimaging techniques in the region with the highest prevalence of HIV in the world, and the
population most representative of the world pandemic.

RESEARCH DESIGN AND METHODS * 110 HIV-infected children, 70 HIV-uninfected controls will be enrolled in study
study duration = 5 years
clinical evaluation and blood labs done every 6 months at Tygerberg Hospital for HIV-infected children
controls will be clinically assessed annually to make sure still HIV-uninfected
medical records available include nadir recorded CD4 levels and highest plasma viral load (PVL) since birth
neuropsych assessments will be performed in child's native language- English, Afrikaans or Xhosa

STUDY OBJECTIVEScompare neuropsych, behavioral and neuroimaging findings of these groups:1) children who received early ART followed by interruption at 1 year (Arm 2 of original CHER trial)

2) children who received early ART followed by interruption at 2 years of age (Arm 3 of original CHER trial) 3) children who received delayed ART (arm 1 on the CHER trial) 4) HIV Unexposed uninfected children 5) HIV Exposed but uninfected children.
To correlate cognitive and clinical development over time with anatomical and metabolic brain development, using neuroimaging in HIV-infected children.
- children have been followed since 7 weeks of ageThe four aims of the proposed study are:
Clinical and comprehensive cognitive assessment of children at 7 and 9 years of age at KID CRU:
- 1.1. Clinical observations (principally: CD4 cell count, plasma viral load). 1.2. Neuropsychological assessment (Griffiths Mental Development Scale and Beery-Buktenica Visual- Motor Integration score).
Image children at 7 and 9 years at CUBIC in a 1 hour session:
- 2.1. High resolution anatomical imaging (brain morphometry and tissue characterization: cortical thickness, cortical T1 values, cortical volumes, subcortical volumes). 2.2. High resolution multi-direction diffusion weighted imaging (white matter characterization: brain structure fractional anisotropy, tractography). 2.3. Single voxel spectroscopy (brain metabolism: absolute concentrations and ratios of N-acetylaspartate, choline, myo-inositol and creatine in peritrigonal white matter, midfrontal gray matter, basal ganglia).
Technical development of pediatric imaging techniques and longitudinal data analysis:
- 3.1. Further development and validation of motion corrected imaging sequences esp. diffusion/T2 imaging. 3.2. Algorithms for data optimization for longitudinal analysis including Jacobian (deformation) analysis.
Capacity building through exchange of technology, students and technical training:
- 4.1. Cape Town student visits to Boston for training in image acquisition and sequence development, pediatric imaging and longitudinal data analysis for brain morphometry. 4.2. Longitudinal brain morphometry analysis courses in Cape Town.
  4.3. Implementation of computational resource for brain image analysis at CHPC.We will acquire three types of imaging data:
Structural imaging: We will collect multiecho MPRAGE (MEMPR) for cortical thickness estimation, cortical parcellation, and estimation of subcortical structure volumes using Freesurfer software. If time permits, we will collect two multiecho FLASH (MEF) scans for estimating T1 relaxation time and proton density (PD). Spectroscopy: We will collect spectra in left peritrigonal white matter, midfrontal gray matter and basal ganglia, using a PRESS sequence with 2 mL voxels and 64 excitations analyzed with LCModel to estimate metabolite ratios and absolute concentrations (since Cr concentrations increase with HIV-associated gliosis).
Diffusion imaging: We will collect a high-resolution (2 mm isotropic), 30 direction, whole brain diffusion tensor volume and analyze with TrackVis, DTIStudio, and the TBSS tool in FSL.*