Using Brain Ultrasound Imaging, Microcirculation and Parenchymal Stiffness to Assess for Mechanisms of Early Neurodevelopmental Disparities among Infants HIV-Exposed Uninfected

Summary/Abstract Each year nearly one million infants are born after fetal exposure to HIV and maternal antiretroviral treatment (ART) yet remain HIV-uninfected. Our work and that of others has shown that infants HIV-exposed uninfected (HEU) are at higher risk of poorer neurocognitive and developmental outcomes compared to infants born HIV- unexposed (HU), even when maternal HIV viral suppression is maintained throughout pregnancy. Infants HEU are at higher risk of motor and expressive language delays compared to infants HU. While neurocognitive and developmental outcomes are driven by the complex interplay of biological, social, and structural factors, early life predictive correlates of poor developmental and neurocognitive outcomes are urgently needed to identify infants who may benefit from early interventions. Brain ultrasound is the initial imaging modality of choice for diagnosis and monitoring of many neonatal brain conditions, including exposure to infections such as cytomegalovirus. Major advantages of ultrasound include its safety, relatively low cost, and that it can be repeated as often as necessary with limited need for patient cooperation. Additionally, advancements in ultrasound technology have evolved into simpler, user-friendly, and more portable equipment that allow studies to be performed by non-sonographers/non-radiologists. Furthermore, with advanced ultrasound technology, including high-resolution microvascular imaging (MVI), shear-wave elastography, and quantitative texture analysis (i.e., radiomics), it is possible to assess not only for structural neonatal and infant brain differences but also tissue differences. Importantly, these advanced ultrasound methods offer the potential to detect differences at an earlier age compared to findings reported with use of magnetic resonance imaging (MRI) in older children who are HEU, recognizing that MRI findings have been associated with neurodevelopmental delays. Testing during the first six months of life provides the opportunity for earlier identification of at-risk infants and provision of earlier interventions. Our preliminary work using basic ultrasound imaging in the neonatal period has identified that neonates who are HEU have shorter corpus callosum length than neonates who are HU, a brain structure known to influence language development, motor skills and cognition. This study will 1) evaluate if differences in corpus callosum length and parenchymal homogeneity identified in our birth cohort persist using low field MRI and correlate with developmental delays at 2 years of age; 2) and using more advance ultrasound features, determine if brain structural, texture, microcirculatory and elasticity differences between infants HEU and those who are HU are associated with volumetric and signal intensity differences on brain low field MRI at 1-year of life; and 3) determine if specific brain ultrasound biomarkers identified at birth are associated with neurodevelopmental outcomes at 2 years of life. Starting life HIV-free among infants who are HEU, has not ensured comparable neurodevelopmental outcomes to that of infants who are HU. The proposed science will position us to identify early brain biomarkers associated with infants in need for early interventions.