There are approximately 450,000 pediatric cancer survivors in the United States . Unfortunately, many of these survivors (up to 75%) experience significant neurocognitive and psychosocial dysfunction associated with chemotherapy (i.e., chemobrain). Chemobrain in pediatrics is particularly concerning because it occurs during the most formative years of development. A major challenge that faces clinical management and research in pediatric oncology is the ability to identify chemotherapy-induced neurocognitive effects early, accurately and objectively. The neural correlates and the trajectory of chemobrain effects that manifest as clinical neurocognitive impairment in this cohort are largely unknown. This knowledge gap creates a barrier to optimally execute treatment options and enrichment intervention programs to minimize chemotherapy-induced cognitive deficits. Thus, it is critical that we clearly define the chemotherapy-induced damage to the developing brain that leads to clinical neurocognitive impairment in pediatric oncology patients. This proposal will use multiparametric MRI to longitudinally evaluate the effects of chemotherapy on the developing brain. We will study: a) cognitive function by event-related task fMRI, b) functional connectivity by resting-state fMRI, c) gray-matter and white-matter microstructural integrity by diffusion-tensor MRI, d) brain volume and cortical thickness by anatomical MRI, e) neurovascular health by fMRI of hypercapnia, and f) oxygen metabolic stress by quantitative blood-oxygen level-dependent (BOLD) fMRI. Comparisons will be made with clinical neurocognitive assessment. Studies will be carried out longitudinally at 4 time points: i) diagnosis, ii) 6 months after chemo initiation, iii) end of therapy (up to 3.5yrs), iv) 1 year after end-of-therapy, along with age- matched healthy controls. In addition, we will study patients 10-25 years post chemo to evaluate the chronic effects of chemotherapy, along with age-matched controls. Our central hypothesis is that chemotherapy induces changes in neurovascular health, oxygen metabolic activity, cognitive function, functional connectivity, and microstructure of the developing brain, that these changes are time dependent, and that they contribute to clinically significant neurocognitive decline in pediatric oncology patients.
The neural correlates and the trajectory of chemobrain effects that manifest in clinical neurocognitive impairment in this cohort are largely unknown. This knowledge gap creates a barrier to optimally execute treatment options and intervention programs to minimize chemotherapy-induced cognitive deficits. Thus, it is critical that we clearly define the chemotherapy-induced damages to the developing brain that lead to clinical neurocognitive impairment in pediatric oncology patients. This proposal will use multiparametric MRI to longitudinally evaluate the effects of chemotherapy on the developing brains of pediatric oncology patients. Our central hypothesis is that chemotherapy induces changes in neurovascular health, oxygen metabolic activity, cognitive function, functional connectivity, and microstructure of the developing brain, that these changes are time dependent, and that they contribute to, or manifest in, clinically significant neurocognitive deficits in pediatric oncology patients.
