Long-term Treatment Related CNS Injury in Survivors of Childhood Cancer

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DESCRIPTION (provided by applicant): Children who received cranial radiation for treatment of childhood cancer are at significant risk for long- term central nervous system (CNS) injury. Our preliminary data suggests long-term memory (delayed recall) is significantly impacted in these adult survivors similar to patterns seen in aging adults with Alzheimer's disease, raising concern that this population may be at risk for early dementia. Furthermore, it is established that cognitive deficits increase with time after exposure to CNS radiation, however, to date, most evaluations of this population have occurred in the first 10 years from exposure. It is unknown whether cognitive status (full scale IQ) worsens beyond this immediate post-treatment period. Ongoing cognitive decline into adulthood would increase risk for many other poor long-term outcomes. The underlying mechanisms of treatment-induced CNS injury and its relationship to long-term cognition are poorly understood. We propose a study to 1) determine the prevalence of long-term memory deficits among 535 adult survivors of childhood ALL treated with cranial radiotherapy and now 15-45 years (mean 30 years) from diagnosis and 2) identify change in cognitive function since the time of the last post-therapy examination (mean 6.9 year from diagnosis) among 145 adult survivors of childhood ALL treated with cranial radiotherapy and now 11-37 years (mean 26 years) from previous examination. In addition, we will use advanced, non-invasive, magnetic resonance imaging techniques to explore associations between long-term memory deficits and 1) alterations in CNS structure and function using advanced MRI volumetric analysis, diffusion tensor imaging and functional MRI and 2) cerbrovasculopathy (including stroke) of both large and small vessels in a randomly selected subset of 140 survivors providing sufficient statistical power to identify associations between structure, function and memory outcomes. The results of this study will guide future screening practices for both neurocognitive deficits and cerbrovasculopathy in adult survivors. If long-term memory deficits are confirmed in this study, future longitudinal investigation will be necessary to determine long-term risk for dementia as well as intervention strategies to prevent or delay dementia. Access to more than 4,000 adult survivors of childhood cancer treated at St. Jude Children's Research Hospital makes this study feasible. PUBLIC HEALTH RELEVANCE: Identifying long-term memory loss and evidence for worsening cognitive status will benefit survivors and those who treat survivors of childhood cancer. Results from this proposed cross-sectional study of radiation exposed adult survivors of childhood cancer will directly inform 1) future outcomes research, 2) formulation of clinical care guidelines, including screening practices 3) development and testing of intervention strategies.