Brain Age in Adult Survivors of Childhood Leukemia and CNS Tumor

摘要

Abstract Long-term survivors of childhood cancer may be at increased risk for accelerated aging and early-onset dementia, particularly survivors of leukemia and central nervous system (CNS) tumor survivors who are treated with neurotoxic therapies. We recently demonstrated shorter telomere length in leukemia and CNS tumors more frequently than community controls and other types of childhood cancer. We have also identified that survivors of leukemia and CNS tumors are at greatest risk for progressive memory decline during the interval of 25 to 40 years following cancer diagnosis. Adult survivors of childhood leukemia and CNS tumor have lower brain white and grey matter volume and smaller hippocampi, consistent with a dementia profile. Compared to non-cancer controls, these survivors demonstrate a lower ratio of hippocampi to cranial vault volume, suggesting loss of brain tissue volume after peak development of the cranium. This lower ratio is associated with memory problems and may indicate accelerated brain aging and early onset dementia. CNS-directed cancer treatment at a young age can limit development of cognitive and brain reserve (i.e., resilience to future brain injury) and reduced reserve is associated with increased risk for dementia in the general population. However, comprehensive assessment of brain aging in adult survivors of childhood cancer has not been reported. We propose to calculate the brain age of a large sample of adult survivors of childhood cancer and community controls. To date, brain imaging scans have already been collected on 793 adult survivors of childhood leukemia, 197 survivors of CNS tumor and 250 community controls matched on age, sex and race. We will compare discrepancies between brain age and chronological age in the survivors and controls and examine associations between brain age discrepancies with treatment, health, functional status and biomarker measures, including cell free mitochondrial DNA, collected in the SJLIFE cohort. This will be the first study to directly examine accelerated cognitive and brain aging in a cohort of adult survivors of childhood cancer treated with neurotoxic therapies as children. These survivors present with symptoms of memory impairment, consistent with dementia and/or Alzheimer's disease. The comprehensive longitudinal data available to us will inform dementia onset and progression, as we follow the survivors in our cohort for the remainder of their life's. Estimates of accelerated brain aging have been shown to predict dementia and mortality in the general population and thus, this metric may serve as a useful biomarker for early detection of dementia and/or Alzheimer's disease in cancer survivors. Results of this study will have major implications for understanding the pathology of dementia and Alzheimer's disease in chronic disease, and will provide invaluable information concerning risk prediction and intervention development.