An Integrated Analysis of Clinical, Genomic, and Imaging Features Reveals Predictors of Neurocognitive Outcomes in a Longitudinal Cohort of Pediatric Cancer Survivors, Enriched with CNS Tumors (Rad ART Pro)

Abstract

BackgroundNeurocognitive deficits in pediatric cancer survivors occur frequently; however, individual outcomes are unpredictable. We investigate clinical, genetic, and imaging predictors of neurocognition in pediatric cancer survivors, with a focus on survivors of central nervous system (CNS) tumors exposed to radiation.MethodsOne hundred eighteen patients with benign or malignant cancers (median diagnosis age: 7; 32% embryonal CNS tumors) were selected from an existing multi-institutional cohort (RadART Pro) if they had: 1) neurocognitive evaluation; 2) available DNA; 3) standard imaging. Utilizing RadART Pro, we collected clinical history, genomic sequencing, CNS imaging, and neurocognitive outcomes. We performed single nucleotide polymorphism (SNP) genotyping for candidate genes associated with neurocognition: COMT, BDNF, KIBRA, APOE, KLOTHO. Longitudinal neurocognitive testing were performed using validated computer-based CogState batteries. The imaging cohort was made of patients with available iron-sensitive (n = 28) and/or T2 FLAIR (n = 41) sequences. Cerebral microbleeds (CMB) were identified using a semi-automated algorithm. Volume of T2 FLAIR white matter lesions (WML) was measured using an automated method based on a convolutional neural network. Summary statistics were performed for patient characteristics, neurocognitive assessments, and imaging. Linear mixed effects and hierarchical models assessed patient characteristics and SNP relationship with neurocognition over time. Nested case-control analysis was performed to compare candidate gene carriers to non-carriers.ResultsCMB presence at baseline correlated with worse performance in 3 of 7 domains, including executive function. Higher baseline WML volumes correlated with worse performance in executive function and verbal learning. No candidate gene reliably predicted neurocognitive outcomes; however, APOE ϵ4 carriers trended toward worse neurocognitive function over time compared to other candidate genes and carried the highest odds of low neurocognitive performance across all domains (odds ratio 2.85, P=0.002). Hydrocephalus and seizures at diagnosis were the clinical characteristics most frequently associated with worse performance in neurocognitive domains (5 of 7 domains). Overall, executive function and verbal learning were the most frequently negatively impacted neurocognitive domains.ConclusionPresence of CMB, APOE ϵ4 carrier status, hydrocephalus, and seizures correlate with worse neurocognitive outcomes in pediatric cancer survivors, enriched with CNS tumors exposed to radiation. Ongoing research is underway to verify trends in larger cohorts.

Evolution and implementation of radiographic response criteria in neuro-oncology

“…These biomarkers have been shown to correlate with cognitive outcomes and may be used to assess brain health in patients with cognitive decline. 74–80 Future research is needed to elucidate how these metrics and biomarkers of treatment-related early CNS damage can be incorporated into response assessment methods.…”

Limited Research Investigating the Value of MRI in Predicting Future Cognitive Morbidity in Survivors of Paediatric Brain Tumours: A Call to Action for Clinical Neuroimaging Researchers

“…Whilst our systematic search strategy was extensive, there were also difficulties in identifying papers due to poor reporting practices. For instance, for some of the studies where the full text was assessed, the timing of MRI in relation to assessment was ambiguous or unclear [47][48][49][50]55]. Factors affecting the number of research articles in this area could include previous focus on survival, where increasing survival rates are now placing a greater need for research on late effects.…”

“…In a small number of cases, the text was ambiguous to the order of testing (i.e., [49][50][51][52][53][54]) but did not refer to prediction or other details suggestive of the order, and thus were not included. For other studies, data including MRI which preceded a later neurocognitive assessment existed, due to the inclusion of multiple timepoints, however it was ambiguous in the analyses of interest as to the time points being referred too and so these studies were not included [55,56].…”