Fine-sliced neurocognitiveassessments and high-resolution neuroimagingbiomarkers to diagnose cancer- and chemotherapy-induced cognitive deficits (CCICD) - a pilot study

Background: Significant progress has been made in cancer survival, however there is much room for improvementin supportive cancer care ?Chemo-brain? is the lay language that some patients use to describe a cognitive fog ormental fuzziness that they experience soon after chemotherapy (CT) and that can last more than a decade after CThas ended In this study, we examine the notion of accelerated cognitive aging as a potential side effect of cytotoxicCT While CCICD has been widely researched, its underlying biological mechanisms are yet to be sufficientlyelucidated The long-range goals of this study are to (a) yield clinically valid diagnostic criteria for CCICD by theidentification of fine-sliced neurocognitive measures that can reliably capture within-subject, nuanced, cognitivechanges pre/post CT;and (b) identify brain-based biomarkers that can leverage future systemic therapies oradjunctive medications that are neuroprotective Trial design: The study takes advantage of greater clarity offered by high-resolution neuroimaging (7Tesla) to delve into biomarkers associated with the neurotoxic effects of thecommon chemotherapeutic agents doxorubicin, paclitaxel, docetaxel, and cyclophosphamide on brain metabolismand iron homeostasis, which may result in CCICD We innovate by harnessing magnetic resonance spectroscopy(MRS) together with quantitative susceptibility mapping (QSM) and diffusion tensor imaging (DTI), a trio that hasrarely been combined in 7T imaging, to uncover biomarkers related to CCICD In this high-resolution imaging environment, we hope to individually isolate and track changes in key neuronal metabolites such as glutamate and glutamine using MRS (pre- and post-CT), in a prospective, longitudinal study At these two time-points, wesimultaneously use QSM to identify regions of increased iron deposits (associated with doxorubicin) in the brainalong white matter tracts as well as DTI to assess white matter degeneration We selected fine-sliced measurementsof cognitive updating, mental flexibility and impulse control, the key executive function (EF) deficits associated with CCICD These and other global EF measures are administered pre/post-CT (within a period of 4-6 months), whileassessments of depression, anxiety, sleep, and pain will be administered via a weekly online questionnaire duringCT Eligibility criteria: Eligible patients are adults (age ≥18) with either early stage HER2 negative breast cancer ordiffuse large B-cell lymphoma who will receive curative-intent combination CT, to include cyclophosphamide Patients are excluded if they have a prior history of cancer diagnosis or treatment Patients would have to be 7TMRI compatible Specific Aims: To obtain preliminary estimates of the change in EF measures, brain metabolite,iron concentrations, and white matter degeneration in patients pre- and post-CT, to inform a subsequent largertrial Statistical methods: The proposed sample (N=9) size achieves 74 8% power to detect a 1 SD change with asignificance level of 0 05 using a two-sided, one-sample t-test for the pairwise difference Estimates and 95%confidence intervals will be reported Additionally, the relationship between executive function, brain metabolite, ironconcentrations and white matter degeneration will be explored Present and Target accrual: Accrual has thus far been delayed, partially due to due to COVID-19 restrictions onclinical research, beginning in March 2020 Target accrual is 9 patients Contact information: Kanchna-ramchandran@uiowa edu, Phone: 319-356-0535