Abstract
BACKGROUND: Inflammatory signaling is linked with cancer-related cognitive impairment (CRCI), potentially through modulation of brain-derived neurotrophic factor (BDNF) expression. Here, we evaluate associations between plasma cytokines and BDNF and their relationship with cognition in a longitudinal study of adolescent and young adult cancer patients (AYAC) receiving chemotherapy and non-cancer controls (NC) (Clinicaltrials.gov: NCT03476070). METHODS: Newly diagnosed AYAC (15-39 years old) and age-matched NC completed the Functional Assessment of Cancer Therapy-Cognitive Function questionnaire (FACT-Cog), the Cambridge Neuropsychological Test Automated Battery (CANTAB), and blood draws every 3-6 months up to 12 months (AYAC) or 6 months (NC) from baseline. Plasma levels of cytokines and BDNF were quantified using a multiplexed immunoassay and ELISA, respectively. Biomarker-cognition and cytokine-BDNF associations were analyzed using mixed-effects models with interactions for chemotherapy status for AYAC (during chemotherapy vs. > 30 days post-chemotherapy). RESULTS: One-hundred and seventy-seven participants were included, with 66 AYAC and 111 NC. AYAC had a higher frequency of clinically significant cognitive impairment during and post-chemotherapy compared to NC. In trends unique to AYAC, higher IL-10 was associated with better self-perceived cognition, IL-8 with better multi-tasking, IL-6 with worse multi-tasking, response speed, and attention, and TNF-α with better memory (p < 0.05). Higher BDNF was associated with better memory and response speed (p < 0.05). IL-4, IL-10, TNF-α, and IFN-γ were associated with BDNF levels among AYAC and NC (p < 0.05). CONCLUSIONS: Our large, age-matched study implicates dysregulated cytokine signaling and altered BDNF expression in CRCI among AYAC during and post-chemotherapy. As precision medicine becomes integrated into AYA patient care, plasma BDNF and cytokines may serve as important predictors of CRCI onset. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03476070) on March 3, 2018.