Systemic Biological Mechanisms of Neurocognitive Dysfunction in Long-term Survivors of Childhood Hodgkin Lymphoma.

Abstract

Hodgkin lymphoma (HL) survivors experience neurocognitive impairment despite receiving no central nervous system-directed therapy, though little is known about underlying mechanisms. HL survivors (n=197) and age-, sex- and race/ethnicity-frequency-matched community controls (n=199) underwent standardized neurocognitive testing, and serum collection. Luminex multiplex or ELISA assays measured markers of inflammation and oxidative stress. Linear regression models compared biomarker concentrations between survivors and controls and with neurocognitive outcomes, adjusting for age, sex, race, body mass index, anti-inflammatory medication, and recent infections. HL survivors (mean[SD] current age 36[8] years, 22[8] years post-diagnosis) demonstrated higher concentrations of interleukin-6 (IL-6), high-sensitivity c-reactive protein (hs-CRP), oxidized low-density lipoprotein, and glutathione peroxidase (GPx), compared to controls (p's<0.001). Among survivors, higher concentrations of IL-6 were associated with worse visuomotor processing speed (p=0.046). hs-CRP ≥3 mg/L was associated with worse attention, processing speed, memory, and executive function (p's<0.05). Higher concentrations of malondialdehyde were associated with worse focused attention and visual processing speed (p's<0.05). Homocysteine was associated with worse short-term recall (p=0.008). None of these associations were statistically significant among controls. Among survivors, hs-CRP partially mediated associations between cardiovascular or endocrine conditions and visual processing speed, while IL-6 partially mediated associations between pulmonary conditions and visuomotor processing speed. Neurocognitive function in long-term survivors of HL appears to be associated with inflammation and oxidative stress, both representing potential targets for future intervention trials.