Inflammatory and oxidative stress biomarkers associated with cognitive function in patients with Hodgkin lymphoma treated with chemotherapy

Abstract Background: Cancer-related cognitive impairment (CRCI) is a common and clinically significant issue among cancer patients, negatively impacting quality of life. Inflammation and oxidative stress are believed to play key roles in the development of CRCI. However, most existing evidence is derived from studies in solid tumors, with limited data available for patients with lymphoma. Given that individuals with Hodgkin lymphoma (HL) are typically diagnosed at a relatively young age and often experience long-term survival, there is a critical need to better understand how inflammation and oxidative stress contribute to CRCI in this population. This knowledge could help identify predictive biomarkers and inform targeted interventions for CRCI. Therefore, we examined levels of inflammatory and oxidative stress biomarkers in patients with HL before and after chemotherapy compared to non-cancer controls and assessed their associations with cognitive function in patients. Methods Serum cytokines (interleukin [IL]–4, 6, 8, 10; tumor necrosis factor [TNF]-α), soluble cytokine receptors [sTNFRI, II]), C-reactive protein (CRP), malondialdehyde (MDA), and 8-iso-prostaglandin F2α (8-iso-PGF2α) were measured in 45 patients with HL before (T1) and after chemotherapy (T2) and 46 age- and sex-matched non-cancer controls assessed at the same time-equivalent points enrolled on URCC10055 through the National Cancer Institute Community Oncology Research Program. A comprehensive neuropsychological test battery measured attention, processing speed, and executive function. Adjusting for age, sex, and body mass index, linear mixed models compared log-transformed biomarker levels in patients vs. controls. Linear regression models examined cross-sectional relationships between log-transformed biomarker levels and cognitive performance in patients controlling for the same covariates; linear regression also estimated their longitudinal associations accounting for cognitive scores at T1. Since these analyses were exploratory, we did not perform multiplicity adjustments. Results Patients and controls had similar baseline characteristics (mean age [SD]: 40.6 [15.0] vs. 41.5 [16.6]; 60.0% vs. 58.7% male; 91.1% vs. 91.3% white; 88.9% vs. 89.1% ≥some college). Most patients were in stage I or II (58.5%) and diagnosed with classical HL (84.4%). Patients had higher sTNFRII and CRP levels than controls at T1 and T2, whereas patients had lower MDA levels at T2 (all P<0.05). CRP, MDA, and 8-iso-PGF2α levels decreased over time in patients vs. controls (all P<0.05). Among HL, at T1, higher IL-6 (β= -5.05; 95%CI= -9.15, -0.94; P=0.017) and IL-8 (β= -5.84; 95%CI= -11.51, -0.18; P=0.044) were associated with better focused attention (Trail Making Test-A [TMT-A]); higher TNF-α (β= -0.21; 95%CI= -0.39, -0.02; P=0.033) and sTNFRI (β= -0.25; 95%CI= -0.48, -0.02; P=0.034) were associated with better working memory (One Touch Stockings of Cambridge [OTS]). At T2, higher TNF-α, sTNFRI, and sTNFRII were associated with worse sustained attention (Backward Counting Test [BCT]; β=18.78; 95%CI=0.19, 37.38; P=0.048), focused attention (TMT-A; β=16.33; 95%CI=1.98, 30.67; P=0.027), and working memory (OTS: β=0.27; 95%CI=0.01, 0.53; P=0.046), respectively. Higher sTNFRI and sTNFRII levels at T1 were associated with improvement in verbal fluency (Controlled Oral Word Association [COWA]: β=0.26; 95%CI=0.05, 0.47; P=0.016) and worsening in working memory (OTS: β=2.19; 95%CI=0.16, 4.22; P=0.036), respectively. Longitudinally, increases in MDA were associated with declines in focused attention (TMT-A: β=17.05; 95%CI=2.90, 31.20; P=0.020).Conclusions: Our study highlights the complexity of inflammatory and oxidative stress contributing to CRCI in patients with HL. Compared to controls, patients had greater inflammation pre- and post-chemotherapy, evidenced by higher sTNFRII and CRP levels. However, oxidative stress levels decreased over time in patients, suggesting that chemotherapy may help reduce oxidative stress but not completely remediate the pro-inflammatory burden. Higher sTNFRII levels were associated with executive function impairment both cross-sectionally and prospectively. Increases in MDA were linked to declines in attention and processing speed over time. These findings suggest that immune and oxidative stress markers may serve as early indicators of cognitive vulnerability and potential targets for intervention, warranting future validation in larger studies.