At present, most studies on cognitive impairment after chemotherapy focus on breast cancer and prostate cancer, while relatively few studies on NHL. With the continuous improvement of treatment methods for non-Hodgkin’s lymphoma, the survival time of patients has been prolonged. The quality of life of patients needs to be paid attention to, and it is urgent to study the cognitive impairment of NHL patients.
It has been pointed out in the literature: lymphoma patients show decreased executive function and attention ability after chemotherapy, and some show severe fatigue and severe decline in quality of life (La Carpia et al., 2020; Trachtenberg et al., 2019). The executive function and memory of lymphoma patients who experienced chemotherapy over 3 months were impaired(Williams et al., 2020). The cognitive performance at 1,3, and 6 months after chemotherapy was significantly different from that before chemotherapy. The cognitive performance of the patients after chemotherapy was significantly different from that before chemotherapy, and the cognitive ability gradually declined(Hormozi, Hashemi, & Shahraki, 2019). Memory, processing speed, attention, and executive function are also impaired in chemotherapy(Liu et al., 2018; Paquet et al., 2018; Yamada, Denburg, Beglinger, & Schultz, 2010).
In this study, we found that the VFT and CDT scores of the patients decreased compared with before chemotherapy, and the RM, PM, and ECog-12 scores increased, and the scores were statistically significant. However, no significant difference was found in MMSE and SDMT. (Table 2). A decrease in the VFT score indicates that the patient has a language impairment, and this result indicates that the patient's frontal lobe function is impaired(Parks et al., 2008). Decreased CDT scores indicate impaired visuospatial abilities(Muller et al., 2019). Rising RM and PM scores indicate a retrospective and prospective memory impairment. The rising ECog-12 score indicates impaired subjective aspects of subjective cognition. No change in SDMT indicates no significant change in patient visual and motor function(M. H. Chen, Chiaravalloti, Genova, & Costa, 2020). MMSE is not highly sensitive when detecting mild cognitive impairment(Tariq, Tumosa, Chibnall, Perry, & Morley, 2006). This study failed to find differences in objective cognition.
Compared with the AT group in this study, the patients in the BT group were impaired in language, memory and subjective cognition, but the patients in the objective cognition and execution may not be significantly affected. This may be related to the short-term impairment of only partial cognitive function in our subjects within 2–4 weeks after 2 courses of chemotherapy at the second assessment. The main manifestations were language, memory, visuospatial dysfunction, and no clear differences were found in executive function. A review study showed that prevalence rates determined by trials with short screening methods or larger batteries of tests tended to decline overall over time, with a peak rate during chemotherapy. The review reported incidence rates of 25%, 14%, and 27% at the post-treatment time point, up to 1 year post-treatment, and 1 + year post-treatment, respectively(Whittaker, George, & O'Malley, 2022).
The mechanism of CICI is complex and unclear. Animal experiments have shown that the use of adriamycin can change the levels of cytokines in peripheral blood and central nervous system, which may be closely related to cognitive impairment by destroying the hippocampus and cortex(Raffa, 2011). In clinic, high levels of cytokine which including IL-1 and TNF-αwas associated with increased risk of cognitive decline in patients with traumatic brain injury compared to those with normal cytokine levels(Samatra, Pratiwi, & Widyadharma, 2018).The results of this study show that there is a moderate correlation between the level of IL-6 and Ecog-12, and the increase of IL-6 level indicates the impairment of memory and subjective cognitive function (Table 3, Fig. 1a-1c).
Previous studies have shown that IL-6 is often associated with neutrophil inflammation, such as the recruitment of other inflammatory cells through GM-CSF secretion and the recruitment of macrophages through IL-1β signaling to produce an inflammatory response(Kothur, Wienholt, Brilot, & Dale, 2016). At the same time, it can affect the expression level of brain-derived neurotrophic factor, thereby promoting peripheral immunity and brain response to cause CICI(Yap, Toh, Tan, Acharya, & Chan, 2021). Khan et al found elevated IL-6 levels and cognitive decline after CHOP chemotherapy for NHL patients (Khan, Garg, Bhurani, & Agarwal, 2016).Kesler et al and Cheung et al found that higher IL-6 concentrations were associated with greater self-perception impairment after breast cancer chemotherapy (Cheung et al., 2015; Kesler et al., 2013). Zimmer et al found that higher serum IL-6 concentrations were associated with higher levels of fatigue after chemotherapy for NHL patients (Zimmer et al., 2015).These studies have pointed out that IL-6 is elevated during chemotherapy and the cognitive function of patients is reduced they are consistent with our findings.
Compared with the AT group, the IL-4 level in the BT group was significantly decreased in this study, but the correlation between cognition and IL-4 could not be found. Currently, the impact of I L-4 on cognitive aspects is still controversial. IL-4 plays a protective role in the aging hippocampus(Derecki et al., 2010) and improves cognition by reducing the effects of pro-inflammatory factors on astrocytes and neurons(Boccardi et al., 2018). Some studies have pointed out that patients with lower IL-4 concentrations have more severe cognitive impairment, suggesting that IL-4 may have a protective effect on CICI(Cheung et al., 2015). However, Yap A et al found an inverse correlation between IL-4 and brain-derived neurotrophins in patients with early breast cancer, and the elevation of IL-4 would lead to aggravation of cognitive impairment(Yap et al., 2021). Zhao et al showed that IL-4 was negatively correlated with cognition after chemotherapy in breast cancer patients(Zhao et al., 2020). These studies suggest that IL-4 has the potential to promote cognitive impairment. The correlation between IL-4 and cognition could not be found in this study, probably because the number of cases in this study was too small to find statistical significance. Secondly, IL-4 may not play a relevant role due to the short treatment time of patients. It is also possible that there is no clear relationship between IL-4 and cognition in the early treatment of NHL. In the later stage, increasing the number of experimental cases and long-term follow-up can be considered to clarify the later changes of IL-4 and its relationship with cognition.
In addition, this study also discussed the KPS level and cognition of patients (Figs. 1d-1h). The results showed that there was a moderate correlation between MMSE, SDMT, VFT, CDT, and RM, indicating that the functional status of patients was affected by objective cognition, executive ability, language status and memory. This result suggests that the improvement of cognitive function will partly improve the functional status and improve the subsequent treatment and quality of life.