Neuroinflammation and Its Association with Cognition, Neuronal Markers and Peripheral Inflammation after Chemotherapy for Breast Cancer

SIMPLE SUMMARY: Up to 70% of chemotherapy-treated patients experience problems with memory and concentration, potentially caused by direct and indirect neurotoxicity, such as (neuro-)inflammatory processes. Can neuroinflammation changes be detected in chemotherapy-treated patients with breast cancer using translocator protein [(18)F]DPA714 simultaneous positron emission tomographic- and magnetic resonance imaging? Moreover, what is the association with clinical biomarkers? In a study including 19 chemotherapy-treated breast cancer patients, 18 chemotherapy-naïve and 37 healthy controls, we found significant relative glial overexpression in parietal and occipital brain regions in chemotherapy-treated patients compared to controls, which were associated with cognitive abnormalities and markers of neuronal survival. Shortly after ending chemotherapy, changes in brain neuroinflammation seem to occur, possibly contributing to the cognitive decline seen in breast cancer patients. Additionally, blood levels of an axonal damage marker were 20-fold higher in chemotherapy-treated patients, providing evidence for its use as a biomarker to assess neurotoxic effects of anticancer chemotherapies. ABSTRACT: To uncover mechanisms underlying chemotherapy-induced cognitive impairment in breast cancer, we studied new biomarkers of neuroinflammation and neuronal survival. This cohort study included 74 women (47 ± 10 years) from 22 October 2017 until 20 August 2020. Nineteen chemotherapy-treated and 18 chemotherapy-naïve patients with breast cancer were assessed one month after the completion of surgery and/or chemotherapy, and 37 healthy controls were included. Assessments included neuropsychological testing, questionnaires, blood sampling for 17 inflammatory and two neuronal survival markers (neurofilament light-chain (NfL), and brain-derived neurotrophic factor (BDNF) and PET-MR neuroimaging. To investigate neuroinflammation, translocator protein (TSPO) [(18)F]DPA714-PET-MR was acquired for 15 participants per group, and evaluated by volume of distribution normalized to the cerebellum. Chemotherapy-treated patients showed higher TSPO expression, indicative for neuroinflammation, in the occipital and parietal lobe when compared to healthy controls or chemotherapy-naïve patients. After partial-volume correction, differences with healthy controls persisted (p(FWE) < 0.05). Additionally, compared to healthy- or chemotherapy-naïve controls, cognitive impairment (17–22%) and altered levels in blood markers (F ≥ 3.7, p ≤ 0.031) were found in chemotherapy-treated patients. NfL, an axonal damage marker, was particularly sensitive in differentiating groups (F = 105, p = 4.2 × 10 (−21)), with levels 20-fold higher in chemotherapy-treated patients. Lastly, in chemotherapy-treated patients alone, higher local TSPO expression was associated with worse cognitive performance, higher blood levels of BDNF/NfL, and decreased fiber cross-section in the corpus callosum (p(FWE) < 0.05). These findings suggest that increased neuroinflammation is associated with chemotherapy-related cognitive impairment in breast cancer. Additionally, NfL could be a useful biomarker to assess neurotoxic effects of anticancer chemotherapies.