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

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) [18F]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 (pFWE < 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 (pFWE < 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.

Cerebral glucose changes after chemotherapy and their relation to long-term cognitive complaints and fatigue

“…Although both E and C are unable to cross the BBB at high concentrations (7), they can increase BBB permeability, enabling direct interactions (49). Moreover, at sublethal doses to cancer cells, E induces microglial activation (50), suggesting that treatment with EC is sufficient to induce an inflammatory reaction [observed here and earlier in the parietal/ occipital cortex (8)]. The addition of fluorouracil to the chemococktail induced additional brain responses, as reflected by temporal and insular, but not occipital, relativ e hypermetabolism, suggesting that inflammatory (E) and oxidative stress (E + C) responses alone are insufficient to change metabolism in these regions, but rather require changes in cell proliferation (F + C) (48).…”

Acupuncture ameliorates breast cancer-related fatigue by regulating the gut microbiota-gut-brain axis

“…A study confirmed that the gut barrier of breast cancer patients was severely damaged and the expression levels of the tight junction proteins ZO-1 and occludin were significantly decreased (56). Another interesting study confirmed that central inflammatory factors were highly expressed in patients with cognitive impairment caused by breast cancer chemotherapy (57). In the present study, we found that CRF after breast cancer chemotherapy disrupted tight junction proteins (ZO-1, occludin, and claudin-5) in the gut barrier and stimulated inflammatory cytokine responses (IL-1b, IL-6, and TNF-a) in the gut and hippocampus, which were significantly reversed by acupuncture treatment.…”

A systematic review on the use of quantitative imaging to detect cancer therapy adverse effects in normal-appearing brain tissue

“…Auditory verbal learning scores correlated with NAA in posterior cingulate gyrus ( r 2 = 0.470–0.5, p < 0.01) [ 88 ]. Finally, a higher global deficit score (GDS) was weakly associated with inflammation on TSPO-PET in the frontal lobe after CTx in breast cancer [ 94 ].…”

“…Higher uptake than in controls was observed 16 years after chemo and hormone therapy in postcentral gyrus and corpus callosum after a global normalization, but the effect was opposite in frontal gyri, substantia nigra, and brainstem [92]. Breast cancer survivors reporting chemo-fog were examined using 99 Tc-TRODAT-1 SPECT measuring dopamine transport, reporting a 20-23% decrease in the putamen, caudate, and striatum [93], and TSPO-PET showed signs of neuroinflammation in the occipital and parietal lobes both compared to nontreated patients and a healthy group 4 weeks after (6 months of) CTx [94]. Finally, two studies reported on CTx effects in patients with non-Hodgkin lymphoma.…”