Neuroinflammation as potential precursor of leukoencephalopathy in early-stage breast cancer patients: A cross-sectional PET-MRI study

Abstract

Background: Although chemotherapy-induced leukoencephalopathy has been described in case and cohort studies, literature remains inconclusive about its prevalence and mechanisms. Therefore, we investigated the presence of leukoencephalopathy after multiagent chemotherapy in women treated for breast cancer and potential underlying neuroinflammatory processes. Methods: In this exploratory study, 15 chemotherapy-treated and 15 age-matched chemotherapy-naïve patients with early-stage breast cancer, as well as 15 healthy controls underwent simultaneous PET-MR neuroimaging, including T1-weighted MPRAGE, T2-weighted FLAIR and dynamic PET with the 18-kDA translocator protein (TSPO) radioligand [ 18 F]DPA-714. Total and regional (juxtacortical, periventricular, deep white matter and infratentorial) lesion burden were compared between the groups with one-way ANOVA. With paired t-tests, [ 18 F] DPA-714 volume of distribution [V T , including partial volume correction (PVC)] in lesioned and normal appearing white matter (NAWM) were compared within subjects, to investigate inflammation. Finally, two general linear models were used to examine the predictive values of neurofilament light-chain (NfL) serum levels on (1) total lesion burden or (2) PVC [ 18 F]DPA-714 V T of lesions showing elevated inflammation. Results: No significant differences were found in total or localized lesion burden. However, significantly higher (20-45%) TSPO uptake was observed in juxtacortical lesions (p ≤ 0.008, t ≥ 3.90) compared to NAWM in both cancer groups, but only persisted for chemotherapy-treated patients after PVC (p = 0.005, t = 4.30). NfL serum levels were not associated with total lesion volume or tracer uptake in juxtacortical lesions. Conclusion: This multimodal neuroimaging study suggests that neuroinflammatory processes could be involved in the development of juxtacortical, but not periventricular or deep white matter, leukoencephalopathy shortly after chemotherapy for early-stage breast cancer.

Changes in leukoencephalopathy and serum neurofilament after (neo)adjuvant chemotherapy for breast cancer

“…For example, a woman who completed chemotherapy that was comparable to the treatment in the current study (doxorubicin, cyclophosphamide, and docetaxel) presented with higher WML volumes than her healthy, chemotherapy-naïve, monozygotic twin (9.8 versus 6.2 mL) [24] . By contrast, more recent cross-sectional studies did not observe difference between breast cancer patients and healthy controls from one month [25] , six months [26] , ten years [11] or 20 years post-chemotherapy [27] . In the current study, we present the first prospective evidence for increased WML post-chemotherapy, more specifically in the deep WM.…”

“…For instance, persistent microglial activation can induce disrupted/dysregulated myelination, eventually resulting in axonal damage [ 28 , 29 ]. In our previous work, we observed increased neuroinflammation in juxtacortical lesions when compared to normal-appearing WM [25] , suggesting inflammatory pathways concurring with WM pathology (possibly with underlying demyelination). In the current study, deep, rather than juxtacortical WM lesion volumes increased.…”

Dietary zinc protects against methotrexate-induced neurotoxicity in rats via modulation of oxidative stress, inflammation and neuronal energy metabolism

“…Chemotherapy-induced neurotoxicity usually manifests as leucoencelopathy, cognitive deficits, peripheral neuropathy and mood disorders [9,10]. Increased neuro-immune response, oxidative stress and the release of pro-inflammatory cytokines in the brain have been suggested as important mechanisms in the development of chemotherapy-induced neurotoxicity [9,[11][12][13][14].…”