Genetic Modulation of Neurocognitive Development in Cancer Patients throughout the Lifespan: a Systematic Review

Blommaert

Weehaeghe

et al. 2021

Cancers

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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.

Section: Introductionmentioning

confidence: 99%

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

Blommaert

Weehaeghe

et al. 2021

Cancers

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“…While underlying mechanisms remain largely unknown, CRCI is hypothesized to be a complex interaction of vulnerability (i.e. mechanisms involved in DNA damage/repair or immune regulation [5] ), cancer biology, aging, and both direct or indirect toxic treatment effects [ 2 , 6 ]. Some chemotherapeutic agents are known to cross the blood brain barrier (BBB), which can directly cause brain damage in areas important for cognitive functioning.…”

Section: Introductionmentioning

confidence: 99%

Blood and neuroimaging biomarkers of cognitive sequelae in breast cancer patients throughout chemotherapy: A systematic review

Vissers

Smeets

et al. 2022

Translational Oncology

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Highlights Differences observed in all blood marker categories, from on-therapy until years later. Differences observed in metabolic and blood cell markers, even pre-chemotherapy. Blood markers were associated with cognition mainly years post-chemotherapy. Structural brain metrics associated with cognition shortly and years post-treatment.

“…Thirdly, diagnosis-related emotional stress can have a negative influence on the development of leukoencephalopathy and cognitive problems 8,69 . Lastly, the detection of polymorphisms in genes responsible for neurogenesis could help clinicians to predict the patient's susceptibility to leukoencephalopathy in the future 29,70 . The combination of more advanced neuroimaging techniques, detection of biomarkers, identification of genes involving neurogenesis or neuronal plasticity and a universal cognitive assessment protocol, should provide more clarity about long-term effects of leukoencephalopathy in cancer patients in the future.…”

Section: Methodological Considerations and Limitationsmentioning

confidence: 99%

Prevalence of leukoencephalopathy and its potential cognitive sequelae in cancer patients

Journal of Chemotherapy

Meylaers

Deprez

et al. 2020

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Due to the rising use of chemotherapy in cancer patients and growing survival rates, therapy-induced neurotoxic side effects are increasingly reported. Given the ambiguity about the prevalence and severity of leukoencephalopathy, one of such toxic side effects, in non-central nervous system (CNS) cancer patients, we performed a systematic literature search using the PubMed/Medline database to summarize existing literature regarding leukoencephalopathy epidemiology in non-CNS cancer patients and its potential cognitive sequelae. The search was based on the following terms: ('MRI' OR 'T2-weighted MRI' OR 'FLAIR') AND ('cancer' OR 'tumor' OR 'leukemia' OR 'neoplasms') AND ('chemotherapy' OR 'radiotherapy') AND ('posterior reversible encephalopathy' OR 'leukoencephalopathy' OR 'cerebral ischemia' OR 'stroke'). Thirtytwo studies discussing the occurrence of leukoencephalopathy in cancer patients were included, of which the majority investigated Acute Lymphoblastic Leukemia (ALL) patients (n=22).Regularly scanned ALL patients showed a prevalence of leukoencephalopathy between 17 -87%, and 15 -83% of patients presented with leukoencephalopathy when only scanned after a CNS event. When diagnosed with posterior reversible encephalopathy syndrome, 100% of patients showed leukoencephalopathy because its diagnosis is based in part on observable lesions. An increased prevalence was observed in ALL patients treated with higher doses of methotrexate (5 g/m2 MTX, 42 -87%) when compared to lower doses (< 5 g/m2, 32 -67%). By contrast, in breast cancer patients, white matter lesions were mainly detected in case of neurological symptoms, but not (yet) clearly associated with chemotherapy administration in general. However, chemotherapy treatment was associated with more infratentorial microbleeds in breast cancer patients. Up to 50% of other (neurologically asymptomatic) solid tumor patients presented white matter lesions, even years after treatment. When cognitive data were investigated, lesioned patients showed lower scores on neurocognitive tests in 50% of studies, years after ending therapy.In conclusion, leukoencephalopathy is well-documented for ALL patients (with a focus on methotrexate), but there is a lack of knowledge for other intravenous chemotherapeutics, other oncological populations, wider age ranges and risk factors (e.g. history of CNS event). Furthermore, the long-term neuropsychological impact and potential risk for neurodegenerative processes due to leukoencephalopathy remains inconclusive.Hence, large international databanks, epidemiological and prospective case-control studies are necessary to stratify risk groups for CNS-related side effects.