The association between pro-inflammatory cytokines, regional cerebral metabolism, and cognitive complaints following adjuvant chemotherapy for breast cancer

Pomykala, Kelsey L.; Ganz, Patricia A.; Bower, Julienne E.; Kwan, Lorna; Castellon, Steven A.; Mallam, S.; Cheng, I-Ning; Ahn, Ryun Sup; Breen, Elizabeth C.; Irwin, Michael R.; Silverman, D. H. S.

doi:10.1007/s11682-013-9243-2

Cited by 107 publications

(118 citation statements)

References 54 publications

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“…53 Several studies 50,54,55 have implicated cytokine-mediated neuroinflammation in cognitive impairment and brain injury among breast cancer survivors treated with ANTHR-containing regimens. However, inflammation and associated cognitive deficits are also present prior to initiation of adjuvant therapies.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors

2016

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IMPORTANCE Chemotherapy exposure is a known risk factor for cancer-related cognitive impairments. Anthracycline-based regimens are commonly used chemotherapies that have been shown to be associated with cognitive impairment and brain changes in clinical studies. OBJECTIVE To directly compare the effects of anthracycline and nonanthracycline regimens on cognitive status and functional brain connectivity. DESIGN, SETTING, AND PARTICIPANTS In this observational study, we retrospectively examined cognitive and resting state functional magnetic resonance imaging data acquired from 62 primary breast cancer survivors (mean [SD] age, 54.7 [8.5] years) who were more than 2 years off-therapy, on average. Twenty of these women received anthracycline-based chemotherapy as part of their primary treatment, 19 received nonanthracycline regimens, and 23 did not receive any chemotherapy. Participants were enrolled at a single academic institution (Stanford University) from 2008 to 2014, and the study analyses were performed at this time. MAIN OUTCOMES AND MEASURES Cognitive status was measured using standardized neuropsychological tests, and functional brain connectivity was evaluated using resting state functional magnetic resonance imaging with a focus on the brain’s default mode network. RESULTS The anthracycline group demonstrated significantly lower verbal memory performance including immediate recall (F = 3.73; P = .03) and delayed recall (F = 11.11; P < .001) as well as lower left precuneus connectivity (F = 7.48; P = .001) compared with the other 2 groups. Patient-reported outcomes related to cognitive dysfunction (F = 7.27; P = .002) and psychological distress (F = 5.64; P = .006) were similarly elevated in both chemotherapy groups compared with the non–chemotherapy-treated controls. CONCLUSIONS AND RELEVANCE These results suggest that anthracyclines may have greater negative effects than nonanthracycline regimens on particular cognitive domains and brain network connections. Both anthracycline and nonanthracycline regimens may have nonspecific effects on other cognitive domains as well as certain patient reported outcomes. Further research is needed to identify potential methods for protecting the brain against the effects of various chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors

2016

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“…Possible mechanisms of brain injury following breast cancer chemotherapy (BCC) include direct toxicity to neural progenitor cells (Monje and Dietrich, 2012), elevation of cytokine release and oxidative stress (Conroy, et al, 2013b;Ganz, et al, 2013;Kesler, et al, 2013a;Pomykala, et al, 2013b;Vardy, et al, 2007), DNA damage and epigenetic alterations (Conroy, et al, 2013b), deficient estrogen-related protection of healthy brain cells (Hogervorst, 2013) following chemotherapy-induced menopause (Conroy, et al, 2013a) and altered cerebral blood supply through blood vessel damage (Seigers, et al, 2010) and/or chemotherapy-induced anemia (O'Shaughnessy, 2003). Chemotherapy-related mechanisms interact with other factors including cancer pathogenesis (Kesler, et al, 2011), allostatic load (Miller, et al, 2008) and genetic variations (Ahles and Saykin, 2007).…”

Section: Brain Aging Cancer and Chemotherapymentioning

confidence: 99%

“…BCC survivors show elevated neurochemical markers of microglial activity (i.e. myo-inositol) (Kesler, et al, 2013b) and increased peripheral pro-inflammatory cytokines levels (Ganz, et al, 2013;Kesler, et al, 2013a;Kesler, et al, 2013b;Pomykala, et al, 2013b;Vardy, et al,2007). Compared to healthy women, BCC survivors show increased pro-inflammatory cytokine levels with increased age (Kesler, et al, 2013a).…”

Section: Brain Aging Cancer and Chemotherapymentioning

confidence: 99%

“…Two PET studies from the same research group examined both task-related and resting state cerebral metabolism in BCC (Pomykala, et al, 2013b;Silverman, et al, 2007). The earlier study involved 16 BCC survivors 5–10 years post-chemotherapy and 8 healthy female controls (Silverman, et al, 2007) while the later study involved 23 chemotherapy treated and 10 non-chemotherapy treated breast cancer patients assessed after completing chemotherapy and 1 year later (Pomykala, et al, 2013b).…”

Section: Dmn and Chemotherapymentioning

confidence: 99%

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Default mode network as a potential biomarker of chemotherapy-related brain injury

Kesler

2014

Neurobiology of Aging

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Chronic medical conditions and/or their treatments may interact with aging to alter or even accelerate brain senescence. Adult onset cancer, for example, is a disease associated with advanced aging and emerging evidence suggests a profile of subtle but diffuse brain injury following cancer chemotherapy. Breast cancer is currently the primary model for studying these “chemobrain” effects. Given the widespread changes to brain structure and function as well as the common impairment of integrated cognitive skills observed following breast cancer chemotherapy, it is likely that large-scale brain networks are involved. Default mode network (DMN) is a strong candidate considering its preferential vulnerability to aging and sensitivity to toxicity and disease states. Additionally, chemotherapy is associated with several physiologic effects including increased inflammation and oxidative stress that are believed to elevate toxicity in the DMN. Biomarkers of DMN connectivity could aid in the development of treatments for chemotherapy-related cognitive decline. For example, certain nutritional interventions could potentially reduce the metabolic changes (e.g. amyloid beta toxicity) associated with DMN disruption.

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“…IL-1 receptor antagonist (ra) and sTNF-RII). Significant relationships were found between all markers and metabolism at the baseline timepoint, and additionally, baseline levels of IL1ra and sTNFRII were significantly positively associated with increased frontal lobe metabolism at the 1 year follow-up timepoint (Pomykala et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Prevalence, mechanisms, and management of cancer-related cognitive impairment

Janelsins

Kesler

Ahles

et al. 2014

International Review of Psychiatry

561

485

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This review summarizes the current literature on cancer-related cognitive impairment (CRCI) with a focus on prevalence, mechanisms, and possible interventions for CRCI in those who receive adjuvant chemotherapy for non-central nervous system tumors and is primarily focused on breast cancer. CRCI is characterized as deficits in areas of cognition including memory, attention, concentration, and executive function. Development of CRCI can impair quality of life and impact treatment decisions. CRCI is highly prevalent; these problems can be detected in up to 30% of patients prior to chemotherapy; up to 75% of patients report some form of CRCI during treatment, and CRCI is still present in up to 35% of patients many years following completion of treatment. While the trajectory of CRCI is becoming better understood, the mechanisms underlying the development of CRCI are still obscure; however, host characteristics, immune dysfunction, neural toxicity, and genetics may play key roles in the development and trajectory of CRCI. Intervention research is limited, though strategies to maintain function are being studied with promising preliminary findings. This review highlights key research being conducted in these areas, both in patient populations and in animals, which will ultimately result in better understanding and effective treatments for CRCI.

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The association between pro-inflammatory cytokines, regional cerebral metabolism, and cognitive complaints following adjuvant chemotherapy for breast cancer

Cited by 107 publications

References 54 publications

Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors

Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors

Default mode network as a potential biomarker of chemotherapy-related brain injury

Prevalence, mechanisms, and management of cancer-related cognitive impairment

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