Inflammation, Attention, and Processing Speed in Patients With Breast Cancer Before and After Chemotherapy.

BACKGROUND: Inflammation may contribute to cognitive difficulties in patients with breast cancer. We tested 2 hypotheses: inflammation is elevated in patients with breast cancer vs noncancer control participants and inflammation in patients is associated with worse attention and processing speed over the course of chemotherapy. METHODS: Serum cytokines (interleukin [IL]-4, 6, 8, 10; tumor necrosis factor [TNF]-α) and soluble receptors [sTNFRI, II]) were measured in 519 females with breast cancer before and after chemotherapy and 338 females without cancer serving as control participants. Attention and processing speed were measured by Rapid Visual Processing (RVP), Backward Counting (BCT), and Trail Making-A (TMT-A) tests. Linear regression models examined patient vs control cytokines and receptor levels, adjusting for covariates. Linear regression models also examined relationships between patient cytokines and receptor levels and test performance, adjusting for age, body mass index, anxiety, depression, cognitive reserve, and chemotherapy duration. Statistical tests were 2-sided (α = .05). RESULTS: sTNFRI and sTNFRII increased over time in patients relative to controls, whereas IL-4, IL-6, and IL-10 decreased. Prechemotherapy, higher IL-8 associated with worse BCT (ß = 0.610, SE = 0.241, P = .01); higher IL-4 (ß = -1.098, SE = 0.516, P = .03) and IL-10 (ß = -0.835, SE = 0.414, P = .04) associated with better TMT-A. Postchemotherapy, higher IL-8 (ß = 0.841, SE = 0.260, P = .001), sTNFRI (ß = 6.638, SE = 2.208, P = .003), and sTNFRII (ß = 0.913, SE = 0.455, P = .045) associated with worse BCT; higher sTNFRII also associated with worse RVP (ß = -1.316, SE = 0.587, P = .03). At prechemotherapy, higher IL-4 predicted RVP improvement over time (ß = 0.820, SE = 0.336, P = .02); higher sTNFRI predicted worse BCT over time (ß = 5.566, SE = 2.367, P = .02). Longitudinally, increases in IL-4 associated with BCT improvement (ß = -0.564, SE = 0.253, P = .03). CONCLUSIONS: Generally, worse attention and processing speed were associated with higher inflammatory cytokines and receptors and lower anti-inflammatory cytokines in patients; future confirmatory studies are needed.

Relationships between cytokines and cognitive function from pre- to post-chemotherapy in patients with breast cancer.

Cancer-related cognitive decline (CRCD) is a clinically important problem and negatively affects daily functioning and quality of life. We conducted a pilot longitudinal study from pre- to post-chemotherapy in patients with breast cancer to assess changes in inflammation and cognition over time, as well as the impact of baseline cytokine level on post-chemotherapy cognitive scores. We found that concentrations of IL-6, MCP-1, sTNFRI, and sTNFRII significantly increased in patients, while IL-1ß significantly decreased (p < 0.05). After controlling for covariates, increases in IL-6 and MCP-1 were associated with worse executive function and verbal fluency in patients from pre- to post-chemotherapy (p < 0.05). Higher baseline IL-6 was associated with better performance on executive function and verbal fluency post chemotherapy (p < 0.05). Overall, these results suggest that chemotherapy-associated increases in cytokines/receptors is associated with worse cognitive function. Larger studies are needed to confirm these findings.

Associations between inflammatory markers and cognitive function in breast cancer patients receiving chemotherapy.

BACKGROUND: Cancer-related cognitive impairment (CRCI) is often related to chemotherapy. Increased chronic inflammation is believed to play a key role in the development of CRCI related to chemotherapy but studies assessing this hypothesis specifically in patients receiving chemotherapy are rare. METHODS: We assessed several cognitive domains using the Cambridge Neuropsychological Test Automated Battery (CANTAB) in twenty-two breast cancer patients currently receiving chemotherapy. We also measured inflammatory cytokine and receptor (MCP-1, TNF-α, sTNFRI, sTNFRII) concentrations in patient sera using Luminex assays. These concentrations were log-transformed to obtain a normal distribution. Associations between log-transformed cytokines and cognition were evaluated using Pearson correlations and linear regression, taking into account relevant covariates. RESULTS: Increased concentrations of sTNFRI and sTNFRII were associated with poorer performance on the CANTAB Delayed Matching to Sample (DMS, tests visual memory). Increasing sTNFRI levels were negatively correlated with DMS percent correct (r=-0.47, p=0.029) and DMS percent correct after a 12 second (s) delay (r=-0.65, p=0.001). Increasing levels of sTNFRII negatively correlated with DMS percent correct after 12s delay (r=-0.57, p=0.006). After controlling for relevant demographic (i.e. age, education) and clinical variables (i.e. disease stage, regimen type), we found that increased sTNFRI remained significantly related to decline on the DMS at the 12s delay (p=0.018). CONCLUSION: This preliminary study shows a significant association between higher sTNFRI and lower scores on the short-term visual memory delayed match to sample test in breast cancer patients receiving chemotherapy, supporting the hypothesis that sTNFRI is involved in CRCI.

A clinically relevant dose of cyclophosphamide chemotherapy impairs memory performance on the delayed spatial alternation task that is sustained over time as mice age.

BACKGROUND: Cyclophosphamide chemotherapy is a mainstay of adjuvant breast cancer treatment. Unfortunately, this drug is associated with cognitive impairments in cancer patients that may accelerate cognitive aging. Memory is particularly affected in many patients. In order to better understand the precise cognitive impairments caused by this chemotherapy agent, we investigated a clinically relevant dose and administration paradigm on delayed spatial memory abilities in C57BL/6 mice. We utilized a delayed alternation paradigm similar to a delayed match to sample paradigm reported to be sensitive in human neurotoxicology research. METHODS: A dose of 200mg/kg cyclophosphamide was administered intravenously (at weekly intervals) for 4 weeks to C57BL/6 mice starting at 6 ½ months of age. Memory was tested in mice using a reward-based delayed spatial alternation paradigm with delay values of 1.5, 3, 6.1, 12.4 and 25s presented randomly over 80 sessions (16 reinforcers per session), and testing began at the initiation of chemotherapy through 3 months. RESULTS: At the longest delay, i.e., that requiring the greatest memory, mice treated with chemotherapy exhibited a significant decline over time in percent correct which leveled off compared to controls that continued to improve slightly. CONCLUSIONS: Our clinically relevant model shows cyclophosphamide chemotherapy causes a slight decline in delayed spatial memories at the longest delay that is sustained over time as mice age.

IGF-1 partially restores chemotherapy-induced reductions in neural cell proliferation in adult C57BL/6 mice.

Chemotherapeutic agents produce persistent difficulties in memory through an unknown mechanism. We tested the hypothesis that chemotherapeutic agents readily able to cross the blood-brain barrier (cyclophosphamide and fluorouracil), as opposed to those not known to readily cross the barrier (paclitaxel and doxorubicin), reduce neural cell proliferation following chemotherapy. We found that 5-bromo-2-deoxyuridine labeling following chemotherapy given to C57BL/6 mice revealed a similar reduction in neural cell proliferation in the dentate gyrus for all four agents. Insulin-like growth factor 1, a molecule implicated in promoting neurogenesis, counteracted the effects of high doses of chemotherapy on neural cell proliferation.

Iterative multi-channel coherence analysis with applications.

An iterative learning algorithm for performing Multi-Channel Coherence Analysis (MCCA) is developed in this paper. MCCA is an extension of the well-known Canonical Correlation Analysis (CCA) that allows for more than two data channels to be analyzed. This paper discusses a standard method for performing MCCA and compares it to a newly developed data-driven and iterative approach. The proposed algorithm is then tested on two examples and its performance is evaluated in terms of estimation errors with respect to the values obtained using the standard MCCA algorithm. The first example uses a synthesized data set while the second example uses a real data set based on multi-spectral satellite imagery of the Earth's surface.

2,3,7,8-Tetracholorodibenzo-p-dioxin exposure disrupts granule neuron precursor maturation in the developing mouse cerebellum.

The widespread environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been linked to developmental neurotoxicity associated with abnormal cerebellar maturation in both humans and rodents. TCDD mediates toxicity via binding to the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of xenobiotic metabolizing enzymes and growth regulatory molecules. Our previous studies demonstrated that cerebellar granule neuron precursor cells (GNPs) express transcriptionally active AhR during critical developmental periods. TCDD exposure also impaired GNP proliferation and survival in vitro. Therefore, this study tested the hypothesis that TCDD exposure disrupts cerebellar development by interfering with GNP differentiation. In vivo experiments indicated that TCDD exposure on postnatal day (PND) 6 resulted in increased expression of a mitotic marker and increased thickness of the external granule layer (EGL) on PND10. Expression of the early differentiation marker TAG-1 was also more pronounced in postmitotic, premigratory granule neurons of the EGL, and increased apoptosis of GNPs was observed. On PND21, expression of the late GNP differentiation marker GABA(A alpha 6) receptor (GABAR(A alpha 6)) and total estimated cell numbers were both reduced following exposure on PND6. Studies in unexposed adult AhR(-/-) mice revealed lower GABAR(A alpha 6) levels and DNA content. In vitro studies showed elevated expression of the early differentiation marker p27/Kip1 and the GABAR(A alpha 6) in GNPs following TCDD exposure, and the expression patterns of proteins related to granule cell neurite outgrowth, beta III-tubulin and polysialic acid neural cell adhesion molecule, were consistent with enhanced neuroblast differentiation. Together, our data suggest that TCDD disrupts a normal physiological role of AhR, resulting in compromised GNP maturation and neuroblast survival, which impacts final cell number in the cerebellum.