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    Vitamin C alleviates LPS-induced cognitive impairment in mice by suppressing neuroinflammation and oxidative stress. Zhang Xiao-Ying,Xu Zhi-Peng,Wang Wei,Cao Jiang-Bei,Fu Qiang,Zhao Wei-Xing,Li Yang,Huo Xiu-Lin,Zhang Li-Ming,Li Yun-Feng,Mi Wei-Dong International immunopharmacology Neuroinflammation is believed to be one of the primary causes of cognitive impairment. Previous studies showed that the antioxidant vitamin C (Vit C) performs many beneficial functions such as immunostimulant and anti-inflammatory actions, but its role in inflammatory cognitive impairment is unclear. In the current study, we investigated the effect and possible mechanism of action of Vit C in lipopolysaccharide (LPS)-induced cognitive impairment. Intracerebroventricular LPS-induced memory impairment was used as the model for neuroinflammatory cognitive dysfunction. Vit C was administered by intracerebroventricular microinjection 30 min prior to LPS exposure. It was found that Vit C significantly protected animals from LPS-induced memory impairment as evidenced by improved performance in the Morris water maze and novel object recognition tests without changes in spontaneous locomotor activity. Vit C pretreatment inhibited the activation of microglia and the production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Furthermore, Vit C pretreatment markedly decreased the malondialdehyde (MDA) level, increased superoxide dismutase (SOD) activity, and modulated the Bax/Bcl-2 ratio and p-p38 MAPK activation in the hippocampus of LPS-treated mice. Together, these results suggest that vitamin C pretreatment could protect mice from LPS-induced cognitive impairment, possibly through the modulation of oxidative stress and inflammatory responses. 10.1016/j.intimp.2018.10.020
    Association of Cerebrospinal Fluid Neurofilament Light Protein With Risk of Mild Cognitive Impairment Among Individuals Without Cognitive Impairment. Kern Silke,Syrjanen Jeremy A,Blennow Kaj,Zetterberg Henrik,Skoog Ingmar,Waern Margda,Hagen Clinton E,van Harten Argonde C,Knopman David S,Jack Clifford R,Petersen Ronald C,Mielke Michelle M JAMA neurology Importance:Accumulating data suggest that elevated cerebrospinal fluid (CSF) neurofilament light (NfL) and neurogranin (Ng) levels are associated with cognitive decline and may be useful markers of neurodegeneration. However, to our knowledge, previous studies have not assessed these CSF markers in the community, evaluated them with regards to risk of mild cognitive impairment (MCI), or compared their prognostic value with CSF total tau (T-tau) or phosphorylated tau (P-tau). Objective:To determine (1) whether CSF NfL and Ng levels were associated with risk of MCI, (2) the effect size of these markers compared with CSF T-tau or P-tau for risk of MCI, and (3) whether CSF amyloid-β (Aβ42) modified these associations. Design, Setting and Participants:The analyses included 648 participants without cognitive impairment who were enrolled into the prospective population-based Mayo Clinic Study of Aging between January 2004 and December 2015 with available CSF data and at least 1 follow-up visit. Participants were followed up for a median of 3.8 years (interquartile range, 2.6-5.4 years). The CSF NfL and Ng levels were measured using an in-house sandwich enzyme-linked immunosorbent assay. The CSF Aβ42, T-tau, and P-tau levels were measured with automated electrochemiluminescence immunoassays. Cox proportional hazards models, with age as the timescale, were used to assess the association between CSF NfL, Ng, Aβ42, T-tau, or P-tau with risk of MCI after adjusting for sex, education, apolipoprotein E genotype, and the Charlson comorbidity index. To examine CSF Aβ42 as an effect modifier, it was categorized into tertiles; the bottom tertile was defined as having elevated brain amyloid. Main Outcomes and Measures:Risk of MCI. Results:At baseline, the median age of the 648 participants without cognitive impairment was 72.3 years (range, 50.7-95.3 years) and 366 (56.5%) were men; 96 (14.8%) developed incident MCI. Compared with the bottom quartile, the top quartile of CSF NfL was associated with a 3.1-fold increased risk of MCI (hazard ratio, 3.13; 95% CI, 1.36-7.18) in multivariate models. Neither CSF T-tau, P-tau, nor Ng was associated with risk of MCI. There was no interaction between Aβ42 and CSF NfL for risk of MCI. Conclusions and Relevance:Elevated CSF NfL levels but not CSF T-tau, P-tau or Ng are a risk factor for MCI in a community population and are independent of brain amyloid. 10.1001/jamaneurol.2018.3459
    Profile of cognitive impairment and underlying pathology in multiple system atrophy. Koga Shunsuke,Parks Adam,Uitti Ryan J,van Gerpen Jay A,Cheshire William P,Wszolek Zbigniew K,Dickson Dennis W Movement disorders : official journal of the Movement Disorder Society BACKGROUND:The objectives of this study were to elucidate any potential association between α-synuclein pathology and cognitive impairment and to determine the profile of cognitive impairment in multiple system atrophy (MSA) patients. To do this, we analyzed the clinical and pathologic features in autopsy-confirmed MSA patients. METHODS:We retrospectively reviewed medical records, including neuropsychological test data, in 102 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank. The burden of glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were semiquantitatively scored in the limbic regions and middle frontal gyrus. We also assessed concurrent pathologies potentially causing dementia including Alzheimer's disease, hippocampal sclerosis, and cerebrovascular pathology. RESULTS:Of 102 patients, 33 (32%) were documented to have cognitive impairment. Those that received objective testing, deficits primarily in processing speed and attention/executive functions were identified, which suggests a frontal-subcortical pattern of dysfunction. Of these 33 patients with cognitive impairment, 8 patients had concurrent pathologies of dementia. MSA patients with cognitive impairment had a greater burden of neuronal cytoplasmic inclusions in the dentate gyrus than patients without cognitive impairment, both including and excluding patients with concurrent pathologies of dementia. CONCLUSIONS:The cognitive deficits observed in this study were more evident on neuropsychological assessment than with cognitive screens. Based on these findings, we recommend that clinicians consider more in-depth neuropsychological assessments if patients with MSA present with cognitive complaints. Although we did not identify the correlation between cognitive deficits and responsible neuroanatomical regions, a greater burden of neuronal cytoplasmic inclusions in the limbic regions was associated with cognitive impairment in MSA. © 2016 International Parkinson and Movement Disorder Society. 10.1002/mds.26874
    Chronic acrylamide exposure induced glia cell activation, NLRP3 infl-ammasome upregulation and cognitive impairment. Liu Ying,Zhang Xing,Yan Dandan,Wang Yiqi,Wang Na,Liu Yufan,Tan Aijun,Chen Xiaoyi,Yan Hong Toxicology and applied pharmacology Acrylamide (ACR), a potential neurotoxin, is present in diet and drinking water. Dietary exposure contributes to cognitive impairment, but relevant mechanism information is limited. Neuroinflammation plays important roles in neurodegenerative disorders. This study aimed to explore whether chronic acrylamide exposure induced neuronal lesions, microglial activation, NLRP3 inflammasome-mediated neuroinflammation and cognitive impairment. For this purpose, 36 Sprague-Dawley (SD) rats were randomly divided into three groups (n = 12/group) and maintained on treated drinking water providing dosages of 0, 0.5, or 5 mg/kg/day ACR for 12 months. Chronic exposure to ACR caused gait abnormality and cognitive dysfunction, which was associated with neuronal lesions, decrease in synapse associated proteins including synapsin I (SYN1), synaptophysin (SYP) and postsynaptic density protein 95 (PSD95), neurogenesis suppression as shown by reduced brain derived neurotrophic factor (BDNF) and doublecortin (DCX) in the hippocampus and frontal cortex. ACR stimulated glial proliferation and microglial activation by increasing GFAP, Iba-1, Iba-1CD68 positive cells. ACR markedly upregulated the protein levels of NLRP3 inflammasome constituents NLRP3, caspase-1 and increased pro-IL-1β and IL-1β. ACR elevated the protein P62 to suppress NLPR3 inflammasome cleavage. Inflammatory cytokines including TNF-α, IL-6 and Cox-2 were also significantly increased after NF-κB pathway activation, which aggravated neuronal lesions and caused memory deficits. This work helped to propose the possible mechanism of chronic exposure of ACR-induced neurotoxicity. 10.1016/j.taap.2020.114949
    MMP-9-BDNF pathway is implicated in cognitive impairment of male individuals with methamphetamine addiction during early withdrawal. Cheng Mei,Liu Qiang,Wang Yan,Hao Yuling,Jing Pengcheng,Jiao Shaoli,Ma Lin,Pan Chenmin,Wu Yulong Behavioural brain research Cognitive impairment is often concomitant with current and abstinent methamphetamine (METH) misuse. However, the mechanism underlying the pathogenesis of cognitive impairment induced by METH remains unclear. As evidence indicates that brain-derived neurotrophic factor (BDNF) is associated with METH addiction, the present study aimed to investigate whether BDNF and the proteins regulating the BDNF signaling pathway might be implicated in the cognitive impairment of the METH abusers during early withdrawal. A total of 171 male subjects were recruited, including 85 METH abstainers and 86 healthy controls. Cognitive function was evaluated with the Montreal Cognitive Assessment (MoCA) screening tool. The levels of serum proteins that regulate the BDNF signaling pathway were measured using enzyme-linked immunosorbent assay kits. 61.18% METH abstainers were determined to have cognitive impairment (MoCA<26). The serum levels of mBDNF, proBDNF, and MMP-9, as well as the ratio of the mBDNF/proBDNF (M/P) were significantly decreased in the cognition-impaired METH abstainers than in the cognition-unimpaired METH abstainers. mBDNF, proBDNF, TrkB, MMP-9, MMP-9 activity, and M/P were significantly correlated with the MoCA score in the METH abstainers. The combination of mBDNF, TrkB, MMP-9, and MMP-9 activity demonstrated excellent diagnostic potential for cognitive impairment of METH abusers during early withdrawal (AUC = 0.978). The results provide the prospective evidence that the MMP-9-BDNF pathway may underlie the pathogenesis of cognitive impairment in METH abusers during early withdrawal. 10.1016/j.bbr.2019.03.020
    Protective effects of tauroursodeoxycholic acid on lipopolysaccharide-induced cognitive impairment and neurotoxicity in mice. Wu Xian,Liu Caihong,Chen Liang,Du Yi-Feng,Hu Mei,Reed Miranda N,Long Yan,Suppiramaniam Vishnu,Hong Hao,Tang Su-Su International immunopharmacology Accumulating evidence has shown that tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of neurological diseases. However, whether TGR5 agonist TUDCA can improve lipopolysaccharide (LPS)-induced cognitive impairment in mice is less clear. Using a model of cognitive impairment with LPS (2.0 μg) we investigated the effects of TUDCA (200 or 400 μg) on cognitive dysfunction and neurotoxicity in mice. Both Morris water maze and Y-maze avoidance tests showed that TUDCA treatment significantly alleviated LPS-induced behavioral impairments. More importantly, we found that TUDCA treatment reversed TGR5 down-regulation, prevented neuroinflammation via inhibiting NF-κB signaling in the hippocampus of LPS-treated mice. Additionally, TUDCA treatment decreased LPS-induced apoptosis through decreasing TUNEL-positive cells and the overexpression of caspase-3, increasing the ratio of Bcl-2/Bax. TUDCA treatment also ameliorated synaptic plasticity impairments by increasing the ratio of mBDNF/proBDNF, the number of dendritic spines and the expression of synapse-associated proteins in the hippocampus. Our results indicated that TUDCA can improve cognitive impairment and neurotoxicity induced by LPS in mice, which is involved in TGR5-mediated NF-κB signaling. 10.1016/j.intimp.2019.03.065
    A Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction. Hay Meredith,Polt Robin,Heien Michael L,Vanderah Todd W,Largent-Milnes Tally M,Rodgers Kathleen,Falk Torsten,Bartlett Mitchell J,Doyle Kristian P,Konhilas John P The Journal of pharmacology and experimental therapeutics Increasing evidence indicates that decreased brain blood flow, increased reactive oxygen species (ROS) production, and proinflammatory mechanisms accelerate neurodegenerative disease progression such as that seen in vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease and related dementias. There is a critical clinical need for safe and effective therapies for the treatment and prevention of cognitive impairment known to occur in patients with VCID and chronic inflammatory diseases such as heart failure (HF), hypertension, and diabetes. This study used our mouse model of VCID/HF to test our novel glycosylated angiotensin-(1-7) peptide Ang-1-6-O-Ser-Glc-NH2 (PNA5) as a therapy to treat VCID and to investigate circulating inflammatory biomarkers that may be involved. We demonstrate that PNA5 has greater brain penetration compared with the native angiotensin-(1-7) peptide. Moreover, after treatment with 1.0/mg/kg, s.c., for 21 days, PNA5 exhibits up to 10 days of sustained cognitive protective effects in our VCID/HF mice that last beyond the peptide half-life. PNA5 reversed object recognition impairment in VCID/HF mice and rescued spatial memory impairment. PNA5 activation of the Mas receptor results in a dose-dependent inhibition of ROS in human endothelial cells. Last, PNA5 treatment decreased VCID/HF-induced activation of brain microglia/macrophages and inhibited circulating tumor necrosis factor , interleukin (IL)-7, and granulocyte cell-stimulating factor serum levels while increasing that of the anti-inflammatory cytokine IL-10. These results suggest that PNA5 is an excellent candidate and "first-in-class" therapy for treating VCID and other inflammation-related brain diseases. 10.1124/jpet.118.254854
    The triangle of death of neurons: Oxidative damage, mitochondrial dysfunction, and loss of choline-containing biomolecules in brains of mice treated with doxorubicin. Advanced insights into mechanisms of chemotherapy induced cognitive impairment ("chemobrain") involving TNF-α. Ren Xiaojia,Keeney Jeriel T R,Miriyala Sumitra,Noel Teresa,Powell David K,Chaiswing Luksana,Bondada Subbarao,St Clair Daret K,Butterfield D Allan Free radical biology & medicine Cancer treatments are developing fast and the number of cancer survivors could arise to 20 million in United State by 2025. However, a large fraction of cancer survivors demonstrate cognitive dysfunction and associated decreased quality of life both shortly, and often long-term, after chemotherapy treatment. The etiologies of chemotherapy induced cognitive impairment (CICI) are complicated, made more so by the fact that many anti-cancer drugs cannot cross the blood-brain barrier (BBB). Multiple related factors and confounders lead to difficulties in determining the underlying mechanisms. Chemotherapy induced, oxidative stress-mediated tumor necrosis factor-alpha (TNF-α) elevation was considered as one of the main candidate mechanisms underlying CICI. Doxorubicin (Dox) is a prototypical reactive oxygen species (ROS)-generating chemotherapeutic agent used to treat solid tumors and lymphomas as part of multi-drug chemotherapeutic regimens. We previously reported that peripheral Dox-administration leads to plasma protein damage and elevation of TNF-α in plasma and brain of mice. In the present study, we used TNF-α null (TNFKO) mice to investigate the role of TNF-α in Dox-induced, oxidative stress-mediated alterations in brain. We report that Dox-induced oxidative stress in brain is ameliorated and brain mitochondrial function assessed by the Seahorse-determined oxygen consumption rate (OCR) is preserved in brains of TNFKO mice. Further, we show that Dox-decreased the level of hippocampal choline-containing compounds and brain phospholipases activity are partially protected in TNFKO group in MRS study. Our results provide strong evidence that Dox-targeted mitochondrial damage and levels of brain choline-containing metabolites, as well as phospholipases changes decreased in the CNS are associated with oxidative stress mediated by TNF-α. These results are consistent with the notion that oxidative stress and elevated TNF-α in brain underlie the damage to mitochondria and other pathological changes that lead to CICI. The results are discussed with reference to our identifying a potential therapeutic target to protect against cognitive problems after chemotherapy. 10.1016/j.freeradbiomed.2018.12.029
    A mechanistic cohort study evaluating cognitive impairment in women treated for breast cancer. Vardy Janette L,Stouten-Kemperman Myrle M,Pond Gregory,Booth Christopher M,Rourke Sean B,Dhillon Haryana M,Dodd Anna,Crawley Adrian,Tannock Ian F Brain imaging and behavior Some women report cognitive impairment after adjuvant chemotherapy (CTh) for breast cancer. Here we explore cognitive function, and underlying mechanisms with blood tests and functional magnetic resonance imaging (fMRI). Women treated for early breast cancer were recruited to three groups based on self-reported cognitive symptoms (CS) using FACT-Cog scores. CTh + CS+ (n = 44) had received chemotherapy and self-reported cognitive symptoms; CTh + CS- (n = 52) had chemotherapy but did not report cognitive problems; CTh- (n = 30) had not received chemotherapy. Clinical and computer-based neuropsychological tests were performed. Blood tests included 10 cytokines, sex hormones, coagulation factors, and apolipoprotein-E genotype. fMRI (n = 101) was performed while subjects performed an n-back memory task. Participants had median age 50 (range: 29-60) years and were a median of 17 months post-diagnosis. On clinical neuropsychological tests 19% had cognitive impairment using Global Deficit Score, and 36% using International Cancer and Cognition Task Force criteria with no significant differences in cognitive impairment rates between groups. CTh + CS+ had significantly more fatigue, anxiety/depression and poorer quality-of-life than other groups. There was no association between FACT-Cog and neuropsychological scores. There were significant differences in frontal and parietal regions on fMRI scans: CTh- showed hyperactivation compared to chemotherapy-treated groups, CTh + CS+ had more frontal activation than CTh + CS-. Elevated IL-1, IL-2 were associated weakly and IL-8 more strongly with neuropsychological impairment (rho > 0.20). There were no differences in global cognitive impairment between groups. Cognitive symptoms were associated with fatigue and anxiety/depression, but not with objective cognitive impairment. fMRI scans differed among the three groups. 10.1007/s11682-017-9728-5
    [A Structural Model for Chemotherapy Related Cognitive Impairment and Quality of Life in Breast Cancer Patients]. Lee Jung Ran,Oh Pok Ja Journal of Korean Academy of Nursing PURPOSE:This study aimed to develop and test a structural model for chemotherapy-related cognitive impairment of breast cancer patients based on a literature review and Hess and Insel's chemotherapy-related cognitive change model. METHODS:The Participants consisted of 250 patients who were ≥19 years of age. The assessment tools included the Menopause Rating Scale, Symptom Experience Scale, Hospital Anxiety and Depression Scale, Everyday Cognition, and Functional Assessment of Cancer Therapy-Breast Cancer. Data were analyzed using the SPSS 21.0 and AMOS 21.0 programs. RESULTS:The modified model was a good fit for the data. The model fit indices were χ²=423.18 (<.001), χ²/df=3.38, CFI=.91, NFI=.91, TLI=.89, SRMR=.05, RMSEA=.09, and AIC=515.18. Chemotherapy-related cognitive impairment was directly influenced by menopausal symptoms (β=.38, =.002), depression and anxiety (β=.25, =.002), and symptom experiences (β=.19, =.012). These predictors explained 47.7% of the variance in chemotherapy-related cognitive impairment. Depression and anxiety mediated the relations among menopausal symptoms, symptom experiences, and with chemotherapy related cognitive impairment. Depression and anxiety (β=-.51, =.001), symptom experiences (β=-.27, =.001), menopausal symptoms (β=-.22, =.008), and chemotherapy-related cognitive impairment (β=-.15, =.024) had direct effects on the quality of life and these variables explained 91.3%. CONCLUSION:These results suggest that chemotherapy-related toxicity is highly associated with cognitive decline and quality of life in women with breast cancer. Depression and anxiety increased vulnerability to cognitive impairment after chemotherapy. Nursing intervention is needed to relieve chemotherapy-related toxicity and psychological factor as well as cognitive decline for quality of life in patients undergoing chemotherapy. 10.4040/jkan.2019.49.4.375
    Cancer-related cognitive impairment: an update on state of the art, detection, and management strategies in cancer survivors. Lange M,Joly F,Vardy J,Ahles T,Dubois M,Tron L,Winocur G,De Ruiter M B,Castel H Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Advances in diagnostic and therapeutic strategies in oncology have significantly increased the chance of survival of cancer patients, even those with metastatic disease. However, cancer-related cognitive impairment (CRCI) is frequently reported in patients treated for non-central nervous system cancers, particularly during and after chemotherapy. DESIGN:This review provides an update of the state of the art based on PubMed searches between 2012 and March 2019 on 'cognition', 'cancer', 'antineoplastic agents' or 'chemotherapy'. It includes the most recent clinical, imaging and pre-clinical data and reports management strategies of CRCI. RESULTS:Evidence obtained primarily from studies on breast cancer patients highlight memory, processing speed, attention and executive functions as the most cognitive domains impaired post-chemotherapy. Recent investigations established that other cancer treatments, such as hormone therapies and targeted therapies, can also induce cognitive deficits. Knowledge regarding predisposing factors, biological markers or brain functions associated with CRCI has improved. Factors such as age and genetic polymorphisms of apolipoprotein E, catechol-O-methyltransferase and BDNF may predispose individuals to a higher risk of cognitive impairment. Poor performance on neuropsychological tests were associated with volume reduction in grey matter, less connectivity and activation after chemotherapy. In animals, hippocampus-based memory and executive functions, mediated by the frontal lobes, were shown to be particularly susceptible to the effects of chemotherapy. It involves altered neurogenesis, mitochondrial dysfunction or brain cytokine response. An important next step is to identify strategies for managing cognitive difficulties, with primary studies to assess cognitive training and physical exercise regimens. CONCLUSIONS:CRCI is not limited to chemotherapy. A multidisciplinary approach has improved our knowledge of the complex mechanisms involved. Nowadays, studies evaluating cognitive rehabilitation programmes are encouraged to help patients cope with cognitive difficulties and improve quality of life during and after cancer. 10.1093/annonc/mdz410
    Neuronal autoantibodies associated with cognitive impairment in melanoma patients. Bartels F,Strönisch T,Farmer K,Rentzsch K,Kiecker F,Finke C Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Cancer-related cognitive impairment is an important complication in cancer patients, yet the underlying mechanisms remain unknown. Over the last decade, the field of paraneoplastic neurological syndromes has been dramatically changed by the discovery of new neuronal autoantibodies, some of them associated with cognitive impairment. We aimed to assess the prevalence of neuronal autoantibodies in melanoma patients and their association with neurological and cognitive dysfunction. PATIENTS AND METHODS:A total of 157 consecutive melanoma patients with a median age of 63 years were recruited at the Department of Dermatology, Charité-Universitätsmedizin Berlin and tested for neuronal autoantibodies. A comprehensive neuropsychological assessment was carried out in a selected subgroup of 84 patients after exclusion of patients with confounding factors for a cognitive dysfunction, including brain metastases, relevant medication, and neurological disorders. RESULTS:Neuronal autoantibodies were found in 22.3% of melanoma patients. The most frequent antibodies were IgA/IgM anti-NMDAR antibodies. Applying the International Cognition and Cancer Task Force criteria, 36.9% had cognitive impairment, however, with a threefold higher odds in antibody-positive compared with antibody-negative patients (57.1% versus 30.2%, OR = 3.1, 95% CI: 1.1 to 8.6; P = 0.037). In patients with anti-NMDAR antibodies, this impairment increased with higher antibody titers (P = 0.007). Antibody-positive patients had a significantly impaired overall cognitive performance (z-value: -0.38 ± 0.69 versus 0.00 ± 0.56; P = 0.014) as well as significant impairments in tests of memory, attention, and executive function. In a multiple linear regression analysis, autoantibodies were an independent risk factor for cognitive impairment (B = -0.282; 95% CI: -0.492 to -0.071; P = 0.009). Autoantibody seropositivity was associated with immune checkpoint inhibitor treatment and a history of autoimmune diseases. CONCLUSIONS:A large number of melanoma patients harbor neuronal autoantibodies that are associated with significant cognitive impairment affecting memory, attention, and executive function. Neuronal autoantibodies might represent a pathophysiological factor and possible biomarker in the development of cancer-related cognitive impairment. 10.1093/annonc/mdz083
    Associations between inflammatory markers and cognitive function in breast cancer patients receiving chemotherapy. Williams AnnaLynn M,Shah Raven,Shayne Michelle,Huston Alissa J,Krebs Marcia,Murray Nicole,Thompson Bryan D,Doyle Kassandra,Korotkin Jenna,van Wijngaarden Edwin,Hyland Sharon,Moynihan Jan A,Cory-Slechta Deborah A,Janelsins Michelle C Journal of neuroimmunology 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. 10.1016/j.jneuroim.2017.10.005
    Effect of dexmedetomidine on the cognitive function of patients undergoing gastric cancer surgery by regulating the PI3K/AKT signaling pathway. Wang Zhiyuan,Shen Zijin,Wang Haibin,Zhang Lin,Dong Rong Oncology letters Effect of dexmedetomidine on the cognitive function of patients undergoing gastric cancer surgery by regulating the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway was investigated. A total of 110 patients who were diagnosed and underwent radical gastrectomy in Ruijin Hospital North, Shanghai Jiaotong University School of Medicine from July 2016 to July 2018 were selected. In the experimental group, 60 patients were treated with dexmedetomidine infusion. In the control group, 50 patients were injected with 0.9% sodium chloride injection during the same period. The expression levels of serum inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), PI3K and AKT of patients were compared between the two groups before and after surgery for 1 day. The number of adverse reactions in the two groups was compared. The correlation between mini-mental state examination (MMSE) score and the expression levels of serum IL-6, PI3K and AKT was compared. The levels of serum TNF-α, IL-6, PI3K and AKT after operation for 1 day of patients in the two groups were significantly higher than those before operation (P<0.05), and were lower in the experimental than in the control group (P<0.05). The number of postoperative cognitive dysfunction of patients in the experimental group was lower than that of patients in the control group (P<0.05). The total number of adverse reactions in the control group was higher than that of patients in the experimental group (P<0.05). The MMSE scores of the two groups were decreased at 1 day after operation and were significantly lower in the control group than in the experimental group (P<0.05). The MMSE score was negatively correlated with the expression levels of serum TNF-α, IL-6, PI3K and AKT (P<0.001). Dexmedetomidine can effectively reduce the expression levels of postoperative inflammatory factors in patients undergoing gastric cancer surgery, improve the postoperative cognitive function by regulating PI3K-Akt signaling pathway and promotes the recovery of postoperative cognitive function. 10.3892/ol.2019.11224
    Influence of combined epidural anesthesia on cognitive function, inflammation and stress response in elderly liver cancer patients undergoing surgery. Su Yang,Pu Yanan,Zhao Zhengnan,Yang Xianglong Oncology letters Effects of combined epidural anesthesia on the cognitive function, inflammation and stress response in the elderly liver cancer patients undergoing surgery were explored. Elderly liver cancer patients (n=100) undergoing surgery in the Second Affiliated Hospital of Dalian Medical University from January 2015 to December 2018 were enrolled and randomly divided into observation group (n=50) and control group (n=50). In control group only conventional anesthesia was performed using 2 µg/kg fentanyl, 1.5 mg/kg propofol and 0.2 mg/kg atracurium, in addition to the procedures in the control group, combined epidural anesthesia was administered using 0.5% bupivacaine for 15 sec and maintained via 0.25% bupivacaine in the observation group. The anesthetic effect was observed and the arterial oxygen saturation (SaO), heart rate (HR), mean arterial pressure (MAP) and mini-mental state examination (MMSE) and cognitive function scores by cognitive abilities screening instrument (CASI) were evaluated in the patients, and their blood was drawn to detect the inflammatory factors interleukin (IL)-6, IL-1 and tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), norepinephrine and epinephrine. The observation group exhibited a better anesthetic effect and obviously smaller decreases in the SaO and MAP and increase in HR than the control group (P<0.05). The MMSE and CASI scores, and the content of IL-1, IL-6, TNF-α, MDA, CAT, norepinephrine and epinephrine in the observation group was obviously lower than that in the control group (P<0.05), while the content of SOD was evidently higher than that in the control group (P<0.05). Overall postoperative conditions in the observation group was superior to the control group (P<0.05), with the incidence rate of cognitive disorder lower than that in the control group (P<0.05). Combined epidural anesthesia dramatically improves the postoperative conditions and cognitive function and relieve inflammatory and stress responses in the patients with a better anesthetic effect, thus holding promise for application. 10.3892/ol.2020.11395
    Assessment of cognitive function in patients with metastatic cancer: Are we using the right tools? Kurita Geana Paula,Sandvad Marlene,Lundorff Lena,De Mattos-Pimenta Cibele Andrucioli,Højsted Jette,Sjøgren Per Palliative & supportive care OBJECTIVE:This study aimed at analyzing the validity and reliability of the continuous reaction time (CRT) test, the finger-tapping test (FTT), the Digit Span Test (DST), the Trail Making Test - part B (TMTB), and the Mini-Mental State Examination (MMSE) in patients with metastatic cancer. METHOD:Eighty adult patients and 81 healthy controls were assessed between July of 2010 and November of 2015. The neuropsychological tests were analyzed regarding construct/discriminant/criterion validity and reliability. RESULTS:In terms of construct validity, it was not possible to estimate a model for the MMSE because of a skewed response distribution. For discriminant validity, patients were slower on two measures of the CRT (p = 0.00483, p = 0.00030) and FTT dominant hand (p = 0.00306). Regarding sensitivity and specificity, only the DST and TMTB seemed to predict cognitive deficit; however, the ROC curve areas were ≤ 0.73. In terms of criterion validity, there were few significant correlations between the tests and the sociodemographic and clinical variables, and for the most part were very weak. Reliability was deemed to be adequate for the TMTB, DST, and FTT. SIGNIFICANCE OF RESULTS:The findings of the full validation analyses were not clear-cut. However, CRT test, DST, FTT, and TMTB demonstrated partial positive results, indicating that these tests have good potential for use in clinical settings and require further study. 10.1017/S1478951517000694
    Cognitive function and fatigue after diagnosis of colorectal cancer. Vardy J,Dhillon H M,Pond G R,Rourke S B,Xu W,Dodd A,Renton C,Park A,Bekele T,Ringash J,Zhang H,Burkes R,Clarke S J,Tannock I F Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Cognitive impairment and fatigue have been associated with cancer and its treatment. We present baseline data from a large longitudinal study that evaluates cognitive function, fatigue, and potential underlying mechanisms following diagnosis of colorectal cancer (CRC). PATIENTS AND METHODS:We evaluated CRC patients with stage I-III disease before or after surgery, participants with limited metastatic disease and healthy controls (HC). Neuropsychological evaluation included clinical and computerised tests. Participants completed questionnaires for fatigue and quality of life (QOL)-(FACT-F), anxiety/depression, and cognitive symptoms (FACT-Cog). Ten cytokines, clotting factors, sex hormones, carcinoembryonic antigen (CEA), and apolipoprotein E genotype were evaluated. Primary end points were cognitive function on clinical tests evaluated by a Global Deficit score (GDS) and fatigue. Associations between test results, demographic, and disease related factors were explored. RESULTS:We assessed 291 participants with early-stage disease [median age 59 (23-75) years, 63% men], 72 with metastatic disease, and 72 HC. Using GDS, 45% (126/281) of participants with early-stage CRC had cognitive impairment versus 15% (11/72) of HC (odds ratio 4.51, 95% confidence interval 2.28-8.93; P < 0.001), with complex processing speed, attention/working memory, and verbal learning efficiency being most affected. Women with early-stage CRC had greater cognitive impairment than men [55/105 (52%) versus 71/176 (40%), P < 0.050]. Cognitive symptoms were self-reported by 21% (59/286) of early-stage patients versus 17% (12/72) of HC; fatigue by 52% (149/287) of early-stage patients and 26% (19/72) of HC (P < 0.0001). Women reported more fatigue than men (P = 0.003). Fatigue, QOL, anxiety/depression, and cognitive symptoms were associated with each other (r = 0.43-0.71), but not with neuropsychological performance. Most cytokines were elevated in cancer patients. Cognitive function was not associated with cytokines, sex hormones, clotting factors, CEA, or apolipoprotein E genotype. CONCLUSIONS:The incidence of cognitive impairment was three to five times higher in CRC patients than HC, with women having higher impairment rates than men. The cognitive impairment profile suggests dysfunction primarily in fronto-subcortical brain systems. TRIAL REGISTRATION:NCT00188331. 10.1093/annonc/mdu448
    Role of stress, age and adjuvant therapy in the cognitive function of patients with breast cancer. Papanastasiou Artemis,Seliniotaki Theodora,Rizos Emmanouil,Kampoli Katerina,Ntavatzikos Anastasios,Arkadopoulos Nikolaos,Tsionou Christina,Spandidos Demetrios A,Koumarianou Anna Oncology letters According to data largely obtained from retrospective studies, it has been postulated that chemotherapy exerts an aggravating effect on the cognitive function of patients with breast cancer. Potential individual factors related to the effects of chemotherapy on cognitive function have been indicated, such as age-related cognitive dysfunction and stress. Elderly patients differ from non-elderly patients as regards higher cognitive related comorbidities, such as dementia, as well as regarding lower stress levels, indicating that 'chemobrain' may differentially affect these two age groups. The aim of this review was to discuss the effects of stress and chemotherapy on cognitive dysfunction and identify any potential age-related differences in patients with breast cancer treated with adjuvant chemotherapy. For this purpose, a systematic review of the literature was carried out on the PubMed, Scopus and Web of Science databases. The inclusion criteria were original articles published in peer-reviewed journals, elderly and non-elderly patients with breast cancer, reporting on stress and at least one cognitive parameter pre- and/or post-treatment. Eight studies met the preset criteria and were further analyzed. In total, the data of 1,253 women were included, of whom 800 patients with breast cancer were treated with surgery only, systemic treatment only, or both. Although all the studies included a non-elderly breast cancer patient subpopulation, only two of the studies included patients over 65 years of age. All studies indicated a statistically significant association of stress with various domains of cognitive dysfunction in patients, as shown by either self-completed questionnaires, neuropsychological testing or both. An age over 60 years was linked to fewer cognitive difficulties mediated by lower levels of stress. Thus, the evidence supports the association of stress with cognitive deficits in patients with breast cancer, regardless of the type of cancer-related treatment. Therefore, stress should be appropriately addressed. However, further research is required to investigate the association of stress with cognitive function in elderly patients with breast cancer. 10.3892/ol.2019.10361
    Remifentanil on T lymphocytes, cognitive function and inflammatory cytokines of patients undergoing radical surgery for cervical cancer. Lu X-Y,Chen M,Chen D-H,Li Y,Liu P-T,Liu Y European review for medical and pharmacological sciences OBJECTIVE:To explore the effects of remifentanil on cognitive function, T lymphocyte subsets and inflammatory cytokines of patients undergoing radical surgery for cervical cancer. PATIENTS AND METHODS:A total of 70 patients undergoing radical surgery for cervical cancer in our hospital from August 2014 to January 2017 were selected. They were divided into control group (n=35) and experimental group (n=35). The patients in the control group received intravenous drip of fentanyl, while those in the experimental group received intravenous drip of remifentanil in the surgery. All the patients returned to the wards after surgery. The eye-opening time, extubation time and awaking time of the patients were collected and recorded by specialized surgical nurses. Moreover, the cognitive function of the patients was assessed at the beginning of the surgery and 3 h, 6 h, 12 h, and 24 h after surgery. Blood was drawn at 24 h after surgery, and quantitative analysis of T lymphocyte subsets and inflammatory cytokines of the patients was conducted. RESULTS:The eye-opening time, extubation time, and awaking time in the remifentanil group were significantly earlier than those in the fentanyl group after surgery (p<0.05). At the same time after surgery, the score of mini-mental state examination (MMSE) in the remifentanil group was higher than that in the fentanyl group. The difference was statistically significant (p<0.05). The patients in the experimental group had a relatively low occurrence of cognitive disorder after surgery (p<0.05). The impacts of remifentanil on each type of T lymphocytes and inflammatory cytokines of the patients after surgery were smaller than those of fentanyl. The differences were statistically significant (p<0.05). CONCLUSIONS:Remifentanil can wake patients up early after surgery. Meanwhile, it results in small inflammatory response and stress response, and low occurrence of postoperative cognitive dysfunction in patients. Therefore, it is worthy of being vigorously promoted for clinical application. 10.26355/eurrev_201805_14987
    Cognitive Function in Patients With Colorectal Cancer Who Do and Do Not Receive Chemotherapy: A Prospective, Longitudinal, Controlled Study. Vardy Janette L,Dhillon Haryana M,Pond Gregory R,Rourke Sean B,Bekele Tsegaye,Renton Corrinne,Dodd Anna,Zhang Haibo,Beale Philip,Clarke Stephen,Tannock Ian F Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Cognitive dysfunction is reported in people with cancer. Therefore, we evaluated longitudinal changes in cognitive function and underlying mechanisms in people with colorectal cancer (CRC) and healthy controls (HCs). PATIENTS AND METHODS:Participants completed cognitive assessments and questionnaires reporting cognitive symptoms, fatigue, quality of life, and anxiety/depression at baseline (before chemotherapy, if given) and 6, 12, and 24 months. Blood tests included cytokines, clotting factors, apolipoprotein E genotype, and sex hormones. Primary end point was overall cognitive function measured by the Global Deficit Score at 12 months. RESULTS:We recruited 289 patients with localized CRC (173 received chemotherapy; median age, 59 years; 63% male), 73 patients with limited metastatic/recurrent CRC, and 72 HCs. Cognitive impairment was more frequent in patients with localized CRC than HCs at baseline (43% v 15%, respectively; P < .001) and 12 months (46% v 13%, respectively; P < .001), with no significant effect of chemotherapy. Attention/working memory, verbal learning/memory, and complex processing speed were most affected. Cognitive impairment was similar in patients with localized and metastatic CRC. Cytokine levels were elevated in patients with CRC compared with HCs. There was no association between overall cognitive function and fatigue, quality of life, anxiety/depression, or any blood test. Cognitive symptoms at 12 months were reported in 25% of patients with localized CRC versus 17% of HCs (P = .19). More participants who received chemotherapy had cognitive symptoms at 6 months (32%) versus those who did not (16%; P = .007), with no significant difference at 12 months (29% v 21%, respectively; P = .19). Objective cognitive function was only weakly associated with cognitive symptoms. CONCLUSION:Patients with CRC had substantially more cognitive impairment at every assessment than HCs, with no significant added effect of chemotherapy. Mechanisms of cognitive impairment remain unknown. 10.1200/JCO.2015.63.0905
    Predicting Patient Reported Outcomes of Cognitive Function Using Connectome-Based Predictive Modeling in Breast Cancer. Henneghan Ashley M,Gibbons Chris,Harrison Rebecca A,Edwards Melissa L,Rao Vikram,Blayney Douglas W,Palesh Oxana,Kesler Shelli R Brain topography Being able to predict who will likely experience cancer related cognitive impairment (CRCI) could enhance patient care and potentially reduce economic and human costs associated with this adverse event. We aimed to determine if post-treatment patient reported CRCI could also be predicted from baseline resting state fMRI in patients with breast cancer. 76 newly diagnosed patients (n = 42 planned for chemotherapy; n = 34 not planned for chemotherapy) and 50 healthy female controls were assessed at 3 times points [T1 (prior to treatment); T2 (1 month post chemotherapy); T3 (1 year after T2)], and at yoked intervals for controls. Data collection included self-reported executive dysfunction, memory function, and psychological distress and resting state fMRI data converted to connectome matrices for each participant. Statistical analyses included linear mixed modeling, independent t tests, and connectome-based predictive modeling (CPM). Executive dysfunction increased over time in the chemotherapy group and was stable in the other two groups (p < 0.001). Memory function decreased over time in both patient groups compared to controls (p < 0.001). CPM models successfully predicted executive dysfunction and memory function scores (r > 0.31, p < 0.002). Support vector regression with a radial basis function (SVR RBF) showed the highest performance for executive dysfunction and memory function (r = 0.68; r = 0.44, p's < 0.001). Baseline neuroimaging may be useful for predicting patient reported cognitive outcomes which could assist in identifying patients in need of surveillance and/or early intervention for treatment-related cognitive effects. 10.1007/s10548-019-00746-4
    Sevoflurane Effect on Cognitive Function and the Expression of Oxidative Stress Response Proteins in Elderly Patients undergoing Radical Surgery for Lung Cancer. Qin Yang,Ni Jinping,Kang Li,Zhong Zhidong,Wang Liren,Yin Shuzhou Journal of the College of Physicians and Surgeons--Pakistan : JCPSP OBJECTIVE:To investigate the effects of sustained inhalation of sevoflurane on cognitive function and the expression of oxidative stress response proteins such as NADPH oxidase subunits NOX2 and NOX4 in elderly patients undergoing radical surgery for lung cancer. STUDY DESIGN:An experimental study. PLACE AND DURATION OF STUDY:Department of Anesthesiology, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, China, from February 2016 to October 2017. METHODOLOGY:Elderly patients who underwent radical surgery for lung cancer were divided into the sevoflurane group and the propofol group, with 52 cases in each group. Sustained inhalation of sevoflurane and propofol was administered to maintain anesthesia in the respective groups. Cognitive function and lung function parameters were compared between the two groups. Serum S100 &beta; levels and expression of NOX2 and NOX4 proteins in peripheral blood mononuclear cells of the two groups were determined. RESULTS:At 24 hours after surgery, the lung function indices of the sevoflurane group such as FEV1, FVC and VC were higher than those of the propofol group (p<0.001, p=0.008 and p=0.002, respectively). At the end of the surgery and at 24 hours after surgery, the MMSE scores of the sevoflurane group were higher than the propofol group (all p<0.001). S100 levels were lower than the propofol group (p=0.003 and p<0.001, respectively). Levels of NADPH oxidase subunits NOX2 and NOX4 proteins in peripheral blood mononuclear cells of the sevoflurane group were lower than the propofol group (p=0.033, p<0.001, p<0.001and p<0.001, respectively). CONCLUSION:Compared with intravenous anesthesia with propofol, general anesthesia with sevoflurane inhalation has little effect on the short-term cognitive function in elderly patients undergoing radical surgery for lung cancer, and can effectively improve lung function. The mechanism may be related to the reduction of the expression of NOX2 and NOX4 proteins. 10.29271/jcpsp.2019.01.12
    Potential Effect of Immunotherapy Agents on Cognitive Function in Cancer Patients. Joly Florence,Castel Hélène,Tron Laure,Lange Marie,Vardy Janette Journal of the National Cancer Institute A paradigm shift is occurring in cancer therapy, where instead of targeting tumor cells, immunotherapy agents (IA) target the immune system to overcome cancer tolerance and to stimulate an antitumor immune response. IA using immune checkpoint inhibitors (CPI) or chimeric antigen receptor T-cells have emerged as the most encouraging approaches to treat cancer patients. CPI are reported to induce moderate-to-severe neurologic immune-related adverse events in less than 1% of patients, whereas chimeric antigen receptor T-cell therapy is associated with frequent neurological toxicities that can be severe or even fatal. Cognitive difficulties have been described following chemotherapy and targeted therapy, but not specifically explored in patients receiving IA. The aim of this review is to establish a picture of the first published studies suggesting some biological and physiopathological effects of IA on cognitive functions among cancer patients. The first results originate from a preclinical study evaluating the role of CPI associated with peripheral radiation on cognitive dysfunction and the recent discovery of the central nervous lymphatic system allowing leukocytes to penetrate the central nervous system. Evaluating possible side effects of IA on cognitive function will be an important challenge for future clinical trials and for better understanding the underlying mechanisms through preclinical animal models. 10.1093/jnci/djz168
    The Role of Inflammation in the Pain, Fatigue, and Sleep Disturbance Symptom Cluster in Advanced Cancer. Kwekkeboom Kristine L,Tostrud Lauren,Costanzo Erin,Coe Christopher L,Serlin Ronald C,Ward Sandra E,Zhang Yingzi Journal of pain and symptom management CONTEXT:Symptom researchers have proposed a model of inflammatory cytokine activity and dysregulation in cancer to explain co-occurring symptoms including pain, fatigue, and sleep disturbance. OBJECTIVES:We tested the hypothesis that psychological stress accentuates inflammation and that stress and inflammation contribute to one's experience of the pain, fatigue, and sleep disturbance symptom cluster (symptom cluster severity, symptom cluster distress) and its impact (symptom cluster interference with daily life, quality of life). METHODS:We used baseline data from a symptom cluster management trial. Adult participants (N = 158) receiving chemotherapy for advanced cancer reported pain, fatigue, and sleep disturbance on enrollment. Before intervention, participants completed measures of demographics, perceived stress, symptom cluster severity, symptom cluster distress, symptom cluster interference with daily life, and quality of life and provided a blood sample for four inflammatory biomarkers (interleukin-1β, interleukin-6, tumor necrosis factor-α, and C-reactive protein). RESULTS:Stress was not directly related to any inflammatory biomarker. Stress and tumor necrosis factor-α were positively related to symptom cluster distress, although not symptom cluster severity. Tumor necrosis factor-α was indirectly related to symptom cluster interference with daily life, through its effect on symptom cluster distress. Stress was positively associated with symptom cluster interference with daily life and inversely with quality of life. Stress also had indirect effects on symptom cluster interference with daily life, through its effect on symptom cluster distress. CONCLUSION:The proposed inflammatory model of symptoms was partially supported. Investigators should test interventions that target stress as a contributing factor in co-occurring pain, fatigue, and sleep disturbance and explore other factors that may influence inflammatory biomarker levels within the context of an advanced cancer diagnosis and treatment. 10.1016/j.jpainsymman.2018.01.008
    Tumor-Associated Fatigue in Cancer Patients Develops Independently of IL1 Signaling. Grossberg Aaron J,Vichaya Elisabeth G,Christian Diana L,Molkentine Jessica M,Vermeer Daniel W,Gross Phillip S,Vermeer Paola D,Lee John H,Dantzer Robert Cancer research Fatigue is the most common symptom of cancer at diagnosis, yet causes and effective treatments remain elusive. As tumors can be highly inflammatory, it is generally accepted that inflammation mediates cancer-related fatigue. However, evidence to support this assertion is mostly correlational. In this study, we directly tested the hypothesis that fatigue results from propagation of tumor-induced inflammation to the brain and activation of the central proinflammatory cytokine, IL1. The heterotopic syngeneic murine head and neck cancer model (mEER) caused systemic inflammation and increased expression of in the brain while inducing fatigue-like behaviors characterized by decreased voluntary wheel running and exploratory activity. Expression of in the brain was not associated with any alterations in motivation, measured by responding in a progressive ratio schedule of food reinforcement, depression-like behaviors, or energy balance. Decreased wheel running occurred prior to detection in the brain, when systemic inflammation was minimal. Furthermore, mice null for two components of IL1β signaling, the type 1 IL1 receptor or the receptor adapter protein MyD88, were not protected from tumor-induced decreases in wheel running, despite attenuated cytokine action and expression. Behavioral and inflammatory analysis of four additional syngeneic tumor models revealed that tumors can induce fatigue regardless of their systemic or central nervous system inflammatory potential. Together, our results show that brain IL1 signaling is not necessary for tumor-related fatigue, dissociating this type of cancer sequela from systemic cytokine expression. These findings challenge the current understanding of fatigue in cancer patients, the most common and debilitating sequela associated with malignancy. . 10.1158/0008-5472.CAN-17-2168
    Sleep disturbance and cancer-related fatigue symptom cluster in breast cancer patients undergoing chemotherapy. Fox Rina S,Ancoli-Israel Sonia,Roesch Scott C,Merz Erin L,Mills Sarah D,Wells Kristen J,Sadler Georgia Robins,Malcarne Vanessa L Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer PURPOSE:Sleep disturbance and cancer-related fatigue (CRF) are among the most commonly reported symptoms associated with breast cancer and its treatment. This study identified symptom cluster groups of breast cancer patients based on multidimensional assessment of sleep disturbance and CRF prior to and during chemotherapy. METHODS:Participants were 152 women with stage I-IIIA breast cancer. Data were collected before chemotherapy (T1) and during the final week of the fourth chemotherapy cycle (T2). Latent profile analysis was used to derive groups of patients at each timepoint who scored similarly on percent of the day/night asleep per actigraphy, the Pittsburgh Sleep Quality Index global score, and the five subscales of the Multidimensional Fatigue Symptom Inventory-Short Form. Bivariate logistic regression evaluated if sociodemographic/medical characteristics at T1 were associated with group membership at each timepoint. RESULTS:Three groups (Fatigued with sleep complaints, Average, Minimal symptoms) were identified at T1, and five groups (Severely fatigued with poor sleep, Emotionally fatigued with average sleep, Physically fatigued with average sleep, Average, Minimal symptoms) at T2. The majority of individuals in a group characterized by more severe symptoms at T1 were also in a more severe symptom group at T2. Sociodemographic/medical variables at T1 were significantly associated with group membership at T1 and T2. CONCLUSIONS:This study identified groups of breast cancer patients with differentially severe sleep disturbance and CRF symptom profiles prior to and during chemotherapy. Identifying groups with different symptom management needs and distinguishing groups by baseline sociodemographic/medical variables can identify patients at risk for greater symptom burden. 10.1007/s00520-019-04834-w
    Cognitive and motor aspects of cancer-related fatigue. Feng Li Rebekah,Regan Jeniece,Shrader Joseph A,Liwang Josephine,Ross Alexander,Kumar Saloni,Saligan Leorey N Cancer medicine BACKGROUND:Cancer-related fatigue (CRF) is a debilitating symptom frequently reported by patients during and after treatment for cancer. CRF is a multidimensional experience and is often solely assessed by self-report measures. The goal of the study is to examine the physical and cognitive aspects of self-reported CRF using a cognitive function test and a physical fatigue index in order to provide objective measures that can characterize the CRF phenotype. METHODS:A total of 59 subjects with nonmetastatic prostate cancer receiving external beam radiation therapy were included in the study. Fatigue was measured using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaire. Cognitive characteristics of CRF was measured using the Stroop Color-Word Interference computerized test and the motor aspect of fatigue was measured using the static fatigue test using a handgrip dynamometer. FINDINGS:Functional Assessment of Cancer Therapy-Fatigue scores significantly correlated with the Stroop Interference score, but not performance accuracy in all test conditions. Fatigued subjects exhibited a more rapid decline to 50% of maximal strength and increased static fatigue index in the handgrip test, whereas maximal grip strength was not affected. CONCLUSIONS:The results suggest that CRF exhibits both cognitive and physical characteristics. Subjective fatigue was associated with increased time required to overcome cognitive interference, but not cognitive performance accuracy. Fatigued patients exhibited decreased physical endurance and the ability to sustain maximal strength over time. These objective measures may serve as valuable tools for clinicians to detect cognitive and physical impairment associated with CRF. 10.1002/cam4.2490
    Effects of an Exercise Intervention on Cancer-Related Fatigue and Its Relationship to Markers of Oxidative Stress. Repka Chris P,Hayward Reid Integrative cancer therapies BACKGROUND:Although the underlying mechanisms of cancer-related fatigue (CRF) are not fully characterized, treatment-associated oxidative stress may play a role. The purpose of this study was to determine the effect of an exercise intervention on the relationship between CRF and oxidative stress. METHODS:Upon cessation of radiation or chemotherapy, 8 cancer patients participated in a 10-week exercise intervention (EX), while 7 continued standard care (CON). Blood draws and fatigue questionnaires were administered to cancer patients before and after the intervention as well as to 7 age-matched individuals with no cancer history. Changes in plasma 8-hydroxy-deoxyguanosine (8-OHdG), protein carbonyls, antioxidant capacity, and fatigue were compared between groups. Correlations between CRF and oxidative stress were evaluated. RESULTS:Mean total fatigue scores decreased significantly (5.0 ± 2.2 to 2.6 ± 1.5, P < .05) in EX, but not in CON. Antioxidant capacity significantly increased (+41%; P < .05) and protein carbonyls significantly decreased (-36%; P < .05) in EX, but not in CON. Increases in antioxidant capacity were significantly correlated with reductions in affective ( r = -.49), sensory ( r = -.47), and cognitive fatigue ( r = -.58). Changes in total ( r = .46) and affective ( r = .47) fatigue exhibited significant correlations with changes in 8-OHdG over time, while behavioral ( r = .46) and sensory ( r = .47) fatigue changes were significantly correlated with protein carbonyls. CONCLUSIONS:Oxidative stress may be implicated in CRF, while improved antioxidant capacity following an exercise intervention may play a role in mitigating CRF in cancer survivors. 10.1177/1534735418766402
    Inflammation- and angiogenesis-related biomarkers are correlated with cancer-related fatigue in colorectal cancer patients: Results from the ColoCare Study. Himbert Caroline,Ose Jennifer,Lin Tengda,Warby Christy A,Gigic Biljana,Steindorf Karen,Schrotz-King Petra,Abbenhardt-Martin Clare,Zielske Lin,Boehm Juergen,Ulrich Cornelia M European journal of cancer care Cancer-related fatigue is one of the most common side effects of colorectal cancer treatment and is affected by biomedical factors. We investigated the association of inflammation- and angiogenesis-related biomarkers with cancer-related fatigue. Pre-surgery (baseline) serum samples were obtained from n = 236 newly diagnosed colorectal cancer patients. Meso Scale Discovery assays were performed to measure levels of biomarkers for inflammation and angiogenesis (CRP, SAA, IL-6, IL-8, MCP-1, sICAM-1, sVCAM-1, TNFα, VEGFA and VEGFD). Cancer-related fatigue was assessed with the EORTC QLQ-30 questionnaire at baseline and 6 and 12 months post-surgery. We tested associations using Spearman's partial correlations and logistic regression analyses, adjusting for age, sex and body mass index. sICAM-1 and VEGFD showed a significant positive correlation with cancer-related fatigue at baseline and 6-, and 12-month follow-up (sICAM-1: r = 0.19, p = 0.010; r = 0.24, p = 0.004; r = 0.25, p = 0.006; VEGFD: r = 0.20, p = 0.006; r = 0.15, p = 0.06; r = 0.23, p = 0.01 respectively). Biomarkers of inflammation and angiogenesis measured prior to surgery are associated with cancer-related fatigue in colorectal cancer patients throughout various time points. Our results suggest the involvement of overexpressed sICAM-1 and VEGFD in the development of fatigue. 10.1111/ecc.13055
    The role of neuro-immune interactions in cancer-related fatigue: Biobehavioral risk factors and mechanisms. Bower Julienne E Cancer Fatigue is a common and distressing symptom in both patients with cancer and cancer survivors. There is substantial variation in the severity and persistence of cancer-related fatigue that may be driven by individual differences in host factors, including characteristics that predate the cancer experience as well as responses to cancer and its treatment. This review examines biobehavioral risk factors linked to fatigue and the mechanisms through which they influence fatigue across the cancer continuum, with a focus on neuro-immune processes. Among psychosocial risk factors, childhood adversity is a strong and consistent predictor of cancer-related fatigue; other risk factors include history of depression, catastrophizing, lack of physical activity, and sleep disturbance, with compelling preliminary evidence for loneliness and trait anxiety. Among biologic systems, initial work suggests that alterations in immune, neuroendocrine, and neural processes are associated with fatigue. The identification of key risk factors and underlying mechanisms is critical for the development and deployment of targeted interventions to reduce the burden of fatigue in the growing population of cancer survivors. Given the multidimensional nature of fatigue, interventions that influence multiple systems may be most effective. 10.1002/cncr.31790
    Molecular epidemiology, cancer-related symptoms, and cytokines pathway. Reyes-Gibby Cielito C,Wu Xifeng,Spitz Margaret,Kurzrock Razelle,Fisch Michael,Bruera Eduardo,Shete Sanjay The Lancet. Oncology The Human Genome Project and HapMap have led to a better appreciation of the importance of common genetic variation in determining cancer risk, created potential for predicting response to therapy, and made possible the development of targeted prevention and therapeutic interventions. Advances in molecular epidemiology can be used to explore the role of genetic variation in modulating the risk for severe and persistent symptoms, such as pain, depression, and fatigue, in patients with cancer. The same genes that are implicated in cancer risk might also be involved in the modulation of therapeutic outcomes. For example, polymorphisms in several cytokine genes are potential markers for genetic susceptibility both for cancer risk and for cancer-related symptoms. These genetic polymorphisms are stable markers and easily and reliably assayed to explore the extent to which genetic variation might prove useful in identifying patients with cancer at high-risk of symptom development. Likewise, they could identify subgroups who might benefit most from symptom intervention, and contribute to developing personalized and more effective therapies for persistent symptoms. 10.1016/S1470-2045(08)70197-9
    Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy. Liu Lianqi,Mills Paul J,Rissling Michelle,Fiorentino Lavinia,Natarajan Loki,Dimsdale Joel E,Sadler Georgia Robins,Parker Barbara A,Ancoli-Israel Sonia Brain, behavior, and immunity Fatigue and sleep disturbances are two of the most common and distressing symptoms reported by cancer patients. Fatigue and sleep are also correlated with each other. While fatigue has been reported to be associated with some inflammatory markers, data about the relationship between cancer-related sleep disturbances and inflammatory markers are limited. This study examined the relationship between fatigue and sleep, measured both subjectively and objectively, and inflammatory markers in a sample of breast cancer patients before and during chemotherapy. Fifty-three women with newly diagnosed stage I-III breast cancer scheduled to receive at least four 3-week cycles of chemotherapy participated in this longitudinal study. Fatigue was assessed with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and objective sleep was measured with actigraphy. Three inflammatory markers were examined: Interleukin-6 (IL-6), Interleukin-1 receptor antagonist (IL-1RA) and C-reactive protein (CRP). Data were collected before (baseline) and during cycle 1 and cycle 4 of chemotherapy. Compared to baseline, more fatigue was reported, levels of IL-6 increased and IL-1RA decreased during chemotherapy. Reports of sleep quality remained poor. Mixed model analyses examining changes from baseline to each treatment time point revealed overall positive relationships between changes in total MFSI-SF scores and IL-6, between changes in total PSQI scores and IL-6 and IL-1RA, and between total wake time at night and CRP (all p's<0.05). These relationships suggest that cancer-related fatigue and sleep disturbances may share common underlying biochemical mechanisms. 10.1016/j.bbi.2012.02.001
    Exploring Relationships Among Peripheral Amyloid Beta, Tau, Cytokines, Cognitive Function, and Psychosomatic Symptoms in Breast Cancer Survivors. Henneghan Ashley,Haley Andreana P,Kesler Shelli Biological research for nursing OBJECTIVE:Accelerated brain aging has been proposed to explain cancer-related cognitive impairment, but empirical evidence for this relationship is lacking. The purpose of this study was to evaluate amyloid beta (Aβ) and tau, biomarkers of neurodegeneration, in relation to cognition in breast cancer survivors (BCSs). We explored relationships among peripheral concentrations of Aβ42, Aβ-40, tau, and cytokines; cognitive function; and psychosomatic symptoms in a cohort of BCSs post-chemotherapy. METHODS:This secondary analysis of a cross-sectional study was conducted with 65 BCSs. Serum total Aβ-42, Aβ-40, and tau levels were measured with single molecule array technology. Cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α, granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon [IFN]-g, IL-10, IL-12, IL-13, IL1-b, IL-2, IL-4, IL-5, IL-7, and IL-8) were simultaneously measured in serum using multiplex assays. Cognitive function was measured with five standardized neuropsychological tests and psychosomatic symptoms (stress, loneliness, anxiety, depressive symptoms, fatigue, sleep quality, and daytime sleepiness) with self-report questionnaires. Data analyses included correlations and random forest regression (RFR). RESULTS:Significant correlations were identified among hip-to-waste ratio, number of treatment modalities, Aβ-42, Aβ-40, and tau levels (s = .27-.35, s < .05). RFR modeling including Aβ-42, Aβ-40, tau, and cytokines as features explained significant variance in cognitive function ( = .71, = 9.01, < .0001) and psychosomatic symptoms ( = .74, = 10.22, < .0001). CONCLUSIONS:This study suggests that neurodegenerative biomarkers interact with cytokines to influence cognitive functioning and psychosomatic symptoms in BCSs following chemotherapy, but additional research is needed. 10.1177/1099800419887230
    C-reactive protein predicts fatigue independently of depression in breast cancer patients prior to chemotherapy. Pertl Maria M,Hevey David,Boyle Noreen T,Hughes Martina M,Collier Sonya,O'Dwyer Anne-Marie,Harkin Andrew,Kennedy M John,Connor Thomas J Brain, behavior, and immunity Heightened inflammatory activity has been proposed as a mechanism for the development of cancer-related fatigue (CRF), a common and distressing condition that can negatively affect quality of life. Inflammation is also implicated in the pathogenesis of depression, and depression is a strong predictor of CRF. Thus, the role of the pro-inflammatory cytokine network in CRF may be mediated by depression or both conditions may share similar underlying physiological processes. The current study investigated associations between fatigue, depression and inflammatory cytokine (IFN-γ, IL-6, TNF-α) and CRP concentrations, as well as kynurenine pathway (KP) activation, in 61 breast cancer patients prior to chemotherapy. Changes in inflammatory markers and KP activation over time were also explored, and associations with changes in fatigue and depression were examined. Higher levels of CRP were significantly correlated with fatigue and depression before chemotherapy; nevertheless, CRP predicted fatigue independently of depression. Although greater kynurenine concentrations were associated with increased immune activation, there was no evidence that the KP played a role in fatigue or depression. Furthermore, no relationships emerged between either fatigue or depression and IFN-γ, IL-6, or TNF-α before chemotherapy. Nevertheless, kynurenine levels pre- and post-treatment significantly predicted changes in depression, suggesting that heightened KP activation may contribute to depressive symptoms in patients treated for cancer. In addition, IL-6 significantly covaried with fatigue. These preliminary findings provide some support for the idea that low-grade inflammation contributes to the development of CRF, independently of depression; however, there was no evidence that this is mediated by KP activity. 10.1016/j.bbi.2013.07.177
    The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Lacourt Tamara E,Vichaya Elisabeth G,Chiu Gabriel S,Dantzer Robert,Heijnen Cobi J Frontiers in behavioral neuroscience Chronic or persistent fatigue is a common, debilitating symptom of several diseases. Persistent fatigue has been associated with low-grade inflammation in several models of fatigue, including cancer-related fatigue and chronic fatigue syndrome. However, it is unclear how low-grade inflammation leads to the experience of fatigue. We here propose a model of an imbalance in energy availability and energy expenditure as a consequence of low-grade inflammation. In this narrative review, we discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. Low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy production; increases reactive oxygen species; and reduces insulin sensitivity. These effects result in reduced glucose availability and, thereby, reduced cellular energy. In addition, emerging evidence suggests that chronic low-grade inflammation is associated with increased willingness to exert effort under specific circumstances. Circadian-rhythm changes and sleep disturbances might mediate the effects of inflammation on cellular-energy availability and non-adaptive energy expenditure. In the second part of the review, we present evidence for these metabolic pathways in models of persistent fatigue, focusing on chronic fatigue syndrome and cancer-related fatigue. Most evidence for reduced cellular-energy availability in relation to fatigue comes from studies on chronic fatigue syndrome. While the mechanistic evidence from the cancer-related fatigue literature is still limited, the sparse results point to reduced cellular-energy availability as well. There is also mounting evidence that behavioral-energy expenditure exceeds the reduced cellular-energy availability in patients with persistent fatigue. This suggests that an inability to adjust energy expenditure to available resources might be one mechanism underlying persistent fatigue. 10.3389/fnbeh.2018.00078
    Interleukin 6-independent metabolic reprogramming as a driver of cancer-related fatigue. Grossberg Aaron J,Vichaya Elisabeth G,Gross Phillip S,Ford Bianca G,Scott Kiersten A,Estrada Darlene,Vermeer Daniel W,Vermeer Paola,Dantzer Robert Brain, behavior, and immunity Fatigue is a common and debilitating symptom of cancer with few effective interventions. Cancer-related fatigue (CRF) is often associated with increases in inflammatory cytokines, however inflammation may not be requisite for this symptom, suggesting other biological mediators also play a role. Because tumors are highly metabolically active and can amplify their energetic toll via effects on distant organs, we sought to determine whether CRF could be explained by metabolic competition exacted by the tumor. We used a highly metabolically active murine E6/E7/hRas model of head and neck cancer for this purpose. Mice with or without tumors were submitted to metabolic constraints in the form of voluntary wheel running or acute overnight fasting and their adaptive behavioral (home cage activity and fasting-induced wheel running) and metabolic responses (blood glucose, ketones, and liver metabolic gene expression) were monitored. We found that the addition of running wheel was necessary to measure activity loss, used as a surrogate for fatigue in this study. Tumor-bearing mice engaged in wheel running showed a decrease in blood glucose levels and an increase in lactate accumulation in the skeletal muscle, consistent with inhibition of the Cori cycle. These changes were associated with gene expression changes in the livers consistent with increased glycolysis and suppressed gluconeogenesis. Fasting also decreased blood glucose in tumor-bearing mice, without impairing glucose or insulin tolerance. Fasting-induced increases in wheel running and ketogenesis were suppressed by tumors, which was again associated with a shift from gluconeogenic to glycolytic metabolism in the liver. Blockade of IL-6 signaling with a neutralizing antibody failed to recover any of the behavioral or metabolic outcomes. Taken together, these data indicate that metabolic competition between the tumor and the rest of the organism is an important component of fatigue and support the hypothesis of a central role for IL-6-independent hepatic metabolic reprogramming in the pathophysiology of CRF. 10.1016/j.bbi.2020.05.043
    Perceived cognitive impairment in people with colorectal cancer who do and do not receive chemotherapy. Dhillon Haryana M,Tannock Ian F,Pond Gregory R,Renton Corrinne,Rourke Sean B,Vardy Janette L Journal of cancer survivorship : research and practice PURPOSE:Cognitive symptoms are common after cancer, but poorly associated with neuropsychological results. We previously reported colorectal cancer (CRC) patients had more cognitive impairment than controls. Here, we explore relationships between cognitive symptoms and neuropsychological domains. METHODS:Subjects with CRC (N = 362) and 72 healthy controls completed neuropsychological assessments and Functional Assessment of Cancer Therapy-Cognition (FACT-COG) at baseline (pre-chemotherapy) and 6, 12, and 24 months. Associations between neuropsychological and FACT-COG scores were explored: perceived cognitive impairment (PCI), perceived cognitive ability (PCA), impact of PCI on quality of life (CogQOL). RESULTS:Of 362 CRC subjects, 289 had loco-regional disease and 173 received chemotherapy (CTh+). At baseline, groups did not differ on total FACT-COG, PCI, or PCA scores. All scores, except PCA, were worse at 6 months in CTh+. CRC patients not receiving chemotherapy did not differ from controls on FACT-COG domains. PCA associated weakly (r = 0.28-0.34) with attention/executive function, visual memory, and global deficit score. There was no association between PCI and neuropsychological domains. Fatigue, anxiety/depression, and poorer quality of life were associated with PCI and CogQOL (r = 0.44-0.51) in CRC patients. CONCLUSIONS:No association was seen between total FACT-COG or PCI, and neuropsychological domains. A weak-moderate association was found between PCA and attention/executive function and visual memory. TRIAL REGISTRATION:The study was registered with clinicaltrials.gov (trial registration: NCT00188331). IMPLICATIONS FOR CANCER SURVIVORS:Cognitive symptoms are associated with fatigue, anxiety/depression, and poorer quality of life, and do not appear to be related to actual cognitive performance. Rates were lower than that reported in breast cancer survivors. Cognitive symptoms were greatest in those who received chemotherapy, with no significant difference between the non-chemotherapy survivors and healthy controls. 10.1007/s11764-017-0656-6
    Cognitive Dysfunction and Its Predictors in Adult Patients With Cancer Receiving Chemotherapy: A Cross-Sectional Correlational Study. Wazqar Dhuha Youssef The journal of nursing research : JNR BACKGROUND:Chemotherapy-related cognitive dysfunction, one of the most frequently reported symptoms in patients with cancer, has a negative impact on the daily lives of patients. No research has examined cognitive dysfunction and its potential predictors in adult patients with cancer receiving chemotherapy in Saudi Arabia. PURPOSE:The purpose of this study was to examine the sociodemographic, clinical, and psychological factors associated with cognitive dysfunction in adult patients with cancer receiving chemotherapy. METHODS:A cross-sectional correlational study was carried out with a convenience sample of 100 adult patients with cancer receiving chemotherapy at a university teaching hospital in Saudi Arabia. The Montreal Cognitive Assessment, the Hospital Anxiety and Depression Scale, and sociodemographic and clinical surveys were completed by participants. Descriptive statistics and linear regression were used to analyze the data. RESULTS:The data showed that the participants experienced moderate-to-severe cognitive dysfunction. Participants performed poorly in the divided attention and memory cognitive domains. Age, educational level, and depression factors were found to be significant predictors of cognitive dysfunction. CONCLUSIONS/IMPLICATIONS FOR PRACTICE:Cognitive dysfunction is commonly seen in patients with cancer receiving chemotherapy. Chemotherapy, age, and psychological factors increase susceptibility to cognitive dysfunction in adult patients with cancer. Oncology nurses should be aware that patients with cancer may be extremely vulnerable to cognitive dysfunction. Furthermore, age and psychological factors must be considered when developing symptom management and supportive care intervention programs to reduce the incidence of negative cognitive outcomes in this population. 10.1097/jnr.0000000000000340
    Chemotherapy-related cognitive impairment: mechanisms, clinical features and research perspectives. Cascella Marco,Di Napoli Raffaela,Carbone Domenico,Cuomo Gaia Francesca,Bimonte Sabrina,Muzio Maria Rosaria Recenti progressi in medicina The term chemotherapy-related cognitive impairment (CRCI), or cognitive dysfunction, or chemo fog, or chemo brain, is referred to a decline in a variety of neuropsychological tasks after chemotherapy, or following other anticancer treatments such as radiation therapy or surgery, in patients with non-central nervous system cancers. Furthermore, several pieces of evidence suggest that clinical manifestations of cognitive impairment may occur in cancer patients, prior to chemotherapy or in those not treated with cancer therapies. In these circumstances, it should be more appropriate to use the term cancer-related cognitive dysfunction. Because there is no consensus about its definition and diagnostic criteria, no specific test for CRCI diagnose exists. Whatever the cause, this manifestation of central nervous system toxicity is of increasing concern as the survival rates for cancer have improved steadily and, in turn, cognitive dysfunction can negatively impact the patients and cancer survivors' quality of life. The aim of this work is to offer an overview of the topic and recommendations for future research. 10.1701/3031.30289
    Age- and gender-dependent changes in circulating concentrations of tumor necrosis factor-α, soluble tumor necrosis factor receptor-1 and sulfated glycosaminoglycan in healthy people. Komosinska-Vassev Katarzyna,Olczyk Pawel,Winsz-Szczotka Katarzyna,Klimek Katarzyna,Olczyk Krystyna Clinical chemistry and laboratory medicine BACKGROUND:In this study, the effect of gender and physiological ageing on circulating concentrations of plasma sulfated glycosaminoglycans (sGAG) as well as molecules involved in pro- (tumor necrosis factor-α; TNF-α) and anti-inflammatory responses (soluble tumor necrosis factor receptor-1, sTNF-RI) were assessed. The relationships between sGAG and molecules involved in age-dependent extracellular matrix (ECM) remodeling during physiological ageing were also investigated. METHODS:Circulating TNF-α and sTNF-RI were measured in 91 healthy volunteers using enzyme-linked immunosorbent assays. sGAG were quantified using an Alcian blue-binding assay. RESULTS:A linear age-related decline in plasma sGAG was found during the first five decades of life (r=-0.61, p<0.05), followed by an increase occurring only in females (r=0.46, p<0.05). Circulating TNF-α concentrations were inversely correlated with age (r=-0.24, p<0.05) over the lifetime. For TNF-α, the observed changes were gender specific. Serum sTNF-RI concentrations were not affected by age in either men or women. A significant positive correlation was found between the concentrations of TNF-α and both sGAG (r=0.22, p<0.05) and sTNF-RI (r=0.21, p<0.05). CONCLUSIONS:Our data demonstrate that physiological ageing is associated with ECM remodeling, reflected by plasma sGAGs concentrations. Changes in the ECM metabolism during the ageing process were influenced by circulating TNF-α. Furthermore, serum concentrations of biomolecules involved in pro- and anti-inflammatory responses are not increased in healthy elderly subjects. 10.1515/CCLM.2011.007
    Symptom clusters in patients with breast cancer receiving radiation therapy. Chow Selina,Wan Bo Angela,Pidduck William,Zhang Liying,DeAngelis Carlo,Chan Stephanie,Yee Caitlin,Drost Leah,Leung Eric,Sousa Philomena,Lewis Donna,Lam Henry,Chow Ronald,Lock Michael,Chow Edward European journal of oncology nursing : the official journal of European Oncology Nursing Society PURPOSE:Symptoms experienced by breast cancer patients often cluster together in groups known as "symptom clusters". The aim was to determine the symptom clusters in women with non-metastatic breast cancer treated by radiation therapy (RT). METHODS:Edmonton Symptom Assessment Scale (ESAS) scores were taken from breast cancer patients receiving RT before, at completion of RT, and after RT. Exploratory factor analysis (EFA), principal component analysis (PCA), and hierarchical cluster analysis (HCA) were used to identify symptom clusters among the nine ESAS items at all three time points. RESULTS:This study included 1224 patients. The PCA and EFA identified the same two symptom clusters before the start of RT: 1) pain, tiredness, nausea, drowsiness, appetite, and dyspnea; 2) depression, anxiety, and wellbeing. The HCA further split the symptoms into three clusters. Wellbeing, depression, and anxiety consistently clustered together. Among the ESAS scores collected at the end of and after RT, each statistical method identified different symptom clusters. For the symptom clusters experienced at the end of RT, the following symptoms were always in the same cluster: wellbeing, depression, and anxiety; nausea and appetite; drowsiness and dyspnea. Following RT, depression and anxiety consistently clustered together, with nausea and appetite in a second cluster. CONCLUSION:Among the symptom clusters derived before, at the end of RT, and after RT, the following symptoms consistently presented together: depression and anxiety, nausea and appetite, pain and tiredness, and drowsiness, dyspnea, and tiredness. Understanding symptom clusters in this population can improve management of symptoms. 10.1016/j.ejon.2019.07.004