Peripheral Inflammatory Markers Research Articles

Inflammatory Blood Biomarker Kynurenine Is Linked With Elevated Neuroinflammation and Neurodegeneration in Older Adults: Evidence From Two 1H-MRS Post-Processing Analysis Methods.

Rationale and ObjectivesPro-inflammatory processes have been argued to play a role in conditions associated with cognitive decline and neurodegeneration, like aging and obesity. Only a limited number of studies have tried to measure both peripheral and central biomarkers of inflammation and examined their interrelationship. The primary aim of this study was to examine the hypothesis that chronic peripheral inflammation would be associated with neurometabolic changes that indicate neuroinflammation (the combined elevation of myoinositol and choline), brain gray matter volume decrease, and lower cognitive functioning in older adults.Materials and MethodsSeventy-four older adults underwent bio-impedance body composition analysis, cognitive testing with the Montreal Cognitive Assessment (MoCA), blood serum analysis of inflammatory markers interleukin-6 (IL-6) and kynurenine, magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS) of the brain. Neurometabolic findings from both Tarquin and LCModel 1H-MRS post-processing software packages were compared. The regions of interest for MRI and 1H-MRS measurements were dorsal posterior cingulate cortex (DPCC), left hippocampal cortex (HPC), left medial temporal cortex (MTC), left primary sensorimotor cortex (SM1), and right dorsolateral prefrontal cortex (DLPFC).ResultsElevated serum kynurenine levels were associated with signs of neuroinflammation, specifically in the DPCC, left SM1 and right DLPFC, and signs of neurodegeneration, specifically in the left HPC, left MTC and left SM1, after adjusting for age, sex and fat percentage (fat%). Elevated serum IL-6 levels were associated with increased Glx levels in left HPC, left MTC, and right DLPFC, after processing the 1H-MRS data with Tarquin. Overall, the agreement between Tarquin and LCModel results was moderate-to-strong for tNAA, tCho, mIns, and tCr, but weak to very weak for Glx. Peripheral inflammatory markers (IL-6 and kynurenine) were not associated with older age, higher fat%, decreased brain gray matter volume loss or decreased cognitive functioning within a cohort of older adults.ConclusionOur results suggest that serum kynurenine may be used as a peripheral inflammatory marker that is associated with neuroinflammation and neurodegeneration, although not linked to cognition. Future studies should consider longitudinal analysis to assess the causal inferences between chronic peripheral and neuroinflammation, brain structural and neurometabolic changes, and cognitive decline in aging.

Biomarkers of neuroprogression and late staging in bipolar disorder: A systematic review.

Bipolar disorder may undertake a progressive course in a subset of patients, and research efforts have been made to understand the biological basis underlying this process. This systematic review examined the literature available on biological markers associated with illness progression in bipolar disorder. Peer-reviewed articles were assessed using Embase, PsycINFO and PubMed, as well as from external sources. After initial screening, a total of 871 citations from databases and other sources were identified. Participants with a diagnosis of bipolar disorder were included in our systematic review; however, studies with participants younger than 15 or older than 65 were excluded. All studies were assessed using the Newcastle-Ottawa Scale assessment tool, and data pertaining to the results were extracted into tabular form using Google Sheets and Google Documents. The systematic review was registered on PROSPERO international prospective register of systematic reviews (ID Number: CRD42020154305). A total of 35 studies were included in the systematic review. Increased ventricular size and reduction of grey matter volume were the most common brain changes associated with illness progression in bipolar disorder. Among the several biomarkers evaluated in this systematic review, findings also indicate a role of peripheral inflammatory markers in this process. The studies evaluating the biological basis of the illness progression in bipolar disorder are still scarce and heterogeneous. However, current evidence supports the notion of neuroprogression, the pathophysiological process related to progressive brain changes associated with clinical progression in patients with bipolar disorder. The increase in peripheral inflammatory biomarkers and the neuroanatomical changes in bipolar disorder suggest progressive systemic and structural brain alterations, respectively.

Inflammation subtypes in psychosis and their relationships with genetic risk for psychiatric and cardiometabolic disorders

Cardiometabolic disorders have known inflammatory implications, and peripheral measures of inflammation and cardiometabolic disorders are common in persons with psychotic disorders. Inflammatory signatures are also related to neurobiological and behavioral changes in psychosis. Relationships between systemic inflammation and cardiometabolic genetic risk in persons with psychosis have not been examined. Thirteen peripheral inflammatory markers and genome-wide genotyping were assessed in 122 participants (n ​= ​86 psychosis, n ​= ​36 healthy controls) of European ancestry. Cluster analyses of inflammatory markers classified higher and lower inflammation subgroups. Single-trait genetic risk scores (GRS) were constructed for each participant using previously reported GWAS summary statistics for the following traits: schizophrenia, bipolar disorder, major depressive disorder, coronary artery disease, type-2 diabetes, low-density lipoprotein, high-density lipoprotein, triglycerides, and waist-to-hip ratio. Genetic correlations across traits were quantified. Principal component (PC) analysis of the cardiometabolic GRSs generated six PC loadings used in regression models to examine associations with inflammation markers. Functional module discovery explored biological mechanisms of the inflammation association of cardiometabolic GRS genes. A subgroup of 38% persons with psychotic disorders was characterized with higher inflammation status. These higher inflammation individuals had lower BACS scores (p ​= ​0.038) compared to those with lower inflammation. The first PC of the cardiometabolic GRS matrix was related to higher inflammation status in persons with psychotic disorders (OR ​= ​2.037, p ​= ​0.001). Two of eight modules within the functional interaction network of cardiometabolic GRS genes were enriched for immune processes. Cardiometabolic genetic risk may predispose some individuals with psychosis to elevated inflammation which adversely impacts cognition associated with illness.

Youth depression and inflammation: Cross-sectional network analyses of C-Reactive protein, interleukin-6 and symptoms in a population-based sample

BackgroundInflammation-related proteins constitute a promising avenue in studying biological correlates of major depressive disorder (MDD). However, MDD is a heterogeneous condition – a crucial aspect to be considered in association studies. We examined whether inflammatory proteins are associated with categorical diagnosis, a dimensional total sum-score, and specific depressive symptoms among youths. MethodsWe analyzed data from the 1993 Pelotas Birth Cohort, a population-based study in Brazil that followed individuals up to age 22 years. Categorical psychiatric diagnoses were derived using adapted modules of the Mini International Neuropsychiatric Interview (MINI). Dimensional symptomatology was assessed using the Brazilian Portuguese version of the Center for Epidemiological Studies–Depression Scale–Revised (CESD-R). We estimated network structures that included individual depressive symptoms as measured by CESD-R items, peripheral inflammatory markers (C-Reactive Protein [CRP] and Interleukin-6 [IL-6]), as well as relevant covariates. ResultsWe evaluated 2586 participants (mean age = 22.5[SD = 0.33]) There were no associations between concentrations of inflammatory proteins and categorical diagnosis of MDD or with CESD-R total sum-scores. In symptom-specific analysis, CRP and IL-6 were positively connected to somatic and cognitive items. DiscussionWe found cross-sectional connections of two commonly studied inflammatory proteins and specific depressive symptoms. Conducting symptom-specific analyses in relation to biological markers might advance our understanding of the heterogeneity of MDD.

Effects of an intravenous ketamine infusion on inflammatory cytokine levels in male and female Sprague\u2013Dawley rats

BackgroundKetamine, a multimodal dissociative anesthetic drug, is widely used as an analgesic following traumatic injury. Although ketamine may produce anti-inflammatory effects when administered after injury, the immunomodulatory properties of intravenous (IV) ketamine in a non-inflammatory condition are unclear. In addition, most preclinical studies use an intraperitoneal (IP) injection of ketamine, which limits its clinical translation as patients usually receive an IV ketamine infusion after injury.MethodsHere, we administered sub-anesthetic doses of a single IV ketamine infusion (0, 10, or 40 mg/kg) to male and female Sprague–Dawley rats over a 2-h period. We collected blood samples at 2- and 4-h post-ketamine infusion to determine plasma inflammatory cytokine levels using multiplex immunoassays.ResultsThe 10 mg/kg ketamine infusion reduced spontaneous locomotor activity in male and female rats, while the 40 mg/kg infusion stimulated activity in female, but not male, rats. The IV ketamine infusion produced dose-dependent and sex-specific effects on plasma inflammatory cytokine levels. A ketamine infusion reduced KC/GRO and tumor necrosis factor alpha (TNF-α) levels in both male and female rats, interleukin-6 (IL-6) levels in female rats, and interleukin-10 (IL-10) levels in male rats. However, most cytokine levels returned to control levels at 4-h post-infusion, except for IL-6 levels in male rats and TNF-α levels in female rats, indicating a different trajectory of certain cytokine changes over time following ketamine administration.ConclusionsThe current findings suggest that sub-anesthetic doses of an IV ketamine infusion may produce sex-related differences in the effects on peripheral inflammatory markers in rodents, and further research is warranted to determine potential therapeutic effects of an IV ketamine infusion in an inflammatory condition.

Gut microbiota is causally associated with poststroke cognitive impairment through lipopolysaccharide and butyrate

BackgroundPoststroke cognitive impairment (PSCI) is prevalent in stroke patients. The etiology of PSCI remains largely unknown. We previously found that stroke induces gut microbiota dysbiosis which affects brain injury. Hereby, we aimed to investigate whether the gut microbiota contributes to the pathogenesis of PSCI.Methods83 stroke patients were recruited and their cognitive function were measured by Montreal Cognitive Assessment (MoCA) scores 3 months after stroke onset. The peripheral inflammatory factor levels and gut microbiota compositions of the patients were analyzed. Fecal microbiota transplantation from patients to stroke mice was performed to examine the causal relationship between the gut microbiota and PSCI. The cognitive function of mice was evaluated by Morris water maze test.Results34 and 49 stroke patients were classified as PSCI and non-PSCI, respectively. Compared with non-PSCI patients, PSCI patients showed significantly higher levels of gut Enterobacteriaceae, lipopolysaccharide (LPS) and peripheral inflammation markers. Consistently, stroke mice that received microbiota from PSCI patients (PSCI mice) presented a higher level of Enterobacteriaceae, intestinal Toll-like receptor-4 (TLR4) expression, circulating LPS, LPS-binding protein (LBP) and inflammatory cytokines, and a lower level of fecal butyrate, severer intestine destruction and cognitive impairment than mice that received microbiota from nPSCI patients (nPSCI mice). In addition, we observed exacerbations in blood–brain barrier (BBB) integrity, microglial activation, neuronal apoptosis in the CA1 region of the hippocampus, and Aβ deposition in the thalamus of PSCI mice in comparison with nPSCI mice. Intraperitoneal injection of LPS after stroke caused similar pathology to those seen in PSCI mice. Supplementation with sodium butyrate (NaB) via drinking water rescued these detrimental changes in PSCI mice.ConclusionsOur data indicate a cause–effect relationship between gut microbiota and PSCI for the first time, which is likely mediated by inflammation-regulating metabolites including LPS and butyrate.

Methylation of the AIM2 gene: An epigenetic mediator of PTSD-related inflammation and neuropathology plasma biomarkers.

Posttraumatic stress disorder (PTSD) is associated with inflammation and various forms of chronic disease. The Absent in Melanoma 2 (AIM2) gene has been implicated in mechanisms of inflammation and anxiety, and methylation at a particular locus in this gene (cg10636246) has previously been shown to influence the association between PTSD and elevated C-reactive protein levels in blood. We tested if this association might extend to other indicators of inflammation and to plasma-based measures of neuropathology in a cohort of post-9/11 US military veterans. Using a Bayesian approach, mediation models were tested cross-sectionally (n = 478) and longitudinally (n = 298). Peripheral markers of inflammation and neuropathology were measured with ultra-sensitive Single Molecule Array (Simoa®) technology. Analyses revealed indirect effects of PTSD symptom severity on peripheral indices of both inflammation (interleukin [IL]6, IL-10, tumor necrosis factor-α; indirect standardized [std.] ß range = 0.018-0.023, all p-values adjusted for multiple testing [padj ] < 0.05) and neuropathology (neurofilament light [NFL]; indirect std. ß = -0.018, padj = 0.02) via AIM2 methylation. This indirect effect was also evident when predicting IL-10 at a follow-up assessment (indirect std. ß = -0.018, padj = 0.04) controlling for baseline IL-10. Given that AIM2 methylation mediated the association between PTSD symptoms and multiple inflammatory and neuropathology markers, our results suggest that AIM2 methylation may offer clinical utility for indexing risk for adverse health outcomes associated with these peripheral indices of inflammation and neuropathology. Results also suggest a possible shared etiology underlying the frequent co-occurrence of inflammation and neuropathology.

Plasma Cystatin C Correlates with Plasma NfL Levels and Predicts Disease Progression in Parkinson’s Disease

Introduction: Previous studies reported increased plasma levels of cystatin C (Cys-C) in Parkinson’s disease (PD) and claimed for a possible association with disease severity and progression. The aim of this study was to evaluate plasma Cys-C in PD and healthy controls (HC) and test its association with markers of peripheral inflammation, neurodegeneration, and clinical progression in a longitudinal study. Methods: Plasma Cys-C, high-sensitive C-reactive protein, interleukin 6, and neurofilament light chain (NfL) were assessed at the baseline in 71 consecutive non-demented PD and 69 HC. PD patients underwent an extensive motor and cognitive assessment at baseline and after 2 years of follow-up. The association of Cys-C with disease severity was evaluated in a multilinear model adjusted for the effect of age, sex, disease duration, and peripheral inflammation. Results: Cys-C levels appeared to be higher in PD compared to controls and correlated with the plasma neuronal marker NfL (r = 0.204, p = 0.046). In longitudinal analyses, PD patients with higher Cys-C levels exhibited faster motor progression at 2 years of follow-up independently from the peripheral inflammatory profile. Conclusions: Cys-C was associated with higher NfL levels and a remarkably faster motor progression in PD independently from peripheral inflammation. Further studies are needed in order to understand the mechanisms underpinning the association of Cys-C with higher neuronal damage markers in neurodegenerative diseases.

Peripheral inflammatory cytokines and motor symptoms in persons with Parkinson's disease

BackgroundMany of the motor symptoms of Parkinson's disease (PD) impact quality of life and are not fully ameliorated by current pharmacological and surgical treatments. A better understanding of the pathophysiology underlying these symptoms is needed. Previous research has suggested that inflammation may play a significant role in PD pathophysiology and progression, but there is limited research exploring how inflammation directly relates to motor symptoms in PD. Thus, the purpose of this study was to evaluate associations between peripheral immune inflammatory markers and motor symptoms of PD, specifically, tremor, bradykinesia, and postural and gait instability. We hypothesized that peripheral inflammatory cytokines would predict the severity of motor symptoms in persons with PD, and that there will be higher levels of peripheral inflammatory cytokine markers in persons with PD when compared to age-matched healthy older adults. MethodsTwenty-six participants with PD and fourteen healthy older adults completed the study. For participants with PD, the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) was recorded and scored by two Movement Disorders Neurologists masked to the study. A blood sample was collected from both participants with PD and the healthy older adults. Through the MILLIPLEX® map High Sensitivity Human Cytokine Kit, key inflammation-related markers were analyzed (TNF-α, IFN-γ, IL-1β, IL-8, IL-2, IL-7, IL-5, IL-13, IL, 4, IL-10 IL-12p70, GM-CSF, and IL-6). ResultsResults revealed significantly higher levels of IL-6 in persons with PD when compared to healthy older adults (p ​= ​0.005). Moreover, results revealed that higher levels of IL-4 (p ​= ​0.011) and lower levels of IFNγ (p ​= ​0.003) significantly predicted more severe tremor in persons with PD. No other associations between the peripheral inflammation markers and other motor symptoms were observed. ConclusionsOverall, these results are consistent with a growing body of literature that implicates inflammatory cytokines in the PD, and further suggests that inflammatory cytokines, or lack thereof, may be associated with tremor in persons with PD.

The relationship between peripheral blood inflammatory markers and diabetic macular edema in patients with severe diabetic retinopathy.

Diabetic macular edema (DME) is a serious complication of diabetic retinopathy (DR). Recent studies have shown that inflammation is closely associated with the development of DME, and peripheral blood inflammatory markers [white blood cell (WBC) count and its subtypes] are relatively simple and easy to detect. Here, we investigated the relationship between peripheral blood inflammatory markers and macular edema in patients with severe DR (including both severe non-proliferative DR and proliferative DR). A total of 42 patients with severe DR were included in this study and divided into two groups: a severe DR with DME group (DME group, n=18) and a severe DR without DME group (non-DME group, n=24). Ophthalmologic findings and hematologic results were retrospectively retrieved from hospitalization records and databases. The neutrophil percentage was significantly higher in the DME group (62.52%±8.21%) than in the non-DME group (57.30%±8.17%) (P<0.05); in contrast, the lymphocyte percentage was significantly lower in the DME group (28.09%±7.45%) than in the non-DME group (33.54%±7.29%) (P<0.05). Logistic regression analysis showed a significant correlation between lymphocyte percentage and DME [odds ratio (OR) =0.654, 95% CI: 0.436-0.851; P=0.011]. Lymphocyte percentage can be used as an inflammatory marker for the development of DME in patients with severe DR.

CSF and Serum Levels of Inflammatory Markers in PD: Sparse Correlation, Sex Differences and Association With Neurodegenerative Biomarkers.

BackgroundAn involvement of the central-nervous and peripheral, innate and adaptive immune system in the pathogenesis of Parkinson's disease (PD) is nowadays well established.ObjectivesWe face several open questions in preparation of clinical trials aiming at disease-modification by targeting the immune system: Do peripheral (blood) inflammatory profiles reflect central (CSF) inflammatory processes? Are blood/CSF inflammatory markers associated with CSF levels of neurodegenerative/PD-specific biomarkers?MethodsUsing a multiplex assay we assessed 41 inflammatory markers in CSF/serum pairs in 453 sporadic PD patients. We analyzed CSF/serum correlation as well as associations of inflammatory markers with clinical outcome measures (UPDRS-III, H&Y, MoCA) and with CSF levels of α-synuclein, Aβ1−42, t-Tau, p181-Tau and NFL. All analyses were stratified by sex as the immune system shows relevant sex-specific differences.ResultsCorrelations between CSF and serum were sparse and detected in only 25% (9 out of 36) of the analysable inflammatory markers in male PD patients and in only 38% (12 out of 32) of female PD patients. The most important pro-inflammatory mediators associated with motor and cognitive decline as well as with neurodegenerative/PD-specific biomarkers were FABP, ICAM-1, IL-8, MCP-1, MIP-1-beta, and SCF. Results were more robust for CSF than for serum.InterpretationLevels of central-nervous and peripheral inflammatory markers might be regulated independently of each other with CSF inflammatory markers reflecting CNS pathology more accurately than peripheral markers. These findings along with sex-specific characteristics have to be considered when designing clinical trials aiming at disease-modification by targeting the immune system.

Modifying the maternal microbiota alters the gut–brain metabolome and prevents emotional dysfunction in the adult offspring of obese dams

Maternal obesity disturbs brain-gut-microbiota interactions and induces negative affect in the offspring, but its impact on gut and brain metabolism in the offspring (F1) are unknown. Here, we tested whether perinatal intake of a multispecies probiotic could mitigate the abnormal emotional behavior in the juvenile and adult offspring of obese dams. Untargeted NMR-based metabolomic profiling and gene-expression analysis throughout the gut-brain axis were then used to investigate the biology underpinning behavioral changes in the dams and their offspring. Prolonged high-fat diet feeding reduced maternal gut short-chain fatty acid abundance, increased markers of peripheral inflammation, and decreased the abundance of neuroactive metabolites in maternal milk during nursing. Both juvenile (postnatal day [PND] 21) and adult (PND112) offspring of obese dams exhibited increased anxiety-like behavior, which were prevented by perinatal probiotic exposure. Maternal probiotic treatment increased gut butyrate and brain lactate in the juvenile and adult offspring and increased the expression of prefrontal cortex PFKFB3, a marker of glycolytic metabolism in astrocytes. PFKFB3 expression correlated with the increase in gut butyrate in the juvenile and adult offspring. Maternal obesity reduced synaptophysin expression in the adult offspring, while perinatal probiotic exposure increased expression of brain-derived neurotrophic factor. Finally, we showed that the resilience of juvenile and adult offspring to anxiety-like behavior was most prominently associated with increased brain lactate abundance, independent of maternal group. Taken together, we show that maternal probiotic supplementation exerts a long-lasting effect on offspring neuroplasticity and the offspring gut-liver-brain metabolome, increasing resilience to emotional dysfunction induced by maternal obesity.

Impact of endothelial inflammation on depression in patients with cerebral microangiopathy: a prospective study

Epidemiological studies demonstrate a strong relationship between depression and cerebral microangiopathy (CM) associated with arterial hypertension (AH) and cerebral atherosclerosis, but the pathogenetic mechanisms underlying this relationship are not fully understood.Objective: to evaluate the relationship between the level of peripheral markers of endothelial inflammation and depression severity in patients with CM.Patients and methods. The level of peripheral markers of endothelial inflammation was assessed by enzyme immunoassay, and the severity of depression was assessed using the HADS scale in 262 patients with CM. All patients had correction of hypotensive, antiplatelet, anticoagulant, lipid-lowering, hypoglycemic therapy. Observation of the patients lasted 3 months with an assessment of the follow-up clinical and laboratory parameters. Results and discussion. Comparative analysis shown that in the group of patients with clinically significant depression (n=146) C-reactive protein (CRP) level was составил 6.11 mg/l, monocytic chemoatactic factor-1 (МСР-1) – 2.02 ng/ml, which differed significantly from the group f patients with subclinical depression (n=116): CRP – 2.03 mg/l, МСР-1 – 0.66 ng/ml (р&lt;0.05). Correlation analysis showed a direct strong significant linear relationship between the depression severity and the level of CRP (correlation coefficient r=0.85, p&gt;&lt;0.05). A similar significant correlation was found between the depression severity and the MCP-1 level – a direct strong linear relationship (r=0.8, p&gt;&lt;0.05). The odds ratio assessment revealed that increased peripheral markers of endothelial inflammation are associated with clinically significant depression. The use of drugs aimed at correcting the main cardiovascular risk factors contributed to a significant normalization of the levels of peripheral markers of inflammation (p&gt;&lt;0.05), accompanied by a reduction in depressive symptoms in patients with CM without the use of specific antidepressant therapy. Conclusion. The study revealed a relationship between altered levels of peripheral markers of inflammation and the severity of depression in patients with CM associated with hypertension and cerebral atherosclerosis. The normalization of the peripheral markers of endothelial inflammation contributed to the restoration of the emotional background. Keywords: endothelial inflammation; inflammatory markers; depression; cerebral microangiopathy&gt;˂0.05). Correlation analysis showed a direct strong significant linear relationship between the depression severity and the level of CRP (correlation coefficient r=0.85, p˂0.05). A similar significant correlation was found between the depression severity and the MCP-1 level – a direct strong linear relationship (r=0.8, p˂0.05). The odds ratio assessment revealed that increased peripheral markers of endothelial inflammation are associated with clinically significant depression. The use of drugs aimed at correcting the main cardiovascular risk factors contributed to a significant normalization of the levels of peripheral markers of inflammation (p˂0.05), accompanied by a reduction in depressive symptoms in patients with CM without the use of specific antidepressant therapy.Conclusion. The study revealed a relationship between altered levels of peripheral markers of inflammation and the severity of depression in patients with CM associated with hypertension and cerebral atherosclerosis. The normalization of the peripheral markers of endothelial inflammation contributed to the restoration of the emotional background.

Associations between heart rate variability, peripheral inflammatory markers and major depressive disorder

Background: Measures for the irregularity of the heartbeat, for example respiratory sinus arrhythmia, have been implicated as a measure for restorative functions of the vegetative nervous system. Methods: In the current observational study, we investigated 265 subjects, 70 of whom had a lifetime history of major depression, with a plethysmographic heartbeat monitor, blood sampling, as well as a range of psychiatric questionnaires. Results: Subjects with a history of MDE had significantly reduced respiratory sinus arrhythmia (RSA) as compared to never-depressed controls; in the whole sample, higher RSA went with lower anxiety/fear variables, especially in subscores related to cardiac symptoms as well as being afraid of dying. A reduced RSA was also associated with an increased concentration of cytokines (TNFa, IL1a, IL6, IFNg) and thyroid-stimulating hormone in the serum, pointing to a possible triangular relationship between immune system, vegetative nervous system, and emotional dysregulation. Limitations: We used a plethysmographic device for the measurement of heartbeat instead of an electrocardiogram, and had a single time point only. Conclusions: This data corroborate the idea that a disequilibrium of the vegetative nervous, especially if accompanied by a dysregulation system in immune function, can increase the risk for depression. Conversely, vagal stimulation and anti-inflammatory treatments may support the treatment with antidepressants.

Abstract P1-08-29: The influence of pre-treatment peripheral blood inflammatory markers on post-treatment response in patients with locally advanced breast cancer (LABC) from Saudi Arabia

Abstract Background: Inflammation is a recognized factor in cancer progression and resistance to treatment. Several studies correlated inflammation-related peripheral blood indices (PBI) to disease progression and poor survival in various cancers and different populations. Nonetheless, inflammation is affected by the distinctive characteristics and environmental exposure of each population. There is no prior study addressing the association of pre-treatment inflammatory markers with outcomes in patients with BC from Saudi Arabia. In this study, we evaluated post-treatment response of LABC in relation to inflammation-related PBI. Methods: We retrospectively analyzed the data of female patients with LABC undergoing neoadjuvant chemotherapy (NACT). Demographics, BMI, clinicopathologic characteristics and stage of the tumor, follow-up status and response to treatment were collected. Outcomes were evaluated in relation to pre-treatment PBI that were grouped based on the local laboratory cutoff values. Response rate (RR) and type was assessed according to post-NACT radiologic evaluation of the breast and subcategorized into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Results: A total of 172 female patients with BC met the eligibility criteria from January 2014 to December 2019. The mean age at diagnosis was 53±11, and BMI was 31±6. Left BC accounted for 55% and the majority was invasive ductal carcinoma in 85.5%, moderately differentiated in 51%, stage III (AJCC 8th edition) in 73%, and HR-positive tumor in 79%. HER2-positive BC was reported in 32% and TNBC in 10%. Radiologic (CR) accounted for the majority of RR (71.5%). A higher percentage of patients with normal red cell distribution width (RDW) and low neutrophil to lymphocyte ratio (NLR) had radiologic CR with a significant P-value of (0.003) and (0.014), respectively (Table 1). Conclusion: Among several peripheral blood indices, only RDW and NLR significantly influenced post-treatment response in this cohort. They can be explored further to potentially predict response after systemic therapy in patients with LABC. The great advantage of these biomarkers stems from their availability and affordability in routine clinical practice. Table 1.Post-treatment response type &amp; distribution according to inflammation-related peripheral blood indicesVariablesCR(N=123)PR(N=20)SD(N=23)PD(N=6)P valueN=172N(%)N(%)N(%)N(%)NLR High &amp;gt;322(81%)2(7%)0(0%)3(11%)0.014Low ≤3101(70%)18(12%)23(15%)3(2%)RDW High &amp;gt;14.122(92%)2(8%)0(0%)0(0%)0.003Normal 11-14.1100(69%)18(12%)23(16%)5(3%)Low &amp;lt;111(50%)0(0%)0(0%)1(50%) Citation Format: Atlal Abusanad, Abdullah M Alghamdi, Ahmed M Saggaf, Tala Gazzaz, Rival Brika. The influence of pre-treatment peripheral blood inflammatory markers on post-treatment response in patients with locally advanced breast cancer (LABC) from Saudi Arabia [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-29.

Individuals with both higher recent negative affect and physical pain have higher levels of C-reactive protein

Conceptualizing physical pain and negative affect as potentially interactive, we hypothesized that higher levels of peripheral inflammatory markers would be observed consistently only among individuals with both higher negative affect and pain symptomatology. Participants were generally healthy midlife adults from the Bronx, NY (N ​= ​212, Mage ​= ​46.77; 60.8% Black, 25.5% Hispanic/Latina/o) recruited as part of a larger study. Key measures were: reported pain intensity and pain interference at baseline, recent negative affect averaged from self-reports 5x/day for 7 days, and peripheral inflammatory markers (C-reactive protein [CRP] and a composite cytokine measure based on seven cytokines). Controlling for age, BMI, gender, and education, recent negative affect significantly interacted with both pain variables to explain variance in CRP, with higher CRP levels observed only in individuals with both higher negative affect and either higher pain intensity or pain interference. These findings contribute to an emerging literature suggesting that negative affect, pain, and inflammation are related in important and complex ways.

Impulsive and aggressive traits and increased peripheral inflammatory status as psychobiological substrates of homicide behavior in schizophrenia

Background and objectivesAn association between inflammation and psychopathological domains of psychotic disorders is widely acknowledged; however, the involvement of inflammatory processes in the underlying pathophysiology of violent behavior in schizophrenia is yet to be elucidated. In this study, we aimed to address the differences in impulsive and aggressive traits as well as C-reactive protein (CRP) to albumin ratio (CAR) as a marker of inflammation between schizophrenia patients with a history of homicide and those without any history of interpersonal violence or criminal background. MethodsThe study population consisted of 80 male DSM-5 schizophrenia patients who were classified into two groups: homicidal (n=40) and non-violent (n=40). Impulsive and aggressive traits were evaluated with Barratt Impulsivity Scale-11 (BIS-11), and the Buss-Warren Aggression Questionnaire (BWAQ), respectively. For the calculation of CAR, the CRP and albumin levels were obtained from the file records of routine blood screenings performed in the month before the patients were included in the study. ResultsWhen adjusted for age, all subscale scores of the BIS-11 as well as BWAQ Total, Physical and Hostility scores were significantly higher in the homicidal group than in the control group. CRP and CAR were significantly higher, and albumin was significantly lower in the homicidal patients than the controls when adjusted for age, body-mass index and smoking status. Univariate and stepwise multivariate regression models indicated that BIS-11 Non-planning, BWAQ Total, BWAQ Hostility and CAR were independent predictors of belonging to the homicidal patient group, after stepwise adjustment for all potential confounders. ConclusionsOur findings suggest that certain impulsive and aggressive traits as well as CAR, as a proxy marker of peripheral inflammation, may contribute towards homicidal tendencies and may predict a specific predisposition towards lethal violence in schizophrenia. The study highlights inflammation as a potential biological correlate of a specific behavioral phenotype (homicide) in schizophrenia.

Physical activity as an adjuvant therapy for depression and influence on peripheral inflammatory markers: A randomized clinical trial

IntroductionRegular exercise is recommended for people with major depressive disorder (MDD) by major treatment guidelines (e.g. the NICE guideline, 2009). In addition, an effect of antidepressant (AD) treatment on pro-inflammatory markers has been reported. However, it remains unclear whether physical activity as an adjuvant to AD treatment increases clinical response rates and is associated with levels of inflammatory markers. MethodsA four-week single-blind clinical trial involving forty people with major MDD, divided into an AD group (sertraline) and AD + exercise (40 min/day, four times weekly for four weeks) group was conducted. Peripheral inflammatory markers (IL-12, IL-10, IL-8, IL-6, IL-1β, TNF-α) and cortisol were collected at baseline and at endpoint. ResultsWe observed a significant decrease in cortisol levels over time, but this change did not differ between the AD and AD + exercise groups. None of the other inflammatory markers showed a significant change in level during the trial. Also, most of the individuals who achieved remission were from the AD + exercise group. ConclusionAlthough our study failed to find that the association of physical activity as an adjunct to antidepressants promotes a change in cortisol or interleukins in people with MDD, we found that cortisol seems to be the most sensitive biomarker to antidepressant treatment. Further studies involving larger samples of, longer duration and with other classes of antidepressants and types of exercise should be conducted to better elucidate the link between inflammatory markers and depression.

Abstract TP59: Higher White Blood Cell Count In The First Week After Stroke Predicts Worse Cognitive Outcomes In A Population With Smaller Ischemic Strokes

Introduction: Infection after stroke is more common with large strokes and thus peripheral markers of inflammation are not well defined in stroke survivors with smaller strokes. We sought here to define the prevalence of infection, low grade fever (T≥38°C), and white blood cell count over 11x10 3 /mL (WBC&gt;11) in the first week after stroke in subjects with smaller stroke sizes, and to ask how inflammation in the acute period affects cognitive outcomes in this population. Methods: We performed systematic chart review of hospitalization after ischemic stroke (up to 7 days) in 65 subjects enrolled in the StrokeCog study who returned for testing 5-13 months later (median stroke volume 6 mL, [IQR 0.5, 16.6]). We assessed infection (CDC consensus criteria), highest WBC, and presence of T≥38°C. Mann-Whitney U test and general linear models were used to assess whether WBC in the first week predicted outcomes at follow-up: MoCA, Stroke Impact Scale Depression (SIS3), a global cognitive score, and composite scores of memory, motor functioning, processing speed, language, and spatial ability. Models were adjusted when appropriate for age, sex, and stroke size or NIHSS at admission. Results: Infection and T≥38°C were each present in 8%, and WBC&gt;11 in 18% of participants within 7 days of stroke. Since only high WBC was present in a substantial proportion of subjects, we compared outcomes in high (&gt;11) vs. normal (≤11) WBC. Subjects with high WBC had larger strokes (13cc [6.6, 38.6] vs. 3.2[0.4, 10.6], p= 0.027) and worse admission NIHSS (10[4,13)] vs 2[1,5], p =0.003). In addition, WBC&gt;11 in the first week was associated with worse mood and lower scores in memory, language, and global cognition months later. After adjustment, WBC remained significantly predictive of mood ( p =.039) and global cognition ( p =0.003); language remained significant if adjusted for stroke size ( p =0.010) but not NIHSS ( p =0.19). Conclusions: Infection and T≥38°C are uncommon during acute hospitalization of ischemic stroke survivors who can return to complete comprehensive testing batteries 5-13 months later. WBC&gt;11 within the first week after stroke may be a marker of later inflammation and predicts more chronic depression and worse cognitive outcomes in this population.

Serum inflammatory markers and their associations with white matter integrity of the corpus callosum in schizophrenia patients and healthy controls

Schizophrenia is associated with disrupted integrity of white matter microstructure of a variety of brain regions, especially the corpus callosum (CC). Chronic subclinical inflammation is considered to be one of the factors involved in the pathogenesis of this disease, and increased levels of peripheral inflammatory markers are often observed in schizophrenia patients. Therefore, we decided to investigate whether the integrity of the corpus callosum is correlated with levels of these markers. A total of 50 patients with stable chronic schizophrenia (SCH) and 30 controls (CON) were enrolled in the study. All participants underwent psychiatric evaluation, neuroimaging, and blood sampling including the measurement of serum concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL − 10), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and C-reactive protein (CRP). Additional potentially related factors, such as age, gender, BMI, smoking, disease duration, and treatment were included in the analysis. Significantly higher IL-6 and IFN-γ levels were observed in SCH compared to CON. In SCH, IFN-γ was positively correlated with mean diffusivity of region 2 of the CC. In CON, IL-6 was inversely correlated with fractional anisotropy of region 1 of the CC. These results support the potential influence of peripheral inflammatory markers on the integrity of the CC in schizophrenia, but require verification in longitudinal studies.