Publications by authors named "Suzi Hong"

61 Publications

Systemic Inflammation and Cognitive Decrements in Patients with Stage B Heart Failure.

Psychosom Med 2021 Oct 12. Epub 2021 Oct 12.

College of Behavioral and Community Sciences, University of South Florida, Tampa, FL, USA Department of Psychiatry, University of California School of Medicine, San Diego, CA, USA Department of Family Medicine and Public Health, University of California School of Medicine, San Diego, CA, USA Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA Behavioral Medicine Research Center, University of Miami, Miami, Florida, USA; Department of Psychology, University of Miami, Coral Gables, Florida, USA; Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, Florida, USA Department of Medicine, University of California School of Medicine, San Diego, CA, USA Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.

Objective: To investigate the role of systemic inflammation in reduced cognitive functioning in patients with early-stage heart failure (HF), while taking associations with other cardiovascular risk factors into account.

Methods: Patients with stage B HF (n = 270; mean age 66.1 ± 10.1) were examined cross-sectionally for relationships among cardiovascular disease (CVD) and psychological risk factors, c-reactive protein (CRP) and Montreal Cognitive Assessment (MoCA) scores. A subsample (n = 83), at high-risk for stage C HF (B-type natriuretic peptide (BNP) levels >65 pg/mL) were followed for 12-months for relationships between CRP levels and cognitive function.

Results: Baseline smoking (c2 = 6.33), unmarried (c2 = 12.0), hypertension (c2 = 5.72), greater body mass index (d = .45), and physical fatigue (d = .25) were related to higher CRP levels (p's < .05). Cross-sectionally, CRP levels were negatively related to MoCA scores, beyond CVD (DR2 = .022, b = -.170, p < .010) and psychological risk factors (DR2 = .016, b = .145, p < .027) and related to MCI criteria (odds ratio = 1.35, 95% CI 1.00 - 1.81, p = .046). Across 12-months, BNP high-risk patients with CRP levels ≥3 mg/L had lower MoCA scores (23.6; 95% CI 22.4 - 24.8) than patients with CRP levels <3 mg/L (25.4; 95% CI 24.4 - 26.5) (p = .024).

Conclusion: Patients with stage B HF and heightened CRP levels had greater cognitive impairment at baseline and follow-up, independent of CVD and potentially psychological risk factors. Low-grade systemic inflammation may be one mechanism involved in cognitive dysfunction at early stages of HF.
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http://dx.doi.org/10.1097/PSY.0000000000001033DOI Listing
October 2021

Independent and Joint Impacts of Acid-Producing Diets and Depression on Physical Health among Breast Cancer Survivors.

Nutrients 2021 Jul 15;13(7). Epub 2021 Jul 15.

Division of Epidemiology and Biostatistics, School of Public Health, San Diego State University, San Diego, CA 92182, USA.

The purpose of this study was to examine the independent and joint associations of acid-producing diets and depressive symptoms with physical health among breast cancer survivors. We studied a cohort of 2944 early stage breast cancer survivors who provided dietary, physical health, demographic, and lifestyle information at baseline, year 1, and year 4. We assessed the intakes of acid-producing diets via two commonly used dietary acid load scores: potential renal acid load (PRAL) and net endogenous acid production (NEAP). Physical health was measured using the Rand 36-Item Short Form Health Survey (SF-36), consisting of physical functioning, role limitation due to physical function, bodily pain, general health, and overall physical health subscales. Increased dietary acid load and depression were each independently and significantly associated with reduced physical health subscales and overall physical health. Further, dietary acid load and depression were jointly associated with worse physical health. For instance, depressed women with dietary acid load higher than median reported 2.75 times the risk (odds ratio = 2.75; 95% confidence interval: 2.18-3.47) of reduced physical function and 3.10 times the risk of poor physical health (odds ratio = 3.10; 95% confidence interval: 2.53-3.80) compared to non-depressed women with dietary acid load lower than median. Our results highlight the need of controlling acid-producing diets and the access of mental care for breast cancer survivors.
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http://dx.doi.org/10.3390/nu13072422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308757PMC
July 2021

Daily Cannabis Use is Associated With Lower CNS Inflammation in People With HIV.

J Int Neuropsychol Soc 2021 07;27(6):661-672

Department of Psychiatry, University of California, San Diego, USA.

Objective: Recent cannabis exposure has been associated with lower rates of neurocognitive impairment in people with HIV (PWH). Cannabis's anti-inflammatory properties may underlie this relationship by reducing chronic neuroinflammation in PWH. This study examined relations between cannabis use and inflammatory biomarkers in cerebrospinal fluid (CSF) and plasma, and cognitive correlates of these biomarkers within a community-based sample of PWH.

Methods: 263 individuals were categorized into four groups: HIV- non-cannabis users (n = 65), HIV+ non-cannabis users (n = 105), HIV+ moderate cannabis users (n = 62), and HIV+ daily cannabis users (n = 31). Differences in pro-inflammatory biomarkers (IL-6, MCP-1/CCL2, IP-10/CXCL10, sCD14, sTNFR-II, TNF-α) by study group were determined by Kruskal-Wallis tests. Multivariable linear regressions examined relationships between biomarkers and seven cognitive domains, adjusting for age, sex/gender, race, education, and current CD4 count.

Results: HIV+ daily cannabis users showed lower MCP-1 and IP-10 levels in CSF compared to HIV+ non-cannabis users (p = .015; p = .039) and were similar to HIV- non-cannabis users. Plasma biomarkers showed no differences by cannabis use. Among PWH, lower CSF MCP-1 and lower CSF IP-10 were associated with better learning performance (all ps < .05).

Conclusions: Current daily cannabis use was associated with lower levels of pro-inflammatory chemokines implicated in HIV pathogenesis and these chemokines were linked to the cognitive domain of learning which is commonly impaired in PWH. Cannabinoid-related reductions of MCP-1 and IP-10, if confirmed, suggest a role for medicinal cannabis in the mitigation of persistent inflammation and cognitive impacts of HIV.
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http://dx.doi.org/10.1017/S1355617720001447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288448PMC
July 2021

Searching for host immune-microbiome mechanisms in obsessive-compulsive disorder: A narrative literature review and future directions.

Neurosci Biobehav Rev 2021 06 24;125:517-534. Epub 2021 Feb 24.

Department of Psychiatry, University of California San Diego, La Jolla, California, United States; Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, California, United States.

Obsessive-compulsive disorder (OCD) is disabling and often treatment-refractory. Host immunity and gut microbiota have bidirectional communication with each other and with the brain. Perturbations to this axis have been implicated in neuropsychiatric disorders, but immune-microbiome signaling in OCD is relatively underexplored. We review support for further pursuing such investigations in OCD, including: 1) gut microbiota has been associated with OCD, but causal pathogenic mechanisms remain unclear; 2) early environmental risk factors for OCD overlap with critical periods of immune-microbiome development; 3) OCD is associated with increased risk of immune-mediated disorders and changes in immune parameters, which are separately associated with the microbiome; and 4) gut microbiome manipulations in animal models are associated with changes in immunity and some obsessive-compulsive symptoms. Theoretical pathogenic mechanisms could include microbiota programming of cytokine production, promotion of expansion and trafficking of peripheral immune cells to the CNS, and regulation of microglial function. Immune-microbiome signaling in OCD requires further exploration, and may offer novel insights into pathogenic mechanisms and potential treatment targets for this disabling disorder.
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http://dx.doi.org/10.1016/j.neubiorev.2021.02.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106658PMC
June 2021

Trajectories of Depressive Symptoms, Neurocognitive Function, and Viral Suppression With Antiretroviral Therapy Among Youth With HIV Over 36 months.

J Acquir Immune Defic Syndr 2021 06;87(2):851-859

Department of Psychiatry, University of California San Diego, La Jolla, CA.

Background: Depression and neurocognitive impairment are highly prevalent among persons living with HIV and associated with poorer clinical outcomes; however, longitudinal studies of depression-neurocognition relationships in youth living with HIV (YLWH), and the role of antiretroviral therapy (ART), are lacking. This study tested whether (1) depressive symptomatology, across somatic, cognitive, and affective symptom domains, improved with ART and (2) more severe depressive symptoms at baseline were associated with poorer neurocognitive function and poorer HIV suppression.

Setting: Data were collected from 181 YLWH (18-24 years) who were treatment-naive, a subset of whom (n = 116) initiated ART.

Methods: Participants were categorized into elevated (DS) or nonelevated (non-DS) depressive symptom groups at entry (Beck Depression Inventory-II ≥14) and followed for 36 months. Neurocognition (5-domain battery) and depressive symptoms were repeatedly assessed. Longitudinal models examined depressive symptomatology, neurocognition, and odds of HIV nonsuppression by group.

Results: Greater improvements in depressive symptoms were observed in the DS group over 36 months [beta = -0.14, (-0.24 to -0.03)], particularly within cognitive and affective domains. Verbal learning performance increased in the DS group [beta = 0.13, (0.01 to 0.24)], whereas psychomotor function improved somewhat in the non-DS group [beta = -0.10, (-0.22 to 0.00)]. Adjusted for ART adherence, odds of HIV nonsuppression did not significantly differ by group [odds ratio = 0.22, (0.04 to 1.23)]; however, greater somatic symptoms at study entry were associated with an increased risk of nonsuppression over time [odds ratio = 2.33 (1.07 to 5.68)].

Conclusion: Depressive symptoms were associated with differential neurocognitive trajectories, and somatic depressive symptoms at baseline may predict poorer subsequent HIV suppression. Identifying and treating depressive symptoms at ART initiation may benefit neurocognitive and clinical outcomes in YLWH.
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http://dx.doi.org/10.1097/QAI.0000000000002653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131211PMC
June 2021

Inflammation at the interface of physical and neuropsychiatric outcomes: Investigation of neuroendocrine regulatory pathways to inform therapeutics.

Authors:
Suzi Hong

Brain Behav Immun 2020 08 27;88:270-274. Epub 2020 Apr 27.

Department of Family Medicine & Public Health, University of California San Diego, USA; Department of Psychiatry, University of California San Diego, 9500 Gilman Dr. MC0804, La Jolla, California 92093-0804, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2020.04.076DOI Listing
August 2020

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms.

Brain Behav Immun 2020 07 13;87:34-39. Epub 2020 Apr 13.

Department of Psychiatry, University of California San Diego, 9500 Gilman Dr. MC0804, La Jolla, CA 92093-0804, USA; Department of Family Medicine and Public Health, Department of Psychiatry, University of California San Diego, 9500 Gilman Dr. MC0804, La Jolla, CA 92093-0804, USA. Electronic address:

The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals' lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.
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http://dx.doi.org/10.1016/j.bbi.2020.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152874PMC
July 2020

Effects of Caloric Intake and Aerobic Activity in Individuals with Prehypertension and Hypertension on Levels of Inflammatory, Adhesion and Prothrombotic Biomarkers-Secondary Analysis of a Randomized Controlled Trial.

J Clin Med 2020 Feb 28;9(3). Epub 2020 Feb 28.

Department of Psychiatry, University of California, San Diego, CA 92093, USA.

Background: Cardiopulmonary fitness and low calorie diets have been shown to reduce inflammation but few studies have been conducted in individuals with elevated blood pressure (BP) in a randomized intervention setting. Thereby, adhesion biomarkers, e.g., soluble intercellular adhesion molecule (sICAM)-3, have not been examined so far.

Methods: Sixty-eight sedentary prehypertensive and mildly hypertensive individuals (mean age ± SEM: 45 ± 1 years; mean BP: 141/84 ± 1/1 mmHg) were randomized to one of three 12-week intervention groups: cardio training and caloric reduction, cardio training alone, or wait-list control group. Plasma levels of inflammatory, adhesion and prothrombotic biomarkers were assessed. In a second step, intervention groups were combined to one sample and multivariate regression analyses were applied in order to account for exercise and diet behavior changes.

Results: There were no significant differences among the intervention groups. In the combined sample, greater caloric reduction was associated with a larger increase of sICAM-3 ( = 0.026) and decrease of C-reactive protein ( = 0.018) as a result of the interventions. More cardio training was associated with increases of sICAM-3 ( = 0.046) as well as interleukin-6 ( = 0.004) and a decrease of tumor necrosis factor- ( = 0.017) levels. Higher BP predicted higher plasminogen activator inhibitor (PAI)-1 ( = 0.001), and greater fitness predicted lower PAI-1 levels ( = 0.006) after the intervention.

Conclusions: In prehypertensive and hypertensive patients, plasma levels of the adhesion molecule sICAM-3 and inflammatory biomarkers have different response patterns to cardio training with and without caloric reduction. Such anti-inflammatory and anti-thrombotic effects may have implications for the prevention of atherothrombotic cardiovascular disease among individuals at increased risk.
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http://dx.doi.org/10.3390/jcm9030655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141349PMC
February 2020

Differing salivary microbiome diversity, community and diurnal rhythmicity in association with affective state and peripheral inflammation in adults.

Brain Behav Immun 2020 07 14;87:591-602. Epub 2020 Feb 14.

Department of Psychiatry, United States; Center for Microbiome Innovation, United States; Department of Family Medicine and Public Health, University of California, San Diego, United States. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2020.02.004DOI Listing
July 2020

Higher soluble CD14 levels are associated with lower visuospatial memory performance in youth with HIV.

AIDS 2019 12;33(15):2363-2374

aDivision of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Duke University School of Medicine, Durham bUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina cUniversity of California San Diego, La Jolla, California dChildren's Diagnostic & Treatment Center, Fort Lauderdale, Florida eHunter College, CUNY, New York, New York fUniversity of Houston, Houston, Texas gNIH, Bethesda, Maryland, USA.

Objective: HIV-associated neurocognitive disorders persist despite early antiretroviral therapy (ART) and optimal viral suppression. We examined the relationship between immunopathogenesis driven by various pathways of immune activation and discrete neurocognitive performance domains in youth with HIV (YWH).

Design: Observational cross-sectional study.

Methods: YWH, ages 20-28 years, enrolled in Adolescent Medicine Trials Network 071/101 were assessed for biomarkers of macrophage, lymphocyte activation, and vascular inflammation using ELISA/multiplex assays. Standardized neurocognitive tests were performed, and demographically adjusted z-scores were combined to form indices of attention, motor, executive function, verbal, and visuospatial memory. Cross-sectional analysis of the relationship between 18 plasma inflammatory biomarkers and each neurocognitive domain was performed. Linear regression models were fit for each combination of log-transformed biomarker value and neurocognitive domain score, and were adjusted for demographics, socioeconomic status, substance use, depression, CD4 T-cell count, HIV viral load, and ART status.

Results: Study included 128 YWH [mean age 23.8 (SD 1.7) years, 86% men, 68% African American]. Verbal and visuospatial memory domains were most significantly impaired in the cohort (z = -1.59 and -1.0, respectively). Higher sCD14 was associated with impaired visuospatial memory, which remained robust after adjusting for other biomarkers, demographics, and HIV-associated covariates. Among biomarkers of vascular inflammation, sICAM-1 was negatively associated with verbal memory and attention, whereas sVCAM-1 was positively associated with executive function and visuospatial memory. Specific neurocognitive domains were not associated with sCD163, LPS, or CCL2 levels.

Conclusion: Impaired visuospatial memory in YWH is associated with immune activation, as reflected by higher sCD14.
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http://dx.doi.org/10.1097/QAD.0000000000002371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905124PMC
December 2019

Self-reported sleep disturbances are associated with poorer cognitive performance in older adults with hypertension: a multi-parameter risk factor investigation.

Int Psychogeriatr 2020 07;32(7):815-825

Department of Psychiatry, University of California, San Diego, USA.

Objectives: Given the evidence of multi-parameter risk factors in shaping cognitive outcomes in aging, including sleep, inflammation, cardiometabolism, and mood disorders, multidimensional investigations of their impact on cognition are warranted. We sought to determine the extent to which self-reported sleep disturbances, metabolic syndrome (MetS) factors, cellular inflammation, depressive symptomatology, and diminished physical mobility were associated with cognitive impairment and poorer cognitive performance.

Design: This is a cross-sectional study.

Setting: Participants with elevated, well-controlled blood pressure were recruited from the local community for a Tai Chi and healthy-aging intervention study.

Participants: One hundred forty-five older adults (72.7 ± 7.9 years old; 66% female), 54 (37%) with evidence of cognitive impairment (CI) based on Montreal Cognitive Assessment (MoCA) score ≤24, underwent medical, psychological, and mood assessments.

Measurements: CI and cognitive domain performance were assessed using the MoCA. Univariate correlations were computed to determine relationships between risk factors and cognitive outcomes. Bootstrapped logistic regression was used to determine significant predictors of CI risk and linear regression to explore cognitive domains affected by risk factors.

Results: The CI group were slower on the mobility task, satisfied more MetS criteria, and reported poorer sleep than normocognitive individuals (all p < 0.05). Multivariate logistic regression indicated that sleep disturbances, but no other risk factors, predicted increased risk of evidence of CI (OR = 2.00, 95% CI: 1.26-4.87, 99% CI: 1.08-7.48). Further examination of MoCA cognitive subdomains revealed that sleep disturbances predicted poorer executive function (β = -0.26, 95% CI: -0.51 to -0.06, 99% CI: -0.61 to -0.02), with lesser effects on visuospatial performance (β = -0.20, 95% CI: -0.35 to -0.02, 99% CI: -0.39 to 0.03), and memory (β = -0.29, 95% CI: -0.66 to -0.01, 99% CI: -0.76 to 0.08).

Conclusions: Our results indicate that the deleterious impact of self-reported sleep disturbances on cognitive performance was prominent over other risk factors and illustrate the importance of clinician evaluation of sleep in patients with or at risk of diminished cognitive performance. Future, longitudinal studies implementing a comprehensive neuropsychological battery and objective sleep measurement are warranted to further explore these associations.
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http://dx.doi.org/10.1017/S1041610219001492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011648PMC
July 2020

COMT Val158Met Polymorphism, Cardiometabolic Risk, and Nadir CD4 Synergistically Increase Risk of Neurocognitive Impairment in Men Living With HIV.

J Acquir Immune Defic Syndr 2019 08;81(5):e148-e157

Department of Psychiatry, University of California, San Diego, CA.

Objective: The Val allele of the Val158Met single-nucleotide polymorphism of the catechol-o-methyltransferase gene (COMT) results in faster metabolism and reduced bioavailability of dopamine (DA). Among persons living with HIV, Val carriers display neurocognitive deficits relative to Met carriers, presumably due to exacerbation of HIV-related depletion of DA. COMT may also impact neurocognition by modulating cardiometabolic function, which is often dysregulated among persons living with HIV. We examined the interaction of COMT, cardiometabolic risk, and nadir CD4 on neurocognitive impairment (NCI) among HIV+ men.

Methods: Three hundred twenty-nine HIV+ men underwent COMT genotyping and neurocognitive and neuromedical assessments. Cohort-standardized z scores for body mass index, systolic blood pressure, glucose, triglycerides, and high-density lipoprotein cholesterol were averaged to derive a cardiometabolic risk score (CMRS). NCI was defined as demographically adjusted global deficit score of ≥0.5. Logistic regression modeled NCI as a function of COMT, CMRS, and their interaction, covarying for estimated premorbid function, race/ethnicity, and HIV-specific characteristics. Follow-up analysis included the 3-way interaction of COMT, CMRS, and nadir CD4.

Results: Genotypes were 81 (24.6%) Met/Met, 147 (44.7%) Val/Met, and 101 (30.7%) Val/Val. COMT interacted with CMRS (P = 0.02) such that higher CMRS increased risk of NCI among Val/Val [odds ratio (OR) = 2.13, P < 0.01], but not Val/Met (OR = 0.93, P > 0.05) or Met/Met (OR = 0.92, P > 0.05) carriers. Among Val/Val, nadir CD4 moderated the effect of CMRS (P < 0.01) such that higher CMRS increased likelihood of NCI only when nadir CD4 <180.

Discussion: Results suggest a tripartite model by which genetically driven low DA reserve, cardiometabolic dysfunction, and historical immunosuppression synergistically enhance risk of NCI among HIV+ men, possibly due to neuroinflammation and oxidative stress.
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http://dx.doi.org/10.1097/QAI.0000000000002083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625879PMC
August 2019

Sex-specific roles of cellular inflammation and cardiometabolism in obesity-associated depressive symptomatology.

Int J Obes (Lond) 2019 10 14;43(10):2045-2056. Epub 2019 May 14.

Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, United States.

Background: Obesity and depression are complex conditions with stronger comorbid relationships among women than men. Inflammation and cardiometabolic dysfunction are likely mechanistic candidates for increased depression risk, and their prevalence differs by sex. Whether these relationships extend to depressive symptoms is poorly understood. Therefore, we analyzed sex in associations between inflammation and metabolic syndrome (MetS) criteria on depressive symptomatology. Specifically, we examined whether sex positively moderates the relationship between depressive symptoms and inflammation among women, and whether MetS has parallel effects among men.

Methods: Depressive symptoms, MetS, and inflammation were assessed in 129 otherwise healthy adults. Depressive symptoms were assessed using Beck Depression Inventory (BDI-Ia). Monocyte inflammation regulation (BARIC) was quantified using flow cytometry measurement of TNF-α suppression by β-agonist. Moderation effects of sex on associations between BARIC, MetS criteria, and BDI were estimated using two-way ANOVA and linear regression, adjusting for BMI, and by sex subgroup analyses.

Results: Obese individuals reported more depressive symptoms. Sex did not formally moderate this relationship, though BDI scores tended to differ by BMI among women, but not men, in subgroup analysis. Poorer inflammation control and higher MetS criteria were correlated with somatic depressive symptoms. Sex moderated associations between MetS criteria and somatic symptoms; among men, MetS criteria predicted somatic symptoms, not among women. Subgroup analysis further indicated that poorer inflammation control tended to be associated with higher somatic symptoms in women.

Conclusions: These results indicate that obesity-related inflammation and MetS factors have sex-specific effects on depressive symptoms in a non-clinical population. Although pathophysiological mechanisms underlying sex differences remain to be elucidated, our findings suggest that distinct vulnerabilities to depressive symptoms exist between women and men, and highlight the need to consider sex as a key biological variable in obesity-depression relationships. Future clinical studies on comorbid obesity and depression should account for sex, which may optimize therapeutic strategies.
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http://dx.doi.org/10.1038/s41366-019-0375-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774832PMC
October 2019

Inflammation and exercise: Inhibition of monocytic intracellular TNF production by acute exercise via β-adrenergic activation.

Brain Behav Immun 2017 Mar 21;61:60-68. Epub 2016 Dec 21.

Department of Psychiatry, University of California, San Diego, USA. Electronic address:

Regular exercise is shown to exert anti-inflammatory effects, yet the effects of acute exercise on cellular inflammatory responses and its mechanisms remain unclear. We tested the hypothesis that sympathoadrenergic activation during a single bout of exercise has a suppressive effect on monocytic cytokine production mediated by β adrenergic receptors (AR). We investigated the effects of 20-min moderate (65-70% VO peak) exercise-induced catecholamine production on LPS-stimulated TNF production by monocytes in 47 healthy volunteers and determined AR subtypes involved. We also examined the effects of β-agonist isoproterenol and endogenous β- and α-agonists epinephrine and norepinephrine, and receptor-subtype-specific β- and α-antagonists on TNF production in a series of in vitro investigations. LPS-stimulated TNF production by peripheral blood monocytes was determined intracellularly by flow cytometry, using an intracellular protein transport inhibitor. Percent TNF-producing monocytes and per-cell TNF production with and without LPS was suppressed by exercise with moderate to large effects, which was reversed by a β-AR antagonist in spite that plasma TNF levels did not change. This inhibitory response in TNF production by exercise was mirrored by β-AR agonists in an agonist-specific and dose-dependent manner in vitro: similar isoproterenol (EC=2.1-4.7×10M) and epinephrine (EC=4.4-10×10M) potency and higher norepinephrine concentrations (EC=2.6-4.3×10M) needed for the effects. Importantly, epinephrine levels observed during acute exercise in vivo significantly inhibited TNF production in vitro. The inhibitory effect of the AR agonists was abolished by β-, but not by β- or α-AR blockers. We conclude that the downregulation of monocytic TNF production during acute exercise is mediated by elevated epinephrine levels through β-ARs. Decreased inflammatory responses during acute exercise may protect against chronic conditions with low-grade inflammation.
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http://dx.doi.org/10.1016/j.bbi.2016.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555138PMC
March 2017

Inflammation in Schizophrenia: Cytokine Levels and Their Relationships to Demographic and Clinical Variables.

Am J Geriatr Psychiatry 2017 01 17;25(1):50-61. Epub 2016 Oct 17.

Department of Psychiatry, University of California San Diego, La Jolla, CA; Departments of Neurosciences, University of California San Diego, La Jolla, CA; Sam and Rose Stein Institute for Research on Aging, University of California San Diego, La Jolla, CA; The Center for Healthy Aging, University of California San Diego, La Jolla, CA. Electronic address:

Objective: Inflammation may play a role in the accelerated physical aging reported in schizophrenia, though biomarker findings and associations with demographic and clinical factors are inconsistent.

Methods: In a cross-sectional, case-control design, 95 outpatients with schizophrenia (mean age ± SD: 48.1 ± 10.2 years) and 95 demographically comparable healthy comparison subjects (HCs) (mean age ± SD: 48.1 ± 12.1 years) were studied. Sociodemographic and clinical data were collected, and plasma levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) were assayed. The authors compared cytokine levels, examined demographic and clinical associations, and adjusted for relevant variables with linear models.

Results: Individuals with schizophrenia had higher levels of TNF-α and IL-6 but not IFN-γ than HCs. Age was not related to cytokine levels, and age relationships did not differ between diagnostic groups. Women had higher levels of IL-6. TNF-α and IL-6 levels were significantly correlated with depressive symptoms, and adjustment for depression reduced the group effect for both. Within the HCs, TNF-α levels were associated with physical comorbidity and body mass index. IL-6 levels were significantly correlated with body mass index and within schizophrenia patients, with worse mental and physical well-being. Accounting for physical morbidity and mental well-being reduced group differences in TNF-α and IL-6 levels, respectively. Worse positive symptoms were associated with higher IL-6 levels.

Conclusion: Higher TNF-α and IL-6 levels in schizophrenia patients were associated with depression, physical comorbidity, and mental well-being. Further longitudinal studies are warranted to assess inflammation as a potential treatment target for a subgroup of schizophrenia.
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http://dx.doi.org/10.1016/j.jagp.2016.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164855PMC
January 2017

Elevated Markers of Vascular Remodeling and Arterial Stiffness Are Associated With Neurocognitive Function in Older HIV+ Adults on Suppressive Antiretroviral Therapy.

J Acquir Immune Defic Syndr 2017 Feb;74(2):134-141

*Joint Doctoral Program in Clinical Psychology, SDSU/UCSD, San Diego, CA; Departments of †Psychiatry; ‡Family Medicine and Public Health; §Neurosciences; and ‖Medicine, University of California, San Diego, La Jolla, CA.

Background: HIV is associated with elevated markers of vascular remodeling that may contribute to arterial fibrosis and stiffening and changes in pulse pressure (PP). These changes may, in turn, deleteriously affect autoregulation of cerebral blood flow and neurocognitive function.

Methods: To evaluate these mechanisms, we studied markers of vascular remodeling, PP, and neurocognitive function among older (≥50 years of age) HIV-infected (HIV+, n = 72) and HIV-seronegative (HIV-, n = 36) adults. Participants completed standardized neurobehavioral and neuromedical assessments. Neurocognitive functioning was evaluated using a well-validated comprehensive battery. Three plasma biomarkers of vascular remodeling (ie, angiopoietin 2, Tie-2, and vascular endothelial growth factor, VEGF) were collected.

Results: HIV+ and HIV- participants had similar levels of plasma angiopoietin 2 (P = 0.48), Tie-2 (P = 0.27), VEGF (P = 0.18), and PP (P = 0.98). In a multivariable regression model, HIV interacted with Tie-2 (β = 0.41, P < 0.01) and VEGF (β = -0.43, P = 0.01) on neurocognitive function, such that lower Tie-2 and higher VEGF values were associated with worse neurocognitive function for HIV+ participants. Greater Tie-2 values were associated with increased PP (r = 0.31, P < 0.01). In turn, PP demonstrated a quadratic association with neurocognitive function (β = -0.33, P = 0.01), such that lower and higher, relative to mean sample, PP values were associated with worse neurocognitive function.

Conclusions: These findings indicate that vascular remodeling and altered cerebral blood flow autoregulation contribute to neurocognitive function. Furthermore, HIV moderates the association between vascular remodeling and neurocognitive function but not the association between PP and neurocognitive function.
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http://dx.doi.org/10.1097/QAI.0000000000001230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233588PMC
February 2017

Abnormalities in chemokine levels in schizophrenia and their clinical correlates.

Schizophr Res 2017 03 17;181:63-69. Epub 2016 Sep 17.

Department of Psychiatry, University of California, San Diego, USA; Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, USA; Department of Neurosciences, University of California, San Diego, USA. Electronic address:

Chemokines are promising biomarkers of immune activation and inflammation, but evidence for chemokine abnormalities in schizophrenia and their relationship to clinical factors remains inconclusive. We aimed to understand chemokine-related diagnostic differences and clinical correlates using a comprehensive panel and studying a large, well-characterized sample of adults with and without schizophrenia. We studied 134 outpatients with schizophrenia or schizoaffective disorder and 112 healthy comparison (HC) individuals, 26 to 65years of age. Clinical measures were obtained, and plasma levels of 11 chemokines were assessed using multiplex immunoassay. Schizophrenia vs. HC differences were tested for each chemokine, adjusting for age, gender, body mass index, and current smoking status. We also examined whether age and gender relationships differed between diagnostic groups. Using logistic regression, we created a Chemokine Index (CI) and explored its clinical correlates. Levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1β (MIP-1β/CCL4), Eotaxin-1 (CCL11), thymus and activation-regulated chemokine (TARC/CCL17), and macrophage-derived chemokine (MDC/CCL22) were significantly higher in persons with schizophrenia than HCs. Group differences in TARC were reduced after adjusting for covariates. The CI, a linear combination of Eotaxin-1 and MDC levels, was positively associated with age, duration of schizophrenia, and severity of negative symptoms. Levels of chemokines with neuroimmune regulatory effects were higher in individuals with schizophrenia, particularly in older and chronic patients. Treatments aimed at normalizing chemokine levels might improve mental and physical health among schizophrenia patients as they age.
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http://dx.doi.org/10.1016/j.schres.2016.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357211PMC
March 2017

Glucocorticoid mediated regulation of inflammation in human monocytes is associated with depressive mood and obesity.

Psychoneuroendocrinology 2016 Apr 12;66:195-204. Epub 2016 Jan 12.

Department of Psychiatry, University of California San Diego, United States. Electronic address:

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is observed in various conditions, including depression and obesity, which are also often related. Glucocorticoid (GC) resistance and desensitization of peripheral GC receptors (GRs) are often the case in HPA dysregulation seen in depression, and GC plays a critical role in regulation of inflammation. Given the growing evidence that inflammation is a central feature of some depression cases and obesity, we aimed to investigate the immune-regulatory role of GC-GR in relation to depressive mood and obesity in 35 healthy men and women. Depressive mood and level of obesity were assessed, using Beck Depression Inventory (BDI-Ia) and body mass index (BMI), respectively. We measured plasma cortisol levels via enzyme-linked immunosorbent assay and lipopolysaccharide-stimulated intracellular tumor necrosis factor (TNF) production by monocytes, using flow cytometry. Cortisol sensitivity was determined by the difference in monocytic TNF production between the conditions of 1 and 0 μM cortisol incubation ("cortisol-mediated inflammation regulation, CoMIR"). GR vs. mineralocorticoid receptor (MR) antagonism for CoMIR was examined by using mifepristone and spironolactone. A series of multiple regression analyses were performed to investigate independent contribution of depressive mood vs. obesity after controlling for age, gender, systolic blood pressure (SBP), and plasma cortisol in predicting CoMIR. CoMIR was explained by somatic subcomponents of depressive mood (BDI-S: β=-0.499, p=0.001), or BMI (β=-0.466, p<0.01) in separate models. The effects of BMI disappeared when BDI-S was controlled for in the model, while BDI-S remained a significant independent predictor for CoMIR (β=-0.369, p<0.05). However, BMI remained the only independent predictor when BDI-T or BDI-C were controlled for in the model. Mediation analyses also revealed that the relationship between BMI and CoMIR was mediated by BDI-S. The exploratory findings of the relative GR vs. MR roles in CoMIR, using GR and MR blockers, indicated that CoMIR in our cellular model was predominantly mediated by GRs at the higher cortisol dose (1 μM). There was initial indication that greater obesity and somatic depressive symptoms were associated with smaller efficacy of the blockers, which warrants further investigation. Our findings, although in a preclinical sample, signify the shared pathophysiology of immune dysregulation in depression and obesity and warrant further mechanistic investigation.
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http://dx.doi.org/10.1016/j.psyneuen.2016.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792525PMC
April 2016

Beta-adrenergic receptor mediated inflammation control by monocytes is associated with blood pressure and risk factors for cardiovascular disease.

Brain Behav Immun 2015 Nov 20;50:31-38. Epub 2015 Aug 20.

Department of Psychiatry, University of California San Diego, USA.

Overwhelming data indicate that individuals with even mildly elevated blood pressure (BP) are at great risk for developing clinical hypertension and future cardiovascular disease (CVD). There remains a lack of consensus regarding treatment strategies for mildly elevated BP, termed prehypertension, and the knowledge of pathophysiology and mechanisms of its clinical outcomes remains limited. Our primary aim was to investigate βAR-mediated inflammation control (BARIC) responses of blood monocytes to isoproterenol (Iso) in relation to BP and CVD risk factors, including obesity, depressive mood, fasting glucose, triglycerides, and cholesterol levels in the 64 prehypertensive compared to 84 individuals with normal BP. BARIC was determined by measuring the degree of inhibition in lipopolysaccharides-stimulated monocytic intracellular TNF production by ex vivo Iso treatment (10(-8)M). Depressive mood was assessed by Beck Depression Inventory (BDI). Fasting metabolic and lipid panels were assessed, and plasma levels of inflammatory cytokines TNF, IL-1β, IL-6 were measured in a subset to confirm proinflammatory state of prehypertensive participants. Prehypertensive participants were older, heavier, included more men, and presented higher levels of fasting glucose, triglycerides, cholesterol, and plasma TNF compared to normotensive participants (p's<.05). BARIC was significantly attenuated in the prehypertensive compared to normotensive group (p<.05). BARIC was negatively associated with systolic BP, diastolic BP, age, BMI, fasting glucose, triglycerides, total and low density cholesterol levels, and somatic depressive symptoms in all participants (p's<.0001 to .05). However, among the prehypertensive individuals BARIC was positively associated with SBP even after controlling for the covariates (age, gender, race, BMI, glucose and lipid panel, somatic BDI scores) (p<.05). This differing nature of the BARIC-SBP relationship between the two BP groups may be attributed to moderating factors such as cardiorespiratory fitness or depressive symptoms that could not be clearly deciphered in this current study. Nonetheless, our findings indicate the associations between inflammation dysregulation mediated by sympathoadrenal activation and BP that is observable even among individuals with normal to mildly elevated BP. BARIC may be a useful and sensitive indicator of elevated risk for vascular inflammatory disease that can be detected even at lower BP levels, especially given its associations with traditional CVD risk factors and the critical role of monocytes in atherogenic processes.
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http://dx.doi.org/10.1016/j.bbi.2015.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631657PMC
November 2015

Progenitor cells are mobilized by acute psychological stress but not beta-adrenergic receptor agonist infusion.

Brain Behav Immun 2015 Oct 6;49:49-53. Epub 2015 Mar 6.

Department of Clinical Psychology, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

Objectives: Stimuli that activate the sympathetic nervous system, such as acute psychological stress, rapidly invoke a robust mobilization of lymphocytes into the circulation. Experimental animal studies suggest that bone marrow-derived progenitor cells (PCs) also mobilize in response to sympathetic stimulation. Here we tested the effects of acute psychological stress and brief pharmacological β-adrenergic (βAR) stimulation on peripheral PC numbers in humans.

Methods: In two studies, we investigated PC mobilization in response to an acute speech task (n=26) and βAR-agonist (isoproterenol) infusion (n=20). A subset of 8 participants also underwent the infusion protocol with concomitant administration of the βAR-antagonist propranolol. Flow cytometry was used to enumerate lymphocyte subsets, total progenitor cells, total haematopoietic stem cells (HSC), early HSC (multi-lineage potential), late HSC (lineage committed), and endothelial PCs (EPCs).

Results: Both psychological stress and βAR-agonist infusion caused the expected mobilization of total monocytes and lymphocytes and CD8(+) T lymphocytes. Psychological stress also induced a modest, but significant, increase in total PCs, HSCs, and EPC numbers in peripheral blood. However, infusion of a βAR-agonist did not result in a significant change in circulating PCs.

Conclusion: PCs are rapidly mobilized by psychological stress via mechanisms independent of βAR-stimulation, although the findings do not exclude βAR-stimulation as a possible cofactor. Considering the clinical and physiological relevance, further research into the mechanisms involved in stress-induced PC mobilization seems warranted.
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http://dx.doi.org/10.1016/j.bbi.2015.02.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561221PMC
October 2015

Cerebrospinal fluid (CSF) CD8+ T-cells that express interferon-gamma contribute to HIV associated neurocognitive disorders (HAND).

PLoS One 2015 26;10(2):e0116526. Epub 2015 Feb 26.

Department of Medicine, and University of California San Diego, La Jolla, CA, United States of America.

Background: HIV associated neurocognitive disorders (HAND) continue to affect cognition and everyday functioning despite anti-retroviral treatment (ART). Previous studies focused on mechanisms related to monocyte/macrophage mediated inflammation. However, in the ART era, there is increasing evidence for the involvement of CD8+ T-cells in CNS pathogenesis.

Methods: To investigate the relationship between T-cell responses and neurocognitive impairment (NCI), cerebrospinal fluid (CSF) and peripheral blood CD4+ and CD8+ T-cell intracellular cytokine (IFNγ, IL-2, TNFα) and lytic marker (CD107a) expression were assessed in HIV infected subjects who underwent comprehensive neurocognitive (NC) evaluation and either initiated or changed ART.

Results: Data were collected from 31 participants at 70 visits. The frequency of cytokine expressing T-cells in CSF was significantly higher than in peripheral blood for CD4+T-cells: TNFα, IL-2, IFNγ and CD8+T-cells: IL-2 and IFNγ. Analysis of T-cell activity and NCI as a function of CSF HIV RNA levels suggested a general association between NCI, high CSF CD8+ (but not CD4+T-cell) cytokine expression and CSF HIV RNA <103 copies/ml (p<0.0001). Specifically, CSF CD8+ T-cell IFNγ expression correlated with severity of NCI (r = 0.57, p = 0.004). Multivariable analyses indicated that CSF CD8+T-cell IFNγ and myeloid activation (CD163) contributed equally and independently to cognitive status and a composite variable produced the strongest correlation with NCI (r = 0.83, p = 0.0001). In contrast, CD8+ cytolytic activity (CD107a expression) was negatively correlated with NCI (p = 0.05) but was dependent on CD4 levels >400/μl and low CSF HIV RNA levels (<103 copies/ml). In our longitudinal analysis of 16 subjects, higher CSF CD8+IFNγ expression at baseline predicted NC decline at follow-up (p = 0.02). Severity of NCI at follow-up correlated with level of residual HIV RNA in CSF.

Conclusions: Presence of IFNγ expressing CD8+ T-cells, absence of cytolytic CD8+ T-cells, high myeloid activation, and failure of ART to suppress HIV replication in CSF contribute to increased risk of HAND.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116526PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342256PMC
November 2015

Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications.

Brain Behav Immun 2015 Mar 22;45:1-12. Epub 2014 Oct 22.

Geriatric Research Clinical and Education Center, Veterans Affairs Puget Sound Health Care System and Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, United States.

Individuals living with HIV who are optimally treated with combination antiretroviral therapy (cART) can now lead an extended life. In spite of this remarkable survival benefit from viral suppression achieved by cART in peripheral blood, the rate of mild to moderate cognitive impairment remains high. A cognitive decline that includes impairments in attention, learning and executive function is accompanied by increased rates of mood disorders that together adversely impact the daily life of those with chronic HIV infection. The evidence is clear that cells in the brain are infected with HIV that has crossed the blood-brain barrier both as cell-free virus and within infected monocytes and T cells. Viral proteins that circulate in blood can induce brain endothelial cells to release cytokines, invoking another source of neuroinflammation. The difficulty of efficient delivery of cART to the central nervous system (CNS) contributes to elevated viral load in the CNS, resulting in a persistent HIV-associated neurocognitive disorders (HAND). The pathogenesis of HAND is multifaceted, and mounting evidence indicates that immune cells play a major role. HIV-infected monocytes and T cells not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines such as TNF and IL-1ß, which in turn, further activate microglia and astrocytes. These activated brain resident cells, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection and release neurotoxic factors such as excitatory amino acids and inflammatory mediators, resulting in neuronal dysfunction and death. Cytokines, which are elevated in the blood of patients with HIV infection, may also contribute to brain inflammation by entering the brain from the blood. Host factors such as aging and co-morbid conditions such as cytomegalovirus co-infection and vascular pathology are important factors that affect the HIV-host immune interactions in HAND pathogenesis. By these diverse mechanisms, HIV-1 induces a neuroinflammatory response that is likely to be a major contributor to the cognitive and behavior changes seen in HIV infection.
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http://dx.doi.org/10.1016/j.bbi.2014.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342286PMC
March 2015

Leukocyte ß-adrenergic receptor sensitivity and depression severity in patients with heart failure.

Psychosom Med 2014 Nov-Dec;76(9):726-31

From the Departments of Psychiatry (L.S.R., S.H., T.R., B.W., M.P., P.J.M.), and Department of Medicine (M.G.Z., A.M., B.G.), University of California, San Diego, La Jolla, California; and Research Services (L.S.R., T.R., A.M.), VA San Diego Healthcare System, La Jolla, California.

Objectives: Clinical outcomes are worse for patients with heart failure (HF) and elevated depression symptoms. Depression-related sympathoimmune dysregulation may be one mechanism leading to poorer HF prognosis. Sympathetically mediated adrenergic activity is known to regulate immune activity via β-adrenergic receptors (β-ARs). However, studies show conflicting relationships between leukocyte β-AR sensitivity and depression symptoms. The aim of this study was to determine in patients with HF the relationship of leukocyte β-AR sensitivity with two diverse measures of depression, self-report questionnaire versus clinical diagnostic interview.

Methods: Patients with HF (N = 73, mean [standard deviation] age = 56.3 [13.0]) completed the Beck Depression Inventory-1A and a modified Structured Clinical Interview for the DSM-IV. Leukocyte β-AR sensitivity was determined from isoproterenol-stimulated cyclic adenosine monophosphate levels; plasma norepinephrine and epinephrine were also assessed.

Results: Patients with major depression determined by Structured Clinical Interview for the DSM-IV had significantly higher β-AR sensitivity than did nondepressed patients (F(6,72) = 9.27, p = .003, η = 0.12). The Beck Depression Inventory-1A revealed a more complex relationship. Minimal, mild, and moderate-to-severe depression symptom groups had significant differences in β-AR sensitivity (F(7,72) = 7.03, p = .002, η = 0.18); mild symptoms were associated with reduced β-AR sensitivity and moderate-to-severe symptoms with higher β-AR sensitivity compared with patients with minimal depressive symptoms.

Conclusions: Clinical depression was associated with elevated β-AR sensitivity in patients with HF. By deconstructing depression measurements, a greater depth of information may be garnered to potentially reveal subtypes of depression symptoms and their relation to β-AR sensitivity.
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http://dx.doi.org/10.1097/PSY.0000000000000119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744799PMC
July 2015

Measures of adiposity predict interleukin-6 responses to repeated psychosocial stress.

Brain Behav Immun 2014 Nov 6;42:33-40. Epub 2014 Aug 6.

Department of Psychology and Volen National Center for Complex Systems, Brandeis University, Waltham, MA, United States. Electronic address:

Objective: Overweight and obese individuals, who comprise approximately two-thirds of the U.S. population, are at increased risk for developing a range of diseases. This increased risk may be due in part to maladaptive stress responses within this group, including heightened low-grade inflammation and HPA axis non-habituation. In this study we tested the relationship between adiposity, plasma interleukin-6 (IL-6) and HPA axis responses to repeated stress.

Methods: Sixty-seven healthy participants were exposed to the Trier Social Stress Test (TSST) on two consecutive days. We collected saliva for cortisol measurements at baseline and at 1, 10, 30, 60 and 120min post-TSST, and blood for plasma IL-6 measurements at baseline and 30 and 120min post-TSST.

Results: Stress exposure induced significant increases of cortisol and IL-6 on both days (cortisol: F=38, p<0.001; IL-6: F=90.8; p<0.001), and repeated exposure was related with cortisol habituation (F=8.2; p<0.001) and IL-6 sensitization (F=5.2; p=0.022). BMI and body fat were related with higher cortisol responses to repeated stress (BMI: beta=0.34; p=0.014; body fat: beta=0.29; p=0.045), and with higher IL-6 responses to repeated stress (BMI: beta=0.27, p=0.044; body fat: beta=0.37; p=0.006).

Conclusions: Taken together, individuals with higher measures of adiposity showed less efficient HPA axis habituation as well as sensitization of IL-6 responses to repeated acute stress. These findings point to maladaptive stress response patterns in overweight humans, which, through exposure to higher levels of inflammatory mediators, might partially explain diseases related with overweight and/or obesity.
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http://dx.doi.org/10.1016/j.bbi.2014.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252374PMC
November 2014

Benefit of physical fitness against inflammation in obesity: role of beta adrenergic receptors.

Brain Behav Immun 2014 Jul 16;39:113-20. Epub 2013 Dec 16.

Department of Psychiatry, University of California San Diego, USA.

Evidence shows that both poor physical fitness and obesity are linked to low-grade inflammation and inflammatory diseases. However, their relative roles on inflammation and underlying mechanisms remain unclear. Given the inhibitory effect of catecholamines on inflammatory cytokine production, we speculated that compromised responsiveness of immune cells' beta adrenergic receptors (β-ARs) to agonists may be associated with constitutively elevated levels of inflammatory cytokines. We examined circulating levels of inflammatory cytokines TNF, IL-1β, IL-6 and β-AR sensitivity of, 70 overweight or obese compared to 26 normal-weight, otherwise healthy individuals in order to investigate the associations among obesity, physical fitness, and low-grade inflammation and to examine the role of β-ARs in these relationships. Cardiorespiratory fitness was determined by VO2peak (ml/kg/min) via a treadmill exercise. Beta-AR sensitivity was evaluated by measuring the degree of inhibition in lipopolysaccharides-stimulated monocytic intracellular TNF production by isoproterenol. In all participants, BMI, which was initially a predictor of IL-1β and IL-6 levels independent of demographic characteristics, no longer significantly predicted them after controlling for fitness levels. Among the overweight or obese participants, greater cardiorespiratory fitness was a strong predictor of lower levels of TNF and IL-1β after controlling for the covariates. When β-AR sensitivity was controlled for, however, fitness was no longer a significant predictor of those cytokines. Monocytic β-AR sensitivity was negatively associated with inflammatory marker levels and diminished in obese individuals; however, when fitness was controlled for, the significant weight group differences in β-AR sensitivity disappeared. Our findings indicate that better cardiorespiratory fitness protects against obesity-related low-grade inflammation and β-AR desensitization. Given the significance of β-AR function in pathogenesis of various diseases, clinical implications of its role in the fitness-inflammation association among the obese are profound.
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http://dx.doi.org/10.1016/j.bbi.2013.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059789PMC
July 2014

Effects of Aerobic Fitness and Adiposity on Coagulation Biomarkers in Men vs. Women with Elevated Blood Pressure.

Eur J Cardiovasc Med 2012 Sep 24;2(2):122-128. Epub 2012 Sep 24.

Department of Psychiatry, University of California, San Diego, California.

A hypercoagulable state is a potential mechanism linking elevated blood pressure (BP), adiposity and a sedentary lifestyle to development of coronary heart disease (CHD). We examined relationships among aerobic fitness and adiposity in 76 sedentary subjects with elevated BP. Blood levels of plasminogen activator inhibitor-1 (PAI-1), D-dimer, von Willebrand factor (vWF) and thrombomodulin were assessed as biomarkers of coagulation. In individuals with elevated BP, percent body fat and fitness were associated with biomarkers indicative of a hypercoagulable state, even after demographic and metabolic factors were considered. D-dimer was positively associated with percent body fat (beta=0.37, p=0.003). PAI-1 was higher in men than in women (beta=-0.31, p=0.015) and associated with lower VO2peak (beta=-0.35, p=0.024). Thrombomodulin was positively associated with VO2peak (beta=0.56, p< 0.01). vWF was not significantly associated with fitness or adiposity. Our results emphasise that both percent body fat and physical fitness are important in the maintenance of haemostatic balance.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480183PMC
September 2012

Differential TNF production by monocyte subsets under physical stress: blunted mobilization of proinflammatory monocytes in prehypertensive individuals.

Brain Behav Immun 2013 Jan 6;27(1):101-8. Epub 2012 Oct 6.

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0804, USA.

Elevated blood pressure (BP) and infiltration of the vasculature by monocytes contribute to vascular pathology; but, monocyte migratory characteristics based on differing inflammatory potential under adrenergic activation remains unclear. We compared nonclassical (CD14(+)CD16(++); HLA-DR(+)), intermediate (CD14(++)CD16(+); HLA-DR(++)), and classical (CD14(++)CD16(-); HLA-DR(+/-)) monocyte trafficking and their LPS-stimulated TNF production in response to a physical stressor (20-min treadmill exercise at 65-70% VO(2peak)) in participants with high prehypertension (PHT), mild PHT or normal BP (NBP). To determine adrenergic receptor (AR) sensitivity, pre-exercise cells were also treated with isoproterenol (Iso). When cells were stimulated with LPS, the CD16 molecules were downregulated, and monocyte subsets were differentiated based on HLA-DR expression. Monocyte subpopulations (as % of total monocytes) and intracellular TNF production were evaluated by flow cytometry. TNF production in all subsets decreased post-exercise and with ex-vivo incubation with Iso, irrespective of BP (p<0.001), with nonclassical and intermediate monocytes being a major source of TNF production. Overall, % nonclassical monocytes increased, % intermediate did not change, whereas % classical decreased post-exercise (p<0.001). However, % increase in nonclassical monocytes under exercise-induced adrenergic activation was blunted in high PHT individuals (p<0.05), but not in individuals with mild PHT and NBP. These findings extend our previous reports by showing that the mobilization of proinflammatory monocytes under physical stress is attenuated with even mild BP elevation. This may be indicative of monocytic AR desensitization and/or greater adhesion of "proinflammatory" monocytes to the vascular endothelium in hypertension with potential clinical implications of vascular pathology.
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http://dx.doi.org/10.1016/j.bbi.2012.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518602PMC
January 2013

A pilot study exploring the effects of a 12-week t'ai chi intervention on somatic symptoms of depression in patients with heart failure.

J Altern Complement Med 2012 Aug 30;18(8):744-8. Epub 2012 Jul 30.

Department of Psychiatry, University of California, San Diego, CA 92093, USA.

Background: Patients with chronic heart failure (HF) and with elevated depression symptoms are at greater risk of morbidity and mortality. Somatic symptoms of depression are particularly prevalent in HF and are related to worse disease prognosis. T'ai chi practice is related to increased emotional well-being in various clinical populations; however, relatively little is known about t'ai chi's effects on somatic versus cognitive symptom dimensions of depression in HF.

Purpose: The objective of the study was to measure whether a t'ai chi intervention effectively reduces somatic and/or cognitive symptoms of depression in patients with HF.

Methods: Patients with HF were assigned to either t'ai chi training (n=16) or a usual-care group (n=12). At baseline and after the 12-week intervention period, participants were evaluated for changes in depressive symptoms using Beck Depression Inventory (BDI) total scores (BDI-t) and subcategorized scores of BDI-somatic (BDI-s) and BDI-cognitive (BDI-c), and for symptoms of fatigue using the Multidimensional Fatigue Symptom Inventory-Short Form.

Results: Patients with HF in the t'ai chi group compared to the usual-care group had reduced BDI-s (p≤0.017), but not BDI-c (p=0.50) scores from pre- to postintervention. Although t'ai chi did not significantly reduce fatigue, changes in physical fatigue (p≤0.05) were independently associated with changes in BDI-t scores.

Conclusions: T'ai chi practice reduced somatic symptoms of depression, which have been linked to worse prognosis in HF. Reductions in fatigue appear to explain some but not all of the reductions in somatic symptoms of depression.
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http://dx.doi.org/10.1089/acm.2011.0314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419850PMC
August 2012

Can we jog our way to a younger-looking immune system?

Authors:
Suzi Hong

Brain Behav Immun 2011 Nov 23;25(8):1519-20. Epub 2011 Aug 23.

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0804, USA.

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http://dx.doi.org/10.1016/j.bbi.2011.08.002DOI Listing
November 2011

Stress, exercise, and Alzheimer's disease: a neurovascular pathway.

Med Hypotheses 2011 Jun 12;76(6):847-54. Epub 2011 Mar 12.

University of California San Diego, School of Medicine, Department of Psychiatry, San Diego, CA, USA.

Genetic factors are known to play a role in Alzheimer's disease (AD) vulnerability, yet less than 1% of incident AD cases are directly linked to genetic causes, suggesting that environmental variables likely play a role in the majority of cases. Several recent human and animal studies have examined the effects of behavioral factors, specifically psychological stress and exercise, on AD vulnerability. Numerous animal studies have found that, while stress exacerbates neuropathological changes associated with AD, exercise reduces these changes. Some human studies suggest that psychological stress can increase the risk of developing AD, while other studies suggest that exercise can significantly reduce AD risk. Most animal studies investigating the mechanisms responsible for the effects of these behavioral factors have focused on neuronal processes, including the effects of stress hormones and neurotrophic factors on the neuropathological hallmarks of AD, namely amyloid-beta (Aβ) deposition and tau-phosphorylation. However, cumulative evidence indicates that, in humans, AD is associated with the presence of cerebrovascular disease, and cardiovascular risk factors are associated with increased risk of developing AD. There is an extensive literature demonstrating that behavioral factors, particularly stress and exercise, can powerfully modulate the pathophysiology of vascular disease. Thus, the following model proposes that the influence of stress and exercise on AD risk may be partially due to the effects of these behavioral factors on vascular homeostasis and pathology. These effects are likely due to both indirect modification of AD risk through alterations in vascular risk factors, such as hypertension, diabetes, and aortic stiffening, as well as direct influence on the cerebrovasculature, including changes in cerebral blood flow, angiogenesis, and vascular disease. Future studies examining the effects of behavioral factors on AD risk should incorporate measures of both peripheral and cerebral vascular function to further our understanding of the mechanisms by which behavior can modify AD susceptibility. Greater knowledge of the molecular mechanisms behind these behavioral effects would further our understanding of the disease and lead to innovative treatment and preventive approaches.
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http://dx.doi.org/10.1016/j.mehy.2011.02.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094492PMC
June 2011
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