Restoring a balanced pool of host-derived and microbiota-derived ligands of the aryl hydrocarbon receptor is beneficial after stroke.

Background: Stroke is a major cause of morbidity and mortality, and its incidence increases with age. While acute therapies for stroke are currently limited to intravenous thrombolytics and endovascular thrombectomy, recent studies have implicated an important role for the gut microbiome in post-stroke neuroinflammation. After stroke, several immuno-regulatory pathways, including the aryl hydrocarbon receptor (AHR) pathway, become activated. AHR is a master regulatory pathway that mediates neuroinflammation. Among various cell types, microglia (MG), as the resident immune cells of the brain, play a vital role in regulating post-stroke neuroinflammation and antigen presentation. Activation of AHR is dependent on a dynamic balance between host-derived and microbiota-derived ligands. While previous studies have shown that activation of MG AHR by host-derived ligands, such as kynurenine, is detrimental after stroke, the effects of post-stroke changes in microbiota-derived ligands of AHR, such as indoles, is unknown. Our study builds on the concept that differential activation of MG AHR by host-derived versus microbiome-derived metabolites affects outcomes after ischemic stroke. We examined the link between stroke-induced dysbiosis and loss of essential microbiota-derived AHR ligands. We hypothesize that restoring the balance between host-derived (kynurenine) and microbiota-derived (indoles) ligands of AHR is beneficial after stroke, offering a new potential avenue for therapeutic intervention in post-stroke neuroinflammation. Method: We performed immunohistochemical analysis of brain samples from stroke patients to assess MG AHR expression after stroke. We used metabolomics analysis of plasma samples from stroke and non-stroke control patients with matched comorbidities to determine the levels of indole-based AHR ligands after stroke. We performed transient middle cerebral artery occlusion (MCAO) in aged (18 months) wild-type (WT) and germ-free (GF) mice to investigate the effects of post-stroke treatment with microbiota-derived indoles on outcome. To generate our results, we employed a range of methodologies, including flow cytometry, metabolomics, and 16S microbiome sequencing. Results: We found that MG AHR expression is increased in human brain after stroke and after ex vivo oxygen-glucose deprivation and reperfusion (OGD/R). Microbiota-derived ligands of AHR are decreased in the human plasma at 24 hours after ischemic stroke. Kynurenine and indoles exhibited differential effects on aged WT MG survival after ex vivoOGD/R. We found that specific indole-based ligands of AHR (indole-3-propionic acid and indole-3-aldehyde) were absent in GF mice, thus their production depends on the presence of a functional gut microbiota. Additionally, a time-dependent decrease in the concentration of these indole-based AHR ligands occurred in the brain within the first 24 hours after stroke in aged WT mice. Post-stroke treatment of GF mice with a cocktail of microbiota-derived indole-based ligands of AHR regulated MG-mediated neuroinflammation and molecules involved in antigen presentation (increased CD80, MHC-II, and CD11b). Post-stroke treatment of aged WT mice with microbiota-derived indole-based ligands of AHR reduced both infarct volume and neurological deficits at 24 hours. Conclusion: Our novel findings provide compelling evidence that the restoration of a well-balanced pool of host-derived kynurenine-based and microbiota-derived indole-based ligands of AHR holds considerable therapeutic potential for the treatment of ischemic stroke.

Stabilizing histamine release in gut mast cells mitigates peripheral and central inflammation after stroke.

Stroke is the most common cause of long-term disability and places a high economic burden on the global healthcare system. Functional outcomes from stroke are largely determined by the extent of ischemic injury, however, there is growing recognition that systemic inflammatory responses also contribute to outcomes. Mast cells (MCs) rapidly respond to injury and release histamine (HA), a pro-inflammatory neurotransmitter that enhances inflammation. The gut serves as a major reservoir of HA. We hypothesized that cromolyn, a mast cell stabilizer that prevents the release of inflammatory mediators, would decrease peripheral and central inflammation, reduce MC trafficking to the brain, and improve stroke outcomes. We used the transient middle cerebral artery occlusion (MCAO) model of ischemic stroke in aged (18 mo) male mice to investigate the role of MC in neuroinflammation post-stroke. After MCAO we treated mice with 25 mg/kg body weight of cromolyn (MC stabilizer) by oral gavage. Cromolyn was administered at 3 h, 10 h, 24 h and every 24 h for 3 days post-stroke. Three control groups were used. One group underwent a sham surgery and was treated with cromolyn, one received sham surgery with PBS vehicle and the third underwent MCAO with PBS vehicle. Mice were euthanized at 24 h and 3 days post-stroke. Cromolyn administration significantly reduced MC numbers in the brain at both 24 h and 3 days post-stroke. Infarct volume was not significantly different between groups, however improved functional outcomes were seen at 3 days post-stroke in mice that received cromolyn. Treatment with cromolyn reduced plasma histamine and IL-6 levels in both the 24-h and 3-day cohorts. Gut MCs numbers were significantly reduced after cromolyn treatment at 24 h and 3 days after stroke. To determine if MC trafficking from the gut to the brain occurred after injury, GFP+MCs were adoptively transferred to c-kit-/- MC knock-out animals prior to MCAO. 24 h after stroke, elevated MC recruitment was seen in the ischemic brain. Preventing MC histamine release by cromolyn improved gut barrier integrity and an improvement in stroke-induced dysbiosis was seen with treatment. Our results show that preventing MC histamine release possesses prevents post-stroke neuroinflammation and improves neurological and functional outcomes.

Accelerated epigenetic aging in older adults with HIV disease: associations with serostatus, HIV clinical factors, and health literacy.

The prevalence of older persons with HIV (PWH) disease has increased considerably in the last 20 years, but our understanding of biological factors of aging and their clinical correlates among PWH remains limited. Study participants were 149 persons aged 50 and older, including 107 PWH and 42 seronegatives. All participants completed a blood draw, research medical evaluation, structured psychiatric interview, neurocognitive assessment, questionnaires, and measures of health literacy. Four epigenetic clocks were generated from stored blood samples using standardized laboratory methods. In regression models adjusting for sex and smoking status, PWH had significantly higher epigenetic aging acceleration values than seronegatives on all four indicators. Within the PWH sample, higher levels of epigenetic aging acceleration were moderately associated with lower current CD4 count, AIDS diagnoses, higher scores on the Veterans Aging Cohort Study Index, and lower telomere values. Higher epigenetic aging acceleration indices were also associated with lower health literacy among PWH. PWH experience accelerated aging as measured by a series of epigenetic clocks, which may be linked to immune compromise and risk of all-cause mortality. Health literacy may be a modifiable target for mitigating the risk of accelerated aging among older PWH.

Leucine-Rich Alpha-2-Glycoprotein 1 is a Systemic Biomarker of Early Brain Injury and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

BACKGROUND: After subarachnoid hemorrhage (SAH), early brain injury (EBI) and delayed cerebral ischemia (DCI) lead to poor outcomes. Discovery of biomarkers indicative of disease severity and predictive of DCI is important. We tested whether leucine-rich alpha-2-glycoprotein 1 (LRG1) is a marker of severity, DCI, and functional outcomes after SAH. METHODS: We performed untargeted proteomics using mass spectrometry in plasma samples collected at < 48 h of SAH in two independent discovery cohorts (n = 27 and n = 45) and identified LRG1 as a biomarker for DCI. To validate our findings, we used enzyme-linked immunosorbent assay and confirmed this finding in an internal validation cohort of plasma from 72 study participants with SAH (22 DCI and 50 non-DCI). Further, we investigated the relationship between LRG1 and markers of EBI, DCI, and poor functional outcomes (quantified by the modified Rankin Scale). We also measured cerebrospinal fluid (CSF) levels of LRG1 and investigated its relationship to EBI, DCI, and clinical outcomes. RESULTS: Untargeted proteomics revealed higher plasma LRG1 levels across EBI severity and DCI in both discovery cohorts. In the validation cohort, the levels of LRG1 were higher in the DCI group compared with the non-DCI group (mean (SD): 95 [44] vs. 72 [38] pg/ml, p < 0.05, Student's t-test) and in study participants who proceeded to have poor functional outcomes (84 [39.3] vs. 72 [43.2] pg/ml, p < 0.05). Elevated plasma LRG1 levels were also associated with markers of EBI. However, CSF levels of LRG1 were not associated with EBI severity or the occurrence of DCI. CONCLUSIONS: Plasma LRG1 is a biomarker for EBI, DCI, and functional outcomes after SAH. Further studies to elucidate the role of LRG1 in the pathophysiology of SAH are needed.

Cerebral blood flow is associated with markers of neurodegeneration in Huntington's disease.

INTRODUCTION: The ultimate cause of neuronal death in Huntington's disease (HD) is still uncertain. Apart from impairment in systems handling abnormal proteins, other mechanisms might contribute to neurodegeneration and progression of HD. Decreased cerebral blood flow (CBF) has been described in other neurodegenerative disorders and may play a role in HD. OBJECTIVES: To investigate CBF changes in HD gene carriers. METHODS: A group of 39 HD gene carriers (18 premanifest and 21 manifest HD) and 16 controls underwent a comprehensive clinical evaluation and a brain magnetic resonance imaging protocol that included pseudo-continuous arterial spin labeling to quantify CBF. Regions of interest (ROI) analyses were performed to compare CBF in controls vs premanifest HD vs manifest HD. Correlation analyses were performed to ascertain the relationship between CBF and clinical and biomarkers data. RESULTS: We found a decrease in CBF in bilateral caudate and putamen of patients with manifest HD in comparison with controls. CBF of premanifest HD carriers in the same ROIs was midway between controls and the HD patients, with differences not reaching statistical significance. Lower CBF in caudate and putamen was associated with worse motor symptoms, functionality, and cognitive performance. CBF was also associated with markers of neurodegeneration: higher CBF in caudate and putamen significantly correlated to higher volumes in the same ROI and to lower levels of neurofilament light chain. CONCLUSION: As CBF changes in caudate and putamen nuclei were associated with markers of neurodegeneration and with clinical outcomes, decreased CBF and oxygen supply could emerge as a relevant mechanism contributing to degeneration in HD.

Renin-Angiotensin System in Huntington's Disease: Evidence from Animal Models and Human Patients.

The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside a decrease in the levels and activity of the components of the RAS alternative axis ACE2, Ang-(1-7), and Mas receptors in the striatum, prefrontal cortex, and hippocampus. BACHD mice also displayed a significant increase in mRNA expression of the AT1 receptor, a component of the RAS classical arm, in these key brain regions. Moreover, patients with manifest HD presented higher plasma levels of Ang-(1-7). No significant changes were found in the levels of ACE, ACE2, and Ang II. Our findings provided the first evidence that an imbalance in the RAS classical and counter-regulatory arms may play a role in HD pathophysiology.

Sex differences in global metabolomic profiles of COVID-19 patients.

Coronavirus disease (COVID-19), caused by SARS-CoV-2, leads to symptoms ranging from asymptomatic disease to death. Although males are more susceptible to severe symptoms and higher mortality due to COVID-19, patient sex has rarely been examined. Sex-associated metabolic changes may implicate novel biomarkers and therapeutic targets to treat COVID-19. Here, using serum samples, we performed global metabolomic analyses of uninfected and SARS-CoV-2-positive male and female patients with severe COVID-19. Key metabolic pathways that demonstrated robust sex differences in COVID-19 groups, but not in controls, involved lipid metabolism, pentose pathway, bile acid metabolism, and microbiome-related metabolism of aromatic amino acids, including tryptophan and tyrosine. Unsupervised statistical analysis showed a profound sexual dimorphism in correlations between patient-specific clinical parameters and their global metabolic profiles. Identification of sex-specific metabolic changes in severe COVID-19 patients is an important knowledge source for researchers striving for development of potential sex-associated biomarkers and druggable targets for COVID-19 patients.

Blood Biomarkers of Neuronal/Axonal and Glial Injury in Human Immunodeficiency Virus-Associated Neurocognitive Disorders.

INTRODUCTION: Approximately half of the people living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HANDs). However, the neuropathogenesis of HAND is complex, and identifying reliable biomarkers has been challenging. METHODS: This study included 132 participants aged 50 and older from greater San Diego County. The participants were divided into three groups: PLWH with HAND (n = 29), PLWH without HAND (n = 73), and seronegatives without cognitive impairment (n = 30). Peripheral blood was collected at the clinical assessment, and plasma levels of neurofilament light chain (NfL), phosphorylated Tau 181 (pTau181), and glial fibrillary acidic protein (GFAP) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Plasma levels of NfL (but not pTau181 and GFAP) were significantly associated with HAND at a medium effect size (p = 0.039, Cohen's d = 0.45 for HAND + vs. HAND-). Notably, higher levels of NfL were significantly associated with HAND diagnosis even after adjusting for sex. DISCUSSION: Our data suggest that neuronal degeneration (as evidenced by increased levels of NfL), but not tau pathology or glial degeneration, is related to cognitive status in PLWH. Our results corroborate the view that blood NfL is a promising biomarker of cognitive impairment in PLWH.

Sex differences in the immune response to acute COVID-19 respiratory tract infection.

BACKGROUND: Sex differences in COVID-19 are increasingly recognized globally. Although infection rates are similar between the sexes, men have more severe illness. The mechanism underlying these sex differences is unknown, but a differential immune response to COVID-19 has been implicated in several recent studies. However, how sex differences shape the immune response to COVID-19 remains understudied. METHODS: We collected demographics and blood samples from over 600 hospitalized patients diagnosed with COVID-19 from May 24th 2020 to April 28th, 2021. These patients were divided into two cohorts: Cohort 1 was further classified into three groups based on the severity of the disease (mild, moderate and severe); Cohort 2 patients were longitudinally followed at three time points from hospital admission (1 day, 7 days, and 14 days). MultiPlex and conventional ELISA were used to examine inflammatory mediator levels in the plasma in both cohorts. Flow cytometry was conducted to examine leukocyte responses in Cohort 2. RESULTS: There were more COVID+ males in the total cohort, and the mortality rate was higher in males vs. females. More male patients were seen in most age groups (in 10-year increments), and in most ethnic groups. Males with severe disease had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-8, MCP-1) than females; levels of IL-8, GRO, sCD40L, MIP-1ß, MCP-1 were also significantly higher in severe vs. mild or control patients in males but not in females. Females had significantly higher anti-inflammatory cytokine IL-10 levels at 14 days compared to males, and the level of IL-10 significantly increased in moderate vs. the control group in females but not in males. At 7 days and 14 days, males had significantly more circulating neutrophils and monocytes than females; however, B cell numbers were significantly higher in females vs. males. CONCLUSION: Sex differences exist in hospitalized patients with acute COVID-19 respiratory tract infection. Exacerbated inflammatory responses were seen in male vs. female patients, even when matched for disease severity. Males appear to have a more robust innate immune response, and females mount a stronger adaptive immune response to COVID-19 respiratory tract infection.

Changes in Brain-derived Neurotrophic Factor From Active and Sham Transcranial Direct Current Stimulation in Older Adults With Knee Osteoarthritis.

OBJECTIVES: Previous work has shown effects of transcranial direct current stimulation (tDCS) on clinical pain measures, qualitative sensory testing measures, and peripheral inflammation. The present report extends this research to investigate the effect of tDCS on brain-derived neurotrophic factor (BDNF) levels. MATERIALS AND METHODS: This secondary analysis examined a sample of 40 older adults (50 to 70 y old) with symptomatic knee osteoarthritis randomly assigned in a 1:1 fashion to active (n=20) or sham (n=20) tDCS for 20 minutes on 5 consecutive days. BDNF was measured before the first session and after the final treatment session. Generalized linear modeling evaluated BDNF plasma levels as a function of tDCS group, adjusted for baseline. Bayesian statistical inference was used to quantify the probability that effects of the treatment exist. RESULTS: Generalized linear modeling indicated a 90.4% posterior probability that the sham condition had 49.9% higher BDNF at the end of treatment, controlling for baseline. Follow-up analyses within the active TDCS group supported an association between change in BDNF and change in clinical pain, and exploratory analyses found an effect of tDCS on irisin. DISCUSSION: Results indicated that tDCS could be a potential nonpharmacological treatment to decrease BDNF levels, which may in turn decrease pain. This study adds to a growing literature suggesting that tDCS affects cortical excitability, and consequentially, the neural circuits implicated in pain modulation. In addition to a direct connection to analgesia, BDNF changes may reflect tDCS-induced changes in different cortical areas and/or neural circuits.

Brain injury, endothelial injury and inflammatory markers are elevated and express sex-specific alterations after COVID-19.

OBJECTIVE: Although COVID-19 is a respiratory disease, all organs can be affected including the brain. To date, specific investigations of brain injury markers (BIM) and endothelial injury markers (EIM) have been limited. Additionally, a male bias in disease severity and mortality after COVID-19 is evident globally. Sex differences in the immune response to COVID-19 may mediate this disparity. We investigated BIM, EIM and inflammatory cytokine/chemokine (CC) levels after COVID-19 and in across sexes. METHODS: Plasma samples from 57 subjects at < 48 h of COVID-19 hospitalization, and 20 matched controls were interrogated for the levels of six BIMs-including GFAP, S100B, Syndecan-1, UCHLI, MAP2 and NSE, two EIMs-including sICAM1 and sVCAM1. Additionally, several cytokines/chemokines were analyzed by multiplex. Statistical and bioinformatics methods were used to measure differences in the marker profiles across (a) COVID-19 vs. controls and (b) men vs. women. RESULTS: Three BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNFα were significantly (p < 0.05) elevated in the COVID-19 cohort compared to controls. Bioinformatics analysis reveal a stronger positive association between BIM/CC/EIMs in the COVID-19 cohort. Analysis across sex revealed that several BIMs and CCs including NSE, IL10, IL15 and IL8 were significantly (p < 0.05) higher in men compared to women. Men also expressed a more robust BIM/ EIM/CC association profile compared to women. CONCLUSION: The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.

Apathy is not associated with a panel of biomarkers in older adults with HIV disease.

OBJECTIVE: Apathy is prevalent in HIV disease and can significantly impact personal well-being; however, little is known about its neurobiological substrates in persons with HIV (PWH) disease. METHODS: This cross-sectional, correlational study examined the association between apathy and several plasma biomarkers (tumor necrosis factor alpha, kynurenine, tryptophan, quinolinic acid, brain-derived neurotrophic factor, glial fibrillary acidic protein, neurofilament light chain, and phosphorylated tau at position threonine 181) in 109 PWH and 30 seronegative participants ages 50 and older. Apathy was measured with a composite score derived from subscales of the Frontal Systems Behavior Scale and the Profile of Mood States. RESULTS: Multiple regressions showed that PWH had significantly greater severity of apathy symptoms, independent of both data-driven and conceptually-based covariates. Pairwise correlations in the PWH sample indicated that apathy was not significantly associated with any of the measured biomarkers and all of the effect sizes were small. CONCLUSION: Findings suggest that apathy is not strongly associated with peripheral biomarkers of inflammation, neurotrophic support, or neurodegeneration in older PWH. Limitations of this study include the cross-sectional design, the use of self-report measures of apathy, and low rates of viremia. Longitudinal studies in more representative samples of PWH that include a more comprehensive panel of fluid biomarkers, informant and behavioral indicators of apathy, and relevant psychosocial factors might help to further clarify the neurobiological substrates of this complex neuropsychiatric phenomenon.

Inflammatory Markers Profile in Older Adolescents During Treatment with Selective Serotonin Reuptake Inhibitors.

Objective: This study aimed to investigate the serum levels of inflammatory markers in adolescents with major depressive disorder (MDD) using selective serotonin reuptake inhibitors. Methods: This was an 8-month observational study, involving 30 adolescents with and 38 without (control) MDD diagnosis. Demographic (age and gender) and anthropometric data (weight, height, and calculated body mass index [BMI] z score) were collected. Body composition was assessed with whole-body DXA scan. Depressive and anxiety symptoms were assessed using the Beck Depression and Anxiety Inventories (BDI-II and BAI), respectively. Serum levels of interleukin (IL)-6, IL-8, IL-1ß, tumor necrosis factor, monocyte chemoattractant protein-1 (MCP-1), leptin, resistin, and adiponectin were measured using Bio-Plex Multiplex Immunoassays at baseline and after 8 months. Results: At baseline, patients with MDD and controls did not differ in age, gender, BMI z score, and fat mass index (FMI) z score. At follow-up, 58.3% (21/36) of patients with MDD were in full remission. Patients with MDD had higher levels of resistin at baseline (26274.16 pg/mL [16162.68-54252.72]) than controls (21678.53 pg/mL [11221.17-37343.27]; p < 0.01). This difference remained statistically significant after adjustment for sex, age, and FMI z score. No differences in other inflammatory markers were observed between the groups. By follow up, depressive and anxiety symptom severity had decreased significantly in patients with MDD in parallel with a decrease in the serum levels of TNF (p = 0.02), IL-8 (p < 0.01) and MCP-1 (p = 0.04). Among these markers, BDI-II score was positively correlated with serum levels of MCP-1. Conclusion: These results corroborate the view of involvement of peripheral inflammatory mechanisms in the pathophysiology of MDD in adolescents. This trial is registered at ClinicalTrials.gov: NCT02147184.

Induced Pluripotent Stem Cells (iPSCs) Technology: Potential Targets for Depression.

Major depressive disorder (MDD) is a heterogeneous condition with complex pathophysiology resulting from the interaction between genetic and environmental factors. Despite a reasonable array of therapeutic options, the management of MDD has been marked by an increasing number of treatment resistant cases. Identifying the multiple pathways involved in the pathogenesis of MDD is fundamental to move the field forward and to define novel and more effective therapeutic targets. The current disease models are not able to recapitulate the complexity of this condition. In the last years, induced pluripotent stem cells (iPSCs) have emerged as a unique tool to help the elucidation of the pathophysiology of psychiatric disorders through disease modeling. In addition, the iPSCs may play an important role in the validation of new therapeutic targets.

Microglia Activation in Basal Ganglia Is a Late Event in Huntington Disease Pathophysiology.

OBJECTIVE: To define the role played by microglia in different stages of Huntington disease (HD), we used the TSPO radioligand [11C]-ER176 and PET to evaluate microglial activation in relation to neurodegeneration and in relation to the clinical features seen at premanifest and manifest stages of the disease. METHODS: This is a cross-sectional study in which 18 subjects (6 controls, 6 premanifest, and 6 manifest HD gene carriers) underwent a [11C]-ER176 PET scan and an MRI for anatomic localization. Segmentation of regions of interest (ROIs) was performed, and group differences in [11C]-ER176 binding (used to evaluate the extent of microglial activation) were assessed by the standardized uptake value ratio (SUVR). Microglial activation was correlated with ROIs volumes, disease burden, and the scores obtained in the clinical scales. As an exploratory aim, we evaluated the dynamic functions of microglia in vitro, by using induced microglia-like (iMG) cells from peripheral blood monocytes. RESULTS: Individuals with manifest HD present higher [11C]-ER176 SUVR in both globi pallidi and putamina in comparison with controls. No differences were observed when we compared premanifest HD with controls or with manifest HD. We also found a significant correlation between increased microglial activation and cumulative disease burden, and with reduced volumes. iMG from controls, premanifest HD, and manifest HD patients showed similar phagocytic capacity. CONCLUSIONS: Altogether, our data demonstrate that microglial activation is involved in HD pathophysiology and is associated with disease progression.

The Relationship Between Plasma BDNF and Pain in Older Adults With Knee Osteoarthritis.

Osteoarthritis (OA) is the most prevalent cause of chronic pain and disability in people aged ≥45 years, with the knee being the most affected joint. Neurotrophic factors like brain-derived neurotrophic factor (BDNF), which promotes neurogenesis and neuroplasticity, have been shown to significantly affect chronic pain. This study aimed to investigate the relationship between resting plasma BDNF levels and clinical pain and quantitative sensory testing measures in older adults with knee OA pain. For this secondary analysis, a previously reported dataset was used comprised of older adults with knee OA who underwent quantitative sensory testing. A comprehensive generalized linear model (GLM) was built to understand the relationships between BDNF and important covariates, followed by the elastic net (EN) method for variable selection. GLM was then performed to regress BDNF levels against only the variables selected by EN. The mean age of the sample was 60.4 years (SD = 9.1). Approximately half of the participants were female (53%). Plasma BDNF levels were positively associated with heat pain threshold and the numeric rating scale of pain. Future mechanistic studies are needed to replicate and extend these findings to advance our knowledge of the underlying mechanisms of BDNF in knee OA and other chronic pain conditions.

Decreased Plasma Levels of Angiotensin-Converting Enzyme Among Patients With Bipolar Disorder.

BACKGROUND: Dysfunctions in the renin-angiotensin system (RAS) seem to be involved in the pathophysiology of several mental illness, including schizophrenia and mood disorders. We carried out a cross-sectional study assessing the levels of RAS-related molecules among bipolar disorder (BD) patients compared to healthy controls. METHODS: our sample consisted of 30 outpatients with BD type 1 (10 males, 20 females, age = 35.53 ± 10.59 years, 14 euthymic, 16 experiencing mood episodes) and 30 healthy controls (10 males, 20 females, age = 34.83 ± 11.49 years). Plasma levels of angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), angiotensin-II (Ang II), and angiotensin (1-7) [Ang-(1-7)] were determined by ELISA. RESULTS: BD patients experiencing ongoing mood episodes had significantly lower ACE levels compared to controls (median: 459.00 vs. 514.10, p < 0.05). There was no association between the levels of these biomarkers and clinical parameters. CONCLUSION: Our findings support the involvement of RAS dysfunction in the pathophysiology of BD. Considering the potential therapeutic implications linked to a better understanding of the role of RAS dysfunction in BD, studies allowing a better characterization of RAS-related molecules level and activity across different mood states are of high interest.

Pain and Other Neurological Symptoms Are Present at 3 Months After Hospitalization in COVID-19 Patients.

COVID-19 is an ongoing pandemic with a devastating impact on public health. Acute neurological symptoms have been reported after a COVID-19 diagnosis, however, the long-term neurological symptoms including pain is not well established. Using a prospective registry of hospitalized COVID-19 patients, we assessed pain and neurological function (including functional, cognitive and psychiatric assessments) of several hospitalized patients at 3 months. Our main finding is that 60% of the patients report pain symptoms. 71% of the patients still experienced neurological symptoms at 3 months and the most common symptoms being fatigue (42%) and PTSD (25%). Cognitive symptoms were found in 12%. Our preliminary findings suggests the importance of investigating long-term outcomes and rationalizes the need for further studies investigating the neurologic outcomes and symptoms of pain after COVID-19.

Plasma pro- and anti-inflammatory cytokines may relate to cocaine use, cognitive functioning, and depressive symptoms in cocaine use disorder.

BACKGROUND: Inflammation is implicated in cocaine use and associated problems, including depression and cognitive impairment. OBJECTIVE: We assessed 18 cytokines, cocaine use, cognition, and depression in individuals with Cocaine Use Disorder. Our general hypothesis was that higher pro-inflammatory cytokines would relate to more cocaine use, poorer cognition, and more depression, while higher anti-inflammatory cytokines would relate to less cocaine use, better cognition, and less depression. METHODS: Data were collected from 85 individuals (76.5% male, 80% African American) aged 18-65. The ASI, Shipley-2, and BDI-II assessed frequency and duration of cocaine use, cognition, and depression. Cytokines were tested using Bio-Plex Pro™ assays. Elastic net regression identified which cytokines related to each measure, controlling for confounds. RESULTS: Lower IL-29 (B = -0.08, bootstrapped 95%CI = [-0.24,0.07]), scD163 (B = -0.11, bootstrapped 95%CI = [-0.27,0.04]), Eotaxin-1 CCL11 (B = -0.11, bootstrapped 95%CI = [-0.30,0.08]), and higher APRIL/TNFSF13 (B = 0.11, bootstrapped 95%CI = [-0.08,0.30]) related to more frequent cocaine use. Lower IL-29 (B = -0.24, bootstrapped 95% CI = [-2.26,1.79]) and IL-20 (B = -1.62, bootstrapped 95%CI = [-3.53,0.29]) related to longer duration of cocaine use. Higher Eotaxin-2 CCL24 (B = 2.79, bootstrapped 95%CI = [-0.59,6.17]) and TWEAK (B = 2.83, bootstrapped 95%CI = [-0.80,6.45]) related to better cognition. Finally, higher IL-20 (B = -1.83, bootstrapped 95%CI = [-3.70,0.04]) and Osteocalcin (B = -1.56, bootstrapped 95%CI = [-3.81,0.70]) related to lower depressive symptoms. However, none of these relationships survived bootstrapped analyses. CONCLUSION: Pro- and anti-inflammatory cytokines may relate to cocaine use, cognition, and depression, but inconsistent with our hypotheses, higher pro-inflammatory cytokines related to better functioning in several domains. Additionally, cytokines were selected at low frequencies and demonstrated weak relationships with outcomes. These preliminary findings suggest complex relationships between inflammation and cocaine use.

Brain-derived neurotrophic factor (BDNF) is associated with depressive symptoms in older adults with HIV disease.

Symptoms of depression are common among persons with HIV (PWH) and can have a significant impact on socioeconomic and personal well-being, but little is known about their neurobiological substrates in the context of HIV disease. This study examined the possible role of brain-derived neurotrophic factor (BDNF) in symptoms of depression and other aspects of mood in 109 PWH and 43 seronegative participants aged 50 and older. Participants completed the Profile of Mood States (POMS) which measured six dimensions of mood and was normatively adjusted for sex. A model controlling for medical comorbidities and substance use diagnoses among PWH showed a significant interaction between BDNF and POMS subscales. Planned post hoc analyses revealed that lower BDNF was only associated with higher scores on Depression-Dejection and Confusion-Bewilderment POMS subscales among PWH and at small-to-medium effect sizes. Lower levels of BDNF were associated with AIDS diagnoses and CD4 count, but not with viremia or duration of infection. BDNF levels did not differ between the PWH and HIV - samples, and there were no significant correlations between BDNF and any POMS variable in the HIV - group. Findings implicate BDNF in the neuropathophysiology of specific depressive symptoms in the context of HIV disease. Future studies may examine whether BDNF levels change over time, are sensitive to other aspects of mood disorders in HIV, and are associated with markers of HIV-associated neural injury.