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.

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.

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.

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.

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.

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.

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.

The anti-aging effects of lithium in lymphoblastoid cell lines from patients with bipolar disorder and controls.

Bipolar disorder (BD) has been previously associated with accelerated aging, and recent investigations have started to explore the potential anti-aging effects of BD treatments. Lithium, the most commonly used mood stabilizer, has been suggested to impact telomere length in specific populations, although its effects on other aging biomarkers, such as epigenetic aging, have never been investigated. We assessed the in vitro effects of lithium on telomere length and epigenetic aging in lymphoblastoid cell lines (LCLs) from 14 patients with BD and 14 controls, all matched for age, sex, and ethnicity. Our results showed that telomere length significantly correlated with chronological age in LCLs in both groups and that BD patients have shorter telomere lengths compared to controls at baseline (vehicle treatment), confirming previous in vivo findings. Moreover, lithium treatment significantly increased telomere length in LCLs from patients, but not in controls. On the other hand, epigenetic age did not correlate with chronological age and was not shown to differ between patients and controls. In addition, lithium did not induce any changes in epigenetic age in cells from either patients or controls. Overall, our results support previous reports of an anti-aging effect of lithium based on its modulation of telomere length and suggest a different lithium effect in cells from patients and controls. Finally, we also discuss the limitations of using transformed LCLs for the study of DNA methylation mechanisms.

Clozapine Prevents Poly (I:C) Induced Inflammation by Modulating NLRP3 Pathway in Microglial Cells.

Schizophrenia is a complex psychiatric disorder that exhibits an interconnection between the immune system and the brain. Experimental and clinical studies have suggested the presence of neuroinflammation in schizophrenia. In the present study, the effect of antipsychotic drugs, including clozapine, risperidone, and haloperidol (10, 20 and 20 µM, respectively), on the production of IL-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, IL-18, INF-γ, and TNF-α was investigated in the unstimulated and polyriboinosinic-polyribocytidilic acid [poly (I:C)]-stimulated primary microglial cell cultures. In the unstimulated cultures, clozapine, risperidone, and haloperidol did not influence the cytokine levels. Nevertheless, in cell cultures under strong inflammatory activation by poly (I:C), clozapine reduced the levels of IL-1α, IL-1ß, IL-2, and IL-17. Risperidone and haloperidol both reduced the levels of IL-1α, IL-1ß, IL-2, and IL-17, and increased the levels of IL-6, IL-10, INF-γ, and TNF-α. Based on the results that were obtained with the antipsychotic drugs and observing that clozapine presented with a more significant anti-inflammatory effect, clozapine was selected for the subsequent experiments. We compared the profile of cytokine suppression obtained with the use of NLRP3 inflammasome inhibitor, CRID3 to that obtained with clozapine, to test our hypothesis that clozapine inhibits the NLRP3 inflammasome. Clozapine and CRID3 both reduced the IL-1α, IL-1ß, IL-2, and IL-17 levels. Clozapine reduced the level of poly (I:C)-activated NLRP3 expression by 57%, which was higher than the reduction thay was seen with CRID3 treatment (45%). These results suggest that clozapine might exhibit anti-inflammatory effects by inhibiting NLRP3 inflammasome and this activity is not typical with the use of other antipsychotic drugs under the conditions of strong microglial activation.

The Effect of Transcranial Direct Current Stimulation on Inflammation in Older Adults With Knee Osteoarthritis: A Bayesian Residual Change Analysis.

Transcranial direct current stimulation (tDCS) has demonstrated effectiveness in reducing clinical and experimental measures of pain in patients with chronic pain; however, research examining the mechanisms of action for the effects of tDCS has been lacking. The present study investigated the effect of active tDCS on measures of inflammation and stress. Older adults (aged 50-70 years) with knee osteoarthritis (OA) were randomly assigned to receive daily 20-min sessions of either tDCS (n = 20) or sham tDCS (n = 20) for 5 consecutive days. Participants provided blood samples at baseline and the end of treatment. The following measures of immune function and stress were collected: interleukin (IL)-6 and 10, tumor necrosis factor-α (TNF-α), C-reactive protein, cortisol, and ß-endorphin. Generalized linear modeling evaluated each posttreatment measure as a function of tDCS group, controlling for baseline (measuring residual change, analogous to analysis of covariance). Bayesian statistical inference was used to directly quantify the probability of the effect of active tDCS. IL-6, IL-10, TNF-α, and ß-endorphin demonstrated lower levels of stress and inflammation in the active tDCS group. These findings provide preliminary evidence that active (relative to sham) tDCS is associated with reduced levels of inflammation.

Peripheral Levels of Renin-Angiotensin System Components Are Associated With Cognitive Performance in Huntington's Disease.

The renin-angiotensin system (RAS) has proven to be involved in the pathophysiology of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), serving as a potential therapeutic target and a disease burden marker. Studies have associated negative clinical outcomes with the activation of the classical RAS arm composed of the angiotensin-converting enzyme (ACE) and angiotensin (Ang) II, while suggested positive outcomes with the activation of the counter-regulatory RAS arm involving ACE2 and Ang-(1-7). Huntington's disease (HD) shares many pathological and clinical outcomes with AD and PD, but the evidence of direct involvement of RAS components in the pathophysiology of HD is still limited and needs further investigation. Herein, we investigated peripheral levels of the RAS components Ang II, Ang-(1-7), ACE, and ACE2 in controls, premanifest, and manifest HD gene carriers and their relationship with clinical outcomes. Peripheral blood samples were collected via phlebotomy, and plasma concentrations of RAS components were measured by Enzyme-Linked Immunosorbent Assay. Clinical evaluation included a questionnaire about socio-demographic characteristics, motor, and cognitive assessments. Results showed (1) no significant group differences in plasma concentrations of RAS components; (2) positive correlations between ACE2 and Verbal Fluency Test (VFT) scores; and (3) negative correlations between Ang II and Mini-Mental State Examination scores. These results corroborate the proposed balance between the classical (ACE/Ang II) and the counter-regulatory [ACE2/Ang-(1-7)] arms of the RAS, with the former associated with negative clinical outcomes and the latter with positive effects in HD.

Systematic Review on the Involvement of the Kynurenine Pathway in Stroke: Pre-clinical and Clinical Evidence.

Background: Stroke is the second leading cause of death after ischemic heart disease and the third leading cause of disability-adjusted life-years lost worldwide. There is a great need for developing more effective strategies to treat stroke and its resulting impairments. Among several neuroprotective strategies tested so far, the kynurenine pathway (KP) seems to be promising, but the evidence is still sparse. Methods: Here, we performed a systematic review of preclinical and clinical studies evaluating the involvement of KP in stroke. We searched for the keywords: ("kynurenine" or "kynurenic acid" or "quinolinic acid") AND ("ischemia" or "stroke" or "occlusion) in the electronic databases PubMed, Scopus, and Embase. A total of 1,130 papers was initially retrieved. Results: After careful screening, forty-five studies were included in this systematic review, being 39 pre-clinical and six clinical studies. Despite different experimental models of cerebral ischemia, the results are concordant in implicating the KP in the pathophysiology of stroke. Preclinical evidence also suggests that treatment with kynurenine and KMO inhibitors decrease infarct size and improve behavioral and cognitive outcomes. Few studies have investigated the KP in human stroke, and results are consistent with the experimental findings that the KP is activated after stroke. Conclusion: Well-designed preclinical studies addressing the expression of KP enzymes and metabolites in specific cell types and their potential effects at cellular levels alongside more clinical studies are warranted to confirm the translational potential of this pathway as a pharmacological target for stroke and related complications.

Adjunctive tianeptine treatment for bipolar disorder: A 24-week randomized, placebo-controlled, maintenance trial.

OBJECTIVE: The purpose of this study was to assess the efficacy and tolerability of tianeptine as an adjunctive maintenance treatment for bipolar depression. METHODS: This is a multicenter double-blind randomized placebo-controlled maintenance trial of adjunctive tianeptine 37.5 mg/day. Participants ( n=161) had a Montgomery-Asberg Depression Rating Scale ⩾12 at entry. After eight weeks of open-label tianeptine treatment, those who responded to tianeptine ( n=69) were randomized to adjunctive tianeptine ( n=36) or placebo ( n=33) in addition to usual treatment. Kaplan-Meier estimates and the Mantel-Cox log-rank test were used to evaluate differences in time to intervention for a mood episode between the tianeptine and placebo groups. We also assessed overall functioning, biological rhythms, quality of life, rates of manic switch and serum brain-derived neurotrophic factor levels. RESULTS: There were no differences between adjunctive tianeptine or placebo regarding time to intervention or depression scores in the 24-week double-blind controlled phase. Patients in the tianeptine group showed better performance in the letter-number sequencing subtest from the Wechsler Adult Intelligence Scale at the endpoint ( p=0.014). Tianeptine was well tolerated and not associated with higher risk for manic switch compared to placebo. CONCLUSION: Tianeptine was not more effective than placebo in the maintenance treatment of bipolar depression. There is preliminary evidence suggesting a pro-cognitive effect of tianeptine in working memory compared to placebo.

Biomarkers for bipolar disorder: current status and challenges ahead.

INTRODUCTION: Bipolar disorder (BD) is a chronic psychiatric disorder marked by clinical and pathophysiological heterogeneity. There is a high expectation that personalized approaches can improve the management of patients with BD. For that, identification and validation of potential biomarkers are fundamental. Areas covered: This manuscript will critically review the current status of different biomarkers for BD, including peripheral, genetic, neuroimaging, and neurophysiological candidates, discussing the challenges to move the field forward. Expert commentary: There are no lab or complementary tests currently recommended for the diagnosis or management of patients with BD. Panels composed by multiple biomarkers will probably contribute to stratifying patients according to their clinical stage, therapeutic response, and prognosis.

Exploring the relationship between Endothelin-1 and peripheral inflammation in multiple sclerosis.

BACKGROUND: Identifying pathways linking neuroinflammation and neurodegeneration is essential to help prevent disability progression in people with multiple sclerosis (MS). Endothelin-1 (ET-1) is a potent vasoconstrictor thought to contribute to cerebral hypoperfusion and tissue damage in MS. Its link with the neuroinflammatory process remains poorly investigated. OBJECTIVES: To determine plasma ET-1 levels in treatment-naïve people with MS and controls, and the relationship between ET-1 and other peripheral immune mediator levels as potential markers of the disease process. METHODS: This is a retrospective study that included specimens previously collected from 35 treatment-naïve patients with clinically isolated syndrome highly suggestive of MS or definite MS and 35 sex- and age-matched controls. ET-1 plasma levels were measured by enzyme-linked immunosorbent assay (ELISA), and plasma cytokine levels [interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p70), IL-13, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] were simultaneously measured by Multiplex assay. RESULTS: ET-1 levels were significantly increased in MS patients compared to controls. No significant difference in cytokine levels between the groups were found. However, a significant increase in IFN-γ/IL-4 ratio was observed in patients with MS in comparison with controls, suggestive of Th1 skewed response. Binary logistic regression was performed to ascertain the effects of age, sex, ET-1 and cytokine levels on the likelihood of MS diagnosis. In the final model, ET-1, IL-4 and IFN-γ levels remained as predictors of MS. There was no significant correlation between ET-1 and cytokine levels. CONCLUSIONS: Patients with MS presented increased levels of ET-1 and an immune response biased towards a Th1 profile. Although both ET-1 and Th1 cytokine profile were predictors of MS diagnosis, ET-1 levels were not associated with peripheral immune markers, suggesting that these changes may occur independently.