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The first publication demonstrating that major depressive disorder (MDD) is associated with alterations in the gut microbiota appeared in 2008 (Maes et al., 2008). The purpose of the present study is to delineate a) the microbiome signature of the phenome of depression, including suicidal behaviours (SB) and cognitive deficits; the effects of adverse childhood experiences (ACEs) and recurrence of illness index (ROI) on the microbiome; and the microbiome signature of lowered high-density lipoprotein cholesterol (HDLc). We determined isometric log-ratio abundances or prevalences of gut microbiome phyla, genera, and species by analysing stool samples from 37 healthy Thai controls and 32 MDD patients using 16S rDNA sequencing. Six microbiome taxa accounted for 36% of the variance in the depression phenome, namely Hungatella and Fusicatenibacter (positive associations) and Butyricicoccus, Clostridium, Parabacteroides merdae, and Desulfovibrio piger (inverse association). This profile (labelled enterotype 1) indicates compositional dysbiosis, is strongly predicted by ACE and ROI, and is linked to SB. A second enterotype was developed that predicted a decrease in HDLc and an increase in the atherogenic index of plasma (Bifidobacterium, P. merdae, and Romboutsia were positively associated, while Proteobacteria and Clostridium sensu stricto were negatively associated). Together, enterotypes 1 and 2 explained 40.4% of the variance in the depression phenome, and enterotype 1 in conjunction with HDLc explained 39.9% of the variance in current SB. In conclusion, the microimmuneoxysome is a potential new drug target for the treatment of severe depression and SB and possibly for the prevention of future episodes.

BACKGROUND: The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score". METHODS: The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed. RESULTS: From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex. CONCLUSIONS: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health. ispartof: JOURNAL OF AFFECTIVE DISORDERS vol:326 pages:249-261 ispartof: location:Netherlands status: published

BackgroundAlzheimer’s disease (AD), characterized by gradual brain dysfunction and memory loss, is one of the major elderly health issues worldwide. Neuroinflammation and increased oxidative stress contribute to the pathophysiology of AD, thereby presumably inducing tryptophan (TRP) degradation through the TRP catabolite (TRYCAT) pathway.ObjectivesTo delineate the activity of the TRYCAT pathway along with levels of TRP and tryptophan catabolites (TRYCATs) in AD patients.MethodsWe employed PubMed, Google Scholar, Web of Science, and SciFinder to obtain the relevant articles through a search process lasting the entire February 2022. We found 19 eligible articles which involved 738 patients and 665 healthy controls.ResultsOur result revealed a significant difference (p = 0.008) in the kynurenine (KYN)/TRP ratio (standardized mean difference, SMD = 0.216, 95% confidence interval, CI: 0.057; 0.376), and a significant decrease in TRP in AD patients (SMD = -0.520, 95% CI: -0.738; -0.302, p < 0.0001). Moreover, we also found a significant increase in the central nervous system (CNS, brain and cerebrospinal fluid, CSF) kynurenic acid (KA)/KYN ratio but not in peripheral blood, as well as a significant decrease in plasma KA and xanthurenic acid (XA) in the CNS and blood.ConclusionsAD is characterized by TRP depletion but not by an overactivity of the TRYCAT pathway. IDO-induced production of neurotoxic TRYCATs is not a key factor in the pathophysiology of AD.

AimsThis study aims to examine the associations between paraoxonase 1 (PON)1 status and acute ischemic stroke (AIS) and consequent disabilities.MethodsThis study recruited 122 patients with AIS and 40 healthy controls and assessed the Q192R gene variants, arylesterase (AREase) and chloromethyl phenylacetate (CMPAase) activities, and high-density lipoprotein cholesterol (HDL) in baseline conditions. AREase and CMPAase were measured 3 months later. The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin score (mRS) were assessed at baseline and 3 and 6 months later.ResultsReduced CMPAase and increased AREase activities are significantly associated with AIS and mRS and NIHSS scores (baseline and 3 and 6 months later). The best predictor of AIS/disabilities was a decrease in the z-unit-based composite zCMPAase-zAREase score. Serum high density lipoprotein cholsterol (HDL) was significantly correlated with CMPAase, but not AREase, activity and a lowered zCMPAase+zHDL score was the second best predictor of AIS/disabilities. Regression analysis showed that 34.7% of the variance in baseline NIHSS was explained by zCMPAase-zAREase and zCMPAase+zHDL composites, HDL, and hypertension. Neural network analysis showed that stroke was differentiated from controls with an area under the ROC curve of 0.975 using both new composite scores, PON1 status, hypertension, dyslipidemia, previous stroke as body mass index. The PON1 Q192R genotype has many significant direct and mediated effects on AIS/disabilities, however, its overall effect was not significant.DiscussionPON1 status and the CMPAase-HDL complex play key roles in AIS and its disabilities at baseline and 3 and 6 months later.

BackgroundAutism spectrum disorder (ASD) is a neurodevelopment disorder characterized by impaired social communication and interaction, as well as rigid and unchanging interests and behaviors. In ASD, studies show activated immune-inflammatory and nitro-oxidative pathways which are accompanied by depletion of plasma tryptophan (TRP), increased competing amino acids (CAAs) and activation of the TRP catabolite (TRYCAT) pathway.ObjectivesThis study aims to systematically review and meta-analyze data on peripheral TRP, CAAs, TRYCAT pathway activity, and individual TRYCATs, including kynurenine (KYN) and kynurenic acid (KA) levels, in blood and urine of ASD patients.MethodsAfter searching PubMed, Google Scholar, and SciFinder extensively, a total of 25 full-text papers were included in the analysis, with a total of 6653 participants (3,557 people with ASD and 30,96 healthy controls).ResultsBlood TRP and the TRP/CAAs ratio were not significantly different between ASD patients and controls (standardized mean difference, SMD= −0.227, 95% confidence interval, CI: −0.540; 0.085 and SMD= 0.158, 95%CI: −0.042; 0.359) respectively. The KYN/TRP ratio showed no significant difference between ASD and controls (SMD= 0.001, 95%CI: −0.169; 0.171). Blood KYN and KA levels were not significantly changed in ASD. Moreover, there were no significant differences in urine TRP, KYN and KA levels between ASD and controls. We could not establish increases in neurotoxic TRYCATs in ASD.ConclusionsOur study demonstrates that there are no abnormalities in peripheral blood TRP metabolism, IDO activity, and TRYCAT production in ASD. Reduced TRP availability and elevated neurotoxic TRYCAT levels are not substantial contributors to ASD’s pathophysiology.

BackgroundImmune-inflammatory pathways in major depressive disorder are confined to the major dysmood disorder (MDMD) phenotype (Maes et al., 2022). No studies have addressed the immune profile of first episode MDMD (FE-MDMD).MethodsThis study examines 48 cytokines/chemokines/growth factors, and classical M1, alternative M2, T helper (Th)-1, Th-2, and Th-17 phenotypes, immune-inflammatory response system (IRS), compensatory immunoregulatory system (CIRS), and neuro-immunotoxicity profiles in the acute phase of FE-MDMD (n=71) versus healthy controls (40).ResultsFE-MDMD patients show significantly activated M1, M2, Th-1, IRS, CIRS, and neurotoxicity, but not Th-2 or Th-17, profiles compared to controls. FE-MDMD is accompanied by Th-1 polarization, while there are no changes in M1/M2 or IRS/CIRS ratios. The top single indicator of FE-MDMD was by far interleukin (IL)-16, followed at a distance by TRAIL, IL-2R, tumor necrosis factor (TNF)-β. The severity of depression and anxiety was strongly associated with IRS (positively) and Th-2 (inversely) profiles, whereas suicidal behavior was associated with M1 activation. Around 56-60% of the variance in depression, anxiety, and suicidal behavior scores was explained by IL-16, platelet-derived growth factor (PDGF) (both positively), and IL-1 receptor antagonist (inversely). Increased neurotoxicity is mainly driven by IL-16, TNF-α, TRAIL, IL-6 and chemokine (CCL2, CCL11, CXCL1, CXCL10) signaling. Antidepressant-treated patients show an increased IRS/CIRS ratio as compared with drug-naïve FE-MDMD patients.ConclusionsFE-MDMD is accompanied by positive regulation of the IRS mainly driven by Th-1 polarization and T cell activation (via binding of IL-16 to CD4), and TNF, chemokine, and growth factor signaling.

BackgroundMajor depression (MDD) and bipolar disorder (BD) are linked to immune activation, increased oxidative stress, and lower antioxidant defenses.ObjectivesTo systematically review and meta-analyze all data concerning biomarkers of reverse cholesterol transport (RCT), lipid-associated antioxidants, lipid peroxidation products, and autoimmune responses to oxidatively modified lipid epitopes in MDD and BD.MethodsDatabases including PubMed, Google scholar and SciFinder were searched to identify eligible studies from inception to January 10th, 2023. Guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed.ResultsThe current meta-analysis included 176 studies (60 BD and 116 MDD) and examined 34,051 participants, namely 17,094 with affective disorders and 16,957 healthy controls. Patients with MDD and BD showed a) significantly decreases in RCT (mainly lowered high-density lipoprotein cholesterol and paraoxonase 1); b) lowered lipid soluble vitamins (including vitamin A, D, and coenzyme Q10); c) increased lipid peroxidation and aldehyde formation, mainly increased malondialdehyde (MDA), 4-hydroxynonenal, peroxides, and 8-isoprostanes; and d) Immunoglobulin (Ig)G responses to oxidized low-density lipoprotein and IgM responses to MDA. The ratio of all lipid peroxidation biomarkers / all lipid-associated antioxidant defenses was significantly increased in MDD (standardized mean difference or SMD=0.433; 95% confidence intervals (CI): 0.312; 0.554) and BD (SMD=0.653; CI: 0.501-0.806). This ratio was significantly greater in BD than MDD (p=0.027).ConclusionIn MDD/BD, lowered RCT, a key antioxidant and anti-inflammatory pathway, may drive increased lipid peroxidation, aldehyde formation, and autoimmune responses to oxidative specific epitopes, which all together cause increased immune-inflammatory responses and neurotoxicity.

Background The binary major depressive disorder (MDD) diagnosis is inadequate and should never be used in research. Aims The study's objective is to explicate our novel precision nomothetic strategy for constructing depression models based on adverse childhood experiences (ACEs), lifetime and current phenome, and biomarker (atherogenicity indices) scores. Methods This study assessed recurrence of illness (ROI: namely recurrence of depressive episodes and suicidal behaviors), lifetime and current suicidal behaviors and the phenome of depression, neuroticism, dysthymia, anxiety disorders, and lipid biomarkers (including ApoA, ApoB, free cholesterol and cholesteryl esters, triglycerides, high density lipoprotein cholesterol) in 67 normal controls and 66 MDD patients. We computed atherogenic and reverse cholesterol transport indices. Results We were able to extract one factor from a) the lifetime phenome of depression comprising ROI, and traits such as neuroticism, dysthymia and anxiety disorders, and b) the phenome of the acute phase (based on depression, anxiety and quality of life scores). PLS analysis showed that 55.7% of the variance in the lifetime + current phenome factor was explained by increased atherogenicity, neglect and sexual abuse, while atherogenicity partially mediated the effects of neglect. Cluster analysis generated a cluster of patients with major dysmood disorder, which was externally validated by increased atherogenicity and characterized by increased scores of all clinical features. Conclusions The outcome of depression should not be represented as a binary variable (MDD or not), but rather as multiple dimensional scores based on biomarkers, ROI, subclinical depression traits, and lifetime and current phenome scores including suicidal behaviors.

Neuroticism, a personality trait, can predict major depressive disorder (MDD). The current study aims to determine whether a) neuroticism is a feature of the acute state of MDD, including suicidal behaviors (SB); and b) adverse childhood experiences (ACEs) are associated with neuroticism in MDD. This study included 133 participants, 67 normal controls and 66 MDD patients, and assessed the Big 5 Inventory (BFI), ACEs using the ACE Questionnaire, and the phenome of depression using the Hamilton Depression (HAMD) Rating Scale (HAMD), Beck Depression Inventory (BDI), The State-Trait Anxiety Inventory (STAI) and Columbia Suicide Severity Rating Scale (C-SSRS) scores to assess current SB. Neuroticism was significantly higher in MDD than controls, and it explained 64.9% of the variance in the depression phenome (a latent vector extracted from HAMD, BDI, STAI, and current SB scores). The other BFI domains had much less (extraversion, agreeableness) or no effect (openness, conscientiousness). One latent vector could be extracted from the phenome, lifetime dysthymia, lifetime anxiety disorders and neuroticism scores. Neglect (physical and emotional) and abuse (physical, neglect and sexual) account for approximately 30% of the variance in this latent vector. Partial Least Squares analysis showed that the effects of neglect on the phenome were partially mediated by neuroticism, whereas the effects of abuse were completely mediated by neuroticism. Neuroticism (trait) and the MDD phenome (state) are both manifestations of the same latent core, with neuroticism being a less severe manifestation of major depression, which in fact is a multiplicative manifestation of neuroticism.

The first publication demonstrating that major depressive disorder (MDD) is associated with alterations in the gut microbiota appeared in 2008 (Maes et al., 2008). The purpose of the present study is to delineate a) the microbiome signature of the phenome of depression, including suicidal behaviours and cognitive deficits; the effects of adverse childhood experiences (ACE) and recurrence of illness index (ROI) on the microbiome; and the microbiome signature of lowered high-density lipoprotein cholesterol (HDLc).We determined isometric log-ratio abundances or prevalence of gut microbiome phyla, genera, and species by analyzing stool samples from 37 healthy Thai controls and 32 MDD patients using 16S rDNA sequencing.Six microbiome taxa accounted for 36% of the variance in the depression phenome, namelyHungatellaandFusicatenibacter(positive associations) andButyricicoccus, Clostridium, Parabacteroides merdae, andDesulfovibrio piger(inverse association). This profile (labeled enterotype 1) indicates compositional dysbiosis, is strongly predicted by ACE and ROI, and is linked to suicidal behaviours. A second enterotype was developed that predicted a decrease in HDLc and an increase in the atherogenic index of plasma (Bifidobacterium, P. merdae, andRomboutsia were positively associated, whileProteobacteriaandClostridium sensu strictowere negatively associated). Together, enterotypes 1 and 2 explained 40.4% of the variance in the depression phenome, and enterotype 1 in conjunction with HDLc explained 39.9% of the variance in current suicidal behaviours.In conclusion, the microimmuneoxysome is a potential new drug target for the treatment of severe depression and suicidal behaviours, and possibly for the prevention of future episodes.

BackgroundThe binary major depressive disorder (MDD) diagnosis is inadequate and should never be used in research.AimsThe study’s objective is to explicate our novel precision nomothetic strategy for constructing depression models based on adverse childhood experiences (ACEs), lifetime and current phenome, and biomarker (atherogenicity indices) scores.MethodsThis study assessed recurrence of illness (ROI: namely recurrence of depressive episodes and suicidal behaviors), lifetime and current suicidal behaviors and the phenome of depression, neuroticism, dysthymia, anxiety disorders, and lipid biomarkers (including ApoA, ApoB, free cholesterol and cholesteryl esters, triglycerides, high density lipoprotein cholesterol) in 67 normal controls and 66 MDD patients. We computed atherogenic and reverse cholesterol transport indices.ResultsWe were able to extract one factor from a) the lifetime phenome of depression comprising ROI, and traits such as neuroticism, dysthymia and anxiety disorders, and b) the phenome of the acute phase (based on depression, anxiety and quality of life scores). PLS analysis showed that 55.7% of the variance in the lifetime + current phenome factor was explained by increased atherogenicity, neglect and sexual abuse, while atherogenicity partially mediated the effects of neglect. Cluster analysis generated a cluster of patients with major dysmood disorder, which was externally validated by increased atherogenicity and characterized by increased scores of all clinical features.ConclusionsThe outcome of depression should not be represented as a binary variable (MDD or not), but rather as multiple dimensional scores based on biomarkers, ROI, subclinical depression traits, and lifetime and current phenome scores including suicidal behaviors.

BackgroundThere are strong associations between major depressive disorder (MDD), metabolic syndrome (MetS) and cardiovascular disorder, which may be explained by increased atherogenicity and the microimmuneoxysome (Maes et al., 1994; 2011). The present study was conducted to determine if MDD, the severity of depression, suicidal behaviors, and neuroticism are associated with increased pro-atherogenic versus anti-atherogenic indices (PRO/ANTI-AI) and a reverse cholesterol transport (RCT) index.MethodsThis study included 34 healthy controls, 33 participants with MetS, and MDD patients with (n=31) and without (n=35) MetS, and measured total (TC) and free (FC) cholesterol, high (HDLc) and low (LDLc) density lipoprotein cholesterol, triglycerides (TG), apolipoprotein (ApoA), ApoB, cholesterol esterification rate (CER) and a composite (based on HDLc, ApoA and CER), reflecting RCT.ResultsIn the combined MDD + MetS study group, no associations between MDD and lipids were detected. After the exclusion of all MetS participants, MDD is strongly associated with (a) increased FC, TG, ApoB, Castelli risk index 1, ApoB/ApoA, and (b) decreased HDLc, ApoA and the RCT index. In participants without MetS, there are significant associations between severity of depression, suicidal behaviors, and neuroticism and ApoB/ApoA, Castelli risk, and RCT indices.ConclusionsStudies linking lipids to depressive subtypes can only be interpreted after MetS patients are excluded. The depression phenome, suicidal behaviors, and neuroticism are associated with a lowered RCT and increased atherogenicity, which are likely involved in the microimmuneoxidative pathophysiology of MDD. The RCT is a new drug target to treat and prevent MDD, neuroticism, and suicidal behaviors.

Suicide attempts (SA) frequently occur in patients with mood disorders and schizophrenia, which are both accompanied by activated immune-inflammatory and nitro-oxidative (IONS) pathways.We searched PubMed, Google Scholar, and Web of Science, for articles published from inception until February 1, 2021. We included studies that compared blood biomarkers in psychiatric patients with (SA+) and without SA (SA-) and heathy controls and we combined different IONS biomarkers into immune, inflammatory, and neurotoxic profiles and used meta-analysis (random-effect model with restricted maximum-likelihood) to delineate effect sizes with 95% confidence interval (CI).Our search included 51 studies comprising 4.945 SA+ patients and 24.148 controls. We stratified the control group into healthy controls and SA- patients. SA+ patients showed significantly (p0.001) increased immune activation (SMD: 1.044; CI: 0.599, 1.489), inflammation (SMD: 1.109; CI: 0.505, 1.714), neurotoxicity (SMD: 0.879; CI: 0.465, 1.293), and lowered neuroprotection (SMD: 0.648; CI: 0.354, 0.941) as compared with healthy controls. When compared with SA- patients, those with SA+ showed significant (p0.001) immune activation (SMD: 0.290; CI: 0.183, 0.397), inflammation (SMD: 0.311; CI: 0.191, 0.432), and neurotoxicity (SMD: 0.315; CI: 0.198, 0.432), and lowered neuroprotection (SMD: 0.341; CI: 0.167, 0.515). Patients with current, but not lifetime, SA showed significant (p0.001) levels of inflammation and neurotoxicity as compared with controls.Patients with immune activation are at a higher risk of SA which may be explained by increased neurotoxicity due to inflammation and nitro-oxidative stress. This meta-analysis discovered new biomarkers of SA and therapeutic targets to treat individuals with SA.

BackgroundMultiple sclerosis (MS) is a chronic autoimmune and neuroinflammatory disease of the central nervous system characterized by peripheral activation of immune-inflammatory pathways which culminate in neurotoxicity causing demyelination of central neurons. Nonetheless, the pathophysiology of relapsing-remitting MS (RRMS)-related chronic fatigue, depression, anxiety, cognitive impairments, and autonomic disturbances is not well understood.ObjectivesThe current study aims to delineate whether the remitted phase of RRMS is accompanied by activated immune-inflammatory pathways and if the latter, coupled with erythron variables, explain the chronic fatigue and mood symptoms due to RRMS.Material and MethodsWe recruited 63 MS patients, 55 in the remitted phase of RRMS and 8 with secondary progressive MS, and 30 healthy controls and assessed erythron variables and used a bio-plex assay to measure 27 serum cytokines.ResultsA significant part of the MS patients (46%) displayed activation of the immune-inflammatory response (IRS) and compensatory immune response (CIRS) systems, T helper (Th)1 and Th-17 cytokine profiles. Remitted RRMS patients showed increased chronic fatigue, depression, anxiety, physiosomatic, autonomic, and insomnia scores, which could partly be explained by M1 macrophage, Th1, Th-17, growth factor, and CIRS activation, as well as aberrations in the erythron including lowered hematocrit and hemoglobin levels.ConclusionsAround 50% of remitted RRMS patients show activation of immune-inflammatory pathways in association with mood and chronic-fatigue-like symptoms. IRS and CIRS activation as well as the aberrations in the erythron are new drug targets to treat chronic fatigue and affective symptoms due to MS.

Maes et al. (2008) published the first paper demonstrating that major depressive disorder (MDD) is accompanied by abnormalities in the microbiota-gut-brain axis, as evidenced by elevated serum IgM/IgA to lipopolysaccharides (LPS) of Gram-negative bacteria, such asMorganella morganiiandKlebsiella Pneumoniae. The latter aberrations, which point to increased gut permeability (leaky gut), are linked to activated neuro-immune and oxidative pathways in MDD. To delineate the profile and composition of the gut microbiome in Thai patients with MDD, we examined fecal samples of 32 MDD patients and 37 controls using 16S rDNA sequencing and analyzed α-(Chao and Shannon indices) and β-diversity (Bray-Curtis dissimilarity) and conducted Linear discriminant analysis (LDA) Effect Size (LEfSe) analysis. Neither α-nor β-diversity differed significantly between MDD and controls.Rhodospirillaceae, Hungatella, Clostridium bolteae, Hungatella hathewayi, andClostridium propionicumwere significantly enriched in MDD, while Gracillibacteraceae family,Lutispora, and Ruminococcus genus, Ruminococcus callidus, Desulfovibrio piger, Coprococcus comes, andGemmiger, were enriched in controls. Contradictory results have been reported for all these taxa, with the exception ofRuminococcuswhich is depleted in 6 different MDD studies (one study showed increased abundance), many medical disorders that show comorbidities with MDD, and animal MDD models. Our results may suggest a specific profile of compositional gut dysbiosis in Thai MDD patients with increases in some pathobionts and depletion of some beneficial microbiota. The results suggest that depletion ofRuminococcusmay be a more universal biomarker of MDD that maybe contributes to increased enteral LPS load, LPS translocation, and gut-brain axis abnormalities.

In acute ischemic stroke (AIS), there are no data on whether lipid and protein oxidation and antioxidant biomarkers are associated with the outcome of AIS above and beyond the effects of traditional risk factors, immune and metabolic biomarkers, and measurements of stroke volume. The present study was conducted in 135 mild to moderate AIS patients and 40 controls and assessed the modified raking scale (mRS) at baseline, and 3 and 6 month later. We measured lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products, paraoxonase 1 (PON1) activities and PON1 Q192R genotypes, high density lipoprotein cholesterol (HDL), sulfhydryl (-SH) groups), and diffusion-weighted imaging (DWI) stroke volume and fluid-attenuated inversion recovery (FLAIR) signal intensity. We found that a) AIS is characterized by lower chloromethyl acetate (CMPA)ase PON1 activity, HDL and -SH groups and increased LOOH and neurotoxicity (a composite of LOOH, inflammatory markers and glycated hemoglobin); b) oxidative and antioxidant biomarkers strongly and independently predict mRS scores 3 and 6 months later and DWI stroke volume and FLAIR signal intensity; c) the PON1 Q192R variant has multiple effects on stroke outcome that are mediated by its effects on antioxidant defenses and lipid peroxidation; and d) the PON1 RR variant has a protective effect against lipid peroxidation, neurotoxicity, infarct volume and stroke outcome. Increased lipid peroxidation and lowered activity of the PON1-HDL complex and -SH groups are drug targets to prevent AIS and consequent neurodegenerative processes with loss of function, and increased levels of oxidative reperfusion mediators due to ischemia-reperfusion injury.

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The tryptophan catabolite (TRYCAT) pathway is implicated in the pathophysiology of schizophrenia (SCZ) since the rate-limiting enzyme indoleamine-dioxygenase (IDO) may be induced by inflammatory and oxidative stress mediators. This systematic review searched PubMed, Web of Science, and Google Scholar for papers published from inception until August 2021 and meta-analyzed the association between SCZ and TRYCATs in the central nervous system (CNS) and peripheral blood. We included 61 studies comprising 2813 patients and 2948 healthy controls. In the CNS we found a significant (pincreased IDO activity in the CNS and serum, and reduced KMO activity and a shift towards KA production in the CNS. This CNS TRYCATs profile indicates neuroprotective, negative immunoregulatory and anti-inflammatory effects. Peripheral blood levels of TRYCATs are dissociated from CNS findings except for a modest increase in serum IDO activity.

This study aims to systematically review and meta-analyze the nitro-oxidative stress (O&NS)/antioxidant (ANTIOX) ratio in the peripheral blood of people with mild cognitive impairment (MCI). We searched PubMed, Scopus, Google Scholar, and Web of Science for articles published from inception until July 31, 2021. Forty-six studies on 3.798 MCI individuals and 6.063 healthy controls were included. The O&NS/ANTIOX ratio was significantly higher in MCI than in controls with a Standardized Mean Difference (SMD)=0.378 (95% CI: 0.250; 0.506). MCI individuals showed increased lipid peroxidation (SMD=0.774, 95%CI: 4.416; 1.132) and O&NS-associated toxicity (SMD=0.621, CI: 0.377; 0.865) and reduced glutathione (GSH) defenses (SMD=0.725, 95%CI: 0.269; 1.182) as compared with controls. MCI was also accompanied by significantly increased homocysteine (SMD=0.320, CI: 0.059; 0.581), but not protein oxidation, and lowered non-vitamin (SMD=0.347, CI: 0.168; 0.527) and vitamin (SMD=0.564, CI: 0.129; 0.999) antioxidant defenses. The results show that MCI is at least in part due to increased neuro-oxidative toxicity and suggest that treatments targeting lipid peroxidation and the GSH system may be used to treat or prevent MCI.

To delineate the effects of white matter hyperintensities (WMHs) as measured by Fluid-attenuated inversion recovery (FLAIR) and infarction volume as measured by Diffusion-weighted imaging (DWI) on post-stroke depression symptoms.Baseline National Institutes of Health Stroke Score (NIHSS) and Modified Rankin Scale (mRS) scores, and FLAIR and DWI MRIs to assess WMHs and acute infarct volumes, respectively, were assessed in 47 patients (≥55 years) with acute ischemic stroke and 17 normal controls. The Montgomery-Åsberg Depression Rating Scale (MDRS) was assessed three months after the stroke.The MADRS score was significantly increased in stroke patients as compared with normal controls. The MADRS scale is not unidimensional and cannot be used as an accurate indicator of depression severity in stroke patients. Three months after stroke, key depressive (sadness and inability to feel) and concentration-tension symptoms, and lassitude are significantly predicted by the infarct volume. Right side infarction strongly predicts key depressive symptoms and left side infarction strongly predicts concentration-tension and lassitude scores. Total WMHs significantly predict key depressive and concentration-tension symptoms, and lassitude, with these effects being mediated by right and left DWI stroke volumes and associated disabilities.Interactions between age, hypertension, a chronic atherosclerotic process, and acute stroke account for the onset of key depressive symptoms three months after the acute infarct. Chronic and acute neuro-immune and neuro-oxidative stress pathways associated with the formation of WMHs and acute stroke may explain the incidence of post-stroke key depressive and concentration-tension symptoms, and lassitude.

Objectives To delineate the features of ischemic stroke patients and their caregivers that may predict distress, depression, and anxiety symptoms in the caregivers. Methods The Hospital Anxiety and Depression Score (HADS), Zarit Burden Interview (22 item-ZBI), and Perceived Stress Scale (PSS-10) were used to assess caregivers' burden, stress, depressive, and anxiety symptoms. We performed partial least square-structural equation modeling (PLS-SEM) in order to delineate a multi-step mediation model.Results In this study, 97 stroke patients and their caregivers were included. Multiple regression analysis revealed that ZBI-personal strain and stroke of other determined etiology explained 15.0 percent of the variance in the HADS depression score (p=0.001). We discovered that the caregiver's underlying disease and the National Institute Stroke Score (NIHSS) of the patients explained 13.6 percent of the variance in the total ZBI score of the caregivers (p=0.001). The total ZBI score, the presence of lacunar circulation infarction in the patients, and the caregiver's underlying disease explained 40.9 percent of the variance in the total PSS score of the caregivers (p

A meta-analysis showed a significant association between activated immune-inflammatory and nitro-oxidative (IO&NS) pathways and suicide attempts (SA). There are no data whether suicidal ideation (SI) is accompanied by activated IO&NS pathways and whether there are differences between SA and SI. The current study searched PubMed, Google Scholar, and Web of Science, for articles published from inception until May 10, 2021, and systematically reviewed and meta-analyzed the association between recent SA/SI (< 3 months) and IO&NS biomarkers. We included studies which compared psychiatric patients with and without SA and SI and controls (either healthy controls or patients without SA or SI) and used meta-analysis (random-effect model with restricted maximum-likelihood) to delineate effect sizes with 95% confidence intervals (CI). Our search included 59 studies comprising 4.034 SA/SI cases and 12.377 controls. Patients with SA/SI showed activated IO&NS pathways (SMD: 0.299; CI: 0.200; 0.397) when compared to controls. The immune profiles were more strongly associated with SA than with SI, particularly when compared to healthy controls, as evidenced by activated IO&NS pathways (SMD: 0.796; CI: 0.503; 1.089), an immune-inflammatory response (SMD: 1.409; CI: 0.637; 1.462), inflammation (SMD: 1.200; CI: 0.584; 1.816), and neurotoxicity (SMD: 0.904; CI: 0.431; 1.378). The effects sizes of the IO&NS, immune-inflammatory response and inflammatory profile were significantly greater in SA than in SI. In conclusion: increased neurotoxicity due to inflammation and nitro-oxidative stress and lowered neuroprotection may explain at least in part why psychiatric patients show increased SA and SI. The IO&NS pathways are more pronounced in recent SA than in SI.

Background The Apolipoprotein E4 (ApoE4) genotype is strongly associated with Alzheimer's disease (AD), although the presence of the ApoE4 allele alone is not sufficient to explain AD. The pathophysiology of amnestic mild cognitive impairment (aMCI) remains unclear. Objective This study aims to examine associations between peripheral blood biomarkers coupled with ApoE4 and episodic and semantic memory. Methods The CERAD battery was completed and various biomarkers were assayed in 60 subjects with aMCI, 60 with AD, and 62 healthy controls. Results Deficits in semantic and episodic memory were significantly predicted by anion gap and bicarbonate, albumin, and glucose coupled with ApoE4. Furthermore, these peripheral biomarkers interacted with ApoE to predict greater memory impairments. Conclusions Peripheral blood biomarkers may interact with pathways related to ApoE4 to predict greater semantic and episodic memory impairments, thus contributing to the pathophysiology of aMCI and AD. Our data suggest that the transition from aMCI to AD could at least in some cases be associated with significant interactions between ApoE4 and those peripheral blood biomarkers.

The adoption of Information and Communication Technologies (ICT) in various domains is revolutionizing our lives and the same is true with the healthcare system. Modern technologies are disclosing novel and unforeseen applications and one of them is the development of cognitive interventions for elderly patients, however, the use of Virtual Reality (VR) is at a preliminary stage. This paper aims to propose a treatment for patients with mild cognitive impairment with the help of virtual reality in conjunction with 5G wireless networks. For this purpose, our work can be used to validate the feasibility of online treatment to reduce the treatment cost particularly for patients in remote areas. We apply the case study in Chulalongkorn University, Bangkok, Thailand. Results show that VR technology when used with 5G network, can supplement the traditional medical system and is found to help treat patients suffering from dementia.

BackgroundSuicide attempts (SA) frequently occur in patients with mood disorders and schizophrenia, which are both accompanied by activated immune-inflammatory and nitro-oxidative (IO&NS) pathways.MethodsWe searched PubMed, Google Scholar, and Web of Science, for articles published from inception until February 1, 2021. We included studies that compared blood biomarkers in psychiatric patients with (SA+) and without SA (SA-) and heathy controls and we combined different IO&NS biomarkers into immune, inflammatory, and neurotoxic profiles and used meta-analysis (random-effect model with restricted maximum-likelihood) to delineate effect sizes with 95% confidence interval (CI).FindingsOur search included 51 studies comprising 4.945 SA+ patients and 24.148 controls. We stratified the control group into healthy controls and SA-patients. SA+ patients showed significantly (pConclusionsPatients with immune activation are at a higher risk of SA which may be explained by increased neurotoxicity due to inflammation and nitro-oxidative stress. This meta-analysis discovered new biomarkers of SA and therapeutic targets to treat individuals with SA.

ObjectivePost-stroke depression (PSD) is one of the most frequent psychiatric symptoms after a stroke event. The role of white matter hyperintensities (WMHs) associated with PSD in older patients remains unclear. This study aimed to examine the volume and location of white matter microstructure abnormalities among older patients with early-onset PSD.MethodsOlder (≥55 years) patients with acute cerebral infarction and hospitalized in King Chulalongkorn Memorial Hospital’s stroke unit from October 2019 to September 2020 were recruited. Participants were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) within three months after the onset of stroke. All patients had MRI scans. The brain images were segmented into four regions via left/right, frontal/dorsal plains. Two WMHs volume detections (visual rating vs. semi-automated WMHs volumetric detection) were employed on the fluid-attenuated inversion recovery images (FLAIR) for each segment. The study then investigated the association between WMHs volume and MADRS score with regression analysis.ResultsThe study included twenty-nine patients with acute stroke. Total WMHs volume and segmented regions were not statistically associated with the MADRS score. However, there was a trend in different WHMs volume of the left anterior segment between depressed and non-depressed groups (t-test 2.058, p = 0.055). Further, demographic and clinical data showed no association with depressive symptoms.ConclusionThe volume of WHMs might not contribute to the development of early-onset PSD in older patients. This study showed a potential of a quantitative MRI analysis in clinical practice. Further investigation with a larger group of patients is needed.

Background: Suicide attempts (SA) frequently occur in patients with mood disorders and schizophrenia, which are both accompanied by activated immune-inflammatory and nitro-oxidative (IO&NS) pathways. Methods: We searched PubMed, Google Scholar, and Web of Science, for articles published from inception until February 1, 2021. We included studies that compared blood biomarkers in psychiatric patients with (SA+) and without SA (SA-) and heathy controls and we combined different IO&NS biomarkers into immune, inflammatory, and neurotoxic profiles and used meta-analysis (random-effect model with restricted maximum-likelihood) to delineate effect sizes with 95% confidence interval (CI). Findings: Our search included 51 studies comprising 4.945 SA+ patients and 24.148 controls. We stratified the control group into healthy controls and SA- patients. SA+ patients showed significantly (p

Introduction: Lowered thiol or sulfhydryl (-SH) groups and glutathione (GSH) metabolism may be associated with prostate cancer (PCa) and benign prostatic hyperplasia (BPH). The main objectives of this study were to systematically review and meta-analyze the evidence on the associations among -SH groups, GSH, GSH peroxidase (GPx), GSH reductase (GR) and GSH transferase (GST) and PCa/BPH. Methods: Four electronic databases were searched for studies that reported -SH and GSH variables in PCa/BPH and healthy controls (HC) and the data were meta-analyzed by calculating Hedges’s g with 95% confidence intervals. Results: Twenty studies were included in this meta-analysis including 800 PCa and 791 BPH patients and 592 HC. Total -SH (g=-1.750, -2.341/-1.159), GPx (g=-0.789, -1.234/-0.344), GSH (g=-2.219, -4.132/-0.305), and the combination of -SH, GPx, and GSH (g=-1.271, -1.271/-0.800) were significantly lower in PCa patients than in HC. -SH (g=-1.752, -3.123/-0.381) and the combination of -SH, GPx, and GSH (g=-0.813, -1.298/-0.327) were significantly lower in BPH patients than in HC. GPx was significantly lower in PCa than in BPH patients (g=-0.455, -0.896/-0.014). Heterogeneity levels were very high, but Egger’s test showed that none of the biomarkers showed significant publication bias. Conclusion: Thiol/GPx antioxidant defenses are significantly attenuated in patients with PCa while patients with BPH occupy an intermediate risk group position between PCa patients and HC. Those results suggest that reduced thiol-related antioxidant mechanisms play a crucial role in prostatic disorders, especially in PCa. Future research should examine whether thiols/GPx antioxidants are associated with the onset of PCa/BHP.

Objective The popular clock drawing test (CDT) is easy to administer, acceptable to patients, and has excellent psychometric properties. Although it has been used primarily as a cognitive screening test, many studies have attempted to establish the CDT's ability to localize specific brain lesions or pathology. This systematic review aimed to summarize the evidence on the neuroanatomical correlates of the CDT. Methods Using PRISMA guidelines, the authors systematically reviewed the evidence on neuroanatomical correlates of clock drawing by a systematic search in six databases (Pubmed, CINHL, PsychINFO, HealthStar, Embase, and Web of Science) until January 2018. Studies were included if they reported CDT correlations with anatomical brain lesions documented by neuroimaging. Results Forty-five papers met inclusion criteria. Thirty-one studies identified distinct areas of neuroanatomical correlates of CDT utilizing different scoring methods and imaging techniques. Nine articles reported on the degree of white matter hyperintensities that correlated with lower scores on CDT and the severity of cognitive deficits. Five articles focused on postacute cerebrovascular accidents correlated with CDT performance. A variety of different anatomical lesions, located in all areas of the brain, were associated with abnormalities on the CDT. Conclusions The CDT, regardless of scoring method and population studied, was not associated with any consistent, specific brain localization. This systematic review supports the use of the CDT as a cognitive screening test rather than a method of localizing brain lesions.

Impairments in the Boston Naming Test (BNT), which measures confrontational word retrieval, frequently accompanies Alzheimer's dementia (AD) and may predict a more rapid progression of illness. This study aims to validate the Thai version of the 15-item BNT (T-BNT) in participants with AD and amnestic mild cognitive impairment (aMCI) and to externally validate the T-BNT using clinical and biomarker measurements.This cross-sectional study recruited patients with AD, diagnosed according to NINCDS-ADRDA criteria (n = 60), aMCI, diagnosed using the Petersen criteria (n = 60), and healthy controls (n = 62). We examined the internal consistency, concurrent and discriminant reliability of the T-BNT. We also assessed the Mini Mental State Examination (MMSE), the Verbal Fluency Test (VFT) and the Word List Memory (WLM) tests and measured apolipoprotein E polymorphism and serum levels of folic acid, high-density lipoprotein cholesterol (HDL) and triglycerides.This study validated a 10-item T-BNT (10T-BNT), which yielded good internal consistency (0.92), a one-factor unidimensional structure, and adequate concurrent and discriminant validity. Lower scores on the 10T-BNT highly significantly predict AD, but not aMCI, and are positively associated with VFT and WLM test scores. Furthermore, lowered 10T-BNT scores are significantly associated with the ApoE4 allele, lower folate levels and an increased triglyceride/HDL-cholesterol ratio.This study validated the 10T-BNT and the total score on this scale is strongly associated with AD, impairments in semantic and episodic memory and biomarkers, which are known to modify memory via different mechanisms.

Background: The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) developed a neuropsychological battery (CERAD-NP) to screen patients with Alzheimer’s dementia. Mild cognitive impairment (MCI) has received attention as a pre-dementia stage. Objectives: To delineate the CERAD-NP features of MCI and their clinical utility to externally validate MCI diagnosis. Methods: The study included 60 patients with MCI, diagnosed using the Clinical Dementia Rating, and 63 normal controls. Data were analysed employing receiver operating characteristic analysis, Linear Support Vector Machine, Random Forest, Adaptive Boosting, Neural Network models, and t-distributed stochastic neighbour embedding (t-SNE). Results: MCI patients were best discriminated from normal controls using a combination of Wordlist Recall, Wordlist Memory, and Verbal Fluency Test. Machine learning showed that the CERAD features learned from MCI patients and controls were not strongly predictive of the diagnosis (maximal cross-validation 77.2%), whilst t-SNE showed that there is a considerable overlap between MCI and controls. Conclusions: The most important features of the CERAD-NP differentiating MCI from normal controls indicate impairments in episodic and semantic memory and recall. While these features significantly discriminate MCI patients from normal controls, the tests are not predictive of MCI.