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Background: Sporadic Alzheimer's Disease (AD) is assumed to be associated with different biological/genetic vulnerability, as well as with neuroinflammation, mediated by cytokines. The present study evaluated the role of cytokines in AD., Objective: The aim was to determine the possible association of TNF-α (rs1800629), IL1-α (rs1800587) and IL-10 (rs1800896) polymorphisms with AD, and to assess serum TNF-α, IL-1α and IL-10 concentrations in patients with AD and in subjects with mild cognitive impairment (MCI)., Methods: The study included 645 Caucasian participants: 395 subjects with AD and 250 subjects with MCI. Genotyping was performed using real-time PCR in all 645 subjects, while serum concentrations of TNF-α, IL-1α and IL-10 and were determined using ELISA in 174 subjects., Results: The frequency of the TNF-α rs1800629, IL1-α rs1800587 or IL-10 rs1800896 genotypes did not differ significantly between patients with AD and MCI. Serum concentration of IL-1α and IL-10 were significantly decreased, while the concentration of TNF-α was significantly higher in patients with AD than in MCI subjects. TNF-α, IL1-α or IL-10 concentrations were similar in subjects with AD or MCI subdivided into carriers of the corresponding TNF-α rs1800629, IL1-α rs1800587 or IL-10 rs1800896 genotypes., Conclusion: Similar distribution of the IL1-α rs1800587, TNF-α rs1800629 or IL-10 rs1800896 genotypes in subjects with AD and MCI failed to confirm that these specific risk genotypes are associated with vulnerability to develop AD. Alteration in IL-1α, IL-10 and TNF-α concentrations in patients with AD partially confirmed the association with the neuroinflammatory response in AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease., Objective: The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer's disease., Methods: PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles., Results: We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer's disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications., Conclusion: Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer's disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background & Objectives: Brain-derived neurotrophic factor (BDNF) facilitates neuronal survival, differentiation and synaptic connectivity and affects neurotransmission throughout the brain. However, it has also a modulatory role in energy homeostasis, obesity and cardiovascular function. Obesity, high body mass index (BMI) and dyslipidaemia, among other factors, contribute to coronary heart disease (CHD) development. The exact role of BDNF in development of CHD is not well defined. This study was aimed to evaluate if plasma BDNF concentration was associated with CHD in ethnically homogeneous groups of patients and to correlate plasma BDNF levels with known risk factors for CHD., Methods: Plasma BDNF concentration, BDNF Val66Met polymorphism and other biological and anthropological risk factors for CHD were determined in 208 patients with CHD and 156 healthy controls., Results: Plasma BDNF concentration was significantly (P <0.01) reduced in patients with CHD compared to controls, and it was not influenced by gender, age, smoking or BDNF Val66Met polymorphism. It was considerably correlated with cholesterol (P=0.004), low-density lipoprotein (P=0.006), and diastolic blood pressure (P=0.018) in patients with CHD and with platelet number (P=0.003) in healthy controls., Interpretation & Conclusions: The results revealed lower plasma BDNF concentration in patients with CHD, suggesting that decreased plasma BDNF concentration might be associated with CHD pathogenesis. Longitudinal studies with a large sample need to be conducted to confirm these findings., Competing Interests: None

Objective: Cognition is a complex trait representing a set of all mental abilities and processes related to knowledge. Although diverse brain regions are involved, most cognitive processes appear to engage cortical regions. The activity of dopaminergic neurons in prefrontal cortex represents a biological substrate underlying cognitive functions. Alzheimer's Disease (AD) is the most frequent dementia associated with cognitive impairments. Cognitive impairment in AD starts slowly with discrete deterioration in memory, language, thinking and reasoning, but it progresses into more severe and debilitating cognitive dysfunction. Cognitive function is affected by the complex interactions between various genetic, epigenetic, developmental and environmental factors. One of the most studied genes, associated with cognitive disturbances, is the gene coding for Catechol-O-methyltransferase (COMT), the enzyme with major role in dopamine metabolism and modulation of different brain functions. Therefore, COMT is studied as a target for many neuropsychiatric disorders, including dementias and AD. The COMT Val158/108Met functional polymorphism affects significantly the enzyme activity and consequently cognitive performance associated with altered dopamine function. The association of COMT Val158/108Met polymorphism with some cognitive domains and psychosis in AD was reported in some but not in all studies. Besides COMT Val158/108Met polymorphism, other risk genotypes or haplotypes should be evaluated to determine the association of COMT with cognitive decline in AD., Conclusion: Better understanding of the role of COMT in cognitive processes in AD, as well as integration of neurobiological, genetic, genomic and epigenetic data, might help in developing new potential therapies of cognitive impairments and psychotic symptoms, characteristic features of AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide.

Alcohol dependence is a common chronic disorder precipitated by the complex interaction between biological, genetic and environmental risk factors. Recent studies have demonstrated that polymorphisms of the gene encoding the GABAA receptor α2 subunit (GABRA2) are associated with alcohol dependence in different populations of European ancestry. As aggression often occurs in the context of alcohol dependence, the aim of this study was to examine the allelic and haplotypic association of GABRA2 gene with alcohol dependence and related aggressive behavior in subjects of Eastern European (Croatian) origin. Genotyping of the 3 single nucleotide polymorphisms (SNPs) across the GABRA2 gene (rs567926, rs279858 and rs9291283) was performed in patients with alcohol dependence (N=654) and healthy control subjects (N=574). Alcohol-dependent participants were additionally subdivided according to the presence/absence of aggressive behavior and type of alcohol dependence according to the Cloninger's classification. The association of rs279858 with alcohol dependence yielded nominal significance level. Haplotype analysis revealed a high degree of linkage disequilibrium (LD) for rs567926 and rs279858, but not for rs9291283 polymorphism in the GABRA2 gene. In patients with alcohol dependence, the A-C (rs567926 and rs279858) haplotype carriers were more likely to demonstrate aggressive behavior. The same haplotype (present only in 1.6% of all subjects) was significantly more often present in patients with a combination of early onset alcohol abuse and aggression, corresponding to the Cloninger's type II alcoholism subgroup. These findings support the involvement of GABRA2 gene in alcohol dependence-related aggressive behavior., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Neutrophils play an essential role in Alzheimer's disease (AD) pathology. However, the extent of their heterogeneity remains poorly explored, particularly in the context of developing novel therapies targeting these cells. Results: We investigate the population structure of neutrophils purified from peripheral blood samples of AD mice. Utilizing single cell RNA sequencing, we comprehensively map neutrophil populations into six distinct clusters and find that the Neu-5 subset is specially enriched in AD mice. This subset exhibits fewer specific granules and a lower mature score. Gene ontology (GO) analysis reveals that genes involved in cytokine-mediated signaling are downregulated in the Neu-5 cluster. Furthermore, we identify the Ccrl2 gene is specifically upregulated in this subgroup, which is confirmed by flow cytometry in AD mice. Finally, immunohistochemical staining indicates that CCRL2 protein is increased in the brains of AD mice. Conclusions: We identify a unique CCRL2 positive neutrophil cluster, that is specifically enriched in the peripheral blood of AD mice. [ABSTRACT FROM AUTHOR]

Background: Studies of hyperbaric oxygen therapy (HBOT) treatment of mild traumatic brain injury persistent postconcussion syndrome in military and civilian subjects have shown simultaneous improvement in posttraumatic stress disorder (PTSD) or PTSD symptoms, suggesting that HBOT may be an effective treatment for PTSD. This is a systematic review and dosage analysis of HBOT treatment of patients with PTSD symptoms. Methods: PubMed, CINAHL, and the Cochrane Systematic Review Database were searched from September 18 to November 23, 2023, for all adult clinical studies published in English on HBOT and PTSD. Randomized trials and studies with symptomatic outcomes were selected for final analysis and analyzed according to the dose of oxygen and barometric pressure on symptom outcomes. Outcome assessment was for statistically significant change and Reliable Change or Clinically Significant Change according to the National Center for PTSD Guidelines. Methodologic quality and bias were determined with the PEDro Scale. Results: Eight studies were included, all with < 75 subjects/study, total 393 subjects: seven randomized trials and one imaging case-controlled study. Six studies were on military subjects, one on civilian and military subjects, and one on civilians. Subjects were 3-450 months post trauma. Statistically significant symptomatic improvements, as well as Reliable Change or Clinically Significant changes, were achieved for patients treated with 40-60 HBOTS over a wide range of pressures from 1.3 to 2.0 ATA. There was a linear doseresponse relationship for increased symptomatic improvement with increasing cumulative oxygen dose from 1002 to 11,400 atmosphere-minutes of oxygen. The greater symptomatic response was accompanied by a greater and severe reversible exacerbation of emotional symptoms at the highest oxygen doses in 30-39% of subjects. Other side effects were transient and minor. In three studies the symptomatic improvements were associated with functional and anatomic brain imaging changes. All 7 randomized trials were found to be of good-highest quality by PEDro scale scoring. Discussion: In multiple randomized and randomized controlled clinical trials HBOT demonstrated statistically significant symptomatic improvements, Reliable Changes, or Clinically Significant Changes in patients with PTSD symptoms or PTSD over a wide range of pressure and oxygen doses. The highest doses were associated with a severe reversible exacerbation of emotional symptoms in 30- 39% of subjects. Symptomatic improvements were supported by correlative functional and microstructural imaging changes in PTSD-affected brain regions. The imaging findings and hyperbaric oxygen therapy effects indicate that PTSD can no longer be considered strictly a psychiatric disease [ABSTRACT FROM AUTHOR]

Background: Previous retrospective studies have shown a correlation between depression and increased risk of infections, including a moderate rise in sepsis likelihood associated with severe depression and anxiety. To investigate the potential causal links between depression, sepsis, and mortality risks, while considering confounding factors, we employed a Mendelian randomization (MR) approach. Methods: In this two-sample Mendelian randomization study, we analyzed data from a large-scale genome-wide association study on depression, involving 807,553 European individuals (246,363 cases, 561,190 controls). We extracted SNP associations with sepsis and 28-day mortality from UK Biobank GWAS outcomes. The correlation analysis primarily employed the inverse-variance weighted method, supplemented by sensitivity analyses for heterogeneity and pleiotropy assessment. Results: Our analysis revealed a potential causal link between depression and an increased risk of sepsis (OR = 1.246, 95% CI: 1.076–1.442, P = 0.003), but no causal association was found with sepsis-induced mortality risk (OR = 1.274, 95% CI: 0.891–1.823, P = 0.184). Sensitivity analyses confirmed the robustness of these findings. Conclusions: We identified a potential causal association between depression and heightened sepsis risk, while no link was found with sepsis-induced mortality. These findings suggest that effective management of depression could be important in preventing sepsis. [ABSTRACT FROM AUTHOR]

Maintaining diversity in drug development in research into Alzheimer's disease (AD) is necessary to avoid over-reliance on targeting AD neuropathology. Treatments that reduce or prevent the generation of oxidative stress, frequently cited for its causal role in the aging process and AD, could be useful in at-risk populations or diagnosed AD patients. However, in this review, it is argued that clinical research into antioxidants in AD could provide more useful feedback as to the therapeutic value of the oxidative stress theory of AD. Improving comparability between randomized controlled trials (RCTs) is vital from a waste-reduction and priority-setting point of view for AD clinical research. For as well as attempting to improve meaningful outcomes for patients, RCTs of antioxidants in AD should strive to maximize the extraction of clinically useful information and actionable feedback from trial outcomes. Solutions to maximize information flow from RCTs of antioxidants in AD are offered here in the form of checklist questions to improve ongoing and future trials centered around the following dimensions: adhesion to reporting guidelines like CONSORT, biomarker enrichment, simple tests of treatment, and innovative trial design. [ABSTRACT FROM AUTHOR]

Background: The key to the prevention and treatment of Alzheimer's disease (AD) is to be able to predict and diagnose AD at the preclinical or early stage, but the lack of a preclinical model of AD is the critical factor that causes this problem to remain unresolved. Methods: We assessed 18 monkeys in vivo evaluation of pro-inflammatory cytokines and AD pathological biomarkers (n = 9 / type 2 diabetic mellitus (T2DM) group, age 20, fasting plasma glucose (FPG) ≥ 100 mg/dL, and n = 9 / negative control (NC) group, age 17, FPG < 100 mg/dL). Levels of pro-inflammatory cytokines and AD pathological biomarkers was measured by ELISA and Simoa Technology, respectively. 9 monkeys evaluated ex vivo for AD-like pathology (n = 6 / T2DM group, age 22.17, FPG ≥ 126 mg/dL, and n = 3 / NC group, age 14.67, FPG < 100 mg/dL). To evaluate the pathological features of AD in the brains of T2DM monkeys, we assessed the levels of Aβ, phospho-tau, and neuroinflammation using immunohistochemistry, which further confirmed the deposition of Aβ plaques by Bielschowsky's silver, Congo red, and Thioflavin S staining. Synaptic damage and neurodegeneration were assessed by immunofluorescence. Results: We found not only increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) in peripheral blood (PB) and brain of T2DM monkeys but also changes in PB of AD pathological biomarkers such as decreased β-amyloid (Aβ) 42 and Aβ40 levels. Most notably, we observed AD-like pathological features in the brain of T2DM monkeys, including Aβ plaque deposition, p-tau from neuropil thread to pre-neurofibrillary tangles (NFTs), and even the appearance of extracellular NFT. Microglia were activated from a resting state to an amoeboid. Astrocytes showed marked hypertrophy and an increased number of cell bodies and protrusions. Finally, we observed impairment of the postsynaptic membrane but no neurodegeneration or neuronal death. Conclusions: Overall, T2DM monkeys showed elevated levels of peripheral and intracerebral inflammation, positive AD biomarkers in body fluids, and developing AD-like pathology in the brain, including Aβ and tau pathology, glial cell activation, and partial synaptic damage, but no neuronal degeneration or death as compared to the healthy normal group. Hereby, we consider the T2DM monkeys with elevation of the peripheral pro-inflammatory factors and positive AD biomarkers can be potentially regarded as a preclinical AD model. [ABSTRACT FROM AUTHOR]

Schizophrenia (SZ) is a severe progressive neurodegenerative as well as disruptive behavior disorder affecting innumerable people throughout the world. The discovery of potential biomarkers in the clinical scenario would lead to the development of effective methods of diagnosis and would provide an understanding of the prognosis of the disease. Moreover, breakthrough inventions for the treatment and prevention of this mysterious disease could evolve as a result of a thorough understanding of the clinical biomarkers. In this review, we have discussed about specific biomarkers of SZ an emphasis has been laid to delineate (1) diagnostic biomarkers like neuroimmune biomarkers, metabolic biomarkers, oligodendrocyte biomarkers and biomarkers of negative and cognitive symptoms, (2) therapeutic biomarkers like various neurotransmitter systems and (3) prognostic biomarkers. All the biomarkers were evaluated in drug-naïve (at least for 4 weeks) patients in order to achieve a clear comparison between schizophrenic patients and healthy controls. Also, an attempt has been made to elucidate the potential genes which serve as predictors and tools for the determination of biomarkers and would ultimately help in the prevention and treatment of this deadly illness., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Given the unclear etiology and treatment mechanisms of depression, we aim to explore the metabolic differences between patients with major depressive disorder (MDD) and the healthy population, as well as before and after treatment with escitalopram (ESC)., Methods: Recruit first-episode drug-naïve MDD (DN-MDD) patients and healthy controls (HCs). Clinical data and serum samples from all subjects were collected at baseline and patients' samples were collected again after ESC monotherapy for four weeks. Perform non-targeted metabolomic analysis and apply MetaboAnalyst 5.0 to identify differential metabolites and execute KEGG pathway enrichment., Results: Through metabolomic analysis of serum samples, 904 differential metabolites were identified in the DN-MDD group compared to the HCs, and 455 metabolites in treated patients compared to DN-MDD patients. In the pathway analysis, DN-MDD state regulated functions of histidine, beta-alanine, aspartate, and tryptophan metabolism, while ESC treatment produced an influence on the biological process of aspartate and sphingolipid., Conclusion: We respectively depicted metabolism-related biomolecular changes in the serum of patients suffering from MDD and undergoing ESC treatment. Multiple amino acid metabolism pathways were adjusted in MDD patients, and levels of aspartate, arginine and sphingolipids were regulated after ESC monotherapy. These biomolecular changes may bring new insights into the biology and treatment of MDD from the perspective of the serum metabolites., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Internet addiction disorder (IAD) has grown into public health concern of global proportions. Previous studies have indicated that individuals with IAD may exhibit altered levels of serotonin and dopamine, which are known to play crucial roles in depression, anxiety, impulsivity, and addiction. Therefore, polymorphisms in the receptors that mediate the effects of serotonin and dopamine and affect their functional states as well as their activities are suspect. In this study, we aimed to investigate the association between IAD and rs6313 (T102C) polymorphism in the serotonin 2A receptor (5-HT2A) gene, (HTR2A). Methods: Twenty patients with IAD and twenty healthy controls (HCs) were included in this study. Young's Internet Addiction Test (IAT), Self-Rating Anxiety Scale, Self-Rating Depression Scale, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Barratt Impulse Scale, Pittsburgh Sleep Quality Index (PSQI), and Social Support Rating Scale (SSRS) were used to assess the severity of internet addiction, mental status, impulsive traits, sleep quality, and social support. Genotyping was performed to identify rs6313 polymorphisms in the HTR2A gene of all participants. Results: The frequencies of the C and T alleles of HTR2A T102C were 28% and 72% in the IAD group and 53% and 47% in the HCs group, respectively, indicating that the differences between these two groups were significant. No significant difference was observed in the distribution of the CC, CT, and TT genotypes of HTR2A gene T102C between the IAD and the HCs groups. Additionally, there was no difference in the distribution of the frequencies of the HTR2A gene T102C CC and CT+TT genotypes between the two groups. However, the distribution between the TT and CC+CT genotypes showed an apparent statistical difference in the HTR2A gene T102C between the two groups. Correlation analysis indicated that the IAT score was positively correlated with the Y-BOCS and BIS scores for the CC+CT genotype in patients with IAD. Moreover, the IAT score was positively correlated with the PSQI score in patients with IAD carrying the TT genotype. Conclusion: The present study demonstrates that rs6313 in HTR2A is associated with IAD, and that the T allele of rs6313 in HTR2A may be a risk factor for IAD. [ABSTRACT FROM AUTHOR]

Background: Among its functions, brain-derived neurotrophic factor (BDNF) regulates endothelial and macrophage activation, possibly playing a role in atherosclerotic plaque pathophysiology. Given contradicting reports, this study sought to investigate whether blood levels of BDNF differed between patients with coronary heart disease (CHD) and controls. Methods: We explored PubMed, Embase, Web of Science, and Cochrane Library for studies comparing BDNF blood levels in patients with CHD and controls. Random-effect meta-analysis was conducted to calculate the standardized mean differences (SMD) and 95% confidence intervals (CI). The Newcastle-Ottawa scale was used to evaluate the quality of included articles, and statistical analyses were conducted using R version 4.0.4. Results: The final analysis comprised 12 investigations covering 1422 CHD cases and 929 controls with mean ages of 59.66±13.56 and 53.78±13.61 years, respectively. The initial analyses revealed a tendency toward low levels of BDNF in the CHD group compared with the control group (SMD= -0.41; 95% CI, -1.12 to 0.30; P=0.26). After the removal of outliers, the difference achieved statistical difference (SMD= -0.56; 95% CI, -0.93 to -0.19; P<0.01). Subgroup analysis demonstrated no significant difference between serum and plasma BDNF levels (P=0.54); however, subgroup analyses of studies investigating plasma BDNF showed that patients with CHD had significantly lower BDNF levels. Conclusion: Serum and plasma BDNF concentrations were considerably lower in patients with CHD than in healthy controls. Further studies of higher quality are required on the potential role of BDNF as a biomarker of CHD pathophysiology and severity. [ABSTRACT FROM AUTHOR]

The word mad has historically been associated with the psyche, emotions, and abnormal behavior. Dementia is a common symptom among psychiatric disorders or mad (schizophrenia, depression, bipolar disorder) patients. Autophagy/mitophagy is a protective mechanism used by cells to get rid of dysfunctional cellular organelles or mitochondria. Autophagosome/mitophagosome abundance in autophagy depends on microtubule-associated protein light chain 3B (LC3B-II) and autophagy-triggering gene (ATG) which functions as an autophagic biomarker for phagophore production and quick mRNA disintegration. Defects in either LC3B-II or the ATG lead to dysregulated mitophagy-and-autophagy–linked dementia (MAD). The impaired MAD is closely associated with schizophrenia, depression, and bipolar disorder. The pathomechanism of psychosis is not entirely known, which is the severe limitation of today's antipsychotic drugs. However, the reviewed circuit identifies new insights that may be especially helpful in targeting biomarkers of dementia. Neuro-theranostics can also be achieved by manufacturing either bioengineered bacterial and mammalian cells or nanocarriers (liposomes, polymers, and nanogels) loaded with both imaging and therapeutic materials. The nanocarriers must cross the BBB and should release both diagnostic agents and therapeutic agents in a controlled manner to prove their effectiveness against psychiatric disorders. In this review, we highlighted the potential of microRNAs (miRs) as neuro-theranostics in the treatment of dementia by targeting autophagic biomarkers LC3B-II and ATG. Focus was also placed on the potential for neuro-theranostic nanocells/nanocarriers to traverse the BBB and induce action against psychiatric disorders. The neuro-theranostic approach can provide targeted treatment for mental disorders by creating theranostic nanocarriers. [ABSTRACT FROM AUTHOR]

Introduction: Clozapine-induced sialorrhea (CIS) is one of the most common side effects of clozapine use, while the mechanism remains unclear. Methods: A total of 51 schizophrenia patients taking clozapine were selected. Among them, 32 had sialorrhea, and 19 had no sialorrhea. Saliva metabolites were identified using ultra-high-performance liquid chromatography-MS/MS (UHPLC-MS/MS), and the differences in saliva metabolites in each group were analyzed through qualitatively searching HMDB, KEGG, and self-built databases, combined with multivariate statistics. After further evaluation by receiver-operating characteristic curve (ROC) analysis, the screened differential metabolites were enriched and topologically analyzed. Results: The biomarkers potentially related to CIS included 37 differential metabolites involving 17 metabolic pathways, mainly histidine metabolism (p < 0.05, impact = 0.50), pyrimidine metabolism (p < 0.05, impact = 0.08), and β-alanine metabolism (p < 0.05, impact = 0.06). Conclusion: Our study indicates that histidine metabolic pathway may contribute to the mechanism of CIS. [ABSTRACT FROM AUTHOR]

Postoperative delirium (POD) is a common neuropsychiatric complication in geriatric inpatients after hip fracture surgery and its occurrence is associated with poor outcomes. The purpose of this study was to investigate the relationship between preoperative biomarkers in serum and cerebrospinal fluid (CSF) and the development of POD in older hip fracture patients, exploring the possibility of integrating objective methods into future predictive models of delirium. Sixty hip fracture patients were recruited. Blood and CSF samples were collected at the time of spinal anesthesia when none of the subjects had delirium. Patients were assessed daily using the 4AT scale, and based on these results, they were divided into POD and non-POD groups. The Olink® platform was used to analyze 45 cytokines. Twenty-one patients (35%) developed POD. In the subsample of 30 patients on whom proteomic analyses were performed, a proteomic profile was associated with the incidence of POD. Chemokine (C-X-C motif) ligand 9 (CXCL9) had the strongest correlation between serum and CSF samples in patients with POD (rho = 0.663; p < 0.05). Although several cytokines in serum and CSF were associated with POD after hip fracture surgery in older adults, there was a significant association with lower preoperative levels of CXCL9 in CSF and serum. Despite the small sample size, this study provides preliminary evidence of the potential role of molecular biomarkers in POD, which may provide a basis for the development of new delirium predictive models., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

The serotonin receptor subtype 5-HTR1B is widely distributed in the brain with an important role in various behavioral implications including neurological conditions and psychiatric disorders. The neuromodulatory action of 5-HTR1B largely depends upon its arrestin mediated signaling pathway. In this study, we tried to investigate the role of unusually long intracellular loop 3 (ICL3) region of the serotonin receptor 5-HTR1B in interaction with β-arrestin1 (Arr2) to compensate for the absence of the long cytoplasmic tail. Molecular modeling and docking tools were employed to obtain a suitable molecular conformation of the ICL3 region in complex with Arr2 which dictates the specific complex formation of 5-HTR1B with Arr2. This reveals the novel molecular mechanism of phosphorylated ICL3 mediated GPCR-arrestin interaction in the absence of the long cytoplasmic tail. The in-cell disulfide cross-linking experiments and molecular dynamics simulations of the complex further validate the model of 5-HTR1B-ICL3-Arr2 complex. Two serine residues (Ser281 and Ser295) within the 5-HTR1B-ICL3 region were found to be occupying the electropositive pocket of Arr2 in our model and might be crucial for phosphorylation and specific Arr2 binding. The alignment studies of these residues showed them to be conserved only across 5-HTR1B mammalian species. Thus, our studies were able to predict a molecular conformation of 5-HTR1B-Arr2 and identify the role of long ICL3 in the signaling process which might be crucial in designing targeted drugs (biased agonists) that promote GPCR-Arr2 signaling to deter the effects of stress and anxiety-like disorders. [ABSTRACT FROM AUTHOR]

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Introduction: Brain-derived neurotrophic factor (BDNF) and BDNF Val66Met polymorphism have been associated with cardiovascular diseases such as atherosclerosis, congestive heart failure (CHF), hypertension and ischaemic heart disease (IHD). To the authors’ knowledge, such connections have not been described in peripheral artery disease (PAD) yet. Material and methods: 159 PAD subjects and 57 controls were included. All enrolled subjects underwent evaluation of clinical status. Information on comorbidities such as diabetes type 2, hypertension, IHD and CHF, was gathered. Serum concentrations of BDNF were measured by ELISA. Genotypes of the BDNF-AS SNP rs6265 were determined using TaqMan SNP Genotyping Assay. Results: PAD patients had significantly lower BDNF serum concentrations compared to controls (median values of 7.2 vs. 35.1 ng/mL, P < 0.001). Concentrations were significantly lower in patients with concomitant CHF (P < 0.05). The CHF subgroup was characterised by a greater prevalence of diabetes and ischaemic heart disease (P < 0.01). There was no significant difference between BDNF serum concentrations and other comorbidities, ABI, and medical history including disease duration and past interventions. No important correlations were found for BDNF Val66Met polymorphism. Conclusions: The present study adds to the body of evidence associating BDNF and atherosclerosis. The serum BDNF concentrations were lower in PAD, especially in a subgroup with comorbid CHF. These results suggest that a larger cardiovascular burden is connected with decreased BDNF serum concentrations. No evidence was found to support the hypothesis that BDNF gene polymorphism may be a contributing factor in the pathogenesis of cardiovascular diseases such as PAD. [ABSTRACT FROM AUTHOR]

Context: Glucocorticoids have potent effects on the central nervous system. However, while patients with Cushing syndrome frequently report impairments in cognitive function, studies investigating cognitive function in patients with autonomous cortisol secretion (ACS) in adrenal incidentalomas (AIs) are scarce. Objective: The aim of the present study was to evaluate neurocognitive function in patients with ACS. Methods: We prospectively recruited 63 patients with AI, 36 patients with nonfunctional adrenal adenoma (NFA) (46.5 ±10.5 years), and 27 patients with ACS (48.6± 9.1 years); these patients underwent a battery of validated neuropsychological tests. ACS was diagnosed when serum cortisol levels after a 1-mg dexamethasone suppression test (cortisol1 mg DST)=50 nmol/L. Results: Patients with ACS had higher frequency of subjective memory complaints (40.7% vs 13.9%, P<0.05) and higher proportion of mild cognitive impairment (22.2% vs 2.8%, P<0.05) than patients with NFA. Furthermore, patients with ACS had worse performance on working memory and the visuospatial/constructional domain than patients with NFA (all P<0.05). Serum cortisol1 mg DST was negatively correlated with working memory and visuospatial/constructional domains (r= -0.307 and -0.306, respectively, all P<0.05). Performance on working memory and visuospatial/constructional domains gradually deteriorated with increases in serum cortisol1 mg DST (all P values for trend< 0.05). Multivariate linear regression analysis showed that serum cortisol1 mg DST was a significant risk factor for impairment of working memory and visuospatial/constructional domains (B=-0.006 and -0.043, respectively, all P<0.05). Conclusion: This study is the first to report that ACS is accompanied by impaired cognitive function. Consequently, cognitive function assessment should be incorporated into the clinical evaluation of patients with ACS. [ABSTRACT FROM AUTHOR]

Introduction: Neuropsychiatric symptoms are important treatment targets in the management of dementia and can be present at very early clinical stages of neurodegenerative diseases. Increased cortisol has been reported in Alzheimer's disease (AD) and has been associated with faster cognitive decline. Elevated cortisol output has been observed in relation to perceived stress, depression, and anxiety. Dehydroepiandrosterone sulfate (DHEAS) has known anti-glucocorticoid effects and may counter the effects of cortisol. Objectives: We aimed to examine whether CSF cortisol and DHEAS levels were associated with (1) neuropsychiatric symptoms at baseline, (2) changes in neuropsychiatric symptoms over 3 years, and (3) whether these associations were related to or independent of AD pathology. Methods: One hundred and eighteen participants on a prospective study in a memory clinic setting, including patients with cognitive impairment (n = 78), i.e., mild cognitive impairment or mild dementia, and volunteers with normal cognition (n = 40), were included. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). CSF cortisol and DHEAS, as well as CSF AD biomarkers, were obtained at baseline. Neuropsychiatric symptoms were re-assessed at follow-up visits 18 and 36 months from baseline. We constructed linear regression models to examine the links between baseline neuropsychiatric symptoms, the presence of AD pathology as indicated by CSF biomarkers, and CSF cortisol and DHEAS. We used repeated-measures mixed ANCOVA models to examine the associations between the neuropsychiatric symptoms' changes over time, baseline CSF cortisol and DHEAS, and AD pathology. Results: Higher CSF cortisol was associated with higher NPI-Q severity scores at baseline after controlling for covariates including AD pathology status (B = 0.085 [0.027; 0.144], p = 0.027; r = 0.277). In particular, higher CSF cortisol was associated with higher baseline scores of depression/dysphoria, anxiety, and apathy/indifference. Elevated CSF cortisol was also associated with more marked increase in NPI-Q scores over time regardless of AD status (p = 0.036, η2 = 0.207), but this association was no longer significant after controlling for BMI and the use of psychotropic medications. CSF DHEAS was associated neither with NPI-Q scores at baseline nor with their change over time. Cortisol did not mediate the association between baseline NPI-Q and changes in clinical dementia rating sum of boxes over 36 months. Conclusion: Higher CSF cortisol may reflect or contribute to more severe neuropsychiatric symptoms at baseline, as well as more pronounced worsening over 3 years, independently of the presence of AD pathology. Our findings also suggest that interventions targeting the HPA axis may be helpful to treat neuropsychiatric symptoms in patients with dementia. [ABSTRACT FROM AUTHOR]

The study aimed to assess the effect of Electroconvulsive Therapy (ECT) on plasma BDNF levels in patients with resistant schizophrenia. It was a cohort study that included 60 patients with resistant schizophrenia fulfilling the DSM-5 criteria of schizophrenia and APA criteria of resistant schizophrenia. They were divided into two groups, followed over 4 weeks, and compared to their baseline assessment. Group (A) included 45 patients who received 4–10 sessions of ECT while Group (B) included 15 patients who received the usual treatment with antipsychotics without ECT. The assessment included the severity of psychotic symptoms assessed by the Positive and Negative Symptom Scale (PANSS) in addition to plasma BDNF level. Patients in Group (A) had an increased level of BDNF after treatment with a statistically significant difference in comparison to their baseline BDNF level (P = 0.027). Meanwhile, patients in group (B) showed a non-significant increase in BDNF. Patients in both groups improved significantly in all PANSS subscales after treatment. It was concluded that plasma BDNF levels in patients with resistant schizophrenia increase after electroconvulsive therapy in association with clinical improvement. BDNF increases after ECT treatment of resistant schizophrenia. BDNF is not correlated with the severity of psychotic symptoms Patients treated with ECT showed a better response. [ABSTRACT FROM AUTHOR]

Background: Catechol-O-methyltransferase (COMT) has been shown to influence clinical pain, descending modulation, and exercise-induced symptom worsening. COMT regulates nociceptive processing and inflammation, key pathophysiological features of Chronic Fatigue Syndrome and Fibromyalgia (CFS/FM). We aimed to determine the interactions between genetic and epigenetic mechanisms regulating COMT and its influence on inflammatory markers and symptoms in patients with CFS/FM.Methods: A case-control study with repeated-measures design was used to reduce the chance of false positive and increase the power of our findings. Fifty-four participants (28 patients with CFS/FM and 26 controls) were assessed twice within 4 days. The assessment included clinical questionnaires, neurophysiological assessment (pain thresholds, temporal summation, and conditioned pain modulation), and blood withdrawal in order to assess rs4818, rs4633, and rs4680 COMT polymorphisms and perform haplotype estimation, DNA methylation in the COMT gene (both MB-COMT and S-COMT promoters), and cytokine expression (TNF-α, IFN-γ, IL-6, and TGF-β).Results: COMT haplotypes were associated with DNA methylation in the S-COMT promoter, TGF-β expression, and symptoms. However, this was not specific for one condition. Significant between-group differences were found for increased DNA methylation in the MB-COMT promoter and decreased IFN-γ expression in patients.Discussion: Our results are consistent with basic and clinical research, providing interesting insights into genetic-epigenetic regulatory mechanisms. MB-COMT DNA methylation might be an independent factor contributing to the pathophysiology of CFS/FM. Further research on DNA methylation in complex conditions such as CFS/FM is warranted. We recommend future research to employ a repeated-measure design to control for biomarkers variability and within-subject changes. [ABSTRACT FROM AUTHOR]

We aimed to examine the association of CSF tumor necrosis factor-alpha (TNFα) with conversion from mild cognitive impairment (MCI) to dementia. At baseline, there were a total of 129 participants with MCI in this study. The association of CSF TNFα levels with the incidence of dementia were evaluated using Cox proportional hazards regression analysis adjusted for potential confounders. Individuals were categorized into groups based on the CSF TNFα tertiles. Compared to the low group (the reference group), the intermediate group progressed more rapidly to dementia [HR (95% CI) = 2.2 (1.15–4.1); p = 0.016] after adjusting for other covariates. However, the high group did not progress faster than the low group [HR (95% CI) = 1.5 (0.79–2.8); p = 0.214]. Our study suggested a potential non-relationship between CSF TNFα levels and the risk of development of dementia among MCI older people. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a devastating psychiatric disorder afflictingmillions of people around the world. Characterized by severe anxiety, intrusive thoughts, pervasive nightmares, an assortment of somatic symptoms, associations with severe long-term health problems, and an elevated risk of suicide, as much as 40-70% of patients suffer from refractory disease. 3,4-Methylenedioxy-methamphetamine (MDMA), like classic psychedelics such as psilocybin, have been used to enhance the efficacy of psychotherapy almost since their discovery, but due to their perceived potential for abuse and inclusion on USFDA (United States Food and Drug Administration) schedule 1, research into the mechanism by which they produce improvements in PTSD symptomology has been limited. Nevertheless, several compelling rationales have been explored, with the pro-social effects of MDMA thought to enhance therapeutic alliance and thus facilitate therapist-assisted trauma processing. This may be insufficient to fully explain the efficacy of MDMA in the treatment of psychiatric illness. Molecular mechanisms such as the MDMA mediated increase of brain-derived neurotrophic factor (BDNF) availability in the fear memory learning pathways combined with MDMA's pro-social effects may provide a more nuanced explanation for the therapeutic actions of MDMA. [ABSTRACT FROM AUTHOR]

Depression and coronary heart diseases are the common comorbid disorder affecting humans globally. The present study evaluated the effectiveness of rosmarinic acid (RA) against myocardial infarction (MI) in comorbid depression induced by maternal separation in rats. Maternal stress is one of the childhood crises that may be a potential risk factor for coronary heart disease in later part of life. As per protocol, 70–80% of pups were separated daily for 3 h between postnatal day 1 (PND1) and postnatal day 21 (PND21). Forced-swim test, sucrose preference test, and electrocardiography were performed during the experiment. Body weight was measured on PND0, PND35, and PND55. Orally rosmarinic acid (25 mg/kg and 50 mg/kg) and fluoxetine (10 mg/kg) was done from PND35 to PND55. On PND53 and PND54, isoproterenol (100 mg/kg, subcutaneously) was administered to induce myocardial infarction. On PND55, blood was collected and animals sacrificed, and plasma corticosterone, brain-derived neurotrophic factor, cardiac biomarkers, interleukine-10, and anti-oxidant parameters were measured. Rosmarinic acid and fluoxetine ameliorated the maternal separation–induced increase in immobility period, anhedonia, body weight, ST elevation, corticosterone, creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH). At the same time, both drugs elevated the tissue levels of BDNF, IL-10, glutathione, and superoxide dismutase activity. This study provides the first experimental evidence that maternal stress is an independent risk factor of cardiac abnormalities in rats. Moreover, maternal stress synergistically increases the severity of cardiac abnormalities induced by isoproterenol. Interestingly, fluoxetine and rosmarinic acid effectively ameliorated behavioral anomalies and myocardial infarction in maternally separated rats. Schematic representation of possible molecular mechanism of action of rosmarinic acid against MS-induced myocardial infarction. RA, rosmarinic acid; MS, maternal separation; PND, postnatal days; ISO, isoproterenol; BDNF, brain-derived neurotrophic factor; GSH, glutathione; SOD, superoxide dismutase; IL-10, interleukin-10; MI, myocardial infarction [ABSTRACT FROM AUTHOR]

Advanced parental age at delivery and neurological soft signs (NSS) constitute risk factors for schizophrenia. The aim of the current study was to develop a neurobiological diagnostic index by combining them, and without the contribution of clinical symptomatology. The study sample included 133 patients suffering from schizophrenia according to DSM-IV-TR (77 males and 56 females; aged 33.55 ± 11.22 years old) and 122 normal controls (66 males and 56 females; aged 32.89 ± 9.91 years old). The assessment included the Neurological Evaluation Scale (NES), and a number of scales assessing the clinical symptoms and adverse effects. The statistical analysis included exploratory t-test, Pearson Correlation coefficient (R) and Discriminant Function Analysis (DFA). Exploratory t-tests and Pearson's R suggested that sex, parental age and NSS constitute independent components. On the basis of DFA results, the Psychotic Neurological Index was developed. At the cut-off PNI score of 8.5, sensitivity was equal to 94.74 and specificity to 93.44. The current is probably the first study to report on an easily obtainable diagnostic neurobiological marker with identifiable properties which is absolutely independent from the clinical manifestations and could serve in distinguishing between patients with schizophrenia and healthy controls with high efficacy. [ABSTRACT FROM AUTHOR]

11-beta-hydroxysteroid dehydrogenases (11β-HSDs) catalyse the conversion of active 11-hydroxy glucocorticoids (cortisol, corticosterone) and their inert 11-keto forms (cortisone, 11-dehydrocorticosterone). They were first reported in the body and brain 70 years ago, but only recently have they become of interest. 11β-HSD2 is a dehydrogenase, potently inactivating glucocorticoids. In the kidney, 11β-HSD2 generates the aldosterone-specificity of intrinsically non-selective mineralocorticoid receptors. 11β-HSD2 also protects the developing foetal brain and body from premature glucocorticoid exposure, which otherwise engenders the programming of neuropsychiatric and cardio-metabolic disease risks. In the adult CNS, 11β-HSD2 is confined to a part of the brain stem where it generates aldosterone-specific central control of salt appetite and perhaps blood pressure. 11β-HSD1 is a reductase, amplifying active glucocorticoid levels within brain cells, notably in the cortex, hippocampus and amygdala, paralleling its metabolic functions in peripheral tissues. 11β-HSD1 is elevated in the ageing rodent and, less certainly, human forebrain. Transgenic models show this rise contributes to age-related cognitive decline, at least in mice. 11β-HSD1 inhibition robustly improves memory in healthy and pathological ageing rodent models and is showing initial promising results in phase II studies of healthy elderly people. Larger trials are needed to confirm and clarify the magnitude of effect and define target populations. The next decade will be crucial in determining how this tale ends - in new treatments or disappointment., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Recent genome-wide association studies have reported multiple schizophrenia risk loci, yet the functional variants and their roles in schizophrenia remain to be characterized. Here we identify a functional single nucleotide polymorphism (rs2270363: G>A) at the schizophrenia risk locus 16p13.3. rs2270363 lies in the E-box element of the promoter of NMRAL1 and disrupts binding of the basic helix-loop-helix leucine zipper family proteins, including USF1, MAX and MXI1. We validated the regulatory effects of rs2270363 using reporter gene assays and electrophoretic mobility shift assay. Besides, expression quantitative trait loci analysis showed that the risk allele (A) of rs2270363 was significantly associated with elevated NMRAL1 expression in the human brain. Transcription factors knockdown and CRISPR-Cas9-mediated editing further confirmed the regulatory effects of the genomic region containing rs2270363 on NMRAL1. Intriguingly, NMRAL1 was significantly downregulated in the brain of schizophrenia patients compared with healthy subjects, and knockdown of Nmral1 expression affected proliferation and differentiation of mouse neural stem cells, as well as genes and pathways associated with brain development and synaptic transmission. Of note, Nmral1 knockdown resulted in significant decrease of dendritic spine density, revealing the potential pathophysiological mechanisms of NMRAL1 in schizophrenia. Finally, we independently confirmed the association between rs2270363 and schizophrenia in the Chinese population and found that the risk allele of rs2270363 was the same in European and Chinese populations. These lines of evidence suggest that rs2270363 may confer schizophrenia risk by regulating NMRAL1, a gene whose expression dysregulation might be involved in the pathogenesis of schizophrenia by affecting neurodevelopment and synaptic plasticity. [ABSTRACT FROM AUTHOR]

Previous studies have revealed that brain-derived neurotrophic factor (BDNF) levels are inversely associated with the severity of depressive symptoms. In addition, serum BDNF levels tend to increase with improvement in depressive symptoms. There is also evidence that BDNF has a possible role in the pathophysiology of schizophrenia. Therefore, the purpose of this study was to determine whether BDNF levels correlated with depressive symptoms in patients with first-episode and drug-naïve (FEDN) schizophrenia. In this study, 90 patients with FEDN schizophrenia and 60 healthy controls were recruited. The Positive and Negative Syndrome Scale (PANSS) and the 17-item Hamilton Depression Scale (HAMD-17) were used to gage psychopathological and depressive symptoms, respectively. All participants had their BDNF levels measured using a sandwich enzyme-linked immunosorbent test. Serum BDNF levels were lower in patients with FEDN schizophrenia compared with healthy controls. Moreover, patients with depressive symptoms exhibited a higher PANSS total score and a higher general psychopathology score than those without depressive symptoms (p < 0.05). For patients with depressive symptoms, serum BDNF levels were higher than in those without depressive symptoms (p < 0.05). An association between BDNF levels and the positive subscore was also observed (p < 0.01). However, there was no significant association between BDNF levels and HAMD scores (p > 0.05). In conclusion, BDNF levels were shown to be higher in the serum of patients with FEDN schizophrenia with depressive symptoms than in those without. Additionally, low levels of serum BDNF may contribute to the positive symptoms of FEDN schizophrenia but not to depressive symptoms. [ABSTRACT FROM AUTHOR]

The article focuses on the diagnosis and early intervention for schizophrenia and its implications for clinicians and patients. It discusses the challenge in diagnosing the illness in youth and young adults who are in psychosis prodrome phase. It cites objective biomarkers needed for early identification and treatment of young people at risk. It offers information on the Accelerated Medicines Partnership program-Schizophrenia.

BDNF (brain-derived neurotrophic factor) is present in skeletal muscle, controlling muscular metabolism, strength and regeneration processes. However, there is no consensus on BDNF cellular source. Furthermore, while endothelial tissue expresses BDNF in large amount, whether endothelial cells inside muscle expressed BDNF has never been explored. The aim of the present study was to provide a comprehensive analysis of BDNF localization in rat skeletal muscle. Cellular localization of BDNF and activated Tropomyosin-related kinase B (TrkB) receptors was studied by immunohistochemical analysis on soleus (SOL) and gastrocnemius (GAS). BDNF and activated TrkB levels were also measured in muscle homogenates using Western blot analysis and/or Elisa tests. The results revealed BDNF immunostaining in all cell types examined with a prominent staining in endothelial cells and a stronger staining in type II than type I muscular fibers. Endothelial cells but not other cells displayed easily detectable activated TrkB receptor expression. Levels of BDNF and activated TrkB receptors were higher in SOL than GAS. In conclusion, endothelial cells are an important and still unexplored source of BDNF present in skeletal muscle. Endothelial BDNF expression likely explains why oxidative muscle exhibits higher BDNF levels than glycolytic muscle despite higher the BDNF expression by type II fibers. [ABSTRACT FROM AUTHOR]

The projection from dopaminergic neurons to gamma-aminobutyric acid (GABA) interneurons in the prefrontal cortex is involved in the etiology of schizophrenia. The impact of interacting effects between dopamine signals and the expression of GABA on the clinical phenotypes of schizophrenia has not been studied. Since these interactions could be closely involved in prefrontal cortex functions, patients with specific alleles of these relevant molecules (which lead to lower or vulnerable genetic functions) may develop treatment-refractory symptoms. We conducted a genetic association study focusing on COMT and GAD1 genes for a treatment-resistant schizophrenia (TRS) group (n=171), a non-TRS group (n=592), and healthy controls (HC: n=447), and we examined allelic combinations specific to TRS. The results revealed that the percentage of subjects with Met allele of rs4680 on the COMT gene and C/C homozygote of rs3470934 on the GAD1 gene was significantly higher in the TRS group than the other two groups. There was no significant difference between the non-TRS group and HC groups. Considering the direction of functions of these single-nucleotide polymorphisms revealed by previous studies, we speculate that subjects with the Met/CC allelic combination could have a higher dopamine level and a lower expression of GABA in the prefrontal cortex. Our results suggest that an interaction between the dopaminergic signal and GABA signal intensities could differ between TRS patients and patients with other types of schizophrenia and healthy subjects. [ABSTRACT FROM AUTHOR]

Pro/antioxidant imbalance has been reported in schizophrenia (SZ). However, the results of studies are inconsistent and usually do not include other factors that are highly affected by oxidative stress (OS).This cross-sectional study aimed to determine the serum levels of OS markers and their potential connection with schizophrenia. The total sample comprised 147: 98 individuals with SZ −47 first-episode (FS) and 49 chronic patients (CS)—and 49 healthy individuals (HC) as a control group. The examination included clinical variables and serum levels of antioxidants and oxidative damage products. The significant changes were observed in concentrations of all examined markers, without any specific direction of the pro/antioxidant balance shift between SZ and HC. In the regression model adjusted for cofounders, catalase: OR = 0.81 (95%CI: 0.74–0.88); glutathione peroxidase: OR = 1.06 (95%CI: 1.02–1.10); total antioxidant capacity: OR = 0.85 (95%CI: 0.75–0.98); oxidative stress index: OR = 1.25 (95%CI: 1.03–1.52); ferric reducing ability of plasma: OR = 0.79 (95%CI: 0.69–0.89); advanced glycation end products: OR = 1.03 (95%CI: 1.01–1.04); and advanced oxidation protein products (AOPP): OR = 1.05 (95%CI: 1.03–1.07) turned out to be significant predictors of schizophrenia. In the multiple stepwise regression model, pro/antioxidant status and their interaction with the duration of illness-related factors affected schizophrenia symptoms: positive symptoms (FRAPxKYN), negative (DITYR, FRAP, CAT), general (KYN), and over-all psychopathology (KYNxNFK). The results confirm differences in serum levels of oxidative biomarkers between SZ patients and healthy individuals. The pro/antioxidant status could be considered a predictor of schizophrenia and the factor affects patients' symptom severity. [ABSTRACT FROM AUTHOR]

Objective Neurorehabilitation that involves learning new motor skills is one of the promising clinical methods for motor recovery in people with multiple sclerosis (PwMS); therefore, factors that influence the acquisition of motor skills in PwMS need to be investigated. Sleep disturbances are common in PwMS; however, no study has investigated the effect of sleep and sleep-related biomarkers on skill acquisition in PwMS. This study aimed to examine the effect of sleep and sleep-related biomarkers on motor acquisition in PwMS. Methods Forty participants with MS and 40 controls were recruited in this study. To assess motor acquisition, each participant was asked to perform a novel game through a virtual reality (VR) system 5 times (blocks). The main outcome measures for each block were the required time to complete the VR game and the recorded errors. The difference in scores between Block 5 and Block 1 for both outcomes were considered to represent motor skill acquisition. Sleep was assessed by self-report using the Pittsburgh Sleep Quality Index (PSQI) and objectively using sleep monitor technology. Serotonin level was assessed using means of enzyme-linked immunosorbent assay using plasma samples. Results There were significant positive correlations in both groups between motor skill acquisition and PSQI score. In PwMS, significant negative correlation between motor skill acquisition and sleep efficiency and significant positive correlation between motor skill acquisition and sleep latency were also observed. Interestingly, a significant negative correlation was observed between motor skill acquisition and the plasma serotonin level in both groups. Most of these correlations remained significant after controlling for disease severity, fatigue, baseline performance, and cognitive status. Conclusion Sleep quality may influence motor skill acquisition in PwMS. Circulatory serotonin level might explain this relationship. Impact Physical therapists are encouraged to be aware of sleep quality and sleep assessment. Sleep management strategies should be considered when treating PwMS. [ABSTRACT FROM AUTHOR]

The serotonin receptor subtype 5-HTR 1B is widely distributed in the brain with an important role in various behavioral implications including neurological conditions and psychiatric disorders. The neuromodulatory action of 5-HTR 1B largely depends upon its arrestin mediated signaling pathway. In this study, we tried to investigate the role of unusually long intracellular loop 3 (ICL3) region of the serotonin receptor 5-HTR 1B in interaction with β-arrestin1 (Arr2) to compensate for the absence of the long cytoplasmic tail. Molecular modeling and docking tools were employed to obtain a suitable molecular conformation of the ICL3 region in complex with Arr2 which dictates the specific complex formation of 5-HTR 1B with Arr2. This reveals the novel molecular mechanism of phosphorylated ICL3 mediated GPCR-arrestin interaction in the absence of the long cytoplasmic tail. The in-cell disulfide cross-linking experiments and molecular dynamics simulations of the complex further validate the model of 5-HTR 1B -ICL3-Arr2 complex. Two serine residues (Ser281 and Ser295) within the 5-HTR 1B -ICL3 region were found to be occupying the electropositive pocket of Arr2 in our model and might be crucial for phosphorylation and specific Arr2 binding. The alignment studies of these residues showed them to be conserved only across 5-HTR 1B mammalian species. Thus, our studies were able to predict a molecular conformation of 5-HTR 1B -Arr2 and identify the role of long ICL3 in the signaling process which might be crucial in designing targeted drugs (biased agonists) that promote GPCR-Arr2 signaling to deter the effects of stress and anxiety-like disorders., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The kynurenine (Kyn) pathway may play a role in the pathophysiology of schizophrenia. This pathway shows crosstalk with proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), and/or brain-derived neurotrophic factor (BDNF). Moreover, Kyn metabolites affect neurotransmission and cause neurotoxicity. To date, the influence of the Kyn pathway on proinflammatory cytokines and BDNF remains to be fully elucidated. The aim of this study was to investigate the relationships of the Kyn pathway with proinflammatory cytokines, BDNF, and psychiatric symptoms in patients with schizophrenia. Methods: Thirty patients with schizophrenia and ten healthy control participants were recruited for this study. All patients were diagnosed with schizophrenia using the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5). The healthy controls were those who did not fulfill any of the diagnostic criteria in the DSM-5. The serum levels of Kyn and its metabolites, proinflammatory cytokines, and BDNF were measured in patients with schizophrenia and healthy controls. Patients with schizophrenia were also assessed for psychiatric symptoms using the Positive and Negative Syndrome Scale (PANSS). Results: Patients with schizophrenia and healthy controls showed no significant differences in the levels of Kyn and its metabolites, proinflammatory cytokines, and BDNF. A significant positive correlation was found between the serum levels of TNF-α and Kyn (r = 0.53, p = 0.0026) and the Kyn/tryptophan (Trp) value (r = 0.67, p = 0.000046) in the schizophrenia group, but not in the healthy control group. Conclusion: TNF-α affects the Kyn pathway in patients with chronic schizophrenia, but not in the healthy individuals, although serum TNF-α levels showed no difference between the two groups. Associations between the Kyn pathway and the levels of proinflammatory cytokines and BDNF or psychotic symptoms might be complicated in hospitalized patients with chronic schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a severe mental disorder, which has a major impact on the quality of life and imposes a huge burden on the family. However, the pathogenesis of schizophrenia remains unclear and there are no specific biomarkers. Therefore, we intend to explore whether cf-DNA levels are related to the occurrence and development of schizophrenia. Methods: We analyzed and compared the concentration of cf-DNA in 174 SZ patients and 100 matched healthy controls by using quantitative real-time PCR by amplifying the Alu repeats. Results: We found that cf-DNA levels in peripheral blood reliably distinguished SZ patients from healthy controls (P < 0.05). The ROC analysis also supports the above conclusion. By tracking the absolute concentration of serum cf-DNA in primary cases, we found a distinct increase before treatment with antipsychotics, which decreased progressively after treatment. Conclusions: The present work indicates that cf-DNA may improve the efficiency of disease diagnosis, and the level of cf-DNA plays a predictive role in the development of schizophrenia. By evaluating the level of cf-DNA, we might play a certain role in a more reasonable and standardized clinical treatment of schizophrenia. [ABSTRACT FROM AUTHOR]