RESUMO
Reduced brain derived neurotrophic factor (BDNF) concentration is reported to be associated with a cognitive decline in schizophrenia, depending on the stage of the disease. Aim of the study was to examine the possible association between plasma BDNF and cognitive decline in chronic stable schizophrenia and mild cognitive impairment (MCI). The study included 123 inpatients of both sexes with schizophrenia, 123 patients with MCI and 208 healthy control subjects. Cognitive abilities were assessed using mini mental state examination (MMSE), Clock Drawing test (CDT) and cognitive subscale of the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF concentration was determined using ELISA. BDNF concentration was lower in patients with schizophrenia and MCI compared to age-matched healthy controls and was similar in carriers of different BDNF Val/66Met genotypes. The MMSE and CDT scores were lower in patients with schizophrenia compared to healthy controls and subjects with MCI. Reduced plasma BDNF was significantly associated with lower MMSE scores in all subjects. BDNF concentration in patients with schizophrenia was not affected by clinical and demographic factors. BDNF Val66Met polymorphism was not associated with the MMSE scores in all participants. Further studies should include longitudinal follow-up and other cognitive scales to confirm these results and offer cognition-improving strategies to prevent cognitive decline in chronic schizophrenia.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva , Esquizofrenia , Humanos , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/genética , Masculino , Feminino , Disfunção Cognitiva/sangue , Disfunção Cognitiva/genética , Disfunção Cognitiva/diagnóstico , Esquizofrenia/sangue , Esquizofrenia/genética , Pessoa de Meia-Idade , Adulto , Psicologia do Esquizofrênico , Doença Crônica , Testes de Estado Mental e Demência , Idoso , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Alzheimer's disease (AD) is often not recognized or is diagnosed very late, which significantly reduces the effectiveness of available pharmacological treatments. Metabolomic analyzes have great potential for improving existing knowledge about the pathogenesis and etiology of AD and represent a novel approach towards discovering biomarkers that could be used for diagnosis, prognosis, and therapy monitoring. In this study, we applied the untargeted metabolomic approach to investigate the changes in biochemical pathways related to AD pathology. We used gas chromatography and liquid chromatography coupled to mass spectrometry (GC-MS and LC-MS, respectively) to identify metabolites whose levels have changed in subjects with AD diagnosis (N = 40) compared to healthy controls (N = 40) and individuals with mild cognitive impairment (MCI, N = 40). The GC-MS identified significant differences between groups in levels of metabolites belonging to the classes of benzene and substituted derivatives, carboxylic acids and derivatives, fatty acyls, hydroxy acids and derivatives, keto acids and derivatives, and organooxygen compounds. Most of the compounds identified by the LC-MS were various fatty acyls, glycerolipids and glycerophospholipids. All of these compounds were decreased in AD patients and in subjects with MCI compared to healthy controls. The results of the study indicate disturbed metabolism of lipids and amino acids and an imbalance of metabolites involved in energy metabolism in individuals diagnosed with AD, compared to healthy controls and MCI subjects.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Metabolômica , Metaboloma , Espectrometria de Massas , BiomarcadoresRESUMO
Catechol-O-methyl transferase (COMT) gene variants are involved in different neuropsychiatric disorders and cognitive impairments, associated with altered dopamine function. This study investigated the genotypic and haplotypic association of COMT rs4680 and rs4618 polymorphisms with the severity of cognitive and other clinical symptoms in 544 male and 385 female subjects with schizophrenia. COMT rs4818 G carriers were more frequent in male patients with mild abstract thinking difficulties, compared to CC homozygotes or C allele carriers. Male carriers of COMT rs4680 A allele had worse abstract thinking (N5) scores than GG carriers, whereas AA homozygotes were more frequent in male subjects with lower scores on the intensity of the somatic concern (G1) item, compared to G carriers. Male carriers of COMT rs4818-rs4680 GA haplotype had the highest scores on the G1 item (somatic concern), whereas GG haplotype carriers had the lowest scores on G2 (anxiety) and G6 (depression) items. COMT GG haplotype was less frequent in female patients with severe disturbance of volition (G13 item) compared to the group with mild symptoms, while CG haplotype was more frequent in female patients with severe then mild symptoms. These findings suggest the sex-specific genotypic and haplotypic association of COMT variants with a severity of cognitive and other clinical symptoms of schizophrenia.
Assuntos
Catecol O-Metiltransferase , Esquizofrenia , Humanos , Masculino , Feminino , Haplótipos , Catecol O-Metiltransferase/genética , Esquizofrenia/genética , Polimorfismo de Nucleotídeo Único , GenótipoRESUMO
Posttraumatic stress disorder (PTSD) is a severe trauma and stress-related disorder associated with different somatic comorbidities, especially cardiovascular and metabolic disorders, and with chronic low-grade inflammation. Altered balance of the hypothalamic-pituitary-adrenal (HPA) axis, cytokines and chemokines, C-reactive protein, oxidative stress markers, kynurenine pathways, and gut microbiota might be involved in the alterations of certain brain regions regulating fear conditioning and memory processes, that are all altered in PTSD. In addition to the HPA axis, the gut microbiota maintains the balance and interaction of the immune, CNS, and endocrine pathways forming the gut-brain axis. Disbalance in the HPA axis, gut-brain axis, oxidative stress pathways and kynurenine pathways, altered immune signaling and disrupted homeostasis, as well as the association of the PTSD with the inflammation and disrupted cognition support the search for novel strategies for treatment of PTSD. Besides potential anti-inflammatory treatment, dietary interventions or the use of beneficial bacteria, such as probiotics, can potentially improve the composition and the function of the bacterial community in the gut. Therefore, bacterial supplements and controlled dietary changes, with exercise, might have beneficial effects on the psychological and cognitive functions in patients with PTSD. These new treatments should be aimed to attenuate inflammatory processes and consequently to reduce PTSD symptoms but also to improve cognition and reduce cardio-metabolic disorders associated so frequently with PTSD.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/terapia , Sistema Hipófise-Suprarrenal , Sistema Hipotálamo-Hipofisário , Cinurenina/metabolismo , Inflamação/metabolismo , Sistema Imunitário/metabolismoRESUMO
In the last decade, increasing evidence has emerged linking alterations in the brain-derived neurotrophic factor (BDNF) expression with the development of Alzheimer's disease (AD). Because of the important role of BDNF in cognition and its association with AD pathogenesis, the aim of this study was to evaluate the potential difference in plasma BDNF concentrations between subjects with mild cognitive impairment (MCI; N = 209) and AD patients (N = 295) and to determine the possible association between BDNF plasma levels and the degree of cognitive decline in these individuals. The results showed a significantly higher (p < 0.001) concentration of plasma BDNF in subjects with AD (1.16; 0.13-21.34) compared with individuals with MCI (0.68; 0.02-19.14). The results of the present study additionally indicated a negative correlation between cognitive functions and BDNF plasma concentrations, suggesting higher BDNF levels in subjects with more pronounced cognitive decline. The correlation analysis revealed a significant negative correlation between BDNF plasma levels and both Mini-Mental State Examination (p < 0.001) and Clock Drawing test (p < 0.001) scores. In conclusion, the results of our study point towards elevated plasma BDNF levels in AD patients compared with MCI subjects, which may be due to the body's attempt to counteract the early and middle stages of neurodegeneration.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Fator Neurotrófico Derivado do Encéfalo , Biomarcadores , Doença de Alzheimer/diagnóstico , CogniçãoRESUMO
The molecular underpinnings of post-traumatic stress disorder (PTSD) are still unclear due to the complex interactions of genetic, psychological, and environmental factors. Glycosylation is a common post-translational modification of proteins, and different pathophysiological states, such as inflammation, autoimmune diseases, and mental disorders including PTSD, show altered N-glycome. Fucosyltransferase 8 (FUT8) is the enzyme that catalyzes the addition of core fucose on glycoproteins, and mutations in the FUT8 gene are associated with defects in glycosylation and functional abnormalities. This is the first study that investigated the associations of plasma N-glycan levels with FUT8-related rs6573604, rs11621121, rs10483776, and rs4073416 polymorphisms and their haplotypes in 541 PTSD patients and control participants. The results demonstrated that the rs6573604 T allele was more frequent in the PTSD than in the control participants. Significant associations of plasma N-glycan levels with PTSD and FUT8-related polymorphisms were observed. We also detected associations of rs11621121 and rs10483776 polymorphisms and their haplotypes with plasma levels of specific N-glycan species in both the control and PTSD groups. In carriers of different rs6573604 and rs4073416 genotypes and alleles, differences in plasma N-glycan levels were only found in the control group. These molecular findings suggest a possible regulatory role of FUT8-related polymorphisms in glycosylation, the alternations of which could partially explain the development and clinical manifestation of PTSD.
Assuntos
Fucosiltransferases , Transtornos de Estresse Pós-Traumáticos , Humanos , Fucose/metabolismo , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Glicoproteínas/metabolismo , Glicosilação , Polissacarídeos/metabolismo , Transtornos de Estresse Pós-Traumáticos/genéticaRESUMO
Posttraumatic stress disorder (PTSD) is complex neuropsychiatric disorder triggered by a traumatic event and characterized by the symptoms that represent large burden to patients, as well as to society. Lipidomic approach can be applied as a useful tool for discovery of novel diagnostic, prognostic and therapeutic lipid biomarkers of various disorders, whose etiology is complex and still unknown, including PTSD. Since changes in the levels of lipid metabolites might indicate impairments in various metabolic pathways and cellular processes, the aim of this lipidomic study was to determine altered levels of lipid compounds in PTSD. The study enrolled 235 male patients with combat PTSD and 241 healthy male control subjects. Targeted lipidomic analysis of plasma samples was conducted using reverse-phase liquid chromatography coupled with mass spectrometry. Lipids that have been analyzed belong to the group of ceramides, cholesterol esters, diacylglycerols, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins and triglycerides. The levels of fifteen lipid compounds were found to be significantly different between PTSD patients and healthy control subjects, including four phosphatidylcholines, two phosphatidylethanolamines, five sphingomyelins, two cholesterol esters and two ceramides. The lipid metabolites whose levels significantly differed between patients with PTSD and control subjects are associated with various biological processes, including impairments of membrane integrity and function, mitochondrial dysfunction, inflammation and oxidative stress. As these processes might be associated with development and progression of PTSD, altered lipid compounds represent potential biomarkers that could facilitate the diagnosis of PTSD, prediction of the disease, as well as identification of novel treatment approaches in PTSD.
Assuntos
Lipidômica , Transtornos de Estresse Pós-Traumáticos , Biomarcadores , Ceramidas , Ésteres do Colesterol , Humanos , Masculino , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas , Esfingomielinas , Transtornos de Estresse Pós-Traumáticos/diagnósticoRESUMO
Post-traumatic stress disorder (PTSD) is a trauma and stress related disorder frequently associated with cognitive decline. War veterans with PTSD have a higher risk of developing dementia than healthy subjects. Brain derived neurotrophic factor (BDNF) is an important protein that modulates plasticity, memory consolidation and cognitive processes. Lower circulating BDNF levels were related to memory impairment and cognitive deterioration. The aim of this study was to evaluate cognitive deterioration and plasma BDNF concentration in 120 veterans with combat related PTSD, 120 healthy controls, 47 subjects with mild cognitive impairment (MCI) and 76 patients with Alzheimer's disease (AD), and to assess if plasma BDNF concentration might be used as biomarker of cognitive deterioration. Veterans with PTSD had significantly decreased plasma BDNF concentration and worse cognitive performances (assessed using the Mini Mental State Examination, Clock Drawing test and Montreal Cognitive Assessment scores/categories) than healthy subjects, and similarly reduced plasma BDNF and cognitive decline as MCI subjects. Reduced plasma BDNF was found in cognitively impaired subjects. These results suggest that veterans with PTSD should be closely monitored in order to early detect and predict cognitive worsening and promote interventions that might help restore blood BDNF levels and cognitive functions.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Transtornos de Estresse Pós-Traumáticos , Veteranos , Doença de Alzheimer/psicologia , Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva/etiologia , Humanos , Transtornos de Estresse Pós-Traumáticos/complicaçõesRESUMO
Post-traumatic stress disorder (PTSD) is a complex trauma-related disorder, the etiology and underlying molecular mechanisms of which are still unclear and probably involve different (epi)genetic and environmental factors. Protein N-glycosylation is a common post-translational modification that has been associated with several pathophysiological states, including inflammation and PTSD. Hepatocyte nuclear factor-1α (HNF1A) is a transcriptional regulator of many genes involved in the inflammatory processes, and it has been identified as master regulator of plasma protein glycosylation. The aim of this study was to determine the association between N-glycan levels in plasma and immunoglobulin G, methylation at four CpG positions in the HNF1A gene, HNF1A antisense RNA 1 (HNF1A-AS1), rs7953249 and HNF1A rs735396 polymorphisms in a total of 555 PTSD and control subjects. We found significant association of rs7953249 and rs735396 polymorphisms, as well as HNF1A gene methylation at the CpG3 site, with highly branched, galactosylated and sialyated plasma N-glycans, mostly in patients with PTSD. HNF1A-AS1 rs7953249 polymorphism was also associated with PTSD; however, none of the polymorphisms were associated with HNF1A gene methylation. These results indicate a possible regulatory role of the investigated HNF1A polymorphisms with respect to the abundance of complex plasma N-glycans previously associated with proinflammatory response, which could contribute to the clinical manifestation of PTSD and its comorbidities.
Assuntos
Epigênese Genética , Subunidade alfa do Fator 1 Induzível por Hipóxia , Transtornos de Estresse Pós-Traumáticos , Glicosilação , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Polissacarídeos , RNA Antissenso/metabolismo , Transtornos de Estresse Pós-Traumáticos/genéticaRESUMO
Post-traumatic stress disorder (PTSD) is a trauma-related disorder. Platelet monoamine oxidase (MAO-B) is a peripheral biomarker associated with various symptoms in different psychopathologies, but its role in PTSD or different symptoms in PTSD is not clear. This study elucidated the association between platelet MAO-B activity and clinical symptoms occurring in PTSD. Platelet MAO-B activity was determined in 1053 male Caucasian subjects: 559 war veterans with PTSD (DSM-5 criteria), 62 combat exposed veterans who did not develop PTSD, and 432 non-combat exposed healthy controls. Clinical symptoms in PTSD were determined using CAPS and PANSS. Platelet MAO-B activity, controlled for the effect of smoking, was significantly increased in PTSD with severe versus mild and moderate traumatic symptoms, and was significantly decreased in PTSD subjects with severe versus mild positive, psychotic, and depressive symptoms. This finding was further confirmed with reduced platelet MAO-B activity in PTSD veterans with severe versus mild individual items of the PANSS-depressed, PANSS-psychotic, and PANSS-positive subscales. Altered platelet MAO-B activity, controlled for the possible confounders, was associated with the development and severity of different symptoms occurring in PTSD. These findings confirmed the role of platelet MAO-B activity as a peripheral marker of various psychopathological symptoms.
Assuntos
Transtornos Psicóticos , Transtornos de Estresse Pós-Traumáticos , Depressão , Humanos , Masculino , Monoaminoxidase , Fumar , Transtornos de Estresse Pós-Traumáticos/complicaçõesRESUMO
Studies investigating the association between smoking and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reported inconclusive results, while the studies on the association of smoking status with BDNF C270T polymorphism are missing. We aimed to determine the association of smoking and BDNF Val66Met and C270T genetic variants in control subjects and patients with mental disorders. This study included 3502 Caucasian subjects: 918 healthy controls and 2584 patients with mental disorders (519 individuals with posttraumatic stress disorder (PTSD), 419 patients with depression, 996 patients with schizophrenia, and 650 patients with alcohol dependence). The frequency of the BDNF Val66Met and C270T variants were presented in codominant, dominant and recessive models. BDNF C270T, but not BDNF Val66Met polymorphism, was significantly associated with smoking in all groups, since the presence of the C270T T allele was more frequently found in smokers compared to non-smokers. Significant predictors of smoking were sex, age and BDNF C270T genetic variants. However, after detailed analysis of the separate diagnostic entities, the significant association of BDNF C270T polymorphism was confirmed only in healthy subjects, but not in patients with mental disorders; and was not related to number of cigarettes smoked per day. In patients with alcohol dependence, the severity of smoking was significantly associated with BDNF Val66Met variants. This is a first report of the significant association between the BDNF C270T polymorphism and smoking status in the large groups of Caucasian cases/controls.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos Mentais/genética , Polimorfismo Genético , Fumar/epidemiologia , Alcoolismo/genética , Alelos , Estudos de Casos e Controles , Depressão/genética , Feminino , Predisposição Genética para Doença/genética , Voluntários Saudáveis/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/genética , Transtornos de Estresse Pós-Traumáticos/genéticaRESUMO
Alcohol dependence is a chronic relapsing mental disorder with heterogeneous and complex underlying biology. It is frequently associated with nicotine dependence, severity of alcohol dependence symptoms, and diverse alcohol-related phenotypes, including the presence of delirium tremens and withdrawal symptoms, early or late onset of alcohol abuse, aggression, suicidal behavior, and anxiety. While searching for peripheral biomarkers of altered serotonergic (5-HT) function in alcohol dependence and alcohol-related behaviors, we determined a peripheral biomarker, i.e., platelet 5-HT concentration in a large group of Caucasian subjects with alcohol dependence subdivided according to the presence of specific alcohol-related phenotypes and smoking status. Individuals with alcohol dependence (n = 661) of both sexes were evaluated using Structural Clinical Interview based on DSM-IV criteria, while platelet 5-HT concentration was determined using the spectrophotofluorimetric method. Smoking is significantly associated, while sex and age are not, with platelet 5-HT concentration. Severe alcohol dependence and lack of withdrawal symptoms were associated with significantly decreased platelet 5-HT concentration in alcohol-dependent non-smokers. In smokers, significantly lower platelet 5-HT concentration was found in patients with the late onset of alcohol abuse. These results suggested that platelet 5-HT concentration might be used as a peripheral marker of different alcohol-related phenotypes, after controlling for the effects of smoking and sex.
Assuntos
Alcoolismo , Síndrome de Abstinência a Substâncias , Feminino , Humanos , Masculino , Fenótipo , Serotonina , Fumar , Síndrome de Abstinência a Substâncias/complicaçõesRESUMO
Animal and human studies suggest that aggressive behavior may be modulated by brain serotonergic system. Serotonergic (5-HT) dysfunction is associated with post-traumatic stress disorder (PTSD), but also with increased aggression and impulsivity, hallmarks of PTSD. The aim of the study was to investigate the association of platelet 5-HT concentration and various types of aggression and impulsivity in veterans with PTSD. A group of 42 male combat-related PTSD subjects entered the study. Four different aggression facets were measured by the Buss and Perry's Aggression Questionnaire (BPAQ). Verbal and physical types of impulsive aggressive behavior were measured by the subscales of the Zuzul's Aggressiveness Inventory A-87. Impulsivity was determined using Eysenck's IVE questionnaire. PTSD severity was evaluated by Watson's PTSD questionnaire. Platelet serotonin concentration was determined spectrofluorimetrically. Confounding variables were: age, body mass, alcohol use, comorbid depression, and tobacco use. Platelet 5-HT concentration and PTSD severity were independently associated only with impulsive types of aggression, as higher platelet 5-HT concentration and more severe PTSD were related to more impulsive aggression. These results strongly recommend distinguishing between specific types of aggression facets, and advise the importance of theory-based concepts of aggression facets when evaluating the biological correlates of aggression.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Veteranos , Agressão , Humanos , Comportamento Impulsivo , Masculino , Serotonina , Estresse PsicológicoRESUMO
Posttraumatic stress disorder (PTSD) is frequently associated with cognitive disturbances and high prevalence of smoking. This study evaluated cognition in war veterans with PTSD and control subjects, controlled for the effect of smoking and brain derived neurotrophic factor (BDNF) rs6265 and rs56164415 genotypes/alleles. Study included 643 male war veterans with combat related PTSD and 120 healthy controls. Genotyping was done by real time PCR. Cognitive disturbances were evaluated using the Positive and Negative Syndrome Scale (PANSS) cognition subscale and the Rey-Osterrieth Complex Figure (ROCF) test scores. Diagnosis (p < 0.001), BDNF rs56164415 (p = 0.011) and smoking (p = 0.028) were significant predictors of the cognitive decline in subjects with PTSD. BDNF rs56164415 T alleles were more frequently found in subjects with PTSD, smokers and non-smokers, with impaired cognition, i.e., with the higher PANSS cognition subscale scores and with the lower ROCF immediate recall test scores. Presence of one or two BDNF rs56164415 T alleles was related to cognitive decline in PTSD. The T allele carriers with PTSD had advanced cognitive deterioration in smokers and nonsmokers with PTSD, and worse short-term visual memory function. Our findings emphasize the role of the BDNF rs56164415 T allele and smoking in cognitive dysfunction in war veterans with PTSD.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Cognição/fisiologia , Transtornos de Estresse Pós-Traumáticos/genética , Idoso , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Disfunção Cognitiva/complicações , Disfunção Cognitiva/genética , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Veteranos/psicologiaRESUMO
Posttraumatic stress disorder (PTSD) is a severe, multifactorial and debilitating neuropsychiatric disorder, which can develop in a subset of individuals as a result of the exposure to severe stress or trauma. Such traumatic experiences have a major impact on molecular, biochemical and cellular systems, causing psychological and somatic alterations that affect the whole organism. Although the etiology of PTSD is still unclear, it seems to involve complex interaction between various biological genetic and environmental factors. Metabolomics, as one of the rapidly developing "omics" techniques, might be a useful tool for determining altered metabolic pathways and stress-related metabolites as new potential biomarkers of PTSD. The aim of our study was to identify metabolites whose altered levels allow us to differentiate between patients with PTSD and healthy control individuals. The study included two cohorts. The first, exploratory, group included 50 Croatian veterans with PTSD and 50 healthy control subjects, whereas a validation group consisted of 52 veterans with PTSD and 52 control subjects. The metabolomic analysis of plasma samples was conducted using liquid chromatography coupled with mass spectrometry (LC-MS), as well as gas chromatography coupled with mass spectrometry (GC-MS). The LC-MS analysis determined significantly different levels of two glycerophospholipids, PE(18:1/0:0) and PC(18:1/0:0), between control subjects and PTSD patients in both cohorts. The altered metabolites might play a role in multiple cellular processes, including inflammation, mitochondrial dysfunction, membrane breakdown, oxidative stress and neurotoxicity, which could be associated with PTSD pathogenesis.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Veteranos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Espectrometria de Massas , MetabolômicaRESUMO
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.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Genótipo , Polimorfismo Genético , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/imunologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/imunologia , Feminino , Frequência do Gene , Humanos , Interleucina-10/imunologia , Interleucina-1alfa/imunologia , Interleucina-6/sangue , Masculino , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Tobacco smoking is highly prevalent in patients with schizophrenia and alcohol dependence. The underlying neurobiology of nicotine addiction is complex. Rewarding effects of nicotine from cigarettes are associated, among others, with mu-opioid receptors encoded by the OPRM1 gene. The aim of the study was to evaluate the association between two OPRM1 gene polymorphisms, rs1799971 and rs510769, and tobacco smoking in Caucasian patients with schizophrenia, alcohol dependence, and healthy control subjects. The study included 1058 Caucasians (277 patients with schizophrenia, 359 patients with alcohol dependence, and 422 healthy control subjects), subdivided according to the nicotine dependence into smokers (i.e. current smokers) and non-smokers. A significant association was found between the GC haplotype (OPRM1 rs1799971 and rs510769) and smoking in healthy controls, but not in patients with schizophrenia and alcohol dependence. A nominal association was detected in all cases/controls, but this significance did not survive the correction for the multiple testing. This is the first study to reveal that nicotine dependence is associated with the GC haplotype of the OPRM1 rs1799971 and rs510769 in all subjects or specifically in healthy controls. These results did not confirm the strong connection between OPRM1 polymorphisms and nicotine dependence in schizophrenia or alcohol dependence.
Assuntos
Alcoolismo/genética , Estudos de Associação Genética/métodos , Haplótipos/genética , Receptores Opioides mu/genética , Esquizofrenia/genética , Adulto , Alcoolismo/diagnóstico , Alcoolismo/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologiaRESUMO
Antipsychotic drugs target primarily dopaminergic system which makes catechol-O-methyltransferase (COMT) an interesting target in studies searching for treatment response predictors in schizophrenia. The study assessed the association of the COMT rs4680 and rs4818 polymorphisms with therapeutic response to olanzapine, risperidone, clozapine or other antipsychotic medication after 8 weeks of monotherapy in patients with schizophrenia. 521 Caucasian patients with schizophrenia received a monotherapy with olanzapine (10-20 mg/day; N = 190), risperidone (3-6 mg/day; N = 99), or clozapine (100-500 mg/day; N = 102). The fourth group (N = 130) consisted of patients receiving haloperidol (3-15 mg/day), fluphenazine (4-25 mg/day) or quetiapine (50-800 mg/day). Treatment response was defined as a 50% reduction from the baseline positive and negative syndrome scale (PANSS) total and subscale scores, but also as an observed percentage reduction from the initial PANSS0-6 total and subscale scores. Carriers of the COMT rs4680 A allele and carriers of the COMT rs4680-rs4818 C-A haplotype block had greater reduction in the PANSS total scores following olanzapine treatment, compared to carriers of the COMT rs4680 GG genotype and other COMT rs4680-rs4818 haplotypes. The COMT rs4680 A allele, and COMT rs4680-rs4818 C-A haplotype, were significantly associated with therapeutic response in patients treated with olanzapine, but not in patients treated with other antipsychotics.
Assuntos
Antipsicóticos/administração & dosagem , Catecol O-Metiltransferase/genética , Olanzapina/administração & dosagem , Polimorfismo de Nucleotídeo Único , Esquizofrenia/tratamento farmacológico , Adulto , Idoso , Antipsicóticos/uso terapêutico , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina/uso terapêutico , Variantes Farmacogenômicos , Esquizofrenia/genética , Resultado do Tratamento , Adulto JovemRESUMO
Post-traumatic stress disorder (PTSD) develops in a portion of individuals exposed to extreme trauma. Glycosylation is a post-translational modification that affects protein functions and is altered in various pathophysiological states and aging. There are still no validated biomarkers of PTSD. The aim of this study was to evaluate the N-glycomic profile in 543 male Caucasian individuals (299 veterans with PTSD and 244 control subjects). The study included discovery (N = 233) and replication (N = 310) cohort. Hydrophilic interaction HPLC and ultra-performance liquid chromatography were used to separate and detect 39 plasma and 24 IgG N-glycan species, respectively. All results were corrected for the effects of age and multiple testing. Significant results included only significantly altered N-glycans in cases/controls in both cohorts, in the same direction. Results showed that six plasma N-glycans (four increased and two decreased) were altered in PTSD vs. controls in both cohorts, but IgG N-glycans were similar between groups. The severity of PTSD was not associated with different plasma N-glycans. This is the first study detecting alterations in plasma N-glycans in PTSD. These N-glycans are also associated with other neuropsychiatric disorders and inflammation, suggesting possible shared glycosylation mechanisms.