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1.
Proc Natl Acad Sci U S A ; 120(14): e2213880120, 2023 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-36976765

RESUMO

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.


Assuntos
Esquizofrenia , Masculino , Feminino , Humanos , Esquizofrenia/diagnóstico por imagem , Estudos de Casos e Controles , Encéfalo/diagnóstico por imagem , Córtex Cerebral , Imageamento por Ressonância Magnética/métodos , Lateralidade Funcional
2.
Brain Behav Immun ; 115: 191-200, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37848096

RESUMO

BACKGROUND: Clinical trials of anti-inflammatories in schizophrenia do not show clear and replicable benefits, possibly because patients were not recruited based on elevated inflammation status. Interleukin 1-beta (IL-1ß) mRNA and protein levels are increased in serum, plasma, cerebrospinal fluid, and brain of some chronically ill patients with schizophrenia, first episode psychosis, and clinical high-risk individuals. Canakinumab, an approved anti-IL-1ß monoclonal antibody, interferes with the bioactivity of IL-1ß and interrupts downstream signaling. However, the extent to which canakinumab reduces peripheral inflammation markers, such as, high sensitivity C-reactive protein (hsCRP) and symptom severity in schizophrenia patients with inflammation is unknown. TRIAL DESIGN: We conducted a randomized, placebo-controlled, double-blind, parallel groups, 8-week trial of canakinumab in chronically ill patients with schizophrenia who had elevated peripheral inflammation. METHODS: Twenty-seven patients with schizophrenia or schizoaffective disorder and elevated peripheral inflammation markers (IL-1ß, IL-6, hsCRP and/or neutrophil to lymphocyte ratio: NLR) were randomized to a one-time, subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive antipsychotic treatment. Peripheral blood hsCRP, NLR, IL-1ß, IL-6, IL-8 levels were measured at baseline (pre injection) and at 1-, 4- and 8-weeks post injection. Symptom severity was assessed at baseline and 4- and 8-weeks post injection. RESULTS: Canakinumab significantly reduced peripheral hsCRP over time, F(3, 75) = 5.16, p = 0.003. Significant hsCRP reductions relative to baseline were detected only in the canakinumab group at weeks 1, 4 and 8 (p's = 0.0003, 0.000002, and 0.004, respectively). There were no significant hsCRP changes in the placebo group. Positive symptom severity scores were significantly reduced at week 8 (p = 0.02) in the canakinumab group and week 4 (p = 0.02) in the placebo group. The change in CRP between week 8 and baseline (b = 1.9, p = 0.0002) and between week 4 and baseline (b = 6.0, p = 0.001) were highly significant predictors of week 8 change in PANSS Positive Symptom severity scores. There were no significant changes in negative symptoms, general psychopathology or cognition in either group. Canakinumab was well tolerated and only 7 % discontinued. CONCLUSIONS: Canakinumab quickly reduces peripheral hsCRP serum levels in patients with schizophrenia and inflammation; after 8 weeks of canakinumab treatment, the reductions in hsCRP are related to reduced positive symptom severity. Future studies should consider increased doses or longer-term treatment to confirm the potential benefits of adjunctive canakinumab in schizophrenia. Australian and New Zealand Clinical Trials Registry number: ACTRN12615000635561.


Assuntos
Esquizofrenia , Humanos , Esquizofrenia/tratamento farmacológico , Proteína C-Reativa/análise , Anticorpos Monoclonais/uso terapêutico , Interleucina-6 , Austrália , Inflamação/tratamento farmacológico , Doença Crônica , Método Duplo-Cego , Resultado do Tratamento
3.
Artigo em Inglês | MEDLINE | ID: mdl-38995314

RESUMO

PURPOSE: Antipsychotic-induced prolactin elevation may impede protective effects of estrogens in women with schizophrenia-spectrum disorders (SSD). Our study sought to confirm whether the use of prolactin-raising antipsychotics is associated with lower estrogen levels, and to investigate how estrogen and prolactin levels relate to symptom severity and cognition in premenopausal women with SSD. METHODS: This cross-sectional study included 79 premenopausal women, divided in three groups of women with SSD treated with prolactin-sparing antipsychotics (n = 21) or prolactin-raising antipsychotics (n = 27), and age-matched women without SSD (n = 31). Circulating 17ß-estradiol was compared among groups. In patients, we assessed the relationship between prolactin and 17ß-estradiol, and the relationships of these hormones to symptom severity and cognition, using correlation analyses and backward regression models. RESULTS: In women receiving prolactin-raising antipsychotics, 17ß-estradiol levels were lower as compared to both other groups (H(2) = 8.34; p = 0.015), and prolactin was inversely correlated with 17ß-estradiol (r=-0.42, p = 0.030). In the prolactin-raising group, 17ß-estradiol correlated positively with verbal fluency (r = 0.52, p = 0.009), and 17ß-estradiol and prolactin together explained 29% of the variation in processing speed (ß17ß-estradiol = 0.24, ßprolactin = -0.45, F(2,25) = 5.98, p = 0.008). In the prolactin-sparing group, 17ß-estradiol correlated negatively with depression/anxiety (r = -0.57, p = 0.014), and together with prolactin explained 26% of the variation in total symptoms (ß17ß-estradiol = -0.41, ßprolactin = 0.32, F(2,18) = 4.44, p = 0.027). CONCLUSIONS: In women with SSD, antipsychotic-induced prolactin elevation was related to lower estrogen levels. Further, estrogens negatively correlated with symptom severity and positively with cognition, whereas prolactin levels correlated negatively with cognition. Our findings stress the clinical importance of maintaining healthy levels of prolactin and estrogens in women with SSD.

4.
Mol Psychiatry ; 27(9): 3731-3737, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35739320

RESUMO

Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia.


Assuntos
Transtorno Depressivo Maior , Esquizofrenia , Humanos , Encéfalo , Imageamento por Ressonância Magnética/métodos , Obesidade
5.
Psychol Med ; 52(14): 3097-3115, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-33443010

RESUMO

BACKGROUND: Cigarette smoking is associated with worse cognition and decreased cortical volume and thickness in healthy cohorts. Chronic cigarette smoking is prevalent in schizophrenia spectrum disorders (SSD), but the effects of smoking status on the brain and cognition in SSD are not clear. This study aimed to understand whether cognitive performance and brain morphology differed between smoking and non-smoking individuals with SSD compared to healthy controls. METHODS: Data were obtained from the Australian Schizophrenia Research Bank. Cognitive functioning was measured in 299 controls and 455 SSD patients. Cortical volume, thickness and surface area data were analysed from T1-weighted structural scans obtained in a subset of the sample (n = 82 controls, n = 201 SSD). Associations between smoking status (cigarette smoker/non-smoker), cognition and brain morphology were tested using analyses of covariance, including diagnosis as a moderator. RESULTS: No smoking by diagnosis interactions were evident, and no significant differences were revealed between smokers and non-smokers across any of the variables measured, with the exception of a significantly thinner left posterior cingulate in smokers compared to non-smokers. Several main effects of smoking in the cognitive, volume and thickness analyses were initially significant but did not survive false discovery rate (FDR) correction. CONCLUSIONS: Despite the general absence of significant FDR-corrected findings, trend-level effects suggest the possibility that subtle smoking-related effects exist but were not uncovered due to low statistical power. An investigation of this topic is encouraged to confirm and expand on our findings.


Assuntos
Encéfalo , Cognição , Esquizofrenia , Fumar , Humanos , Austrália/epidemiologia , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/epidemiologia , Esquizofrenia/complicações , Fumar/efeitos adversos , Fumar/epidemiologia
6.
Brain Behav Immun ; 101: 423-434, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34808287

RESUMO

BACKGROUND: There is growing evidence for complement system involvement in the pathophysiology of schizophrenia, although the extent and magnitude of complement factor disturbances has not been fully reported. It also remains unclear whether complement abnormalities are characteristic of all patients with schizophrenia or whether they are representative of a subgroup of patients who show signs of heightened inflammation. The aim of the present study was to quantify and compare the levels of a range of complement factors, receptors and regulators in healthy controls and people with schizophrenia and to determine the extent to which the levels of these peripheral molecules relate to measures of brain structure, particularly cortical thickness. METHOD: Seventy-five healthy controls and 90 patients with schizophrenia or schizoaffective disorder were included in the study. Peripheral blood samples were collected from all participants and mRNA expression was quantified in 20 complement related genes, four complement proteins, as well as for four cytokines. T1-weighted structural MRI scans were acquired and analysed to determine cortical thickness measures. RESULTS: There were significant increases in peripheral mRNA encoding receptors (C5ar1, CR1, CR3a), regulators (CD55, C59) and protein concentrations (C3, C3b, C4) in people with schizophrenia relative to healthy controls. C4a expression was significantly increased in a subgroup of patients displaying elevated peripheral cytokine levels. A higher inflammation index score derived from mRNA expression patterns predicted reductions in cortical thickness in the temporal lobe (superior temporal gyrus, transverse temporal gyrus, fusiform gyrus, insula) in patients with schizophrenia and healthy controls. CONCLUSIONS: Analysis of all three major complement pathways supports increased complement activity in schizophrenia and also shows that peripheral C4a up-regulation is related to increased peripheral pro-inflammatory cytokines in healthy controls. Our region-specific, neuroimaging findings linked to an increased peripheral complement mRNA expression pattern suggests a role for complement in cortical thinning. Further studies are required to further clarify clinical and neurobiological consequences of aberrant complement levels in schizophrenia and related psychoses.


Assuntos
Esquizofrenia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Proteínas do Sistema Complemento , Citocinas/metabolismo , Humanos , Inflamação , Imageamento por Ressonância Magnética/métodos , RNA Mensageiro
7.
Mol Psychiatry ; 25(4): 761-775, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30214039

RESUMO

Elevated pro-inflammatory cytokines exist in both blood and brain of people with schizophrenia but how this affects molecular indices of the blood-brain barrier (BBB) is unclear. Eight mRNAs relating to BBB function, a microglia and three immune cell markers were measured by qPCR in the prefrontal cortex from 37 people with schizophrenia/schizoaffective disorder and 37 matched controls. This cohort was previously grouped into "high inflammation" and "low inflammation" subgroups based on cortical inflammatory-related transcripts. Soluble intercellular adhesion molecule-1 (sICAM1) was measured in the plasma of 78 patients with schizophrenia/schizoaffective disorder and 73 healthy controls. We found that sICAM1 was significantly elevated in schizophrenia. An efflux transporter, ABCG2, was lower, while mRNAs encoding VE-cadherin and ICAM1 were higher in schizophrenia brain. The "high inflammation" schizophrenia subgroup had lower ABCG2 and higher ICAM1, VE-cadherin, occludin and interferon-induced transmembrane protein mRNAs compared to both "low inflammation" schizophrenia and "low inflammation" control subgroups. ICAM1 immunohistochemistry showed enrichment in brain endothelium regardless of diagnosis and was localised to astrocytes in some brains. Microglia mRNA was not altered in schizophrenia nor did it correlate with ICAM1 expression. Immune cell mRNAs were elevated in "high inflammation" schizophrenia compared to both "low inflammation" schizophrenia and controls. CD163+ perivascular macrophages were identified by immunohistochemistry in brain parenchyma in over 40% of "high inflammation" schizophrenia brains. People with high levels of cytokine expression and schizophrenia display changes consistent with greater immune cell transmigration into brain via increased ICAM1, which could contribute to other neuropathological changes found in this subgroup of people.


Assuntos
Lobo Frontal/patologia , Macrófagos/metabolismo , Esquizofrenia/genética , Adulto , Astrócitos/metabolismo , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encefalite/patologia , Células Endoteliais/metabolismo , Endotélio/metabolismo , Feminino , Lobo Frontal/metabolismo , Expressão Gênica/genética , Humanos , Inflamação , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Macrófagos/patologia , Masculino , Microglia/metabolismo , Pessoa de Meia-Idade , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Transtornos Psicóticos/patologia , Esquizofrenia/metabolismo
8.
Mol Psychiatry ; 25(11): 2860-2872, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-30940904

RESUMO

The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-D-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes,  leading to DLPFC volume loss, and attention impairment in schizophrenia.


Assuntos
Atenção , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Cinurenina/metabolismo , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Adulto , Feminino , Humanos , Ácido Cinurênico/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Eur Arch Psychiatry Clin Neurosci ; 271(4): 595-607, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33760971

RESUMO

While the biological substrates of brain and behavioural changes in persons with schizophrenia remain unclear, increasing evidence implicates that inflammation is involved. In schizophrenia, including first-episode psychosis and anti-psychotic naïve patients, there are numerous reports of increased peripheral inflammation, cognitive deficits and neuropathologies such as cortical thinning. Research defining the relationship between inflammation and schizophrenia symptomatology and neuropathology is needed. Therefore, we analysed the level of C-reactive protein (CRP), a peripheral inflammation marker, and its relationship with cognitive functioning in a cohort of 644 controls and 499 schizophrenia patients. In a subset of individuals who underwent MRI scanning (99 controls and 194 schizophrenia cases), we tested if serum CRP was associated with cortical thickness. CRP was significantly increased in schizophrenia patients compared to controls, co-varying for age, sex, overweight/obesity and diabetes (p < 0.006E-10). In schizophrenia, increased CRP was mildly associated with worse performance in attention, controlling for age, sex and education (R =- 0.15, p = 0.001). Further, increased CRP was associated with reduced cortical thickness in three regions related to attention: the caudal middle frontal, the pars opercularis and the posterior cingulate cortices, which remained significant after controlling for multiple comparisons (all p < 0.05). Together, these findings indicate that increased peripheral inflammation is associated with deficits in cognitive function and brain structure in schizophrenia, especially reduced attention and reduced cortical thickness in associated brain regions. Using CRP as a biomarker of peripheral inflammation in persons with schizophrenia may help to identify vulnerable patients and those that may benefit from adjunctive anti-inflammatory treatments.


Assuntos
Esquizofrenia , Biomarcadores , Proteína C-Reativa/análise , Cognição , Humanos , Inflamação/diagnóstico por imagem , Imageamento por Ressonância Magnética , Transtornos Psicóticos , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem
10.
Psychol Med ; 50(9): 1475-1489, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31274065

RESUMO

BACKGROUND: In schizophrenia, relative stability in the magnitude of cognitive deficits across age and illness duration is inconsistent with the evidence of accelerated deterioration in brain regions known to support these functions. These discrepant brain-cognition outcomes may be explained by variability in cognitive reserve (CR), which in neurological disorders has been shown to buffer against brain pathology and minimize its impact on cognitive or clinical indicators of illness. METHODS: Age-related change in fluid reasoning, working memory and frontal brain volume, area and thickness were mapped using regression analysis in 214 individuals with schizophrenia or schizoaffective disorder and 168 healthy controls. In patients, these changes were modelled as a function of CR. RESULTS: Patients showed exaggerated age-related decline in brain structure, but not fluid reasoning compared to controls. In the patient group, no moderation of age-related brain structural change by CR was evident. However, age-related cognitive change was moderated by CR, such that only patients with low CR showed evidence of exaggerated fluid reasoning decline that paralleled the exaggerated age-related deterioration of underpinning brain structures seen in all patients. CONCLUSIONS: In schizophrenia-spectrum illness, CR may negate ageing effects on fluid reasoning by buffering against pathologically exaggerated structural brain deterioration through some form of compensation. CR may represent an important modifier that could explain inconsistencies in brain structure - cognition outcomes in the extant literature.


Assuntos
Encéfalo/diagnóstico por imagem , Reserva Cognitiva/fisiologia , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/psicologia , Esquizofrenia/diagnóstico por imagem , Psicologia do Esquizofrênico , Adulto , Fatores Etários , Encéfalo/patologia , Estudos de Casos e Controles , Feminino , Humanos , Inteligência/fisiologia , Imageamento por Ressonância Magnética , Masculino , Memória de Curto Prazo/fisiologia , Pessoa de Meia-Idade , Análise de Regressão
11.
Brain Behav Immun ; 89: 200-208, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32540151

RESUMO

Increased cytokines and increased intercellular adhesion molecule-1 (ICAM1) found in the schizophrenia prefrontal cortex and in the blood may relate to cognitive deficits. Endothelial ICAM1 regulates immune cell trafficking into the brain by binding to integrins located on the surface of leukocytes. Whether the circulating levels of the main ICAM1 adhesion partners, lymphocyte-function associated antigen-1 (LFA1) and complement receptor 3 (CR3), both integrins, are altered in schizophrenia is unknown. Gene expressions of ICAM1, LFA1 and CR3 were measured in leukocytes from 86 schizophrenia patients and 77 controls. Participants were also administered cognitive testing to determine the extent to which cognitive ability was related to molecular measures of leukocyte adhesion. This cohort was previously stratified into inflammatory subgroups based on circulating cytokine mRNAs; thus, gene expressions were analysed by diagnosis and by inflammatory subgroups. Previously measured plasma ICAM1 protein was elevated in "high inflammation" schizophrenia compared to both "high" and "low inflammation" controls while ICAM1 mRNA was unchanged in leukocytes. LFA1 mRNA was decreased and CR3 mRNA was increased in leukocytes from people with schizophrenia compared to controls. LFA1 mRNA levels were positively correlated with working memory and elevated soluble ICAM1 was negatively correlated with verbal memory in schizophrenia. Altogether, some of the cognitive deficits in schizophrenia may be associated with altered expression of molecules that regulate immune cell trafficking.


Assuntos
Esquizofrenia , Adesão Celular , Moléculas de Adesão Celular , Humanos , Molécula 1 de Adesão Intercelular/genética , Antígeno-1 Associado à Função Linfocitária
12.
Australas Psychiatry ; 28(4): 454-458, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32174125

RESUMO

OBJECTIVE: A narrative review to describe the utility of the neutrophil-lymphocyte ratio (NLR) as an inflammatory marker in psychiatric and non-psychiatric disorders and to discuss the potential role of NLR in psychiatric research. CONCLUSIONS: NLR is inexpensive and readily available using division of two measures obtained on routine blood testing. NLR is elevated in a number of psychiatric disorders. It can predict morbidity and mortality in a wide range of non-psychiatric conditions, but this has not been confirmed in psychiatric conditions. It can be calculated in large, pre-existing datasets to investigate clinical correlates of inflammatory processes. NLR may have a future role in identifying patients with an inflammatory phenotype who could benefit from adjunctive anti-inflammatory medications.


Assuntos
Inflamação/sangue , Contagem de Leucócitos , Transtornos Mentais/sangue , Biomarcadores/sangue , Humanos , Inflamação/diagnóstico , Linfócitos , Transtornos Mentais/fisiopatologia , Morbidade , Neutrófilos , Prognóstico
15.
J Neuroinflammation ; 14(1): 188, 2017 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-28923068

RESUMO

BACKGROUND: Increases in pro-inflammatory cytokines are found in the brain and blood of people with schizophrenia. However, increased cytokines are not evident in all people with schizophrenia, but are found in a subset. The cytokine changes that best define this subset, termed the "elevated inflammatory biotype", are still being identified. METHODS: Using quantitative RT-PCR, we measured five cytokine mRNAs (IL-1ß, IL-2 IL-6, IL-8 and IL-18) from peripheral blood of healthy controls and of people with schizophrenia or schizoaffective disorder (n = 165). We used a cluster analysis of the transcript levels to define those with low and those with elevated levels of cytokine expression. From the same cohort, eight cytokine proteins (IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-12, IFNγ and TNFα) were measured in serum and plasma using a Luminex Magpix-based assay. We compared peripheral mRNA and protein levels across diagnostic groups and between those with low and elevated levels of cytokine expression according to our transcription-based cluster analysis. RESULTS: We found an overall decrease in the anti-inflammatory IL-2 mRNA (p = 0.006) and an increase in three serum cytokines, IL-6 (p = 0.010), IL-8 (p = 0.024) and TNFα (p < 0.001) in people with schizophrenia compared to healthy controls. A greater percentage of people with schizophrenia (48%) were categorised into the elevated inflammatory biotype compared to healthy controls (33%). The magnitude of increase in IL-1ß, IL-6, IL-8 and IL-10 mRNAs in people in the elevated inflammation biotype ranged from 100 to 220% of those in the non-elevated inflammatory biotype and was comparable between control and schizophrenia groups. Blood cytokine protein levels did not correlate with cytokine mRNA levels, and plasma levels of only two cytokines distinguished the elevated and low inflammatory biotypes, with IL-1ß significantly increased in the elevated cytokine control group and IL-8 significantly increased in the elevated cytokine schizophrenia group. CONCLUSIONS: Our results confirm that individuals with schizophrenia are more likely to have elevated levels of inflammation compared to controls. We suggest that efforts to define inflammatory status based on peripheral measures need to consider both mRNA and protein measures as each have distinct advantages and disadvantages and can yield different results.


Assuntos
Biomarcadores/sangue , Citocinas/sangue , Transtornos Psicóticos/sangue , Esquizofrenia/sangue , Adulto , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Schizophr Res ; 270: 273-280, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38944973

RESUMO

BACKGROUND: Certain antipsychotics elevate prolactin levels in patients with schizophrenia spectrum disorders (SSD), potentially affecting cognition, symptoms, and hormone levels. This study examines the association between prolactin, testosterone, and estrogen and cognition and symptoms in men with SSD, considering antipsychotic medication. METHODS: This cross-sectional study included 128 men with SSD and 44 healthy men from two trials. Patients were divided into a prolactin-sparing (n = 53) and prolactin-raising group (n = 75) based on antipsychotic medication. We examined the association between hormones (testosterone, estrogen and prolactin), and cognition and symptoms using backward linear regression. Three domains of cognition were assessed including: processing speed, verbal fluency, and working memory, while symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Prolactin levels were highest in the prolactin-raising group, followed by the control group, and lowest in the prolactin-sparing group (H = 45.279, p < .001). Testosterone and estrogen levels did not differ significantly between groups. In the prolactin-raising group, prolactin negatively correlated with testosterone (r(73) = -0.32, p = .005). Higher testosterone predicted better cognitive functioning (working memory: ß = 0.20, p = .007, verbal fluency: ß = 0.30, p = .001) and lower symptom scores (total: ß = -0.21, p = .001; negative: ß = -0.24, p = .002) in men with SSD. Conversely, higher estrogen levels related to slower processing speed (ß = -0.22, p < .001) and higher symptoms scores (ß = 0.23, p = .010) in men with SSD. CONCLUSION: The results suggest positive associations between testosterone and cognition and symptoms in men with SSD, while suggesting that high prolactin levels could relate to lower testosterone levels, possibly worsening cognition and symptoms in men with SSD.


Assuntos
Antipsicóticos , Estrogênios , Prolactina , Esquizofrenia , Testosterona , Humanos , Masculino , Prolactina/sangue , Testosterona/sangue , Adulto , Esquizofrenia/sangue , Esquizofrenia/fisiopatologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/complicações , Estudos Transversais , Estrogênios/sangue , Estrogênios/farmacologia , Antipsicóticos/farmacologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Psicologia do Esquizofrênico , Cognição/fisiologia , Cognição/efeitos dos fármacos , Escalas de Graduação Psiquiátrica , Memória de Curto Prazo/fisiologia , Memória de Curto Prazo/efeitos dos fármacos , Transtornos Psicóticos/sangue , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/fisiopatologia , Adulto Jovem
17.
Schizophr Bull ; 50(2): 403-417, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38102721

RESUMO

BACKGROUND AND HYPOTHESES: Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. STUDY DESIGN: Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. STUDY RESULTS: We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. CONCLUSIONS: The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.


Assuntos
Esquizofrenia , Receptor 3 Toll-Like , Receptor 4 Toll-Like , Receptor 8 Toll-Like , Humanos , Afinamento Cortical Cerebral , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/metabolismo , RNA Mensageiro/metabolismo , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Receptor 1 Toll-Like/metabolismo , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
18.
J Psychiatry Neurosci ; 37(6): 379-88, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22617625

RESUMO

BACKGROUND: Schizophrenia is characterized by deficits in executive control and impairments in emotion processing. This study assessed the nature and extent of potential alterations in the neural substrates supporting the interaction between cognitive control mechanisms and emotion attribution processes in people with schizophrenia. METHODS: Functional magnetic resonance imaging was performed during a verbal emotional go/no-go task. People with schizophrenia and healthy controls responded to word stimuli of a prespecified emotional valence (positive, negative or neutral) while inhibiting responses to stimuli of a different valence. RESULTS: We enrolled 20 people with schizophrenia and 23 controls in the study. Healthy controls activated an extensive dorsal prefrontal-parietal network while inhibiting responses to negative words compared to neutral words, but showed deactivation of the midcingulate cortex while inhibiting responses to positive words compared to neutral words. People with schizophrenia failed to activate this network during response inhibition to negative words, whereas during response inhibition to positive words they did not deactivate the cingulate, but showed increased responsivity in the frontal cortex. LIMITATIONS: Sample heterogeneity is characteristic of studies of schizophrenia and may have contributed to more variable neural responses in the patient sample despite the care taken to control for potentially confounding variables. CONCLUSION: Our results showed that schizophrenia is associated with aberrant modulation of neural responses during the interaction between cognitive control and emotion processing. Failure of the frontal circuitry to regulate goal-directed behaviour based on emotion attributions may contribute to deficits in psychosocial functioning in daily life.


Assuntos
Emoções/fisiologia , Inibição Psicológica , Idioma , Imageamento por Ressonância Magnética/métodos , Rede Nervosa/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Mapeamento Encefálico , Função Executiva/fisiologia , Feminino , Giro do Cíngulo/patologia , Giro do Cíngulo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/instrumentação , Masculino , Rede Nervosa/patologia , Testes Neuropsicológicos , Lobo Parietal/patologia , Lobo Parietal/fisiopatologia , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Adulto Jovem
19.
Cereb Cortex ; 21(8): 1879-88, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21216842

RESUMO

Neuroimaging studies have shown both dorsolateral prefrontal (DLPFC) and inferior parietal cortex (iPARC) activation during probabilistic association learning. Whether these cortical brain regions are necessary for probabilistic association learning is presently unknown. Participants' ability to acquire probabilistic associations was assessed during disruptive 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the left DLPFC, left iPARC, and sham using a crossover single-blind design. On subsequent sessions, performance improved relative to baseline except during DLPFC rTMS that disrupted the early acquisition beneficial effect of prior exposure. A second experiment examining rTMS effects on task-naive participants showed that neither DLPFC rTMS nor sham influenced naive acquisition of probabilistic associations. A third experiment examining consecutive administration of the probabilistic association learning test revealed early trial interference from previous exposure to different probability schedules. These experiments, showing disrupted acquisition of probabilistic associations by rTMS only during subsequent sessions with an intervening night's sleep, suggest that the DLPFC may facilitate early access to learned strategies or prior task-related memories via consolidation. Although neuroimaging studies implicate DLPFC and iPARC in probabilistic association learning, the present findings suggest that early acquisition of the probabilistic cue-outcome associations in task-naive participants is not dependent on either region.


Assuntos
Aprendizagem por Associação/fisiologia , Lobo Parietal/fisiologia , Córtex Pré-Frontal/fisiologia , Aprendizagem por Probabilidade , Adolescente , Adulto , Aprendizagem por Associação/efeitos da radiação , Estudos Cross-Over , Feminino , Humanos , Estudos Longitudinais , Masculino , Lobo Parietal/anatomia & histologia , Lobo Parietal/efeitos da radiação , Córtex Pré-Frontal/anatomia & histologia , Córtex Pré-Frontal/efeitos da radiação , Estudos Prospectivos , Método Simples-Cego , Estimulação Magnética Transcraniana/efeitos adversos , Estimulação Magnética Transcraniana/métodos , Adulto Jovem
20.
Transl Psychiatry ; 12(1): 21, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35027554

RESUMO

Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1ß and IFN-γ mRNAs were increased in patients compared to controls (both p < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1ß mRNA and high levels of plasma CRP defined 'high inflammation' individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying 'high inflammation' compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (all p < 0.01), while NF-κB-inducing kinase mRNAs IKKß and NIK were downregulated in patients (all p < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKß and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.


Assuntos
NF-kappa B , Esquizofrenia , Anti-Inflamatórios , Humanos , Inflamação , Doenças Neuroinflamatórias , Proteínas Serina-Treonina Quinases , Quinase Induzida por NF-kappaB
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