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1.
Mol Psychiatry ; 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33976392

RESUMO

The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3-/- mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1ß, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3-/- mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.

2.
J Hepatol ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33894327

RESUMO

BACKGROUND: Golexanolone is a novel small molecule GABA-A receptor modulating steroid antagonist under development for treatment of cognitive and vigilance disorders due to allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Here we report golexanolone safety, pharmacokinetics (PK) and effects on the electroencephalogram (EEG), subjective sleepiness and cognitive performance in adult patients with cirrhosis. METHODS: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks' dosing with golexanolone (10, 40 or 80mg bid) or placebo. CRT, Psychometric Hepatic Encephalopathy Score (PHES), Animal Naming Test (ANT), Epworth Sleepiness Scale (ESS) and EEG (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days. RESULTS: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 subjects randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p=0.047), MDF (p=0.142) and DT/AB (p=0.021). All subjects also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well. CONCLUSION: Golexanolone was well tolerated and associated with improvement in cognitive performance. The results implicate GABA-A receptor modulating neurosteroids in the pathogenesis of HE and suggest that golexanolone deserves further study as a potential therapeutic. LAY SUMMARY: Many patients with liver cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of the study suggest that golexanolone is well tolerated and may improve cognition as reflected by measures of sleepiness, attention span and brain wave activity and they pave the way for future larger studies of this promising experimental drug. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2016-003651-30.

3.
Sci Rep ; 11(1): 1155, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441847

RESUMO

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

4.
Front Psychiatry ; 11: 586083, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132941

RESUMO

Bipolar disorder is a severe psychiatric disorder which affects more than 1% of the world's population and is a leading cause of disability among young people. For the past 50 years, lithium has been the drug of choice for maintenance treatment of bipolar disorder due to its potent ability to prevent both manic and depressive episodes as well as suicide. However, though lithium has been associated with a multitude of effects within different cellular pathways and biological systems, its specific mechanism of action in stabilizing mood remains largely elusive. Mitochondrial dysfunction and telomere shortening have been implicated in both the pathophysiology of bipolar disorder and as targets of lithium treatment. Interestingly, it has in recent years become clear that these phenomena are intimately linked, partly through reactive oxygen species signaling and the subcellular translocation and non-canonical actions of telomerase reverse transcriptase. In this review, we integrate the current understanding of mitochondrial dysfunction, oxidative stress and telomere shortening in bipolar disorder with documented effects of lithium. Moreover, we propose that lithium's mechanism of action is intimately connected with the interdependent regulation of mitochondrial bioenergetics and telomere maintenance.

5.
Eur J Pain ; 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33064887

RESUMO

BACKGROUND: Dysregulation of the µ-opioid receptor has been reported in fibromyalgia (FM) and was linked to pain severity. Here, we investigated the effect of the functional genetic polymorphism of the µ-opioid receptor gene (OPRM1) (rs1799971) on symptom severity, pain sensitivity and cerebral pain processing in FM subjects and healthy controls (HC). METHODS: Symptom severity and pressure pain sensitivity was assessed in FM subjects (n = 70) and HC (n = 35). Cerebral pain-related activation was assessed by functional magnetic resonance imaging during individually calibrated painful pressure stimuli. RESULTS: Fibromyalgia subjects were more pain sensitive but no significant differences in pain sensitivity or pain ratings were observed between OPRM1 genotypes. A significant difference was found in cerebral pain processing, with carriers of at least one G-allele showing increased activation in posterior cingulate cortex (PCC) extending to precentral gyrus, compared to AA homozygotes. This effect was significant in FM subjects but not in healthy participants, however, between-group comparisons did not yield significant results. Seed-based functional connectivity analysis was performed with the seed based on differences in PCC/precentral gyrus activation between OPRM1 genotypes during evoked pain across groups. G-allele carriers displayed decreased functional connectivity between PCC/precentral gyrus and prefrontal cortex. CONCLUSIONS: G-allele carriers showed increased activation in PCC/precentral gyrus but decreased functional connectivity with the frontal control network during pressure stimulation, suggesting different pain modulatory processes between OPRM1 genotypes involving altered fronto-parietal network involvement. Furthermore, our results suggest that the overall effects of the OPRM1 G-allele may be driven by FM subjects. SIGNIFICANCE: We show that the functional polymorphism of the µ-opioid receptor gene OPRM1 was associated with alterations in the fronto-parietal network as well as with increased activation of posterior cingulum during evoked pain in FM. Thus, the OPRM1 polymorphism affects cerebral processing in brain regions implicated in salience, attention, and the default mode network. This finding is discussed in the light of pain and the opioid system, providing further evidence for a functional role of OPRM1 in cerebral pain processing.

6.
Blood ; 2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32814349

RESUMO

Interferon alpha (IFNα) based therapies can induce hematologic and molecular responses in polycythemia vera (PV); however, patients do not respond equally. Germline genetic factors have previously been implicated in differential drug response. We addressed the effect of common germline polymorphisms on hematologic and molecular response (HR/MR) in PV therapy within the PROUD-PV and CONTINUATION-PV studies including 122 patients with PV receiving ropeginterferon alfa-2b. Genome-wide association studies using longitudinal data on HR and MR over 36 months follow-up did not reveal any associations at genome-wide significance. Further, we performed targeted association analyses at the interferon lambda 4 (IFNL4) locus, well known for its role in hepatitis C viral clearance and recently reported to influence HR during therapy of myeloproliferative neoplasms. While we did not observe any association of IFNL4 polymorphisms with HR in our study cohort, we demonstrated a statistically significant effect of the functionally causative IFNL4 diplotype (haplotype pair including the protein-coding variants rs368234815/rs117648444) on MR (p=3.91x10-4; OR=10.80; 95%CI:[2.39-69.97]) as reflected in differential JAK2V617F mutational burden changes according to IFNL4 diplotype status. Stratification of PV patients based on IFNL4 functionality may allow for optimizing patient management during IFNα treatment.

7.
Brain Behav Immun ; 89: 9-19, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32497779

RESUMO

Some prebiotics and probiotics have been proposed to improve psychiatric symptoms in children with autism. However, few studies were placebo-controlled, and there is no study on persons with an attention deficit hyperactivity disorder (ADHD) diagnosis. Our aim was to study effects of Synbiotic 2000 on psychiatric symptoms and functioning in children and adults with ADHD without an autism diagnosis. Children and adults (n = 182) with an ADHD diagnosis completed the nine weeks randomized double-blind parallel placebo-controlled trial examining effects of Synbiotic 2000 on the primary endpoints ADHD symptoms, autism symptoms and daily functioning, and the secondary endpoint emotion regulation, measured using the questionnaires SNAP-IV, ASRS, WFIRS, SCQ, AQ and DERS-16. Levels at baseline of plasma C-reactive protein and soluble vascular cell adhesion molecule-1 (sVCAM-1), central to leukocyte-endothelial cell adhesion facilitating inflammatory responses in tissues, were measured using Meso Scale Discovery. Synbiotic 2000 and placebo improved ADHD symptoms equally well, and neither active treatment nor placebo had any statistically significant effect on functioning or sub-diagnostic autism symptoms. However, Synbiotic 2000, specifically, reduced sub-diagnostic autism symptoms in the domain restricted, repetitive and stereotyped behaviors in children, and improved emotion regulation in the domain of goal-directed behavior in adults. In children with elevated sVCAM-1 levels at baseline as well as in children without ADHD medication, Synbiotic 2000 reduced both the total score of autism symptoms, and the restricted, repetitive and stereotyped behaviors. In adults with elevated sVCAM-1 at baseline, Synbiotic 2000 significantly improved emotion regulation, both the total score and four of the five subdomains. To conclude, while no definite Synbiotic 2000-specific effect was detected, the analysis of those with elevated plasma sVCAM-1 levels proposed a reduction of autism symptoms in children and an improvement of emotion regulation in adults with ADHD. Trial registration number: ISRCTN57795429.

8.
Mol Neuropsychiatry ; 5(Suppl 1): 44-59, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32399469

RESUMO

Glutamate is implicated in the neuropathology of both major depressive disorder and bipolar disorder. Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the mammalian brain, removing glutamate from the synaptic cleft and transporting it into glia for recycling. It is thereby the principal regulator of extracellular glutamate levels and prevents neuronal excitotoxicity. EAAT2 is a promising target for elucidating the mechanisms by which the glutamate-glutamine cycle interacts with neuronal systems in mood disorders. Forty EAAT2 studies (published January 1992-January 2018) were identified via a systematic literature search. The studies demonstrated that chronic stress/steroids were most commonly associated with decreased EAAT2. In rodents, EAAT2 inhibition worsened depressive behaviors. Human EAAT2 expression usually decreased in depression, with some regional brain differences. Fewer data have been collected regarding the roles and regulation of EAAT2 in bipolar disorder. Future directions for research include correlating EAAT2 and glutamate levels in vivo, elucidating genetic variability and epigenetic regulation, clarifying intracellular protein and pharmacologic interactions, and examining EAAT2 in different bipolar mood states. As part of a macromolecular complex within glia, EAAT2 may contribute significantly to intracellular signaling, energy regulation, and cellular homeostasis. An enhanced understanding of this system is needed.

9.
Brain Behav Immun ; 88: 718-724, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32389698

RESUMO

Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and relapse rates. Even though changes in inflammatory markers and cytokines are known to accompany cachexia associated with somatic disorders such as cancer and chronic kidney disorder, studies on inflammatory markers in AN are rare and typically include few individuals. Here, we utilize an Olink Proteomics inflammatory panel to explore the concentrations of 92 preselected inflammation-related proteins in plasma samples from women with active AN (N = 113), recovered from AN (AN-REC, N = 113), and normal weight healthy controls (N = 114). After correction for multiple testing, twenty-five proteins differed significantly between the AN group and controls (lower levels: ADA, CCL19, CD40, CD5, CD8A, CSF1, CXCL1, CXCL5, HGF, IL10RB, IL12B, 1L18R1, LAP TGFß1, MCP3, OSM, TGFα, TNFRSF9, TNFS14 and TRANCE; higher levels: CCL11, CCL25, CST5, DNER, LIFR and OPG). Although more than half of these differences (N = 15) were present in the comparison between AN and AN-REC, no significant differences were seen between AN-REC and controls. Furthermore, twenty-five proteins correlated positively with BMI (ADA, AXIN1, CASP8, CD5, CD40, CSF1, CXCL1, CXCL5, EN-RAGE, HGF, IL6, IL10RB, IL12B, IL18, IL18R1, LAP TGFß1, OSM, SIRT2, STAMBP, TGFα, TNFRSF9, TNFS14, TRANCE, TRAIL and VEGFA) and four proteins correlated negatively with BMI (CCL11, CCL25, CCL28 and DNER). These results suggest that a dysregulated inflammatory status is associated with AN, but, importantly, seem to be confined to the acute illness state.

10.
Psychiatry Res ; 286: 112865, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32114208

RESUMO

Bipolar disorder (BD) may be associated with accelerated cellular aging. However, previous studies on telomere length (TL), an important biomarker of cellular aging, have yielded mixed results in BD. We aimed to evaluate the hypothesis that BD is associated with telomere shortening and whether this is counteracted by long-term lithium treatment. We also sought to determine whether long-term lithium treatment is associated with increased expression of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase. We determined TL and TERT expression in 100 BD I patients and 100 healthy controls. We also genotyped three single nucleotide polymorphisms associated with TL. TERT expression was significantly increased in BD I patients currently on lithium treatment. TERT expression was also significantly positively correlated with duration of lithium treatment in patients treated for 24 months or more. However, we did not find any significant effect of lithium treatment on TL. Neither did we find significant differences in TL between BD patients and controls. We suggest that long-term lithium treatment is associated with an increase in the expression of TERT. We hypothesize that an increase in TERT expression may contribute to lithium's mood stabilizing and neuroprotective properties by improving mitochondrial function and decreasing oxidative stress.


Assuntos
Envelhecimento/metabolismo , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Senescência Celular/genética , Compostos de Lítio/uso terapêutico , Lítio/uso terapêutico , Telomerase/metabolismo , Adulto , Envelhecimento/genética , Transtorno Bipolar/sangue , Senescência Celular/efeitos dos fármacos , Feminino , Humanos , Compostos de Lítio/farmacologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Reação em Cadeia da Polimerase em Tempo Real , Telomerase/efeitos dos fármacos , Telomerase/genética , Telômero/efeitos dos fármacos , Telômero/genética , Telômero/metabolismo , Homeostase do Telômero/genética , Encurtamento do Telômero/efeitos dos fármacos , Encurtamento do Telômero/genética
11.
Psychiatry Res ; 284: 112677, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31810747

RESUMO

AKT1 encodes a serine/threonine kinase that has as one of its best-known substrates glycogen synthase kinase-3 (GSK3), a primary target for lithium. AKT1 has been previously been implicated as a vulnerability gene for bipolar disorder (BD). We aimed to associate genetic variants in the AKT1 gene with subgroups of BD. BD patients from a Swedish cohort (N = 831) were phenotyped in regards to their psychotic episodes according to mood-congruence in depression and manias, and compared to controls (N = 1,496). All participants were genotyped for SNPs in AKT1 previously implicated to have a role: rs3730358, rs1130214 and rs3803300. None of the effects reported in earlier studies were statistically significant, including the association between rs3803300 and BD without any psychotic symptoms, rs3803300 and mood-congruent psychosis, rs3803300 and the combined groups, as well as the association between the haplotypes formed by rs3730358 and rs1130214 and risk for BD. In a Bayesian analysis, all Bayes' Factors using default priors supported the null hypothesis in the replication set by a factor of between 5 and 1300 times. Analysis of genome wide association data did not reveal any association between BD and the AKT1 region. We conclude AKT1 is less likely to be a vulnerability gene in BD.


Assuntos
Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Proteínas Proto-Oncogênicas c-akt/genética , Adulto , Transtorno Bipolar/diagnóstico , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Suécia/epidemiologia
12.
J Affect Disord ; 260: 597-603, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541970

RESUMO

BACKGROUND: The TIA1 gene encodes a prion-related RNA-binding protein that regulates stress-dependent synaptic plasticity and fear memory in mice. It is unknown whether genetic variation in human TIA1 is associated with differences in stress- and fear-related behavior in people. METHODS: A longitudinal, population-based survey was conducted in Sweden to collect information on demographics, socioeconomic status, exposure to stressful life events and psychiatric symptoms. DNA samples were obtained from study participants to allow genotyping of single-nucleotide polymorphisms in the human TIA1 locus. RESULTS: We identified a single-nucleotide polymorphism in the human TIA1 gene that interacts with exposure to previous-year stressful life events to predict the development of pathological anxiety symptoms in a non-clinical cohort. LIMITATIONS: Sample population is limited in both size and scope, and we did not perform functional analysis of allelic variants of TIA1. CONCLUSIONS: TIA1 may represent a susceptibility locus for stress-dependent psychopathology. These studies support an evolutionarily conserved role of TIA1 in the mammalian brain, and may provide molecular and genetic insight into the development of stress-related psychiatric conditions such as PTSD and anxiety.


Assuntos
Transtornos de Ansiedade/genética , Polimorfismo de Nucleotídeo Único , Estresse Psicológico/genética , Antígeno-1 Intracelular de Células T/genética , Adulto , Alelos , Transtornos de Ansiedade/psicologia , Estudos de Coortes , Feminino , Interação Gene-Ambiente , Técnicas de Genotipagem , Humanos , Acontecimentos que Mudam a Vida , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estresse Psicológico/psicologia , Suécia , Adulto Jovem
13.
Transl Psychiatry ; 9(1): 317, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772217

RESUMO

Early life exposure to infection, anti-infectives and altered immune activity have been associated with elevated risk of some psychiatric disorders. However, the risk from exposure in fetal life has been proposed to be confounded by familial factors. The hypothesis of this study is that antibiotic drug exposure during the fetal period and the first two postnatal years is associated with risk for later development of psychiatric disorders in children. All births in Finland between 1996 and 2012, 1 million births, were studied for antibiotic drug exposure: mothers during pregnancy and the children the first two postnatal years. The children were followed up for a wide spectrum of psychiatric diagnoses and psychotropic drug treatment until 2014. Cox proportional hazards modeling was used to estimate effects of antibiotic drug exposure on offspring psychiatric disorders. Modestly (10-50%) increased risks were found on later childhood development of sleep disorders, ADHD, conduct disorder, mood and anxiety disorders, and other behavioral and emotional disorders with childhood onset (ICD-10 F98), supported by increased risks also for childhood psychotropic medication. The prenatal exposure effects detected were not explained by explored familial confounding, nor by registered maternal infections. To conclude, this longitudinal nation-wide study shows that early life antibiotic drug exposure is associated with an increased risk for childhood development of psychopathology. Given the high occurrence of early-life antibiotic exposure, these findings are of public health relevance. Whether the associations reflect effects of the antibiotic drug use or of the targeted infections remains to be explored further.


Assuntos
Antibacterianos/uso terapêutico , Exposição Materna/efeitos adversos , Transtornos do Neurodesenvolvimento/etiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Adulto , Pré-Escolar , Feminino , Finlândia/epidemiologia , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Transtornos do Neurodesenvolvimento/epidemiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores de Risco
14.
Mol Psychiatry ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712720

RESUMO

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

15.
Sci Rep ; 9(1): 16377, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690807

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

16.
Transl Psychiatry ; 9(1): 180, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371701

RESUMO

Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and, to a large extent, unknown pathophysiology. Structural brain differences, such as global or focal reductions in grey or white matter volumes, as well as enlargement of the sulci and the ventricles, have repeatedly been observed in individuals with AN. However, many of the documented aberrances normalize with weight recovery, even though some studies show enduring changes. To further explore whether AN is associated with neuronal damage, we analysed the levels of neurofilament light chain (NfL), a marker reflecting ongoing neuronal injury, in plasma samples from females with AN, females recovered from AN (AN-REC) and normal-weight age-matched female controls (CTRLS). We detected significantly increased plasma levels of NfL in AN vs CTRLS (medianAN = 15.6 pg/ml, IQRAN = 12.1-21.3, medianCTRL = 9.3 pg/ml, IQRCTRL = 6.4-12.9, and p < 0.0001), AN vs AN-REC (medianAN-REC = 11.1 pg/ml, IQRAN-REC = 8.6-15.5, and p < 0.0001), and AN-REC vs CTRLS (p = 0.004). The plasma levels of NfL are negatively associated with BMI overall samples (ß (±se) = -0.62 ± 0.087 and p = 6.9‧10-12). This indicates that AN is associated with neuronal damage that partially normalizes with weight recovery. Further studies are needed to determine which brain areas are affected, and potential long-term sequelae.


Assuntos
Anorexia Nervosa/sangue , Proteínas de Neurofilamentos/sangue , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem
17.
Blood ; 134(2): 199-210, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31064751

RESUMO

Ph-negative myeloproliferative neoplasms (MPNs) are hematological cancers that can be subdivided into entities with distinct clinical features. Somatic mutations in JAK2, CALR, and MPL have been described as drivers of the disease, together with a variable landscape of nondriver mutations. Despite detailed knowledge of disease mechanisms, targeted therapies effective enough to eliminate MPN cells are still missing. In this study of 113 MPN patients, we aimed to comprehensively characterize the mutational landscape of the granulocyte transcriptome using RNA sequencing data and subsequently examine the applicability of immunotherapeutic strategies for MPN patients. Following implementation of customized workflows and data filtering, we identified a total of 13 (12/13 novel) gene fusions, 231 nonsynonymous single nucleotide variants, and 21 insertions and deletions in 106 of 113 patients. We found a high frequency of SF3B1-mutated primary myelofibrosis patients (14%) with distinct 3' splicing patterns, many of these with a protein-altering potential. Finally, from all mutations detected, we generated a virtual peptide library and used NetMHC to predict 149 unique neoantigens in 62% of MPN patients. Peptides from CALR and MPL mutations provide a rich source of neoantigens as a result of their unique ability to bind many common MHC class I molecules. Finally, we propose that mutations derived from splicing defects present in SF3B1-mutated patients may offer an unexplored neoantigen repertoire in MPNs. We validated 35 predicted peptides to be strong MHC class I binders through direct binding of predicted peptides to MHC proteins in vitro. Our results may serve as a resource for personalized vaccine or adoptive cell-based therapy development.


Assuntos
Antígenos de Neoplasias/genética , Transtornos Mieloproliferativos/genética , Idoso , Calreticulina/genética , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de Trombopoetina/genética , Análise de Sequência de RNA/métodos , Transcriptoma
18.
Transl Psychiatry ; 9(1): 149, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123248

RESUMO

Glutamatergic dysregulation is implicated in the neurobiology of mood disorders. This study investigated the relationship between the anterior cingulate cortex (AC) glutamate, as measured by proton magnetic resonance spectroscopy (1H-MRS), and single-nucleotide polymorphisms (SNPs) from four genes (GLUL, SLC1A3, SLC1A2, and SLC1A7) that regulate the extracellular glutamate in 26 depressed patients with major depressive disorder (MDD; n = 15) and bipolar disorder (BD; n = 11). Two SNPs (rs3812778 and rs3829280), in perfect linkage disequilibrium, in the 3' untranslated region of the EAAT2 gene SLC1A2, were associated with AC glutamate, with minor allele carriers having significantly higher glutamate levels (p < 0.001) in comparison with common allele homozygotes. In silico analysis revealed an association of minor allele carriers of rs3812778/rs382920 with an upregulation of the astrocytic marker CD44 localized downstream of SLC1A2 on chromosome 11. Finally, we tested the disease relevance of these SNPs in a large group of depressed patients [MDD (n = 458); BD (n = 1473)] and found that minor allele carriers had a significantly higher risk for rapid cycling (p = 0.006). Further work is encouraged to delineate the functional impact of excitatory amino acid transporter genetic variation on CD44 associated physiology and glutamatergic neurotransmission, specifically glutamate-glutamine cycling, and its contribution to subphenotypes of mood disorders.


Assuntos
Transtorno Bipolar , Transtorno Depressivo Maior , Transportador 2 de Aminoácido Excitatório/genética , Ácido Glutâmico/metabolismo , Giro do Cíngulo/metabolismo , Adulto , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Estudos de Coortes , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Feminino , Giro do Cíngulo/diagnóstico por imagem , Humanos , Receptores de Hialuronatos/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Espectroscopia de Prótons por Ressonância Magnética
19.
Transl Psychiatry ; 9(1): 150, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123309

RESUMO

Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (rg ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h2SNP) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h2SNP could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental/estatística & dados numéricos , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/terapia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Adulto , Criança , Humanos
20.
Biol Psychiatry ; 86(2): 110-119, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30686506

RESUMO

BACKGROUND: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.


Assuntos
Transtorno Bipolar/genética , Variações do Número de Cópias de DNA/genética , Transtornos Psicóticos/genética , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Estudos de Coortes , Duplicação Gênica/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Transtornos Psicóticos/psicologia , Esquizofrenia/genética
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