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1.
BMC Cancer ; 23(1): 437, 2023 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-37179293

RESUMEN

BACKGROUND: The most common subtype of ovarian cancer (OC) showing immunogenic potential is represented by the high-grade serous ovarian cancer (HGSOC), which is characterized by the presence of tumor-infiltrating immune cells able to modulate immune response. Because several studies showed a close correlation between OC patient's clinical outcome and expression of programmed cell death protein-1 or its ligand (PD-1/PD-L1), the aim of our study was to investigate if plasma levels of immunomodulatory proteins may predict prognosis of advanced HGSOC women. PATIENTS AND METHODS: Through specific ELISA tests, we analyzed plasma concentrations of PD-L1, PD-1, butyrophilin sub-family 3A/CD277 receptor (BTN3A1), pan-BTN3As, butyrophilin sub-family 2 member A1 (BTN2A1), and B- and T-lymphocyte attenuator (BTLA) in one hundred patients affected by advanced HGSOC, before surgery and therapy. The Kaplan-Meier method was used to generate the survival curves, while univariate and multivariate analysis were performed using Cox proportional hazard regression models. RESULTS: For each analyzed circulating biomarker, advanced HGSOC women were discriminated based on long (≥ 30 months) versus short progression-free survival (PFS < 30 months). The concentration cut-offs, obtained by receiver operating characteristic (ROC) analysis, allowed to observe that poor clinical outcome and median PFS ranging between 6 and 16 months were associated with higher baseline levels of PD-L1 (> 0.42 ng/mL), PD-1 (> 2.48 ng/mL), BTN3A1 (> 4.75 ng/mL), pan-BTN3As (> 13.06 ng/mL), BTN2A1 (> 5.59 ng/mL) and BTLA (> 2.78 ng/mL). Furthermore, a lower median PFS was associated with peritoneal carcinomatosis, age at diagnosis > 60 years or Body Mass Index (BMI) > 25. A multivariate analysis also suggested that plasma concentrations of PD-L1 ≤ 0.42 ng/mL (HR: 2.23; 95% CI: 1.34 to 3.73; p = 0.002), age at diagnosis ≤ 60 years (HR: 1.70; 95% CI: 1.07 to 2.70; p = 0.024) and absence of peritoneal carcinomatosis (HR: 1.87; 95% CI: 1.23 to 2.85; p = 0.003) were significant prognostic marker for a longer PFS in advanced HGSOC patients. CONCLUSIONS: The identification of high-risk HGSOC women could be improved through determination of the plasma PD-L1, PD-1, BTN3A1, pan-BTN3As, BTN2A1 and BTLA levels.


Asunto(s)
Neoplasias Ováricas , Neoplasias Peritoneales , Humanos , Femenino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/uso terapéutico , Antígeno B7-H1/metabolismo , Pronóstico , Neoplasias Ováricas/metabolismo , Butirofilinas , Antígenos CD
2.
J Psychiatry Neurosci ; 48(5): E357-E366, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37751917

RESUMEN

BACKGROUND: Among healthy participants, the interindividual variability of brain response to facial emotions is associated with genetic variation, including common risk variants for schizophrenia, a heritable brain disorder characterized by anomalies in emotion processing. We aimed to identify genetic variants associated with heritable brain activity during processing of facial emotions among healthy participants and to explore the impact of these identified variants among patients with schizophrenia. METHODS: We conducted a data-driven stepwise study including samples of healthy twins, unrelated healthy participants and patients with schizophrenia. Participants approached or avoided pictures of faces with negative emotional valence during functional magnetic resonance imaging (fMRI). RESULTS: We investigated 3 samples of healthy participants - including 28 healthy twin pairs, 289 unrelated healthy participants (genome-wide association study [GWAS] discovery sample) and 90 unrelated healthy participants (replication sample) - and 1 sample of 48 patients with schizophrenia. Among healthy twins, we identified the amygdala as the brain region with the highest heritability during processing of angry faces (heritability estimate 0.54, p < 0.001). Subsequent GWAS in both discovery and replication samples of healthy non-twins indicated that amygdala activity was associated with a polymorphism in the miR-137 locus (rs1198575), a micro-RNA strongly involved in risk for schizophrenia. A significant effect in the same direction was found among patients with schizophrenia (p = 0.03). LIMITATIONS: The limited sample size available for GWAS analyses may require further replication of results. CONCLUSION: Our data-driven approach shows preliminary evidence that amygdala activity, as evaluated with our task, is heritable. Our genetic associations preliminarily suggest a role for miR-137 in brain activity during explicit processing of facial emotions among healthy participants and patients with schizophrenia, pointing to the amygdala as a brain region whose activity is related to miR-137.


Asunto(s)
MicroARNs , Esquizofrenia , Humanos , Amígdala del Cerebelo/diagnóstico por imagen , Ira , Estudio de Asociación del Genoma Completo , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/genética , Estudios de Casos y Controles
3.
Nutr Metab Cardiovasc Dis ; 32(7): 1635-1641, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35508458

RESUMEN

BACKGROUND AND AIMS: Remdesivir (GS-5734), an inhibitor of the viral RNA-dependent, RNA polymerase was early identified as a promising therapeutic candidate against COVID-19. Our aim was to evaluate the impact of several metabolic parameters on Remdesivir effectiveness among hospitalized COVID-19 patients. METHODS AND RESULTS: We conducted an observational study on patients with SARS-CoV-2-related pneumonia admitted between May 2020 and September 2021 to the COVID-19 Units of Internal Medicine, Pneumology and Intensive Care of Garibaldi Hospital, Catania, Italy, and treated with Remdesivir. The "Ordinal Scale For Clinical Improvement" was used to assess patients' clinical improvement within 28 days of hospitalization. Short-term mortality rate was also evaluated. A total of 142 patients with SARS-CoV-2-related pneumonia were studied. The prevalence of obesity (20.7% vs. 41.9%, p = 0.03), the average BMI (27.1 ± 4.4 vs. 31.1 ± 6.1, p < 0.01) and the mean LDL-C levels (78 ± 19 mg/dl vs. 103 ± 18 mg/dl, p = 0.03) were significantly lower in early-improved (EI) compared to not-improved (NI) individuals. Obesity was negatively associated to clinical improvement after Remdesivir (OR 0.48, 95%CI 0.17-0.97, p = 0.04). Both obesity (OR 2.82, 95% CI 1.05-7.71, p = 0.04) and dyslipidemia (OR 2.78, 95%CI 1.17-7.16, p = 0.03) were significantly related to patients' mortality. Dyslipidemic subjects experienced a slower clinical improvement than non-dyslipidemic ones (Long-Rank p = 0.04). CONCLUSION: Our study showed that unfavorable metabolic conditions such as obesity and dyslipidemia could predict a worse clinical response to Remdesivir as well as the mortality in hospitalized COVID-19 patients. Further prospective and larger-scale studies are needed to confirm these preliminary findings.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Dislipidemias , Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/efectos adversos , Dislipidemias/diagnóstico , Dislipidemias/tratamiento farmacológico , Dislipidemias/epidemiología , Humanos , Obesidad/diagnóstico , Obesidad/tratamiento farmacológico , SARS-CoV-2
4.
Cerebellum ; 19(1): 40-47, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31637587

RESUMEN

The clinical spectrum of spinocerebellar ataxia type 2 includes motor manifestations and cognitive disturbances in executive functions, memory, and visuoconstructive skills. The relationships between severity of motor disturbances and altered cognition are poorly known. In this study, we assessed patients with spinocerebellar ataxia type 2 and age- and sex-matched healthy control subjects by a test battery including the Mini-mental State Examination, the Wisconsin Card Sorting test, and the Wechsler Memory Scale-Revised. The correlation between severity of motor ataxia (as assessed by a validated and widely used severity scale, the SARA scale, and by an objective automated computerized system of gait analysis) and altered cognition was then evaluated by Spearman correlation analysis. Patients performed worse than healthy controls in almost all administered neuropsychological tests. Nevertheless, only global intellectual abilities and executive functions significantly correlated with the overall severity of ataxia as assessed by the SARA scale, and impaired executive functions alone correlated with performance on several spatio-temporal gait analysis parameters. Our findings would probably suggest a prominent influence of executive functions on motor abilities in patients with spinocerebellar ataxia type 2 and raise the possibility that cognitive pharmaceutical or rehabilitative interventions may be of benefit in the management of motor problems in these patients.


Asunto(s)
Cognición/fisiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Pruebas Neuropsicológicas , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/psicología , Adulto , Anciano , Estudios de Casos y Controles , Disfunción Cognitiva/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ataxias Espinocerebelosas/epidemiología
5.
Proc Natl Acad Sci U S A ; 108(3): 1158-63, 2011 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-21187413

RESUMEN

The D2/AKT1/GSK-3ß signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3ß proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3ß, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.


Asunto(s)
Antipsicóticos/farmacología , Atención/fisiología , Benzodiazepinas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Transducción de Señal/fisiología , Antipsicóticos/uso terapéutico , Atención/efectos de los fármacos , Benzodiazepinas/uso terapéutico , AMP Cíclico/metabolismo , Epistasis Genética , Genotipo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Imagen por Resonancia Magnética , Olanzapina , Fosforilación , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Receptores de Dopamina D2/genética , Esquizofrenia/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
6.
Artículo en Inglés | MEDLINE | ID: mdl-38000716

RESUMEN

BACKGROUND: miR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-wide association studies have implicated miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing. METHODS: Using RNA sequencing data from postmortem prefrontal cortex (N = 522), we identified a coexpression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of coexpression prediction and associated them with functional magnetic resonance imaging activation in healthy volunteers (n1 = 214; n2 = 136; n3 = 2075; n4 = 1800) and with short-term treatment response in patients with schizophrenia (N = 427). RESULTS: In 4652 human participants, we found that 1) schizophrenia risk genes were coexpressed in a biologically validated set enriched for miR-137 targets; 2) increased expression of miR-137 target risk genes was mediated by low prefrontal miR-137 expression; 3) alleles that predict greater gene set coexpression were associated with greater prefrontal activation during emotion processing in 3 independent healthy cohorts (n1, n2, n3) in interaction with age (n4); and 4) these alleles predicted less improvement in negative symptoms following antipsychotic treatment in patients with schizophrenia. CONCLUSIONS: The functional translation of miR-137 target gene expression linked with schizophrenia involves the neural substrates of emotion processing.


Asunto(s)
MicroARNs , Esquizofrenia , Humanos , Estudio de Asociación del Genoma Completo , Encéfalo , MicroARNs/genética , MicroARNs/metabolismo , Emociones
7.
J Neurosci ; 31(18): 6692-8, 2011 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-21543598

RESUMEN

DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val(158) allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val(158) allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val(158) allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.


Asunto(s)
Catecol O-Metiltransferasa/genética , Cognición/fisiología , Metilación de ADN , Memoria a Corto Plazo/fisiología , Corteza Prefrontal/fisiología , Estrés Psicológico/fisiopatología , Adulto , Alelos , Animales , Western Blotting , Catecol O-Metiltransferasa/metabolismo , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Polimorfismo Genético , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Encuestas y Cuestionarios
8.
Front Oncol ; 12: 946319, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36212445

RESUMEN

The most common subtype of ovarian cancer (OC) is the high-grade serous ovarian carcinoma (HGSOC), accounting for 70%-80% of all OC deaths. Although HGSOC is a potentially immunogenic tumor, clinical studies assessing the effectiveness of inhibitors of programmed death protein and its ligand (PD-1/PD-L1) in OC patients so far showed only response rates <15%. However, recent studies revealed an interesting prognostic role of plasma PD-1/PD-L1 and other circulating immunoregulatory molecules, such as the B- and T-lymphocyte attenuator (BTLA), butyrophilin sub-family 3A/CD277 receptors (BTN3A), and butyrophilin sub-family 2 member A1 (BTN2A1), in several solid tumors. Since evidence showed the prognostic relevance of pretreatment serum CA125 levels in OC, the aim of our study was to investigate if soluble forms of inhibitory immune checkpoints can enhance prognostic power of CA125 in advanced HGSOC women. Using specific ELISA tests, we examined the circulating PD-1, PD-L1, pan-BTN3As, BTN3A1, BTN2A1, and BTLA levels in 100 advanced HGSOC patients before treatment, correlating them with baseline serum CA125, age at diagnosis, body mass index (BMI), and peritoneal carcinomatosis. A multivariate analysis revealed that plasma BTN3A1 ≤4.75 ng/ml (HR, 1.94; 95% CI, 1.23-3.07; p=0.004), age at diagnosis ≤60 years (HR, 1.65; 95% CI, 1.05-2.59; p=0.03) and absence of peritoneal carcinomatosis (HR, 2.65; 95% CI, 1.66-4.22; p<0.0001) were independent prognostic factors for a longer progression-free survival (PFS) (≥30 months) in advanced HGSOC women. However, further two-factor multivariate analyses highlighted that baseline serum CA125 levels >401 U/ml and each soluble protein above respective concentration cutoff were covariates associated with shorter PFS (<30 months) and unfavorable clinical outcome, suggesting that contemporary measurement of both biomarkers than CA125 only could strengthen prognostic power of serum CA125 in predicting PFS of advanced HGSOC women. Plasma PD-L1, PD-1, BTN3A1, pan-sBTN3As, BTN2A1, or BTLA levels could be helpful biomarkers to increase prognostic value of CA125.

9.
Neuroimage ; 54(4): 2915-21, 2011 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-21087673

RESUMEN

OBJECTIVE: Pre-synaptic D2 receptors regulate striatal dopamine release and DAT activity, key factors for modulation of motor pathways. A functional SNP of DRD2 (rs1076560 G>T) is associated with alternative splicing such that the relative expression of D2S (mainly pre-synaptic) vs. D2L (mainly post-synaptic) receptor isoforms is decreased in subjects with the T allele with a putative increase of striatal dopamine levels. To evaluate how DRD2 genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans, we have investigated the association of rs1076560 with BOLD fMRI activity during a motor task. To further evaluate the relationship of this circuitry with dopamine signaling, we also explored the correlation between genotype based differences in motor brain activity and pre-synaptic striatal DAT binding measured with [(123)I] FP-CIT SPECT. METHODS: Fifty healthy subjects, genotyped for DRD2 rs1076560 were studied with BOLD-fMRI at 3T while performing a visually paced motor task with their right hand; eleven of these subjects also underwent [(123)I]FP-CIT SPECT. SPM5 random-effects models were used for statistical analyses. RESULTS: Subjects carrying the T allele had greater BOLD responses in left basal ganglia, thalamus, supplementary motor area, and primary motor cortex, whose activity was also negatively correlated with reaction time at the task. Moreover, left striatal DAT binding and activity of left supplementary motor area were negatively correlated. INTERPRETATION: The present results suggest that DRD2 genetic variation was associated with focusing of responses in the whole motor network, in which activity of predictable nodes was correlated with reaction time and with striatal pre-synaptic dopamine signaling. Our results in humans may help shed light on genetic risk for neurobiological mechanisms involved in the pathophysiology of disorders with dysregulation of striatal dopamine like Parkinson's disease.


Asunto(s)
Mapeo Encefálico , Dopamina/metabolismo , Actividad Motora/genética , Corteza Motora/fisiología , Receptores de Dopamina D2/genética , Transducción de Señal/genética , Cuerpo Estriado/fisiología , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Polimorfismo de Nucleótido Simple , Tiempo de Reacción , Tomografía Computarizada de Emisión de Fotón Único , Adulto Joven
10.
Cereb Cortex ; 20(4): 837-45, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19633177

RESUMEN

Previous studies have reported abnormal prefrontal and cingulate activity during attentional control processing in schizophrenia. However, it is not clear how variation in attentional control load modulates activity within these brain regions in this brain disorder. The aim of this study in schizophrenia is to investigate the impact of increasing levels of attentional control processing on prefrontal and cingulate activity. Blood oxygen level-dependent (BOLD) responses of 16 outpatients with schizophrenia were compared with those of 21 healthy subjects while performing a task eliciting increasing levels of attentional control during event-related functional magnetic resonance imaging at 3 T. Results showed reduced behavioral performance in patients at greater attentional control levels. Imaging data indicated greater prefrontal activity at intermediate attentional control levels in patients but greater prefrontal and cingulate responses at high attentional control demands in controls. The BOLD activity profile of these regions in controls increased linearly with increasing cognitive loads, whereas in patients, it was nonlinear. Correlation analysis consistently showed differential region and load-specific relationships between brain activity and behavior in the 2 groups. These results indicate that varying attentional control load is associated in schizophrenia with load- and region-specific modification of the relationship between behavior and brain activity, possibly suggesting earlier saturation of cognitive capacity.


Asunto(s)
Atención/fisiología , Giro del Cíngulo/fisiopatología , Corteza Prefrontal/fisiopatología , Esquizofrenia/patología , Psicología del Esquizofrénico , Adulto , Análisis de Varianza , Mapeo Encefálico , Femenino , Giro del Cíngulo/irrigación sanguínea , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Vías Nerviosas/irrigación sanguínea , Vías Nerviosas/fisiopatología , Pruebas Neuropsicológicas , Oxígeno/sangre , Reconocimiento Visual de Modelos/fisiología , Estimulación Luminosa/métodos , Corteza Prefrontal/irrigación sanguínea , Escalas de Valoración Psiquiátrica , Estadística como Asunto , Adulto Joven
11.
Brain Imaging Behav ; 15(1): 288-299, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32124274

RESUMEN

Convergent findings indicate that cannabis use and variation in the cannabinoid CB1 receptor coding gene (CNR1) modulate prefrontal function during working memory (WM). Other results also suggest that cannabis modifies the physiological relationship between genetically induced expression of CNR1 and prefrontal WM processing. However, it is possible that cannabis exerts its modifying effect on prefrontal physiology by interacting with complex molecular ensembles co-regulated with CB1. Since co-regulated genes are likely co-expressed, we investigated how genetically predicted co-expression of a molecular network including CNR1 interacts with cannabis use in modulating WM processing in humans. Using post-mortem human prefrontal data, we first computed a polygenic score (CNR1-PCI), combining the effects of single nucleotide polymorphisms (SNPs) on co-expression of a cohesive gene set including CNR1, and positively correlated with such co-expression. Then, in an in vivo study, we computed CNR1-PCI in 88 cannabis users and 147 non-users and investigated its interaction with cannabis use on brain activity during WM. Results revealed an interaction between cannabis use and CNR1-PCI in the dorsolateral prefrontal cortex (DLPFC), with a positive relationship between CNR1-PCI and DLPFC activity in cannabis users and a negative relationship in non-users. Furthermore, DLPFC activity in cannabis users was positively correlated with the frequency of cannabis use. Taken together, our results suggest that co-expression of a CNR1-related network predicts WM-related prefrontal activation as a function of cannabis use. Furthermore, they offer novel insights into the biological mechanisms associated with the use of cannabis.


Asunto(s)
Cannabis , Intervención Coronaria Percutánea , Humanos , Imagen por Resonancia Magnética , Memoria a Corto Plazo , Herencia Multifactorial , Corteza Prefrontal
12.
J Neurosci ; 29(4): 1224-34, 2009 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-19176830

RESUMEN

Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D(2) receptors (encoded by DRD(2)) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D(2) proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD(2) polymorphism (rs1076560) causing reduced presynaptic D(2) receptor expression and the DAT 3'-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging (MRI) during memory tasks and structural MRI. Results indicated a significant DRD(2)/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD(2) allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a nonlinear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D(2) knock-out animals (D2R(-/-)) indicate that DAT and D(2) proteins interact in vivo. Together, our results demonstrate that the interaction between genetic variants in DRD(2) and DAT critically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.


Asunto(s)
Cuerpo Estriado/fisiología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Corteza Prefrontal/fisiología , Receptores de Dopamina D2/genética , Adulto , Análisis de Varianza , Animales , Mapeo Encefálico , Cuerpo Estriado/irrigación sanguínea , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Lateralidad Funcional , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Inmunoprecipitación/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Ratones , Ratones Noqueados , Repeticiones de Minisatélite/genética , Vías Nerviosas/irrigación sanguínea , Vías Nerviosas/fisiología , Pruebas Neuropsicológicas , Oxígeno/sangre , Polimorfismo de Nucleótido Simple/genética , Corteza Prefrontal/irrigación sanguínea , Receptores de Dopamina D2/deficiencia , Receptores de Dopamina D2/metabolismo , Reconocimiento en Psicología/fisiología , Análisis de Regresión , Adulto Joven
13.
J Neurosci ; 29(47): 14812-9, 2009 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-19940176

RESUMEN

Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D(2) receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D(2) receptor gene (DRD2) (rs1076560, guanine > thymine or G > T) shifts splicing of the two protein isoforms (D(2) short, mainly presynaptic, and D(2) long) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced "emotion control" compared with GT subjects. Functional magnetic resonance imaging in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D(2) signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.


Asunto(s)
Encéfalo/metabolismo , Dopamina/metabolismo , Emociones/fisiología , Vías Nerviosas/metabolismo , Polimorfismo Genético/genética , Receptores de Dopamina D2/genética , Adulto , Síntomas Afectivos/genética , Síntomas Afectivos/metabolismo , Síntomas Afectivos/fisiopatología , Amígdala del Cerebelo/anatomía & histología , Amígdala del Cerebelo/metabolismo , Encéfalo/anatomía & histología , Análisis Mutacional de ADN , Inteligencia Emocional/genética , Femenino , Marcadores Genéticos/genética , Pruebas Genéticas , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/anatomía & histología , Pruebas Neuropsicológicas , Personalidad , Corteza Prefrontal/anatomía & histología , Corteza Prefrontal/metabolismo , Estrés Psicológico/genética , Estrés Psicológico/fisiopatología , Encuestas y Cuestionarios , Adulto Joven
14.
Brain ; 132(Pt 2): 417-25, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18829695

RESUMEN

Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case-control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.


Asunto(s)
Cuerpo Estriado/fisiopatología , Polimorfismo de Nucleótido Simple , Corteza Prefrontal/fisiopatología , Receptores de Dopamina D2/genética , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Adulto , Alelos , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto Joven
15.
Proc Natl Acad Sci U S A ; 104(51): 20552-7, 2007 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-18077373

RESUMEN

Subcortical dopamine D2 receptor (DRD2) signaling is implicated in cognitive processes and brain disorders, but the effect of DRD2 variants remains ambiguous. We measured allelic mRNA expression in postmortem human striatum and prefrontal cortex and then performed single nucleotide polymorphism (SNP) scans of the DRD2 locus. A previously uncharacterized promoter SNP (rs12364283) located in a conserved suppressor region was associated with enhanced DRD2 expression, whereas previously studied DRD2 variants failed to affect expression. Moreover, two frequent intronic SNPs (rs2283265 and rs1076560) decreased expression of DRD2 short splice variant (expressed mainly presynaptically) relative to DRD2 long (postsynaptic), a finding reproduced in vitro by using minigene constructs. Being in strong linkage disequilibrium with each other, both intronic SNPs (but not rs12364283) were also associated with greater activity of striatum and prefrontal cortex measured with fMRI during working memory and with reduced performance in working memory and attentional control tasks in healthy humans. Our results identify regulatory DRD2 polymorphisms that modify mRNA expression and splicing and working memory pathways.


Asunto(s)
Empalme Alternativo/genética , Regulación de la Expresión Génica , Memoria a Corto Plazo , Neuronas/fisiología , Polimorfismo de Nucleótido Simple , Receptores de Dopamina D2/fisiología , Alelos , Cognición , Cuerpo Estriado/química , Expresión Génica , Genes Reporteros , Genotipo , Humanos , Intrones/genética , Luciferasas/análisis , Luciferasas/genética , Corteza Prefrontal/química , Regiones Promotoras Genéticas , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Receptores de Dopamina D2/genética
16.
Biol Psychiatry ; 87(8): 697-707, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-31948640

RESUMEN

BACKGROUND: Schizophrenia risk is associated with both genetic and environmental risk factors. Furthermore, cognitive abnormalities are established core characteristics of schizophrenia. We aim to assess whether a classification approach encompassing risk factors, cognition, and their associations can discriminate patients with schizophrenia (SCZs) from healthy control subjects (HCs). We hypothesized that cognition would demonstrate greater HC-SCZ classification accuracy and that combined gene-environment stratification would improve the discrimination performance of cognition. METHODS: Genome-wide association study-based genetic, environmental, and neurocognitive classifiers were trained to separate 337 HCs from 103 SCZs using support vector classification and repeated nested cross-validation. We validated classifiers on independent datasets using within-diagnostic (SCZ) and cross-diagnostic (clinically isolated syndrome for multiple sclerosis, another condition with cognitive abnormalities) approaches. Then, we tested whether gene-environment multivariate stratification modulated the discrimination performance of the cognitive classifier in iterative subsamples. RESULTS: The cognitive classifier discriminated SCZs from HCs with a balanced accuracy (BAC) of 88.7%, followed by environmental (BAC = 65.1%) and genetic (BAC = 55.5%) classifiers. Similar classification performance was measured in the within-diagnosis validation sample (HC-SCZ BACs, cognition = 70.5%; environment = 65.8%; genetics = 49.9%). The cognitive classifier was relatively specific to schizophrenia (HC-clinically isolated syndrome for multiple sclerosis BAC = 56.7%). Combined gene-environment stratification allowed cognitive features to classify HCs from SCZs with 89.4% BAC. CONCLUSIONS: Consistent with cognitive deficits being core features of the phenotype of SCZs, our results suggest that cognitive features alone bear the greatest amount of information for classification of SCZs. Consistent with genes and environment being risk factors, gene-environment stratification modulates HC-SCZ classification performance of cognition, perhaps providing another target for refining early identification and intervention strategies.


Asunto(s)
Trastornos del Conocimiento , Disfunción Cognitiva , Esquizofrenia , Cognición , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/genética , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/genética , Estudio de Asociación del Genoma Completo , Humanos , Esquizofrenia/genética
17.
Psychiatry Res ; 173(1): 31-8, 2009 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-19428222

RESUMEN

Earlier imaging studies in schizophrenia have reported abnormal amygdala and prefrontal cortex activity during emotion processing. We investigated with functional magnetic resonance imaging (fMRI) during emotion processing changes in activity of the amygdala and of prefrontal cortex in patients with schizophrenia during 8 weeks of olanzapine treatment. Twelve previously drug-free/naive patients with schizophrenia were treated with olanzapine for 8 weeks and underwent two fMRI scans after 4 and 8 weeks of treatment during implicit and explicit emotional processing. Twelve healthy subjects were also scanned twice to control for potential repetition effects. Results showed a diagnosis by time interaction in left amygdala and a diagnosis by time by task interaction in right ventrolateral prefrontal cortex. In particular, activity in left amygdala was greater in patients than in controls at the first scan during both explicit and implicit processing, while it was lower in patients at the second relative to the first scan. Furthermore, during implicit processing, right ventrolateral prefrontal cortex activity was lower in patients than controls at the first scan, while it was greater in patients at the second relative to the first scan. These results suggest that longitudinal treatment with olanzapine may be associated with specific changes in activity of the amygdala and prefrontal cortex during emotional processing in schizophrenia.


Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiopatología , Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Emociones , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiopatología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Adulto , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Lateralidad Funcional , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Olanzapina , Psicología del Esquizofrénico , Factores de Tiempo
18.
Eur J Neurosci ; 28(10): 2129-36, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19046394

RESUMEN

A common nonsynonymous single nucleotide polymorphism leading to a serine-to-cysteine substitution at amino acid 704 (Ser(704)Cys) in the DISC1 protein sequence has been recently associated with schizophrenia and with specific hippocampal abnormalities. Here, we used multimodal neuroimaging to investigate in a large sample of healthy subjects the putative association of the Ser(704)Cys DISC1 polymorphism with in vivo brain phenotypes including hippocampal formation (HF) gray matter volume and function (as assessed with functional MRI) as well as HF functional coupling with the neural network engaged during encoding of recognition memory. Individuals homozygous for DISC1 Ser allele relative to carriers of the Cys allele showed greater gray matter volume in the HF. Further, Ser/Ser subjects exhibited greater engagement of the HF together with greater HF-dorsolateral prefrontal cortex functional coupling during memory encoding, in spite of similar behavioral performance. These findings consistently support the notion that Ser(704)Cys DISC1 polymorphism is physiologically relevant. Moreover, they support the hypothesis that genetic variation in DISC1 may affect the risk for schizophrenia by modifying hippocampal gray matter and function.


Asunto(s)
Hipocampo/metabolismo , Trastornos de la Memoria/genética , Memoria/fisiología , Proteínas del Tejido Nervioso/genética , Polimorfismo Genético/genética , Esquizofrenia/genética , Adulto , Alelos , Secuencia de Aminoácidos/genética , Sustitución de Aminoácidos/genética , Cisteína/genética , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Genotipo , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Proteínas del Tejido Nervioso/química , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Corteza Prefrontal/fisiopatología , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Serina/genética , Adulto Joven
20.
Schizophr Bull ; 44(4): 834-843, 2018 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-28981847

RESUMEN

The brain functional mechanisms translating genetic risk into emotional symptoms in schizophrenia (SCZ) may include abnormal functional integration between areas key for emotion processing, such as the amygdala and the lateral prefrontal cortex (LPFC). Indeed, investigation of these mechanisms is also complicated by emotion processing comprising different subcomponents and by disease-associated state variables. Here, our aim was to investigate the relationship between risk for SCZ and effective connectivity between the amygdala and the LPFC during different subcomponents of emotion processing. Thus, we first characterized with dynamic causal modeling (DCM) physiological patterns of LPFC-amygdala effective connectivity in healthy controls (HC) during implicit and explicit emotion processing. Then, we compared DCM patterns in a subsample of HC, in patients with SCZ and in healthy siblings of patients (SIB), matched for demographics. Finally, we investigated in HC association of LPFC-amygdala effective connectivity with a genome-wide supported variant increasing genetic risk for SCZ and possibly relevant to emotion processing (DRD2 rs2514218). In HC, we found that a "bottom-up" amygdala-to-LPFC pattern during implicit processing and a "top-down" LPFC-to-amygdala pattern during explicit processing were the most likely directional models of effective connectivity. Differently, implicit emotion processing in SIB, SCZ, and HC homozygous for the SCZ risk rs2514218 C allele was associated with decreased probability for the "bottom-up" as well as with increased probability for the "top-down" model. These findings suggest that task-specific anomaly in the directional flow of information or disconnection between the amygdala and the LPFC is a good candidate endophenotype of SCZ.


Asunto(s)
Amígdala del Cerebelo/fisiología , Conectoma/métodos , Emociones/fisiología , Endofenotipos , Predisposición Genética a la Enfermedad , Corteza Prefrontal/fisiología , Receptores de Dopamina D2/genética , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/fisiopatología , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Imagen por Resonancia Magnética , Masculino , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Esquizofrenia/diagnóstico por imagen , Hermanos , Adulto Joven
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