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Background: Hong Kong is among the many populations that has experienced the combined impacts of social unrest and the COVID-19 pandemic. Despite concerns about further deteriorations in youth mental health globally, few epidemiological studies have been conducted to examine the prevalence and correlates of major depressive episode (MDE) and other major psychiatric disorders across periods of population-level changes using diagnostic interviews. Methods: We conducted a territory-wide household-based epidemiological study from 2019 to 2022 targeting young people aged 15-24 years. MDE, generalised anxiety disorder (GAD), panic disorder (PD), and bipolar disorder (BD) were assessed using the Composite International Diagnostic Interview-Screening Scales in 3340 young people. Psychotic disorders were assessed by experienced psychiatrists according to the DSM. Help-seeking patterns were also explored. Findings: 16.6% had any mental disorder (13.7% 12-month MDE, 2.3% BD, 2.1% GAD, 1.0% PD, 0.6% psychotic disorder). The prevalence of MDE increased from 13.2% during period 1 (May 2019-June 2020) to 18.1% during period 2 (July-December 2020), followed by 14.0% during period 3 (January-June 2021) and 13.2% during period 4 (July 2021-June 2022). Different stressors uniquely contributed to MDE across periods: social unrest-related stressors during period 1, COVID-19 stressors during period 2, and personal stressors during periods 3-4. Lower resilience, loneliness, frequent nightmares, and childhood adversity were consistently associated with MDE. Compared to other conditions, those with MDE showed the lowest service utilisation rate (16.7%). Perceiving services to "cost too much" and "talked to friends or relatives instead" were among the major reasons for not seeking help. MDE was also significantly associated with poorer functioning and health-related quality of life. Interpretation: MDE can be sensitive to population-level changes, although its persistently elevated prevalence across the study period is of concern. Efforts to mitigate their impacts on youth mental health alongside personal risk factors are needed. Further work is required to increase the availability and acceptability of youth-targeted mental health services. Funding: Food and Health Bureau (HKSAR Government).
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Helicobacter pylori infection causes chronic gastric inflammation that contributes to various gastroduodenal diseases, including peptic ulcer and gastric cancer. Despite broad regional variations, the prevalence of resistance to antibiotics used to manage H pylori infection is increasing worldwide; this trend could hinder the success of eradication therapy. To increase awareness of H pylori and improve the diagnosis and treatment of its infection in Hong Kong, our consensus panel proposed a set of guidance statements for disease management. We conducted a comprehensive review of literature published during 2011 and 2021, with a focus on articles from Hong Kong or other regions of China. We evaluated the evidence using the Oxford Centre for Evidence-Based Medicine's 2011 Levels of Evidence and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system and sought consensus through online voting and a subsequent face-to-face meeting, which enabled us to develop and refine the guidance statements. This report consists of 24 statements regarding the epidemiology and burden, screening and diagnosis, and treatment of H pylori. Key guidance statements include a recommendation to use the test-and-treat approach for high-risk individuals, as well as the confirmation that triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin remains a valid first-line option for adults and children in Hong Kong.
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Infecciones por Helicobacter , Helicobacter pylori , Adulto , Niño , Humanos , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/epidemiología , Hong Kong/epidemiología , Consenso , Antibacterianos/uso terapéuticoRESUMEN
RATIONALE: How striatal dopamine synthesis capacity (DSC) contributes to the pathogenesis of negative symptoms in first-episode schizophrenia (SZ) and delusional disorder (DD) has seldom been explored. As negative symptoms during active psychotic episodes can be complicated by secondary influences, such as positive symptoms, longitudinal investigations may help to clarify the relationship between striatal DSC and negative symptoms and differentiate between primary and secondary negative symptoms. OBJECTIVE: A longitudinal study was conducted to examine whether baseline striatal DSC would be related to negative symptoms at 3 months in first-episode SZ and DD patients. METHODS: Twenty-three first-episode age- and gender-matched patients (11 DD and 12 SZ) were consecutively recruited through an early intervention service for psychosis in Hong Kong. Among them, 19 (82.6%) patients (9 DD and 10 SZ) were followed up at 3 months. All patients received an 18F-DOPA PET/MR scan at baseline. RESULTS: Baseline striatal DSC (Kocc;30-60) was inversely associated with negative symptoms at 3 months in first-episode SZ patients (rs = - 0.80, p = 0.010). This association remained in SZ patients even when controlling for baseline negative, positive, and depressive symptoms, as well as cumulative antipsychotic dosage (ß = - 0.69, p = 0.012). Such associations were not observed in first-episode DD patients. Meanwhile, the severity of negative symptoms at 3 months was associated with more positive symptoms in DD patients (rs = 0.74, p = 0.010) and not in SZ patients. CONCLUSIONS: These findings highlight the role of striatal DSC in negative symptoms upon resolution of active psychotic episodes among first-episode SZ patients. Baseline striatal dopamine activity may inform future symptom expression with important treatment implications.
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Dopamina , Trastornos Psicóticos , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Humanos , Estudios Longitudinales , Trastornos Psicóticos/metabolismo , Esquizofrenia Paranoide/metabolismoRESUMEN
BACKGROUND: Whole-exome sequencing (WES) has become an invaluable tool for genetic diagnosis in paediatrics. However, it has not been widely adopted in the prenatal setting. This study evaluated the use of WES in prenatal genetic diagnosis in fetuses with structural congenital anomalies (SCAs) detected on prenatal ultrasound. METHOD: Thirty-three families with fetal SCAs on prenatal ultrasonography and normal chromosomal microarray results were recruited. Genomic DNA was extracted from various fetal samples including amniotic fluid, chorionic villi, and placental tissue. Parental DNA was extracted from peripheral blood when available. We used WES to sequence the coding regions of parental-fetal trios and to identify the causal variants based on the ultrasonographic features of the fetus. RESULTS: Pathogenic mutations were identified in three families (n = 3/33, 9.1%), including mutations in DNAH11, RAF1 and CHD7, which were associated with primary ciliary dyskinesia, Noonan syndrome, and CHARGE syndrome, respectively. In addition, variants of unknown significance (VUSs) were detected in six families (18.2%), in which genetic changes only partly explained prenatal features. CONCLUSION: WES identified pathogenic mutations in 9.1% of fetuses with SCAs and normal chromosomal microarray results. Databases for fetal genotype-phenotype correlations and standardized guidelines for variant interpretation in prenatal diagnosis need to be established to facilitate the use of WES for routine testing in prenatal diagnosis.
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Síndrome CHARGE/genética , Trastornos de la Motilidad Ciliar/genética , Secuenciación del Exoma , Síndrome de Noonan/genética , Líquido Amniótico/metabolismo , Dineínas Axonemales/genética , Síndrome CHARGE/diagnóstico , Trastornos de la Motilidad Ciliar/diagnóstico , ADN/aislamiento & purificación , ADN/metabolismo , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Femenino , Feto/metabolismo , Humanos , Síndrome de Noonan/diagnóstico , Fenotipo , Placenta/metabolismo , Embarazo , Diagnóstico Prenatal , Proteínas Proto-Oncogénicas c-raf/genética , Ultrasonografía PrenatalRESUMEN
Human leukocyte antigen (HLA) genes control the regulation of the human immune system and are involved in immune-related diseases. Population surveys on relationships between single nucleotide polymorphisms (SNP) and HLA alleles are essential to conduct genetic association between HLA variants and diseases. Samples were obtained from our in-house database for epilepsy genetics and pharmacogenetics research. Using 184 epilepsy patients with both genome-wide SNP array and HLA-A/B candidate gene sequencing data, we sought tagging SNPs that completely represent sixHLA risk alleles; in addition, a Hong Kong population-specific reference panel was constructed for SNP-based HLA imputation. The performance of our new panel was compared to a recent Han Chinese panel. Finally, genetic associations of HLA variants with mild skin rash were performed on the combined sample of 408 patients. Common SNPs rs2571375 and rs144295468 were found to successfully tag HLA risk alleles A*31:01 and B*13:01, respectively. HLA-B*15:02 can be predicted by rs144012689 with >95% sensitivity and specificity. The imputation reference panel for the Hong Kong population had comparable performance to the Han Chinese panel due to the large sample size for common HLA alleles, though it retained discordance for imputing rare alleles. No significant genetic associations were found between HLA genetic variants and mild skin rash induced by aromatic antiepileptic drugs. This study provides new information on the genetic structure of HLA regions in the Hong Kong population by identifying tagging SNPs and serving as a reference panel. Moreover, our comprehensive genetic analyses revealed no significant association between HLA alleles and mild skin rash in Hong Kong Han Chinese.
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Anticonvulsivantes/efectos adversos , Pueblo Asiatico/genética , Exantema/inducido químicamente , Exantema/genética , Antígenos HLA/genética , Polimorfismo de Nucleótido Simple/genética , Alelos , Bases de Datos Genéticas/estadística & datos numéricos , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Epilepsia/genética , Femenino , Estudios de Asociación Genética/métodos , Hong Kong/epidemiología , Humanos , MasculinoRESUMEN
BACKGROUND: Gamma-aminobutyric acid (GABA) dysfunction and its consequent imbalance are implicated in the pathophysiology of schizophrenia. Reduced GABA production would lead to a disinhibition of glutamatergic neurons and subsequently cause a disruption of the modulation between GABAergic interneurons and glutamatergic neurons. In this study, levels of GABA, Glx (summation of glutamate and glutamine), and other metabolites in the anterior cingulate cortex were measured and compared between first-episode schizophrenia subjects and healthy controls (HC). Diagnostic potential of GABA and Glx as upstream biomarkers for schizophrenia was explored. METHODS: Nineteen first-episode schizophrenia subjects and fourteen HC participated in this study. Severity of clinical symptoms of patients was measured with Positive and Negative Syndrome Scale (PANSS). Metabolites were measured using proton magnetic resonance spectroscopy, and quantified using internal water as reference. RESULTS: First-episode schizophrenia subjects revealed reduced GABA and myo-inositol (mI), and increased Glx and choline (Cho), compared to HC. No significant correlation was found between metabolite levels and PANSS scores. Receiver operator characteristics analyses showed Glx had higher sensitivity and specificity (84.2%, 92.9%) compared to GABA (73.7%, 64.3%) for differentiating schizophrenia patients from HC. Combined model of both GABA and Glx revealed the best sensitivity and specificity (89.5%, 100%). CONCLUSION: This study simultaneously showed reduction in GABA and elevation in Glx in first-episode schizophrenia subjects, and this might provide insights on explaining the disruption of modulation between GABAergic interneurons and glutamatergic neurons. Elevated Cho might indicate increased membrane turnover; whereas reduced mI might reflect dysfunction of the signal transduction pathway. In vivo Glx and GABA revealed their diagnostic potential for schizophrenia.
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Glutamina/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Esquizofrenia/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Adolescente , Adulto , Femenino , Giro del Cíngulo/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Escalas de Valoración Psiquiátrica , Curva ROC , Esquizofrenia/diagnóstico por imagen , Adulto JovenRESUMEN
This study aimed to assess the psychometric properties of the Chinese version of the Revised Clinical Interview Schedule (C-CIS-R), and explore its applicability as a diagnostic instrument for common mental disorders (CMDs) in Hong Kong. Its psychometric properties were evaluated among 140 patients and 161 healthy controls. In comparison to the diagnoses made by the Structured Clinical Interview for the DSM-IV, the C-CIS-R showed good criterion validity in diagnosing CMDs. The correlation of the total score of C-CIS-R with the 12-item General Health Questionnaire and Hospital Anxiety and Depression Scale was satisfactory, indicating favourable convergent validity as well. The inter-rater and test-retest reliability were also satisfactory. Receiver operating characteristic analyses suggested an optimal cut-off point of 11/12 for detecting diagnosable CMDs (sensitivity: 0.69; specificity: 0.93) and 17/18 for identifying a need for treatment (sensitivity: 0.70; specificity: 0.95). In conclusion, C-CIS-R is a valid diagnostic instrument for CMDs in a Chinese community. Its cut-off points for clinically significant symptoms and treatment needs among Chinese are identical to those adopted in the original English version.
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Pueblo Asiatico/psicología , Trastornos Mentales/diagnóstico , Escalas de Valoración Psiquiátrica/normas , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Hong Kong , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Adulto JovenRESUMEN
Schizophrenia is a complex neurodevelopmental disorder where changes in both hippocampus and memory-related cognitive functions are central. However, the exact relationship between neurodevelopmental-genetic factors and hippocampal-cognitive dysfunction remains unclear. The general aim of our study is to link the occurrence of rare damaging mutations involved in susceptibility gene pathways to the structure and function of hippocampus in order to define genetically and phenotypically based subgroups in schizophrenia. In the present study, by analyzing the exome sequencing and magnetic resonance imaging data in 94 first-episode treatment-naive schizophrenia patients and 134 normal controls, we identified that a cluster of rare damaging variants (RDVs) enriched in DNA repair and cell cycle pathways was present only in a subgroup including 39 schizophrenic patients. Furthermore, we found that schizophrenic patients with this RDVs show increased resting-state functional connectivity (rsFC) between left hippocampus (especially for left dentate gyrus) and left inferior parietal cortex, as well as decreased rsFC between left hippocampus and cerebellum. Moreover, abnormal rsFC was related to the deficits of spatial working memory (SWM; that is known to recruit the hippocampus) in patients with the RDVs. Taken together, our data demonstrate for the first time, to our knowledge, that damaging rare variants of genes in DNA repair and cell cycle pathways are associated with aberrant hippocampal rsFC, which was further relative to cognitive deficits in first-episode treatment-naive schizophrenia. Therefore, our data provide some evidence for the occurrence of phenotypic alterations in hippocampal and SWM function in a genetically defined subgroup of schizophrenia.
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Ciclo Celular/genética , Disfunción Cognitiva/genética , Reparación del ADN/genética , Hipocampo/diagnóstico por imagen , Esquizofrenia/genética , Psicología del Esquizofrénico , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Estudios de Casos y Controles , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Femenino , Neuroimagen Funcional , Eliminación de Gen , Hipocampo/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria a Corto Plazo/fisiología , Mutagénesis Insercional , Polimorfismo de Nucleótido Simple , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/fisiopatología , Memoria Espacial/fisiología , Adulto JovenRESUMEN
BACKGROUND: Relapse is distressingly common after the first episode of psychosis, yet it is poorly understood and difficult to predict. Investigating changes in cognitive function preceding relapse may provide new insights into the underlying mechanism of relapse in psychosis. We hypothesized that relapse in fully remitted first-episode psychosis patients was preceded by working memory deterioration. METHOD: Visual memory and verbal working memory were monitored prospectively in a 1-year randomized controlled trial of remitted first-episode psychosis patients assigned to medication continuation (quetiapine 400 mg/day) or discontinuation (placebo). Relapse (recurrence of positive symptoms of psychosis), visual (Visual Patterns Test) and verbal (Letter-Number span test) working memory and stressful life events were assessed monthly. RESULTS: Remitted first-episode patients (n = 102) participated in the study. Relapsers (n = 53) and non-relapsers (n = 49) had similar baseline demographic and clinical profiles. Logistic regression analyses indicated relapse was associated with visual working memory deterioration 2 months before relapse [odds ratio (OR) 3.07, 95% confidence interval (CI) 1.19-7.92, P = 0.02], more stressful life events 1 month before relapse (OR 2.11, 95% CI 1.20-3.72, P = 0.01) and medication discontinuation (OR 5.52, 95% CI 2.08-14.62, P = 0.001). CONCLUSIONS: Visual working memory deterioration beginning 2 months before relapse in remitted first-episode psychosis patients (not baseline predictor) may reflect early brain dysfunction that heralds a psychotic relapse. The deterioration was found to be unrelated to a worsening of psychotic symptoms preceding relapse. Testable predictors offer insight into the brain processes underlying relapse in psychosis.
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Antipsicóticos/farmacología , Disfunción Cognitiva/fisiopatología , Progresión de la Enfermedad , Memoria a Corto Plazo/fisiología , Trastornos Psicóticos/fisiopatología , Estrés Psicológico/fisiopatología , Adulto , Antipsicóticos/administración & dosificación , Método Doble Ciego , Femenino , Humanos , Masculino , Pronóstico , Trastornos Psicóticos/tratamiento farmacológico , Fumarato de Quetiapina/administración & dosificación , Fumarato de Quetiapina/farmacología , Recurrencia , Inducción de Remisión , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: The genetic influences in human brain structure and function and impaired functional connectivities are the hallmarks of the schizophrenic brain. To explore how common genetic variants affect the connectivities in schizophrenia, we applied genome-wide association studies assaying the abnormal neural connectivities in schizophrenia as quantitative traits. METHOD: We recruited 161 first-onset and treatment-naive patients with schizophrenia and 150 healthy controls. All the participants underwent scanning with a 3 T-magnetic resonance imaging scanner to acquire structural and functional imaging data and genotyping using the HumanOmniZhongHua-8 BeadChip. The brain-wide association study approach was employed to account for the inherent modular nature of brain connectivities. RESULTS: We found differences in four abnormal functional connectivities [left rectus to left thalamus (REC.L-THA.L), left rectus to right thalamus (REC.L-THA.R), left superior orbital cortex to left thalamus (ORBsup.L-THA.L) and left superior orbital cortex to right thalamus (ORBsup.L-THA.R)] between the two groups. Univariate single nucleotide polymorphism (SNP)-based association revealed that the SNP rs6800381, located nearest to the CHRM3 (cholinergic receptor, muscarinic 3) gene, reached genomic significance (p = 1.768 × 10-8) using REC.L-THA.R as the phenotype. Multivariate gene-based association revealed that the FAM12A (family with sequence similarity 12, member A) gene nearly reached genomic significance (nominal p = 2.22 × 10-6, corrected p = 0.05). CONCLUSIONS: Overall, we identified the first evidence that the CHRM3 gene plays a role in abnormal thalamo-orbital frontal cortex functional connectivity in first-episode treatment-naive patients with schizophrenia. Identification of these genetic variants using neuroimaging genetics provides insights into the causes of variability in human brain development, and may help us determine the mechanisms of dysfunction in schizophrenia.
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Conectoma , Corteza Prefrontal/fisiopatología , Receptores Muscarínicos , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Tálamo/fisiopatología , Adulto , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Sitios de Carácter Cuantitativo , Receptor Muscarínico M3RESUMEN
Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.
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Agranulocitosis/inducido químicamente , Antitiroideos/efectos adversos , Carbimazol/efectos adversos , Antígenos HLA-B/genética , Metimazol/efectos adversos , Agranulocitosis/genética , Antitiroideos/administración & dosificación , Carbimazol/administración & dosificación , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento/genética , Metimazol/administración & dosificación , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Propiltiouracilo/administración & dosificación , Propiltiouracilo/efectos adversosRESUMEN
Prenatal exposure to maternal immune activation (MIA) increases the risk of schizophrenia and autism in the offspring. The MIA rodent model provides a valuable tool to directly test the postnatal consequences of exposure to an early inflammatory insult; and examine novel preventative strategies. Here we tested the hypotheses that behavioural differences in the MIA mouse model are accompanied by in vivo and ex vivo alterations in brain biochemistry; and that these can be prevented by a post-weaning diet enriched with n-3 polyunsaturated fatty acid (PUFA). The viral analogue PolyI:C (POL) or saline (SAL) was administered to pregnant mice on gestation day 9. Half the resulting male offspring (POL=21; SAL=17) were weaned onto a conventional lab diet (n-6 PUFA); half were weaned onto n-3 PUFA-enriched diet. In vivo magnetic resonance spectroscopy measures were acquired prior to behavioural tests; glutamic acid decarboxylase 67 (GAD67) and tyrosine hydroxylase protein levels were measured ex vivo. The main findings were: (i) Adult MIA-exposed mice fed a standard diet had greater N-acetylaspartate/creatine (Cr) and lower myo-inositol/Cr levels in the cingulate cortex in vivo. (ii) The extent of these metabolite differences was correlated with impairment in prepulse inhibition. (iii) MIA-exposed mice on the control diet also had higher levels of anxiety and altered levels of GAD67 ex vivo. (iv) An n-3 PUFA diet prevented all the in vivo and ex vivo effects of MIA observed. Thus, n-3 PUFA dietary enrichment from early life may offer a relatively safe and non-toxic approach to limit the otherwise persistent behavioural and biochemical consequences of prenatal exposure to inflammation. This result may have translational importance.
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Conducta Animal/efectos de los fármacos , Ácidos Grasos Omega-3/farmacología , Giro del Cíngulo , Inflamación/inmunología , Complicaciones del Embarazo/inmunología , Efectos Tardíos de la Exposición Prenatal , Animales , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Creatina/metabolismo , Dieta Alta en Grasa/métodos , Suplementos Dietéticos , Femenino , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/metabolismo , Inositol/metabolismo , Masculino , Ratones , Embarazo , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/prevención & control , Inhibición Prepulso/efectos de los fármacos , Sustancias Protectoras/farmacología , DesteteRESUMEN
There is an urgent need for the identification of Alzheimer's disease (AD) biomarkers. Studies have now suggested the promising use of associations with blood metabolites as functional intermediate phenotypes in biomedical and pharmaceutical research. The aim of this study was to use lipidomics to identify a battery of plasma metabolite molecules that could predict AD patients from controls. We performed a comprehensive untargeted lipidomic analysis, using ultra-performance liquid chromatography/mass spectrometry on plasma samples from 35 AD patients, 40 elderly controls and 48 individuals with mild cognitive impairment (MCI) and used multivariate analysis methods to identify metabolites associated with AD status. A combination of 10 metabolites could discriminate AD patients from controls with 79.2% accuracy (81.8% sensitivity, 76.9% specificity and an area under curve of 0.792) in a novel test set. Six of the metabolites were identified as long chain cholesteryl esters (ChEs) and were reduced in AD (ChE 32:0, odds ratio (OR)=0.237, 95% confidence interval (CI)=0.10-0.48, P=4.19E-04; ChE 34:0, OR=0.152, 95% CI=0.05-0.37, P=2.90E-04; ChE 34:6, OR=0.126, 95% CI=0.03-0.35, P=5.40E-04; ChE 32:4, OR=0.056, 95% CI=0.01-0.24, P=6.56E-04 and ChE 33:6, OR=0.205, 95% CI=0.06-0.50, P=2.21E-03, per (log2) metabolite unit). The levels of these metabolites followed the trend control>MCI>AD. We, additionally, found no association between cholesterol, the precursor of ChE and AD. This study identified new ChE molecules, involved in cholesterol metabolism, implicated in AD, which may help identify new therapeutic targets; although, these findings need to be replicated in larger well-phenotyped cohorts.
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Enfermedad de Alzheimer/sangre , Ésteres del Colesterol/sangre , Disfunción Cognitiva/sangre , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/sangre , Estudios de Casos y Controles , Cromatografía Liquida , Disfunción Cognitiva/diagnóstico , Femenino , Humanos , Masculino , Espectrometría de Masas , Análisis Multivariante , Sensibilidad y EspecificidadRESUMEN
In aetiologically complex illnesses such as schizophrenia, there is no direct link between genotype and phenotype. Intermediate phenotypes could help clarify the underlying biology and assist in the hunt for genetic vulnerability variants. We have previously shown that cognition shares substantial genetic variance with schizophrenia; however, it is unknown if this reflects pleiotropic effects, direct causality or some shared third factor that links both, for example, brain volume (BV) changes. We quantified the degree of net genetic overlap and tested the direction of causation between schizophrenia liability, brain structure and cognition in a pan-European schizophrenia twin cohort consisting of 1243 members from 626 pairs. Cognitive deficits lie upstream of the liability for schizophrenia with about a quarter of the variance in liability to schizophrenia explained by variation in cognitive function. BV changes lay downstream of schizophrenia liability, with 4% of BV variation explained directly by variation in liability. However, our power to determine the nature of the relationship between BV deviation and schizophrenia liability was more limited. Thus, while there was strong evidence that cognitive impairment is causal to schizophrenia liability, we are not in a position to make a similar statement about the relationship between liability and BV. This is the first study to demonstrate that schizophrenia liability is expressed partially through cognitive deficits. One prediction of the finding that BV changes lie downstream of the disease liability is that the risk loci that influence schizophrenia liability will thereafter influence BV and to a lesser extent. By way of contrast, cognitive function lies upstream of schizophrenia, thus the relevant loci will actually have a larger effect size on cognitive function than on schizophrenia. These are testable predictions.
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Encéfalo/patología , Trastornos del Conocimiento/etiología , Modelos Genéticos , Esquizofrenia , Adulto , Estudios de Cohortes , Europa (Continente) , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Valor Predictivo de las Pruebas , Escalas de Valoración Psiquiátrica , Esquizofrenia/complicaciones , Esquizofrenia/genética , Esquizofrenia/patología , Estadística como Asunto , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genética , Adulto JovenRESUMEN
Epigenetic processes such as DNA methylation have been implicated in the pathophysiology of neurodevelopmental disorders including schizophrenia and autism. Epigenetic changes can be induced by environmental exposures such as inflammation. Here we tested the hypothesis that prenatal inflammation, a recognized risk factor for schizophrenia and related neurodevelopmental conditions, alters DNA methylation in key brain regions linked to schizophrenia, namely the dopamine rich striatum and endocrine regulatory centre, the hypothalamus. DNA methylation across highly repetitive elements (long interspersed element 1 (LINE1) and intracisternal A-particles (IAPs)) were used to proxy global DNA methylation. We also investigated the Mecp2 gene because it regulates transcription of LINE1 and has a known association with neurodevelopmental disorders. Brain tissue was harvested from 6 week old offspring of mice exposed to the viral analog PolyI:C or saline on gestation day 9. We used Sequenom EpiTYPER assay to quantitatively analyze differences in DNA methylation at IAPs, LINE1 elements and the promoter region of Mecp2. In the hypothalamus, prenatal exposure to PolyI:C caused significant global DNA hypomethylation (t=2.44, P=0.019, PolyI:C mean 69.67%, saline mean 70.19%), especially in females, and significant hypomethylation of the promoter region of Mecp2, (t=3.32, P=0.002; PolyI:C mean 26.57%, saline mean 34.63%). IAP methylation was unaltered. DNA methylation in the striatum was not significantly altered. This study provides the first experimental evidence that exposure to inflammation during prenatal life is associated with epigenetic changes, including Mecp2 promoter hypomethylation. This suggests that environmental and genetic risk factors associated with neurodevelopmental disorders may act upon similar pathways. This is important because epigenetic changes are potentially modifiable and their investigation may open new avenues for treatment.
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Encéfalo/embriología , Encéfalo/inmunología , Metilación de ADN/genética , Metilación de ADN/inmunología , Modelos Animales de Enfermedad , Epigénesis Genética/genética , Epigénesis Genética/inmunología , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/inmunología , Factores de Edad , Animales , Cuerpo Estriado/embriología , Cuerpo Estriado/inmunología , Femenino , Hipotálamo/embriología , Hipotálamo/inmunología , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Endogámicos C57BL , Poli I-C/inmunología , Embarazo , Valores de Referencia , Factores SexualesRESUMEN
UNLABELLED: Undifferentiated nasopharyngeal carcinoma (NPC) has a 100% association with Epstein-Barr virus (EBV). However, only three EBV genomes isolated from NPC patients have been sequenced to date, and the role of EBV genomic variations in the pathogenesis of NPC is unclear. We sought to obtain the sequences of EBV genomes in multiple NPC biopsy specimens in the same geographic location in order to reveal their sequence diversity. Three published EBV (B95-8, C666-1, and HKNPC1) genomes were first resequenced using the sequencing workflow of target enrichment of EBV DNA by hybridization, followed by next-generation sequencing, de novo assembly, and joining of contigs by Sanger sequencing. The sequences of eight NPC biopsy specimen-derived EBV (NPC-EBV) genomes, designated HKNPC2 to HKNPC9, were then determined. They harbored 1,736 variations in total, including 1,601 substitutions, 64 insertions, and 71 deletions, compared to the reference EBV. Furthermore, genes encoding latent, early lytic, and tegument proteins and glycoproteins were found to contain nonsynonymous mutations of potential biological significance. Phylogenetic analysis showed that the HKNPC6 and -7 genomes, which were isolated from tumor biopsy specimens of advanced metastatic NPC cases, were distinct from the other six NPC-EBV genomes, suggesting the presence of at least two parental lineages of EBV among the NPC-EBV genomes. In conclusion, much greater sequence diversity among EBV isolates derived from NPC biopsy specimens is demonstrated on a whole-genome level through a complete sequencing workflow. Large-scale sequencing and comparison of EBV genomes isolated from NPC and normal subjects should be performed to assess whether EBV genomic variations contribute to NPC pathogenesis. IMPORTANCE: This study established a sequencing workflow from EBV DNA capture and sequencing to de novo assembly and contig joining. We reported eight newly sequenced EBV genomes isolated from primary NPC biopsy specimens and revealed the sequence diversity on a whole-genome level among these EBV isolates. At least two lineages of EBV strains are observed, and recombination among these lineages is inferred. Our study has demonstrated the value of, and provided a platform for, genome sequencing of EBV.
Asunto(s)
Variación Genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Neoplasias Nasofaríngeas/virología , Adulto , Secuencia de Bases , Biopsia , Carcinoma , Femenino , Genoma Viral , Herpesvirus Humano 4/clasificación , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutagénesis Insercional , Carcinoma Nasofaríngeo , Filogenia , Eliminación de Secuencia , Adulto JovenRESUMEN
Mental disorders are highly prevalent conditions with immense disease burden. To inform health and social services policy formulation, local psychiatric epidemiological data are required. The Hong Kong Mental Morbidity Survey is a 3-year population-based study in which 5700 community-dwelling Chinese adults aged between 16 and 75 years were interviewed with the aim of evaluating the prevalence, co-morbidity, functional impairment, physical morbidity, and social determinants of significant mental disorders in the population. This paper describes the background and design of the survey, and is the first territory-wide psychiatric epidemiological study in Hong Kong.
Asunto(s)
Pueblo Asiatico/psicología , Encuestas Epidemiológicas/métodos , Trastornos Mentales/epidemiología , Adolescente , Adulto , Anciano , Comorbilidad , Femenino , Hong Kong/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Adulto JovenRESUMEN
BACKGROUND: Alterations in gray matter (GM) are commonly observed in schizophrenia. Accumulating studies suggest that the brain changes associated with schizophrenia are distributed rather than focal, involving interconnected networks of areas as opposed to single regions. In the current study we aimed to explore GM volume (GMV) changes in a relatively large sample of treatment-naive first-episode schizophrenia (FES) patients using optimized voxel-based morphometry (VBM) and covariation analysis. METHOD: High-resolution T1-weighted images were obtained using 3.0-T magnetic resonance imaging (MRI) from 86 first-episode drug-naive patients with schizophrenia and 86 age- and gender-matched healthy volunteers. Symptom severity was evaluated using the Positive and Negative Syndrome Scale (PANSS). GMV was assessed using optimized VBM and in 16 regions of interest (ROIs), selected on the basis of a previous meta-analysis. The relationships between GMVs in the ROIs were examined using an analysis of covariance (ANCOVA). RESULTS: The VBM analysis revealed that first-episode patients showed reduced GMV in the hippocampus bilaterally. The ROI analysis identified reductions in GMV in the left inferior frontal gyrus, bilateral hippocampus and right thalamus. The ANCOVA revealed different patterns of regional GMV correlations in patients and controls, including of inter- and intra-insula, inter-amygdala and insula-postcentral gyrus connections. CONCLUSIONS: Schizophrenia involves regional reductions in GMV and changes in GMV covariance in the insula, amygdala and postcentral gyrus. These findings were evident at the onset of the disorder, before treatment, and therefore cannot be attributable to the effects of chronic illness progression or medication.