RESUMO
The gene encoding adhesion G protein-coupled receptor L3 (ADGRL3, also referred to as latrophilin 3 or LPHN3) has been associated with ADHD susceptibility in independent ADHD samples. We conducted a systematic review and a comprehensive meta-analysis to summarize the associations between the most studied ADGRL3 polymorphisms (rs6551665, rs1947274, rs1947275, and rs2345039) and both childhood and adulthood ADHD. Eight association studies (seven published and one unpublished) fulfilled criteria for inclusion in our meta-analysis. We also incorporated GWAS data for ADGRL3. In order to avoid overlapping samples, we started with summary statistics from GWAS samples and then added data from gene association studies. The results of our meta-analysis suggest an effect of ADGRL3 variants on ADHD susceptibility in children (n = 8724/14,644 cases/controls and 1893 families): rs6551665 A allele (Z score = -2.701; p = 0.0069); rs1947274 A allele (Z score = -2.033; p = 0.0421); rs1947275 T allele (Z score = 2.339; p = 0.0978); and rs2345039 C allele (Z score = 3.806; p = 0.0026). Heterogeneity was found in analyses for three SNPs (rs6551665, rs1947274, and rs2345039). In adults, results were not significant (n = 6532 cases/15,874 controls): rs6551665 A allele (Z score = 2.005; p = 0.0450); rs1947274 A allele (Z score = 2.179; p = 0.0293); rs1947275 T allele (Z score = -0.822; p = 0.4109); and rs2345039 C allele (Z score = -1.544; p = 0.1226). Heterogeneity was found just for rs6551665. In addition, funnel plots did not suggest publication biases. Consistent with ADGRL3's role in early neurodevelopment, our findings suggest that the gene is predominantly associated with childhood ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genéticaRESUMO
BACKGROUND: ADHD diagnosis requires the presence of symptoms before the age of twelve. In clinical assessment of adults, the most frequent strategy to check this criterion is investigating self-report recall of symptoms, despite little evidence on the validity of this approach. We aim to evaluate the recall accuracy and factors associated with its reliability in a large population-based sample of adults. METHODS: Individuals from the 1993 Pelotas Birth Cohort were followed-up from childhood to adulthood. At the age of 22, 3810 individuals were assessed through structured interviews by trained psychologists regarding mental health outcomes, including ADHD diagnosis and ADHD symptoms in childhood. The retrospective recall was compared with available information on ADHD childhood symptoms at the age of eleven. We also assessed factors related to recall accuracy through multiple regression analyses. RESULTS: Self-reported recall of childhood symptoms at 22 years of age had an accuracy of only 55.4%, with sensitivity of 32.8% and positive predictive value of 40.7%. Current inattention symptoms were associated with lower risk and social phobia with higher risk for false-positive endorsement, while higher levels of schooling correlated with lower risk and male gender with higher risk for false-negative endorsement. CONCLUSIONS: Clinicians treating male patients with social phobia and ADHD symptoms should assess even more carefully retrospective recall of ADHD childhood symptoms. Moreover, characteristics associated with recall improvement do not impact accuracy robustly. In this context, the recall of childhood ADHD symptoms seems an unreliable method to characterize the neurodevelopmental trajectory in adults with currently-impairing ADHD symptomatology.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Rememoração Mental , Adulto , Idade de Início , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Brasil/epidemiologia , Feminino , Humanos , Masculino , Análise de Regressão , Reprodutibilidade dos Testes , Estudos Retrospectivos , Autorrelato , Adulto JovemRESUMO
AIM: Few personalised medicine investigations have been conducted for mental health. We aimed to generate and validate a risk tool that predicts adult attention-deficit/hyperactivity disorder (ADHD). METHODS: Using logistic regression models, we generated a risk tool in a representative population cohort (ALSPAC - UK, 5113 participants, followed from birth to age 17) using childhood clinical and sociodemographic data with internal validation. Predictors included sex, socioeconomic status, single-parent family, ADHD symptoms, comorbid disruptive disorders, childhood maltreatment, ADHD symptoms, depressive symptoms, mother's depression and intelligence quotient. The outcome was defined as a categorical diagnosis of ADHD in young adulthood without requiring age at onset criteria. We also tested Machine Learning approaches for developing the risk models: Random Forest, Stochastic Gradient Boosting and Artificial Neural Network. The risk tool was externally validated in the E-Risk cohort (UK, 2040 participants, birth to age 18), the 1993 Pelotas Birth Cohort (Brazil, 3911 participants, birth to age 18) and the MTA clinical sample (USA, 476 children with ADHD and 241 controls followed for 16 years from a minimum of 8 and a maximum of 26 years old). RESULTS: The overall prevalence of adult ADHD ranged from 8.1 to 12% in the population-based samples, and was 28.6% in the clinical sample. The internal performance of the model in the generating sample was good, with an area under the curve (AUC) for predicting adult ADHD of 0.82 (95% confidence interval (CI) 0.79-0.83). Calibration plots showed good agreement between predicted and observed event frequencies from 0 to 60% probability. In the UK birth cohort test sample, the AUC was 0.75 (95% CI 0.71-0.78). In the Brazilian birth cohort test sample, the AUC was significantly lower -0.57 (95% CI 0.54-0.60). In the clinical trial test sample, the AUC was 0.76 (95% CI 0.73-0.80). The risk model did not predict adult anxiety or major depressive disorder. Machine Learning approaches did not outperform logistic regression models. An open-source and free risk calculator was generated for clinical use and is available online at https://ufrgs.br/prodah/adhd-calculator/. CONCLUSIONS: The risk tool based on childhood characteristics specifically predicts adult ADHD in European and North-American population-based and clinical samples with comparable discrimination to commonly used clinical tools in internal medicine and higher than most previous attempts for mental and neurological disorders. However, its use in middle-income settings requires caution.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Maus-Tratos Infantis/estatística & dados numéricos , Transtorno da Conduta/epidemiologia , Depressão/epidemiologia , Inteligência , Família Monoparental/estatística & dados numéricos , Classe Social , Adolescente , Área Sob a Curva , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/epidemiologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/psicologia , Criança , Estudos de Coortes , Transtorno da Conduta/psicologia , Depressão/psicologia , Transtorno Depressivo , Feminino , Humanos , Testes de Inteligência , Modelos Logísticos , Masculino , Mães/psicologia , Estudos Prospectivos , Reprodutibilidade dos Testes , Medição de Risco , Fatores Sexuais , Reino Unido/epidemiologia , Adulto JovemRESUMO
Experimental studies have demonstrated that methylphenidate (MPH) modulates the synaptic vesicle trafficking and synaptotagmin-1 (SytI) mRNA levels. SytI is a regulatory protein of the SNARE complex, a neurotransmitter exocytosis mediator. Despite this evidence, most SNARE complex-related genes have never been evaluated in attention-deficit/hyperactivity disorder (ADHD) pharmacogenetics. This study evaluates, for we believe the first time, polymorphisms on the SNARE complex-related genes STX1A (rs2228607), VAMP2 (26bp Ins/Del) and SYT1 (rs1880867 and rs2251214) on the response to immediate-release methylphenidate (IR-MPH) in a naturalistic sample of adults with ADHD. The sample comprised 433 subjects, of which 272 (62.8%) have completed the short-term IR-MPH treatment (at least 30 days). The main outcome measure was the categorical variable of short-term response to IR-MPH based on the Swanson, Nolan and Pelham Rating Scale version 4 (SNAP-IV), and on the clinical global impression-improvement scale. Additional analyses evaluated the percentage of SNAP-IV symptom reduction for each dimension as well as short- and long- (7 years) term treatment persistence. SYT1-rs2251214 was associated with the categorical short-term response to IR-MPH (P=0.006, PFDR=0.028), and with the percentage of inattention and oppositional defiant disorder symptoms reduction (P=0.007, PFDR=0.028 and P=0.017, PFDR=0.048, respectively). SYT1-rs2251214 was also associated with short-term treatment persistence (P=0.018, PFDR=0.048), and with months of treatment (P=0.002, PFDR=0.016) in the long-term protocol. Our findings suggest that SYT1-rs2251214 presents a broad influence in IR-MPH response variability in adults with ADHD, being involved with both symptom response and treatment persistence. If such findings are replicated, SytI could represent a key element in MPH pharmacodynamics in adults with ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Exocitose/genética , Sinaptotagmina I/genética , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/complicações , Estimulantes do Sistema Nervoso Central , Exocitose/fisiologia , Feminino , Humanos , Masculino , Metilfenidato/farmacologia , Metilfenidato/uso terapêutico , Avaliação de Resultados em Cuidados de Saúde , Polimorfismo Genético , Sinaptotagmina I/metabolismo , Sintaxina 1/genética , Sintaxina 1/metabolismo , Resultado do Tratamento , Proteína 2 Associada à Membrana da Vesícula/genética , Proteína 2 Associada à Membrana da Vesícula/metabolismoRESUMO
OBJECTIVE: There is a lack of available information on the trajectories of attention-deficit/hyperactivity disorder (ADHD) dimensions during adulthood. This study investigates the course and the predictors of change for each ADHD domain in a clinical sample of adults with ADHD. METHOD: Adults with ADHD (n = 344) were followed up for 7 years, with a final retention rate of 66.0%. Trajectories of inattention, hyperactivity, and impulsivity and their potential predictors were examined. RESULTS: On average, symptoms declined in all ADHD domains during follow-up. Despite this, rises in inattentive, hyperactive, and impulsive symptoms were observed in approximately 13%, 25%, and 17% of patients respectively. Different predictors influenced the trajectory of each ADHD dimension. Oppositional defiant disorder and social phobia were associated with the maintenance of symptoms, while alcohol use disorder was associated with both maintenance and rise of symptoms. CONCLUSION: Unexpectedly, a rise in the symptoms after 7 years was not uncommon in adults with ADHD. Prevalent comorbidities have the potential to influence the neurodevelopment and the trajectory of ADHD. Therefore, such predictors should be investigated in population cohorts to better characterize the course of ADHD. Additionally, these findings may be relevant in prevention studies and in strategies for ADHD treatment.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Saúde Mental , Índice de Gravidade de Doença , Adulto , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/fisiopatologia , Comorbidade , Feminino , Seguimentos , Humanos , MasculinoRESUMO
Brain development during childhood and early adolescence is characterized by global changes in brain architecture. Neuroimaging studies have revealed overall decreases in cortical thickness (CT) and increases in fractional anisotropy (FA). Furthermore, previous studies have shown that certain cortical regions display coordinated growth during development. However, there is significant heterogeneity in the timing and speed of these developmental transformations, and it is still unclear whether white and grey matter changes are co-localized. In this multimodal neuroimaging study, we investigated the relationship between grey and white matter developmental changes and asynchronous maturation within brain regions in 249 normally developing children between the ages 7-14. We used structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to analyze CT and FA, respectively, as well as their covariance across development. Consistent with previous studies, we observed overall cortical thinning with age, which was accompanied by increased FA. We then compared the coordinated development of grey and white matter as indexed by covariance measures. Covariance between grey matter regions and the microstructure of white matter tracts connecting those regions were highly similar, suggesting that coordinated changes in the cortex were mirrored by coordinated changes in their respective tracts. Examining within-brain divergent trajectories, we found significant structural decoupling (decreased covariance) between several brain regions and tracts in the 9- to 11-year-old group, particularly involving the forceps minor and the regions that it connects to. We argue that this decoupling could reflect a developmental pattern within the prefrontal region in 9- and 11-year-old children, possibly related to the significant changes in cognitive control observed at this age.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/crescimento & desenvolvimento , Substância Branca/diagnóstico por imagem , Substância Branca/crescimento & desenvolvimento , Adolescente , Criança , Estudos Transversais , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Imagem Multimodal , Tamanho do ÓrgãoRESUMO
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is frequently associated with poorer reading ability; however, the specific neuropsychological domains linking this co-occurrence remain unclear. This study evaluates information-processing characteristics as possible neuropsychological links between ADHD symptoms and RA in a community-based sample of children and early adolescents with normal IQ (⩾70). METHOD: The participants (n = 1857, aged 6-15 years, 47% female) were evaluated for reading ability (reading single words aloud) and information processing [stimulus discriminability in the two-choice reaction-time task estimated using diffusion models]. ADHD symptoms were ascertained through informant (parent) report using the Development and Well-Being Assessment (DAWBA). Verbal working memory (VWM; digit span backwards), visuospatial working memory (VSWM, Corsi Blocks backwards), sex, socioeconomic status, and IQ were included as covariates. RESULTS: In a moderated mediation model, stimulus discriminability mediated the effect of ADHD on reading ability. This indirect effect was moderated by age such that a larger effect was seen among younger children. CONCLUSION: The findings support the hypothesis that ADHD and reading ability are linked among young children via a neuropsychological deficit related to stimulus discriminability. Early interventions targeting stimulus discriminability might improve symptoms of inattention/hyperactivity and reading ability.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Discriminação Psicológica/fisiologia , Dislexia/fisiopatologia , Reconhecimento Visual de Modelos/fisiologia , Leitura , Adolescente , Criança , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: There are still uncertainties on the psychometric validity of the DSM-5 attention deficit hyperactivity disorder (ADHD) criteria for its use in the adult population. We aim to describe the adult ADHD phenotype, to test the psychometric properties of the DSM-5 ADHD criteria, and to calculate the resulting prevalence in a population-based sample in their thirties. METHOD: A cross-sectional evaluation using the DSM-5 ADHD criteria was carried out in 3574 individuals from the 1982 Pelotas Birth Cohort. Through receiver operator curve, latent and regression analyses, we obtained parameters on construct and discriminant validity. Still, prevalence rates were calculated for different sets of criteria. RESULTS: The latent analysis suggested that the adult ADHD phenotype is constituted mainly by inattentive symptoms. Also, inattention symptoms were the symptoms most associated with impairment. The best cut-off for diagnosis was four symptoms, but sensitivity and specificity for this cut-off was low. ADHD prevalence rates were 2.1% for DSM-5 ADHD criteria and 5.8% for ADHD disregarding age-of-onset criterion. CONCLUSIONS: The bi-dimensional ADHD structure proposed by the DSM demonstrated both construct and discriminant validity problems when used in the adult population, since inattention is a much more relevant feature in the adult phenotype. The use of the DSM-5 criteria results in a higher prevalence of ADHD when compared to those obtained by DSM-IV, and prevalence would increase almost threefold when considering current ADHD syndrome. These findings suggest a need for further refinement of the criteria for its use in the adult population.