RESUMO
BACKGROUND: The need for new therapeutics for attention deficit hyperactivity disorder (ADHD) is evident. Brain, cerebrospinal fluid (CSF), and plasma protein biomarkers with causal genetic evidence could represent potential drug targets. However, a comprehensive screen of the proteome has not yet been conducted. METHODS: We employed a three-pronged approach using Mendelian Randomization (MR) and Bayesian colocalization analysis. Firstly, we studied 608 brains, 214 CSF, and 612 plasma proteins as potential causal mediators of ADHD using MR analysis. Secondly, we analysed the consistency of the discovered biomarkers across three distinct subtypes of ADHD: childhood, persistent, and late-diagnosed ADHD. Finally, we extended our analysis to examine the correlation between identified biomarkers and Tourette syndrome and pervasive autism spectrum disorder (ASD), conditions often linked with ADHD. To validate the MR findings, we conducted sensitivity analysis. Additionally, we performed cell type analysis on the human brain to identify risk genes that are notably enriched in various brain cell types. FINDINGS: After applying Bonferroni correction, we found that the risk of ADHD was increased by brain proteins GMPPB, NAA80, HYI, CISD2, and HYI, TIE1 in CSF and plasma. Proteins GMPPB, NAA80, ICA1L, CISD2, TIE1, and RMDN1 showed overlapped loci with ADHD risk through Bayesian colocalization. Overexpression of GMPPB protein was linked to an increase in the risk for all three ADHD subtypes. While ICA1L provided protection against both ASD and ADHD, CISD2 increased the probability of both disorders. Cell-specific studies revealed that GMPPB, NAA80, ICA1L, and CISD2 were predominantly present on the surface of excitatory-inhibitory neurons. INTERPRETATION: Our comprehensive MR investigation of the brain, CSF, and plasma proteomes revealed seven proteins with causal connections to ADHD. Particularly, GMPPB and TIE1 emerged as intriguing targets for potential ADHD therapy. FUNDING: This work was partly funded by the Key R & D Program of Zhejiang (T.L. 2022C03096); the National Natural Science Foundation of China Project (C.Z. 82001413); Postdoctoral Foundation of West China Hospital (C.Z. 2020HXBH163).
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Biomarcadores , Encéfalo , Análise da Randomização Mendeliana , Proteoma , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Proteoma/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Biomarcadores/líquido cefalorraquidiano , Teorema de Bayes , Proteínas Sanguíneas/metabolismo , Predisposição Genética para DoençaRESUMO
Alterations in monoaminergic signaling are suggested as key aspects of the pathophysiology in bipolar disorder and ADHD, but it is not known if the monoamine metabolic profile differs between these disorders. One method to study monoaminergic systems in humans is to measure monoamine end-point metabolite concentrations in cerebrospinal fluid (CSF). Here, we analyzed CSF monoamine metabolite concentrations in 103 adults with bipolar disorder, 72 adults with ADHD, and 113 controls. Individuals with bipolar disorder had significantly higher homovanillic acid (HVA, 264 ± 112 nmol/L, p < 0.001) and 5-hydroxyindoleacetic acid (5-HIAA, 116 ± 42 nmol/L, p = 0.001) concentration, but lower 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG, 38 ± 8 nmol/L, p < 0.001) concentrations than controls (HVA, 206 ± 70 nmol/L; 5-HIAA, 98 ± 31 nmol/L; and MHPG, 42 ± 7 nmol/L). Higher HVA concentrations were associated with a history of psychosis in the bipolar disorder sample. Subjects with ADHD had higher HVA (240 ± 94 nmol/L, p < 0.001) concentrations compared with controls. In addition, SSRI treatment was associated with lower 5-HIAA concentrations in both patient groups. A power analysis indicated that for within-group comparisons, only large effects would be reliably detectable. Thus, there may be moderate-to-small effects caused by medication that were not detected due to the limited size of the sub-groups in these analyses. In conclusion, the present study suggests disorder-specific alterations of CSF monoamine metabolite concentrations in patients with bipolar disorder and ADHD compared with controls; these differences were independent of acute symptoms and medication effects.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Monoaminas Biogênicas/metabolismo , Transtorno Bipolar/líquido cefalorraquidiano , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Biomarcadores/líquido cefalorraquidiano , Transtorno Bipolar/tratamento farmacológico , Feminino , Humanos , Masculino , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Protein biomarker discovery from biological fluids, such as serum, has been widely applied to disorders such as cancer and has more recently also been utilized in neuro-psychiatric disorders with relatively clear biological causes, such as Alzheimer's disease and schizophrenia. The application of the associated technologies for the identification of protein biomarker signatures in neurodevelopmental disorders, such as autism spectrum disorder and attention deficit hyperactivity disorder, is comparatively less well established. The aim of this article is to provide an overview of the various protocols available for such analysis, discuss reports in which these techniques have been previously applied in biomarker discovery/validation in neurodevelopmental disorders, and consider the future development of this area of research.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno Autístico/diagnóstico , Perfilação da Expressão Gênica/métodos , Proteínas/análise , Proteômica/métodos , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Transtorno do Deficit de Atenção com Hiperatividade/urina , Transtorno Autístico/sangue , Transtorno Autístico/líquido cefalorraquidiano , Transtorno Autístico/urina , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/urina , HumanosRESUMO
This study explored differences in intraindividual variability in 3 attention tasks across a large sample of healthy older adults and individuals with very mild dementia of the Alzheimer's type (DAT). Three groups of participants (healthy young adults, healthy older adults, very mild DAT) were administered 3 experimental measures of attentional selection and switching (Stroop, Simon, task switching). The results indicated that a measure of intraindividual variability, coefficient of variation (CoV; SD/M), increased across age and early stage DAT. The CoV in Stroop discriminated the performance of epsilon4 carriers from noncarriers in healthy older controls and the CoV in task switching was correlated with cerebrospinal fluid (CSF) biomarkers predictive of DAT.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Geriatria , Individualidade , Testes Neuropsicológicos , Fatores Etários , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Análise de Variância , Apolipoproteínas E/genética , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Transtorno do Deficit de Atenção com Hiperatividade/genética , Biomarcadores/líquido cefalorraquidiano , Humanos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Escalas de Graduação Psiquiátrica , Psicometria , Tempo de Reação/genética , Tempo de Reação/fisiologia , Proteínas tau/líquido cefalorraquidianoRESUMO
Bipolar disorder with childhood attention-deficit hyperactivity disorder (ADHD) is a subphenotype characterized by earlier age of onset, more frequent mood episodes, more suicide attempts, and more interpersonal violence than pure bipolar patients. The aim of this study was to test the biological validity of using childhood ADHD to subgroup bipolar disorder. The monoamine metabolites, homovanillinic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined in the cerebrospinal fluid (CSF) of 53 euthymic patients with bipolar disorder type 1, with (N = 17) and without (N = 36) a history of childhood ADHD. In addition to structured clinical interviews, childhood ADHD was assessed by a next of kin using the Autism-Tics, ADHD and other comorbidities questionnaire (A-TAC), and by patients themselves using the Wender Utah rating scale (WURS-25). Current ADHD symptoms were assessed by the Brown attention-deficit disorder scale (Brown ADD). Bipolar patients with childhood ADHD had significantly lower CSF concentration (mean +/- SD nmol/l) of HVA (89.0 +/- 32.5 vs. 115.8 +/- 47.1, P = 0.039) and 5-HIAA (88.7 +/- 38.5 vs. 116 +/- 47.9, P = 0.021) than pure bipolar patients. CSF MHPG did not differ between the groups. The WURS-25 score correlated negatively with both HVA (r = -0.27, P = 0.048) and 5-HIAA (r = -0.30, P = 0.027). Likewise, the Brown ADD total score correlated negatively with both HVA (r = -0.34, P = 0.013) and 5-HIAA (r = -0.35, P = 0.011). These findings indicate different monoaminergic function in patients with and without childhood ADHD in bipolar disorder type 1. This lends biological support to the notion that those with childhood ADHD represent a valid subphenotype of bipolar disorder.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Transtorno Bipolar/líquido cefalorraquidiano , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Adulto , Transtorno Bipolar/tratamento farmacológico , Feminino , Seguimentos , Humanos , Entrevista Psicológica , Masculino , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Escalas de Graduação Psiquiátrica , Inquéritos e QuestionáriosRESUMO
Hyperglycemic status may be rarely complicated by Epilepsia partialis continua (EPC) that usually responds to metabolic normalization. Anti-glutamic acid decarboxylase antibodies (GAD-Ab) play a pivotal role in the autoimmune process that leads to clinical onset of type 1 diabetes mellitus (T1DM). GAD-Ab have been recently reported in association with rare forms of refractory epilepsy, with or without association to T1DM. Here we describe a young patient who developed EPC five months after T1DM onset; GAD-Ab were detected in his cerebrospinal fluid with evidence of oligoclonal bands. His epileptic disorder evolved over time into drug-resistant epilepsy with continuous spike-waves during slow sleep and severe behavioral impairment. The role of both metabolic imbalance and GAD autoimmunity is discussed.
Assuntos
Encéfalo/fisiopatologia , Diabetes Mellitus Tipo 1/líquido cefalorraquidiano , Diabetes Mellitus Tipo 1/fisiopatologia , Epilepsia Parcial Contínua/líquido cefalorraquidiano , Epilepsia Parcial Contínua/fisiopatologia , Sono/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Autoanticorpos/líquido cefalorraquidiano , Encéfalo/patologia , Pré-Escolar , Diabetes Mellitus Tipo 1/complicações , Progressão da Doença , Eletroencefalografia , Eletromiografia , Epilepsia Parcial Contínua/complicações , Glutamato Descarboxilase/imunologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Bandas Oligoclonais/líquido cefalorraquidiano , Fatores de TempoRESUMO
Attention-deficit Hyperactivity disorder (ADHD) is a multifactorial disorder clinically characterized by inattentiveness, impulsivity and hyperactivity. The occurrence of this disorder is between 3 and 6% of the children population, with boys predominating over girls at a ratio of 3:1 or more. The research of some candidate genes (DRD4, DAT, DRD5, DBH, 5HTT, HTR1B and SNAP25) brought consistent results confirming the heredity of ADHD syndromes. Dopamine-beta-hydroxylase (DBH) is an enzyme responsible for the conversion of dopamine into noradrenaline. Alteration of the dopamine/noradrenaline levels can result in hyperactivity. The DBH protein is released in response to stimulation. DBH activity, derived largely from sympathetic nerves, can be measured in human plasma. Patients with ADHD showed decreased activities of DBH in serum and urine. Low DBH levels correlate indirectly with the seriousness of the hyperkinetic syndrome in children [19,20]. In the DBH gene, the G444A, G910T, C1603T, C1912T, C-1021T, 5 -ins/del and TaqI polymorphisms occur frequently and may affect the function of gene products or modify gene expression and thus influence the progression of ADHD. This article reviews the DBH itself and polymorphisms in the DBH gene that influence the DBH activity in the serum and the CSF level of DBH. All those are evaluated in connection with ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/enzimologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Dopamina beta-Hidroxilase/sangue , Dopamina beta-Hidroxilase/genética , Polimorfismo Genético/genética , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Criança , Dopamina beta-Hidroxilase/líquido cefalorraquidiano , HumanosRESUMO
Research consistently indicates that in animals and adults, reduced central serotonergic (5-HT) function is associated with increased aggression. This relationship has been elucidated via cerebrospinal fluid monoamine metabolite levels, hormonal responses to pharmacologic challenge using serotonergic probes, platelet receptor binding studies, and, more recently, through molecular genetic approaches. In contrast, studies examining the relationship of 5-HT to aggression in children have been characterized by inconsistent findings. The literature examining the relationship between central 5-HT function and aggression is reviewed. Several hypotheses that might account for the discrepancies in the child literature are examined.
Assuntos
Agressão/psicologia , Transtornos do Comportamento Infantil/líquido cefalorraquidiano , Transtornos do Comportamento Infantil/psicologia , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Transtornos do Comportamento Infantil/genética , Meio Ambiente , Família/psicologia , Humanos , Monoaminoxidase/líquido cefalorraquidiano , Comportamento SocialRESUMO
This study examines cerebrospinal fluid from patients with three neuropsychiatric diseases of childhood for the presence and levels of several cytokines relevant to cell-mediated (type 1) and humoral (type 2) immunity. The patient groups include childhood-onset schizophrenia (n = 22), obsessive-compulsive disorder (OCD) (n = 24), and attention deficit hyperactivity disorder (n = 42). The cytokines examined include IL-2, IFN-gamma, TNF-beta/LT, IL-4, IL-5, IL-10, and TNF-alpha. Patients with OCD had a preponderance of type 1 cytokines. IL-4 was detectable only in samples from patients with schizophrenia. IL-10 was rarely detected and never in patients with OCD. Few patients with schizophrenia had detectable amounts of IFN-gamma in CSFL. We conclude that there is a relative skewing of CSFL profiles toward type 1 cytokines in patients with OCD, whereas in schizophrenia the relative preponderance is toward type 2 mediators. Patients with attention deficit hyperactivity disorder exhibited profiles intermediate between OCD and schizophrenia. We infer that cell-mediated immunity may be involved in the etiopathogenesis of OCD, whereas a relative lack of cell-mediated immunity and involvement of humoral immunity may be present in schizophrenia. These data provide a rationale for immune-based strategies of study and therapeutics in childhood neuropsychiatric disease.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Citocinas/líquido cefalorraquidiano , Transtorno Obsessivo-Compulsivo/líquido cefalorraquidiano , Esquizofrenia Infantil/líquido cefalorraquidiano , Transtorno do Deficit de Atenção com Hiperatividade/imunologia , Criança , Humanos , Imunidade , Masculino , Transtorno Obsessivo-Compulsivo/imunologia , Esquizofrenia Infantil/imunologiaRESUMO
Central dopaminergic activity has been assumed to play a role in the efficacy of stimulant drugs in attention deficit/hyperactivity disorder (ADHD), although supporting evidence has been scant. This study examined baseline cerebrospinal fluid (CSF) of boys with ADHD in relation to response to three different stimulant drugs. Forty five boys with DSM-III-R-diagnosed ADHD had a lumbar puncture before double-blind trials of methylphenidate, dextroamphetamine, and placebo. Sixteen also received pemoline as part of a subsequent open trial. Stepwise linear regressions determined significant predictors of drug response. Our prior report of a positive significant correlation between CSF homovanillic acid (HVA) and ratings of hyperactivity on placebo was replicated in a new sample of 20 boys. After baseline symptom severity, CSF HVA was the best predictor of stimulant drug response, with significant independent contribution to four of the ten measures of hyperactivity that changed significantly with medication. Higher HVA predicted better drug response, and lower HVA was associated with worsening on some measures. This supports the mediating role of central dopaminergic activity in stimulant drug efficacy in childhood hyperactivity.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Comportamento/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/uso terapêutico , Ácido Homovanílico/líquido cefalorraquidiano , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Monoaminas Biogênicas/líquido cefalorraquidiano , Criança , Estudos Cross-Over , Dextroanfetamina/uso terapêutico , Método Duplo-Cego , Humanos , Masculino , Metilfenidato/uso terapêutico , Pemolina/uso terapêutico , Escalas de Graduação Psiquiátrica , Análise de RegressãoRESUMO
Cerebrospinal fluid (CSF), plasma, and urinary monoamine metabolites were determined for 29 boys, aged 6-12, with attention-deficit hyperactivity disorder (ADHD). Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), the metabolites of serotonin, dopamine, and norepinephrine, respectively, correlated significantly with behavioral measures of aggression and impulsivity/hyperactivity. However, these correlations were in the unexpected direction; for example, CSF 5-HIAA correlated positively with the Brown-Goodwin Lifetime History of Aggression Scale. HVA in CSF was positively correlated with several measures of hyperactivity. The replicability of these findings, as well as possible socioenvironmental effects, and the predictive value of CSF monoamines in prepubertal hyperactivity are the subjects of ongoing study.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Neurotransmissores/líquido cefalorraquidiano , Agressão/efeitos dos fármacos , Agressão/fisiologia , Agressão/psicologia , Atenção/efeitos dos fármacos , Atenção/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Dextroanfetamina/uso terapêutico , Método Duplo-Cego , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Comportamento Impulsivo/líquido cefalorraquidiano , Comportamento Impulsivo/diagnóstico , Comportamento Impulsivo/tratamento farmacológico , Comportamento Impulsivo/psicologia , Masculino , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Metilfenidato/uso terapêutico , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologiaRESUMO
A 2-year prospective follow-up study of 100% (N = 29) of a sample of children and adolescents with disruptive behavior disorders found that the baseline lumbar cerebrospinal fluid monoamine metabolite concentration and autonomic nervous system activity predicted some subsequent outcomes. The 5-hydroxyindoleacetic acid concentration significantly predicted severity of physical aggression during follow-up. The skin conductance level significantly predicted institutionalization. Correlations were in predicted directions with lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and autonomic activity correlated with poor outcome. Moreover, in multivariate analyses, which included nonlaboratory measures as predictors, cerebrospinal fluid and autonomic measures still contributed significantly to the prediction. However, hypothesized predictions of cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations for suicide attempts and of low autonomic nervous system activity for arrests were not supported thus far. Patients are still at risk; consequently, these results must be considered preliminary. Nonetheless, the results suggest that further investigation of relationships between biological factors and outcome of children with disruptive behavior disorders is warranted.
Assuntos
Transtornos do Comportamento Infantil/diagnóstico , Adolescente , Agressão/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Criança , Transtornos do Comportamento Infantil/líquido cefalorraquidiano , Feminino , Seguimentos , Resposta Galvânica da Pele , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Institucionalização , Masculino , Análise Multivariada , Probabilidade , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
Disruptive behavior disorders and obsessive-compulsive disorder have been associated with serotonergic dysfunction as well as particular body habitus findings in pediatric patients. Somatostatin, a peptide which stimulates serotonin release and inhibits growth hormone release, was measured in the cerebrospinal fluid (CSF) of 10 children with disruptive behavior disorders and in 10 age-, sex-, and race-matched pairs of obsessive-compulsive disorder patients. Decreased concentrations of somatostatin were found in disruptive behavior disorder patients relative to obsessive-compulsive children, even after controlling for differences in Tanner stage. In contrast to studies in adults, those patients in a depressed state did not have lower CSF somatostatin concentration.
Assuntos
Transtornos do Comportamento Infantil/líquido cefalorraquidiano , Transtorno Obsessivo-Compulsivo/líquido cefalorraquidiano , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Criança , Transtornos do Comportamento Infantil/diagnóstico , Transtorno Depressivo/líquido cefalorraquidiano , Feminino , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Masculino , Transtorno Obsessivo-Compulsivo/diagnósticoRESUMO
Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, a metabolite of serotonin, were measured in relation to aggression, impulsivity, and social functioning in 29 children and adolescents with disruptive behavior disorders. The cerebrospinal fluid 5-hydroxyindoleacetic acid level was low compared with that of age-, sex-, and race-matched patients with obsessive-compulsive disorder. Within the disruptive group, significant negative correlations with age-corrected 5-hydroxyindoleacetic acid level were seen for the child's report of aggression toward people and the expressed emotionality of the child toward his or her mother; other correlations of age-corrected 5-hydroxyindoleacetic acid level with measures of aggression were in the expected negative direction but did not reach statistical significance. Impulsivity per se and socioenvironmental factors were not significantly related to cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.
Assuntos
Transtornos do Comportamento Infantil/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Adolescente , Fatores Etários , Agressão/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Criança , Transtornos do Comportamento Infantil/psicologia , Feminino , Humanos , Masculino , Relações Mãe-Filho , Transtorno Obsessivo-Compulsivo/líquido cefalorraquidiano , Escalas de Graduação Psiquiátrica , Ajustamento SocialRESUMO
Seasonal variation of cerebrospinal fluid (CSF) monoamines, particularly 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) has been reported for psychiatrically ill and normal adults. Circannual variability was examined for a group of 72 children (mean age = 159.4 +/- 40.3 (SD), range 77-238 months), with a primary diagnosis of obsessive-compulsive disorder (OCD) or disruptive behavior disorder (DBD) (attention deficit disorder, oppositional disorder and/or conduct disorder), from whom CSF had been obtained systematically. There were no seasonal differences in mean concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), HVA, or 5-HIAA, either for the group as a whole, for the separate diagnostic (OCD vs DBD) categories or for the pre-pubertal subgroup. Log-corrected HVA concentrations for the Tanner IV and V subgroup differed by season with summer concentrations less than those of fall (P = 0.06) and winter (P = 0.005). The results suggest that pubertal changes may play a role in any expression of circannual variability.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Transtornos do Comportamento Infantil/líquido cefalorraquidiano , Glicóis/líquido cefalorraquidiano , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Transtorno Obsessivo-Compulsivo/líquido cefalorraquidiano , Estações do Ano , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Criança , Transtornos do Comportamento Infantil/diagnóstico , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/diagnósticoRESUMO
Whether the lumbar cerebrospinal fluid (CSF) concentration gradient of monoamine metabolites found in adults is influenced by age or pubertal status was studied in 26 children ranging from 6.5 to 17.3 years of age. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were assayed by high-power liquid chromatography (HPLC) with electrochemical detection. Eight patients were prepubertal (Tanner stage I). The slopes in units of picomoles/milliliter/milliliter for regression lines for CSF monoamine metabolite concentrations versus milliliter of CSF collected were 5.07 +/- 0.65, 10.13 +/- 2.0, and 0.67 +/- 0.22 for 5-HIAA, HVA, and MHPG, respectively, for the group as a whole. Significant correlations with age, height, weight, or Tanner stage were not found for the HVA or MHPG concentration gradients. Tanner stage and 5-HIAA slope were significantly correlated. Three of eight prepubertal patients had nonsignificant 5-HIAA gradients. CSF studies in pediatric populations must control for aliquot collected, as the size of the gradient could produce differences sufficient to mimic a "positive" clinical study if the aliquots collected are not the same.
Assuntos
Desenvolvimento Infantil , Glicóis/líquido cefalorraquidiano , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Criança , Transtornos do Comportamento Infantil/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/líquido cefalorraquidiano , Puberdade/líquido cefalorraquidianoRESUMO
Following the hypothesis that attention deficit disorder in adults (attention deficit disorder, residual type; ADD, RT), as well as in children, is associated with decreased central dopaminergic activity, the authors measured lumbar cerebrospinal fluid monoamine metabolites in a group of adults with ADD, RT and matched control subjects. Patients were then entered into a double-blind, placebo-controlled trial of methylphenidate. It was predicted that the patients would have lower levels of homovanillic acid (HVA), the major dopamine metabolite in humans. Patients who had a significant response to methylphenidate showed a trend in this direction. Nonresponding patients had significantly higher levels of HVA than controls.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Fenilacetatos/líquido cefalorraquidiano , Adulto , Ensaios Clínicos como Assunto , Método Duplo-Cego , Feminino , Humanos , Masculino , Metilfenidato/farmacologiaRESUMO
Lumbar cerebrospinal fluid homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and probenecid were measured in four subgroups of neuropsychiatrically disturbed children and a contrast group of pediatric patients. With the exception of a serotonin metabolite difference between autistic and nonautistic psychotic children, there were no significant differences in metabolite concentrations among autistic, nonautistic psychotic, aphasic, and cognitively and attentionally impaired groups, or between the developmentally disabled and contrast groups of children. Younger children had higher concentrations of HVA than older children. Girls had significantly lower HVA/probenecid ratios than boys, which did not appear to be related to underlying neuropsychiatric disorder. Significant probenecid-metabolite correlations indicate the importance of measuring probenecid in the cerebrospinal fluid in clinical studies.
Assuntos
Dopamina/metabolismo , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Transtornos Mentais/metabolismo , Fenilacetatos/líquido cefalorraquidiano , Serotonina/metabolismo , Adolescente , Fatores Etários , Afasia/líquido cefalorraquidiano , Afasia/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/líquido cefalorraquidiano , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno Autístico/líquido cefalorraquidiano , Transtorno Autístico/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Probenecid/líquido cefalorraquidiano , Transtornos Psicóticos/líquido cefalorraquidiano , Transtornos Psicóticos/metabolismo , Fatores SexuaisRESUMO
Epidemiologic and pharmacologic evidence suggests that abnormalities of catecholaminergic systems in the brain play a role in the pathogenesis of minimal brain dysfunction, but previous attempts to document a neurochemical abnormality have been unsuccessful. To better define central nervous system mechanisms in children with MBD, we have utilized the probenecid loading technique to determine the concentrations of metabolites in the CSF of a clinically homogeneous group of children with MBD. CSF concentrations of homovanillic acid, the principal metabolite of dopamine, correlated directly with CSF probenecid in 26 control subjects (r = 0.05, p less than 0.01) and in six children with MBD (r = 0.91, p less than 0.05). Concentration of HVA (ng/ml) per unit of probenecid (mug/ml) was found to be significantly lower in children with MBD (9.8 +/- 1.5, mean +/- SEM) compared to those in control subjects (16.5 +/- 1.5), suggesting reduced turnover of brain dopamine in the MBD group. CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the principle metabolite of serotonin, did not differ significantly between the groups. Our findings indicate that there may be a neurochemical abnormality in MBD.