Unaltered dopamine transporter availability in adult attention deficit hyperactivity disorder

OBJECTIVE: The authors examined whether patients with attention deficit hyperactivity disorder (ADHD) have altered striatal dopamine transporter levels, which may explain psychostimulant effects in this disorder. METHOD: Single photon emission computed tomography and [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([(123)I]beta-CIT) were used to assess dopamine transporter availability in nine adult patients with ADHD (eight of whom were stimulant naive) and nine age- and gender-matched healthy comparison subjects. RESULTS: Striatal [(123)I]beta-CIT binding did not differ significantly between the ADHD and comparison subjects. CONCLUSIONS: The findings suggest that a hypothesized dysregulation of dopamine function in ADHD does not entail altered dopamine transporter levels.     

多巴胺转运体基因与注意缺损多动障碍

目的　探讨注意缺损多动障碍（ＡＤＨＤ） 与多巴胺转运体（ＤＡＴ１） 基因间的关系。方法　分别采用基于单体型和基于基因型的单体型相对风险分析方法,在上海地区汉族人群中对ＡＤＨＤ 与ＤＡＴ１ 基因微卫星多态性进行遗传关联分析。结果　①上海地区汉族人中,ＤＡＴ１ 基因多态以４８０ ｂｐ 重复片段为主,其基因频率为９２％ 。②以父母双亲为对照,经ＧＨＲＲ 和ＨＨＲＲ 分析,ＤＡＴ１ 基因与ＡＤＨＤ 均无关联。结论　上海地区汉族人群中ＤＡＴ１ 基因多态与ＡＤＨＤ 无关。     

The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD)

The dopamine transporter is elevated in adults with attention deficit hyperactivity disorder (ADHD) compared with healthy controls [Lancet 354 (1999) 2132]. The findings have been confirmed by others in a different population using a different probe for the dopamine transporter. Notwithstanding the need to confirm these findings in a multi-center trial, several hypotheses are presented to account for these observations. A premise that elevated transporter levels result from medication is not supported by current data. Other possibilities, including hypertrophy of dopamine neuronal terminals in the striatum, dysfunctional regulation of dopamine or dopamine receptors, or anomalies in the dopamine transporter gene are presented as hypotheses. The feasibility of exploring these mechanisms in animal models or in human subjects is explored.     

The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample

Genetic variation of the dopamine transporter gene (DAT1) is of particular interest in the study of attention-deficit hyperactivity disorder (ADHD), since stimulant drugs interact directly with the transporter protein. Association between ADHD and the 10-repeat allele of a 40-bp VNTR polymorphism that lies within the 3'-UTR of DAT1 was first reported in 1995, a finding that has been replicated in at least six independent samples from Caucasian populations. We analysed the DAT1 polymorphism in a sample of 110 Taiwanese probands with a DSM-IV diagnosis of ADHD and found evidence of increased transmission of the 10-repeat allele using TRANSMIT (chi(2)=10.8, 1 d.f., p=0.001, OR=2.9, 95% CI 1.4-6.3). These data give rise to a similar odds ratio to that observed in Caucasian poplulations despite a far higher frequency of the risk allele in this Taiwanese population; 82.3% in the un-transmitted parental alleles and 94.5% in the ADHD probands. These data support the role of DAT1 in ADHD susceptibility among Asian populations.     

Incoherence of neuroimaging studies of attention deficit/hyperactivity disorder

Neuroimaging studies have been conducted with increasing frequency in recent years in attempts to identify structural and functional abnormalities in the brains of persons with attention deficit/hyperactivity disorder. Although the results of these studies are frequently cited in support of a biologic etiology for this disorder, inconsistencies among studies raise questions about the reliability of the findings. The present review shows that no specific abnormality in brain structure or function has been convincingly demonstrated by neuroimaging studies. Implications regarding stimulant treatment for attention deficit/hyperactivity disorder are discussed.     

Schizotypy, attention deficit hyperactivity disorder, and dopamine genes

Previous research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of Schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features.     

The dopamine theory of attention deficit hyperactivity disorder (ADHD).

Clinical, animal and neuroanatomical studies of differential isomer and dosage effects of CNS stimulant medications on behaviour are reviewed. Wender's hypothesis that an underlying biochemical abnormality and a disorder of reinforcement was the primary deficit in "MBD" children is restated in terms of a disorder of polysynaptic dopaminergic circuits, between prefrontal and striate centres. Wender's notion of a disorder of reinforcement is broadened to include a disorder of planning and correction of behaviour, including capacity for cortical control of automatic instinctual motor programmes. The dopamine hypothesis of Attention Deficit Hyperactivity Disorder (ADHD) is examined from the point of view of differential dose effects of CNS stimulant medications, and theories of neural control. Clinical, animal and neuropharmacological studies are reviewed. Implications of the findings for understanding clinical and side effects in ADHD children of stimulants are discussed.     

Association between the dopamine transporter gene and the inattentive subtype of attention deficit hyperactivity disorder in Taiwan

Attention deficit hyperactivity disorder (ADHD) is a common heritable childhood psychiatric disorder. Since methylphenidate, one of the main drugs used to treat ADHD, targets the dopamine transporter, this study examined the linkage disequilibrium (LD) structure of the dopamine transporter gene (DAT1) and investigated whether the DAT1 gene was associated with ADHD. This Chinese family-based association sample consisted of 273 DSM-IV diagnosed ADHD probands and their family members (n = 906). We screened 15 polymorphisms across the DAT1 gene, including 14 single nucleotide polymorphism (SNP) markers and the variable number of tandem repeat (VNTR) polymorphism in 3′-untranslated region (3′UTR). Calculations of pairwise LD revealed three main haplotype blocks (HBs): HB1 (intron 2 through intron 6), HB2 (intron 8 through intron 11), and HB3 (3′UTR). Family-Based Association Tests showed that no allele was significantly more transmitted than expected to the ADHD children for these 15 markers. Haplotype-Based Association Tests showed that a haplotype rs27048 (C)/rs429699 (T) was significantly associated with the inattentive subtype (P = 0.008). In quantitative analyses, this haplotype also demonstrated significant association with the inattention severity (P = 0.012). Our finding of the haplotype rs27048 (C)/rs429699 (T) as a novel genetic marker in the inattentive ADHD subtype suggests that variation in the DAT1 gene may primarily affect the inattentive subtype of ADHD.     

Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples.

Molecular genetic studies in attention deficit hyperactivity disorder (ADHD) have focussed on candidate genes within the dopamine system, which is thought to be the main site of action of stimulant drugs, the primary pharmacological treatment of the disorder. Of particular interest are findings with the dopamine transporter gene (DAT1), since stimulant drugs interact directly with the transporter protein. To date, there have been eight published association studies of ADHD with a 480 base-pair allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the gene, five that support an association and three against. We have analysed the same VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children with DSM-IV ADHD, using the transmission disequilibrium test (TDT). Results from the UK (chi(2) = 8.97, P = 0.001, OR = 1.95), but not the Turkish sample (chi(2) = 0.93, P = 0.34) support association and linkage between genetic variation at the DAT1 locus and ADHD. When considered alongside evidence from other published reports, there is only modest evidence for the association, consistent with a very small main effect for the 480-bp allele (chi(2) = 3.45, P = 0.06, OR = 1.15), however we find significant evidence of heterogeneity between the combined dataset (chi(2) = 22.64, df = 8, P = 0.004).     

Gait in attention deficit hyperactivity disorder

Abstract Background Cognitive function and the loading of attention presumably play an important role in gait as well as in fall risk, but previous work has not demonstrated this in any cause-and-effect way. Objectives To gain insight into the relationship between gait and cognitive function, we sought: (1) To compare the gait rhythmicity (stride time variability) of children with attention deficit hyperactivity disorder (ADHD) to controls, (2) To test the hypothesis that dual tasking leads to increased stride-to-stride variability in ADHD, and (3) To test whether pharmacological treatment that relieves ADHD symptoms reduces stride-to-stride variability. Patients and Methods Gait was quantified in children with ADHD and in age-matched healthy controls under single task and dual task conditions on three occasions: off medications (both groups) and, in the ADHD group, after double blinded, randomized administration of methylphenidate (MPH) or placebo. Results At baseline, children with ADHD tended to walk with increased stride-to-stride variability compared to the controls during the single task condition (p = 0.09). During dual task walking, stride time variability was significantly reduced in the children with ADHD (p < 0.004), but not in the controls. In the children with ADHD, the placebo did not significantly affect stride-to-stride variability or the dual tasking response. In contrast, stride time variability was significantly reduced on MPH (p < 0.001) such that dual tasking no longer affected variability. Conclusions The present findings demonstrate alterations in the gait of children with ADHD, support a cause and effect link between cognitive function and gait, and suggest that enhancement of attention abilities may, in certain populations, improve gait rhythmicity.     

Genes and attention deficit hyperactivity disorder

The initial molecular genetic studies of attention deficit hyperactivity disorder (ADHD) evaluated two candidate genes (DAT and DRD4) suggested by dopamine theories of this common disorder and its treatment with stimulant medication. The initial reports of weak associations with ADHD have been replicated by many (but not all) investigators, as is expected for genes with small effects. This literature is reviewed, along with emerging literature generated by active research groups investigating additional genes that might contribute to the genetic basis of this complex disorder.     

Multicomponent attention deficits in attention deficit hyperactivity disorder

The aim of this study was to examine the specific aspects of attention, such as selective attention, sustained attention, and short-term memory in children with attention deficit hyperactivity disorder, combined subtype (ADHD-C). A total of 40 children with a diagnosis of ADHD from the 4th edition of the Diagnostic and Statistical Manual, aged 6-11 years old were compared with 40 controls matched for age and gender on a battery of tests. Short-term memory span and attention was measured by Visual Aural Digit Span Test-Revised. Stroop test and the Turkish version of Cancellation Test were used to assess selective and sustained attention, respectively. In order to check for factor structure in two groups on the test scores, principal component analysis was conducted for both groups separately. Relative to the comparison children, children with ADHD showed significant deficits on tests that are related to different aspects of attention. The results are consistent with the theories explaining the biological basis of ADHD by scattered attention networks in the brain, which have reciprocal dynamic interactions. Further comparative studies are needed to elucidate whether the cognitive processes that are known to be assessed by these tests are specific to ADHD.     

A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition of early childhood onset characterised by marked inattention, hyperactivity and impulsiveness. Molecular genetic investigations of ADHD have found positive associations with the 480-bp allele of a VNTR situated in the 3' untranslated region of DAT1 and allele 7 of a VNTR in exon 3 of DRD4. A number of independent studies have attempted to replicate these findings but the results have been inconsistent. We used both family-based and case control approaches to examine these polymorphisms in a sample of 137 children diagnosed with ICD-10, DSM-IV or DSM-III-R ADHD. We found no evidence of association with the DAT1 polymorphism, despite a sample size that has up to 80% power to detect a previously reported effect size. We observed a significant increase in the DRD4 7 repeat allele amongst ADHD probands (21.7%) and their parents (18.9% in mothers, 22.3% in fathers), compared to ethnically matched controls (12.8%). However TDT analysis showed no preferential transmission of allele 7 to ADHD probands.     

Genetics of attention deficit hyperactivity disorder

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention deficit hyperactivity disorder (ADHD). Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. In contrast to a handful of genome-wide scans conducted thus far, many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. Yet, even these associations are small and consistent with the idea that the genetic vulnerability to ADHD is mediated by many genes of small effects. These small effects emphasize the need for future candidate gene studies to implement strategies that will provide enough statistical power to detect such small effects.     

Neurobiology of attention deficit hyperactivity disorder

This article addresses the current understanding of the neurobiological bases of attention deficit hyperactivity disorder (ADHD), focusing on empiric research findings that connect genetic and environmental factors to structural and functional brain abnormalities, ultimately leading to a set of age-dependent behavioral manifestations. Section one presents evidence for genetic risk factors for ADHD and discusses the role of potential environmental factors in the etiology of the disorder. Section two focuses on brain imaging studies and how they have helped generate different hypotheses regarding the pathophysiology of ADHD. Finally, the article addresses the longitudinal course of symptoms in ADHD from infancy to adulthood in an attempt to place biological findings for this complex brain disorder in the context of maturation and development.     

Psychosocial interventions in attention deficit hyperactivity disorder

This brief overview of psychosocial treatment approaches to attention deficit hyperactivity disorder (ADHD) concentrates on the two that receive the greatest research support, parent training in child behavior management and teacher training in classroom management. Cognitive-behavioral training of children who have ADHD has little evidence of efficacy and group social skills training has mixed or limited evidence of effectiveness. Research should focus on more theoretically driven psychosocial treatment approaches, on potential side effects or adverse events associated with this form of intervention, and on the complex pathways that affect impairment in major life activities that could guide subsequent treatment design for such impairments.     

Atypical outcome in attention deficit hyperactivity disorder

This report describes the course of psychiatric illness in two boys. Both presented with attention deficit hyperactivity disorder (ADHD) in midchildhood; after puberty, one boy developed a schizophrenic illness while the other boy developed a major affective illness. Although the major ADHD outcome studies have found no link between the childhood occurrence of ADHD and psychosis in adulthood, occasionally such a link may exist. The theoretical and practical implications of this finding are discussed. It should be noted, however, that such outcome is highly atypical and very rare.