Regional differences in cerebral perfusion associated with the α-2A-adrenergic receptor genotypes in attention deficit hyperactivity disorder

Abstract

Background: Neurobiologic studies have suggested that dysregulation of central noradrenergic systems may be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD), and it has been hypothesized that genetic changes in the norepinephrine pathways might contribute to dysfunction of the prefrontal cortex circuits in ADHD. We previously reported decreased cerebral blood flow in the right lateral prefrontal cortex and both orbitofrontal cortices in children with ADHD. Genetic investigations have shown that the α-2A-adrenergic receptor gene (ADRA2A) is associated with ADHD. Our aim was to examine whether the presence of a risk allele of the ADRA2A MspI polymorphism is associated with differences in regional cerebral blood flow in boys with ADHD. Methods: We recruited 21 Korean boys with ADHD (mean age 9.9, standard deviation [SD] 2.7 yr) and 11 age-and sex-matched controls (mean age 10.6 [SD 2.1] yr). Each participant underwent technetium-99m-hexamethylpropylene amine oxime ( 99m Tc-HMPAO) single-photon emission computed tomography. We performed image analyses with voxel-wise t statistics using SPM2. Results: We found regional hypoperfusion in the prefrontal regions, including the right orbitofrontal and right medial gyri, and the bilateral putamen and cerebellum in boys with ADHD relative to controls (p < 0.0005, uncorrected for multiple comparisons). Boys with ADHD who carried the C allele (n = 13) at the ADRA2A MspI polymorphism had reduced perfusion in the bilateral orbitofrontal regions compared with those without the C allele (n = 8) (p < 0.0005, uncorrected for multiple comparisons). Limitations: This study was limited by the small sample size, and we did not obtain genetic data from the controls. Conclusion: Our findings suggest that regional differences in cerebral perfusion in the orbitofrontal cortex represent an intermediate neuroimaging phenotype associated with the ADRA2A MspI polymorphism; these data support the validity of the noradrenergic hypothesis regarding the pathophysiology of ADHD.

Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood

“…This gene encodes alpha2A subtype and it contains no introns in either its coding or untranslated sequences. There is an extensive literature on the gene and many findings suggesting association to ADHD (e.g., Kim et al, 2010; Roman et al, 2005; Roman et al, 2003; Waldman et al, 2006), as well as metabolic traits (e.g., glycemic phenotypes, blood pressure) (for meta-analysis see Talmud et al, 2011) and substance abuse (Clarke et al, 2012; Merenakk et al, 2011; Prestes et al, 2007). Given the neurobiological implications, this gene should be considered a strong candidate in future alcohol abuse studies.…”

1H MRSI of middle frontal gyrus in pediatric ADHD

“…Given that simultaneous regional deficits in four different metabolite signals were recorded in this investigation, some type of osmotic disturbance or dysfunction is perhaps the most parsimonious explanation. Many SPECT (Amen & Carmichael, 1997; Kim et al, 2002, 2010; Kaya et al, 2002; Lorberboym et al, 2004), PET (Ernst et al, 2003), and perfusion MRI (O'Gorman et al, 2009) studies have measured, often lateralized, effects of ADHD on rCBF. The patterns of lateralization can be complex.…”

Functional dysconnectivity of corticostriatal circuitry and differential response to methylphenidate in youth with attention-deficit/hyperactivity disorder

“…60 However, we had previously reported that the ADRA2A MspI polymorphism was associated with decreased regional cerebral blood flow in bilateral orbitofrontal cortices of Korean children with ADHD. 61 The present finding suggests the need for future research on whether resting-state functional connectivity could provide useful information in pharmacogenetic studies of ADHD.…”