Glutamate imbalance in key structure of the default mode network in adults with attention-deficit/hyperactivity disorder.

The default mode network (DMN) is atypically active in patients with ADHD, likely contributing to the inattention patterns observed in patients with the disorder. Nonetheless, magnetic resonance spectroscopy (MRS) studies have rarely targeted the posterior cingulate cortex, a key DMN region, and little is known about the biochemical setting within this network in patients with ADHD. We aimed to assess the differences in metabolite profiles of the posterior cingulate cortex-a key region of the DMN-between patients with ADHD and controls. Five brain metabolites-glutamate, inositol, N-acetyl aspartate, choline, and creatine-were measured through MRS in the posterior cingulate cortex of patients and controls in a 3.0 T scanner. Between-group comparison of neurometabolite concentrations in PCC was performed using multivariate analysis of covariance. A total of 88 patients and 44 controls were included in the analysis. Patients with ADHD showed lower levels of glutamate in the posterior cingulate cortex compared to controls (p = 0.003). Lower concentrations of glutamate in the posterior cingulate cortex suggest that a glutamatergic imbalance within the posterior cingulate cortex might play a role in the pathogenesis of ADHD. Further understanding of the causes and consequences of such glutamate decrease might help explain how some glutamate-related drug effects impact on ADHD symptomatology.

The symptomatology of Attention-Deficit/Hyperactivity Disorder and the genetic control of vitamin D levels.

OBJECTIVES: Vitamin D deficiency has been associated with psychiatric disorders and behavioral phenotypes such as Attention-Deficit/Hyperactivity Disorder (ADHD). Considering that vitamin D levels are polygenic, we aim to evaluate the overall effects of its genetic architecture on symptoms of inattention, hyperactivity, and impulsivity and on the serum levels of vitamin D in two independent samples of adults, as well as the specific effects of five relevant polymorphisms in vitamin D-related genes. METHODS: We evaluated 870 subjects from an ADHD sample (407 cases and 463 controls) and 319 subjects from an academic community (nutrigenetic sample). Vitamin D serum levels were obtained through Elisa test and genetic data by TaqMan™ allelic discrimination and Infinium PsychArray-24 BeadChip genotyping. Polygenic Scores (PGS) were calculated on PRSice2 based on the latest GWAS for Vitamin D and statistical analyses were conducted at Plink and SPSS software. RESULTS: Vitamin D PGSs were associated with inattention in the ADHD sample and with hyperactivity when inattention symptoms were included as covariates. In the nutrigenetic sample, CYP2R1 rs10741657 and DHCR7 rs12785878 were nominally associated with impulsivity and hyperactivity, respectively, and both with vitamin D levels. In the clinical sample, RXRG rs2134095 was associated with impulsivity. DISCUSSION: Our findings suggest a shared genetic architecture between vitamin D levels and ADHD symptoms, as evidenced by the associations observed with PGS and specific genes related to vitamin D levels. Interestingly, differential effects for vitamin D PGS were found in inattention and hyperactivity, which should be considered in further studies involving ADHD.

Association between telomere length with alcohol use disorder and internalizing/externalizing comorbidities in a Brazilian male sample.

BACKGROUND: Shortening telomere length (TL) is an important ageing marker associated with substance use disorder (SUD). However, the influence of psychiatric and clinical comorbidities and alcohol-related outcomes has not been much explored in the context of TL in individuals with alcohol use disorder (AUD) and may be a source of heterogeneity in AUD studies. Therefore, our aim was to investigate the influence of AUD, alcohol-related outcomes, and common psychiatric comorbidities on TL in men with AUD and healthy controls (HC). METHODS: Men with AUD (n = 108, mean age = 52.4, SD = 8.6) were recruited in a detoxification unit, and HC (n = 80, mean age = 50.04, SD = 9.1) from the blood bank, both located in Brazil. HC had no current or lifetime diagnosis of any substance use disorder. Psychiatric comorbidities were assessed using SCID-I. TL ratio was measured in triplicates using quantitative multiplex PCR. RESULTS: Telomere length did not differ between individuals with AUD and HC (p = 0.073) or was associated with AUD-related outcomes, trauma, or clinical comorbidities. Individuals with externalizing disorders had longer TL when comparing with those with internalizing disorders (p = 0.018) or without comorbidity (p = 0.018). CONCLUSION: Our findings indicate that TL was influenced by the presence of psychiatric comorbidity rather than case or control status. These results were adjusted for potential confounders, such as age.

Refining patterns of MEF2C effects in white matter microstructure and psychiatric features.

Several GWAS reported Myocyte Enhancer Factor 2 C (MEF2C) gene associations with white matter microstructure and psychiatric disorders, and MEF2C involvement in pathways related to neuronal development suggests a common biological factor underlying these phenotypes. We aim to refine the MEF2C effects in the brain relying on an integrated analysis of white matter and psychiatric phenotypes in an extensively characterized sample. This study included 870 Brazilian adults (47% from an attention-deficit/hyperactivity disorder outpatient clinic) assessed through standardized psychiatric interviews, 139 of which underwent a magnetic resonance imaging scan. We evaluated variants in the MEF2C region using two approaches: 1) a gene-wide analysis, which uses the sum of polymorphism effects, and 2) SNP analyses, restricted to the independent variants within the gene. The outcomes included psychiatric phenotypes and fractional anisotropy for brain images. Results: The gene-wide analyses pointed to a nominal association between MEF2C and the Temporal Portion of the Superior Longitudinal Fasciculus (SLFTEMP). The SNP analysis identified four independent variants significantly associated with SLFTEMP and one (rs4218438) with Substance Use Disorder. Our findings showing specific associations of MEF2C variants with temporal-frontal circuitry components may help to elucidate how the MEF2C gene underlies a broad range of psychiatric phenotypes since these regions are relevant to executive and cognitive functions.

Dissecting the cross-trait effects of the FOXP2 GWAS hit on clinical and brain phenotypes in adults with ADHD.

The Forkhead box P2 (FOXP2) encodes for a transcription factor with a broad role in embryonic development. It is especially represented among GWAS hits for neurodevelopmental disorders and related traits, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, neuroticism, and risk-taking behaviors. While several functional studies are underway to understand the consequences of FOXP2 variation, this study aims to expand previous findings to clinically and genetically related phenotypes and neuroanatomical features among subjects with ADHD. The sample included 407 adults with ADHD and 463 controls. Genotyping was performed on the Infinium PsychArray-24 BeadChip, and the FOXP2 gene region was extracted. A gene-wide approach was adopted to evaluate the combined effects of FOXP2 variants (n = 311) on ADHD status, severity, comorbidities, and personality traits. Independent risk variants presenting potential functional effects were further tested for association with cortical surface areas in a subsample of cases (n = 87). The gene-wide analyses within the ADHD sample showed a significant association of the FOXP2 gene with harm avoidance (P = 0.001; PFDR = 0.015) and nominal associations with hyperactivity symptoms (P = 0.026; PFDR = 0.130) and antisocial personality disorder (P = 0.026; PFDR = 0.130). An insertion/deletion variant (rs79622555) located downstream of FOXP2 was associated with the three outcomes and nominally with the surface area of superior parietal and anterior cingulate cortices. Our results extend and refine previous GWAS findings pointing to a role of FOXP2 in several neurodevelopment-related phenotypes, mainly those involving underlying symptomatic domains of self-regulation and inhibitory control. Taken together, the available evidence may constitute promising insights into the puzzle of the FOXP2-related pathophysiology.

The course of attention-deficit/hyperactivity disorder through midlife.

The course of ADHD from childhood up to young adulthood has been characterized in several studies. However, little is known about the course of symptoms into middle age and beyond. This study aims to evaluate predictors of ADHD trajectories in midlife based on three assessments. The follow-up sample comprised 323 adults with ADHD, evaluated at baseline and seven and thirteen years later, from the average ages of 34 up to 47 years old. ADHD status at reassessments was used to characterize trajectories. Demographics, ADHD features, comorbidities, and polygenic scores for ADHD and genetically correlated psychiatric disorders were evaluated to predict ADHD trajectories. Study retention rate was 67% at T2 (n = 216) and 62% at T3 (n = 199). Data from patients evaluated three times showed that 68.8% coursed stable, 25.5% unstable, and 5.7% remission trajectory of ADHD. Women, individuals with more severe syndromes, higher frequency of comorbidities at reassessments, and genetic liability to depression present a higher probability of a stable trajectory. Our findings shed light on midlife ADHD trajectories and their gender, genomic and clinical correlates.

Emerging findings of glutamate-glutamine imbalance in the medial prefrontal cortex in attention deficit/hyperactivity disorder: systematic review and meta-analysis of spectroscopy studies.

One of the main challenges in investigating the neurobiology of ADHD is our limited capacity to study its neurochemistry in vivo. Magnetic resonance spectroscopy (MRS) estimates metabolite concentrations within the brain, but approaches and findings have been heterogeneous. To assess differences in brain metabolites between patients with ADHD and healthy controls, we searched 12 databases screening for MRS studies. Studies were divided into 'children and adolescents' and 'adults' and meta-analyses were performed for each brain region with more than five studies. The quality of studies was assessed by the Newcastle-Ottawa Scale. Thirty-three studies met our eligibility criteria, including 874 patients with ADHD. Primary analyses revealed that the right medial frontal area of children with ADHD presented higher concentrations of a composite of glutamate and glutamine (p = 0.02, SMD = 0.53). Glutamate might be implicated in pruning and neurodegenerative processes as an excitotoxin, while glutamine excess might signal a glutamate depletion that could hinder neurotrophic activity. Both neuro metabolites could be implicated in the differential cortical thinning observed in patients with ADHD across all ages. Notably, more homogeneous designs and reporting guidelines are the key factors to determine how suitable MRS is for research and, perhaps, for clinical psychiatry. Results of this meta-analysis provided an overall map of the brain regions evaluated so far, addressed the role of glutamatergic metabolites in the pathophysiology of ADHD, and pointed to new perspectives for consistent use of the tool in the field.

Caffeine-related genes influence anxiety disorders in children and adults with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders (AD) frequently co-occur, increasing morbidity and challenging treatment. Caffeine is a central nervous system stimulant and acts in the brain through adenosine receptors, influencing attention, alertness, and anxiety. In the present study, we performed a gene-set analysis to verify if genes related to caffeine response are associated with anxiety disorders in 240 children and 406 adults with ADHD. We demonstrated an association between the gene-set with AD in children (P = 0.0054) and with the number of anxiety disorders in adults (P = 0.0197). In order to test if this effect is a result of anxiety in general or is related to AD comorbid with ADHD, we evaluated the association between caffeine gene-set with AD in an adult control sample. The gene-set was neither associated with the AD presence (P = 0.3008) nor with the number of AD (P = 0.5594) in this control sample. We also test this gene set with ADHD (n = 55,374) and AD (n = 18,186) GWAS summary statistics, and we did not observe significant results with ADHD (P = 0.5587) or AD (P = 0.3930). These findings suggest the caffeine-related genes play a role in the etiology of an anxiety disorder phenotype present in children and adults with ADHD.

Attention-deficit/hyperactivity disorder and brain metabolites from proton magnetic resonance spectroscopy: a systematic review and meta-analysis protocol.

Despite major advances in the study of the brain, investigations on neurochemistry in vivo still lack the solid ground of more established methods, such as structural and functional magnetic resonance imaging. Proton magnetic resonance spectroscopy (MRS) is a technique that might potentially fill in this gap. Nevertheless, studies using this approach feature great methodological heterogeneity, such as varying voxel of choice, differences on emphasized metabolites, and absence of a standardized unit. In this study, we present a methodology for creating a systematic review and meta-analysis for this kind of scientific evidence using the prototypical case of attention-deficit/hyperactivity disorder. Systematic review registration: International Prospective Register of Systematic Reviews (PROSPERO), CRD42018112418.

Reduced fronto-striatal volume in attention-deficit/hyperactivity disorder in two cohorts across the lifespan.

Attention-Deficit/Hyperactivity Disorder (ADHD) has been associated with altered brain anatomy in neuroimaging studies. However, small and heterogeneous study samples, and the use of region-of-interest and tissue-specific analyses have limited the consistency and replicability of these effects. We used a data-driven multivariate approach to investigate neuroanatomical features associated with ADHD in two independent cohorts: the Dutch NeuroIMAGE cohort (n = 890, 17.2 years) and the Brazilian IMpACT cohort (n = 180, 44.2 years). Using independent component analysis of whole-brain morphometry images, 375 neuroanatomical components were assessed for association with ADHD. In both discovery (corrected-p = 0.0085) and replication (p = 0.032) cohorts, ADHD was associated with reduced volume in frontal lobes, striatum, and their interconnecting white-matter. Current results provide further evidence for the role of the fronto-striatal circuit in ADHD in children, and for the first time show its relevance to ADHD in adults. The fact that the cohorts are from different continents and comprise different age ranges highlights the robustness of the findings.

Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both children and adults. The Soluble N-ethylmaleimide sensitive factor Attachment REceptors (SNARE) complex has been implicated in ADHD pathophysiology since it is a key component of neurotransmitter release events and neurodevelopment processes, and SNPs in this complex have been associated with ADHD. Here we aim to analyze the effects of SNARE complex variants on ADHD susceptibility and its clinical heterogeneity in affected adults. We tested the association between ADHD and polymorphisms on the SNARE genes STX1A (rs2228607), SYT1 (rs1880867 and rs2251214), VAMP2 (26bp Ins/Del) and SNAP25 (rs6108461 and rs8636) on a sample comprised of 548 adults with ADHD and 644 non-affected controls. Regarding clinical heterogeneity, we further investigated the effects of associated SNPs on age at onset of impairment due to ADHD and on relevant externalizing behaviors (i.e. school suspensions/expulsions and problems with law/authority) and comorbidities (i.e. Substance Use Disorder, Oppositional Defiant Disorder, Conduct Disorder and Antisocial Personality Disorder). We replicated a previously reported association between SYT1-rs2251214 and ADHD in adulthood. This SNP was also associated with age at onset of impairment due to ADHD symptoms and with a range of externalizing phenotypes. These findings involving SYT1 suggest that variation in neurotransmitter exocytosis mechanisms may represent an underlying genetic factor shared by a spectrum of externalizing behaviors and disorders, including - but not restricted to - ADHD.

SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond.

Multiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depicted here suggests that the SNARE complex may exert distinct roles throughout development, with age-specific effects of genetic variants in psychiatric disorders. Such perspective should be considered in future studies regarding SNARE complex genes.