Search

Gray matter disruptions have been found consistently in Attention-deficit/Hyperactivity Disorder (ADHD). The organization of these alterations into brain structural networks remains largely unexplored. We investigated 508 participants (281 males) with ADHD (N = 210), their unaffected siblings (N = 108), individuals with subthreshold ADHD (N = 49), and unrelated healthy controls (N = 141) with an age range from 7 to 18 years old from 336 families in the Dutch NeuroIMAGE project. Source based morphometry was used to examine structural brain network alterations and their association with symptoms and cognitive performance. Two networks showed significant reductions in individuals with ADHD compared to unrelated healthy controls after False Discovery Rate correction. Component A, mainly located in bilateral Crus I, showed a ADHD/typically developing difference with subthreshold cases being intermediate between ADHD and typically developing controls. The unaffected siblings were similar to controls. After correcting for IQ and medication status, component A showed a negative correlation with inattention symptoms across the entire sample. Component B included a maximum cluster in the bilateral insula, where unaffected siblings, similar to individuals with ADHD, showed significantly reduced loadings compared to controls; but no relationship with individual symptoms or cognitive measures was found for component B. This multivariate approach suggests that areas reflecting genetic liability within ADHD are partly separate from those areas modulating symptom severity.

While gray matter (GM) anomalies have been reported for attention-deficit/hyperactivity disorder (ADHD), investigating their associations with cognitive deficits and individual symptom domains can help pinpoint the neural underpinnings critical for the pathology of ADHD, particularly the persist form of ADHD. In this work, we performed both independent component analysis and voxel-based morphometry analysis on whole brain GM of 486 adults including 214 patients, 96 unaffected siblings, and 176 healthy controls, in relation to cognition and symptoms. Independent component analysis revealed that higher GM volume in inferior semilunar lobule, inferior frontal gyri, and superior and middle frontal gyri was associated with better working memory performance, and lower GM volume in cerebellar tonsil and culmen was associated with more severe inattention symptoms. Consistently, voxel-based morphometry analysis showed that higher GM volume in multiple regions of frontal lobe, cerebellum and temporal lobe was related to better working memory performance. Focusing on the networks derived from ICA, our results integrated prefrontal regions and cerebellar regions through associations with working memory and inattention symptoms, lending support for the theory of ‘cool’-cognition dysfunction being mediated by inferior fronto-striato-cerebellar networks in ADHD. Siblings showed intermediate cognitive impairments between patients and controls but presented GM anomalies in unique focal regions, suggesting they are a separate group potentially affected by the shared genetic and environmental risks with ADHD patients. Keywords: Adult ADHD, Independent component analysis, Prefrontal cortex, Cerebellum, Working memory

Probiotics are microorganisms that provide health benefits when consumed. In animals, probiotics reverse gut microbiome-related alterations in depression-like symptoms, in cognition, and in hormonal stress response. However, in humans, a causal understanding of the gut-brain link in emotion and cognition is lacking. Additionally, whether the effects of probiotics on neurocognition are visible only in presence of stress, remains unclear. We investigated the effects of a multispecies probiotic (Ecologic®Barrier) on specific neurocognitive measures of emotion reactivity, emotion regulation, and cognitive control using fMRI. Critically, we also tested whether probiotics can buffer against the detrimental effects of acute stress on working memory. In a double blind, randomized, placebo-controlled, between-subjects intervention study, 58 healthy participants were tested once before and once after a 28-day intervention.Without stress induction, probiotics did not affect brain, behavioral, or related self-report measures. However, relative to placebo, the probiotics group did show a significant stress-related increase in working memory performance after supplementation. This change was associated with intervention-related neural changes in frontal cortex during cognitive control exclusively in the probiotics group. Overall, our results show neurocognitive effects of a multispecies probiotic in healthy women only under challenging situations, buffering against the detrimental effects of stress on cognition. Keywords: Probiotic, Neuroimaging, Cognitive control, Emotion, Stress, Working memory

Objective: Changes in microbial composition are observed in various psychiatric disorders, but their specificity to certain symptoms or processes remains unclear. This study explores the associations between the gut microbiota composition and the Research Domain Criteria (RDoC) domains of functioning, representing symptom domains, specifically focusing on stress-related and neurodevelopmental disorders in patients with and without psychiatric comorbidity., Methods: The gut microbiota was analyzed in 369 participants, comprising 272 individuals diagnosed with a mood disorder, anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, and/or substance use disorder, as well as 97 psychiatrically unaffected individuals. The RDoC domains were estimated using principal component analysis (PCA) with oblique rotation on a range of psychiatric, psychological, and personality measures. Associations between the gut microbiota and the functional domains were assessed using multiple linear regression and permanova, adjusted for age, sex, diet, smoking, medication use and comorbidity status., Results: Four functional domains, aligning with RDoC's negative valence, social processes, cognitive systems, and arousal/regulatory systems domains, were identified. Significant associations were found between these domains and eight microbial genera, including associations of negative valence with the abundance of the genera Sellimonas, CHKCI001, Clostridium sensu stricto 1, Oscillibacter, and Flavonifractor; social processes with Sellimonas; cognitive systems with Sporobacter and Hungatella; and arousal/regulatory systems with Ruminococcus torques (all p FDR  < 0.05)., Conclusion: Our findings demonstrate associations between the gut microbiota and the domains of functioning across patients and unaffected individuals, potentially mediated by immune-related processes. These results open avenues for microbiota-focused personalized interventions, considering psychiatric comorbidity. However, further research is warranted to establish causality and elucidate mechanistic pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Irritability worsens prognosis and increases mortality in individuals with Attention-Deficit and Hyperactivity Disorder (ADHD) and/or Borderline Personality Disorder (BPD). However, treatment options are still insufficient. The aim of this randomized, double blind, placebo-controlled study was to investigate the superiority of a synbiotic over placebo in the management of adults with ADHD and/or BPD and high levels of irritability. The study was conducted between February 2019 and October 2020 at three European clinical centers located in Hungary, Spain and Germany. Included were patients aged 18-65 years old diagnosed with ADHD and/or BPD and high levels of irritability (i.e., an Affectivity Reactivity Index (ARI-S) ≥ 5, plus a Clinical Global Impression-Severity Scale (CGI-S) score ≥ 4). Subjects were randomized 1(synbiotic):1(placebo); the agent was administered each day, for 10 consecutive weeks. The primary outcome measure was end-of-treatment response (i.e., a reduction ≥ 30 % in the ARI-S total score compared to baseline, plus a Clinical Global Impression-Improvement (CGI-I) total score of < 3 (very much, or much improved) at week 10). Between-treatment differences in secondary outcomes, as well as safety were also investigated. Of the 231 included participants, 180 (90:90) were randomized and included in the intention-to-treat-analyses. Of these, 117 (65 %) were females, the mean age was 38 years, ADHD was diagnosed in 113 (63 %), BPD in 44 (24 %), both in 23 (13 %). The synbiotic was well tolerated. At week 10, patients allocated to the synbiotic experienced a significantly higher response rate compared to those allocated to placebo (OR: 0.2, 95 % CI:0.1 to 0.7; P = 0.01). These findings suggest that that (add-on) treatment with a synbiotic may be associated with a clinically meaningful improvement in irritability in, at least, a subgroup of adults with ADHD and/or BPD. A superiority of the synbiotic over placebo in the management of emotional dysregulation (-3.6, 95 % CI:-6.8 to -0.3; P = 0.03), emotional symptoms (-0.6, 95 % CI:-1.2 to -0.05; P = 0.03), inattention (-1.8, 95 % CI: -3.2 to -0.4; P = 0.01), functioning (-2.7, 95 % CI: -5.2 to -0.2; P = 0.03) and perceived stress levels (-0.6, 95 % CI: -1.2 to -0.05; P = 0.03) was also suggested. Higher baseline RANK-L protein levels were associated with a significantly lower response rate, but only in the synbiotic group (OR: 0.1, 95 % CI: -4.3 to - 0.3, P = 0.02). In the placebo group, higher IL-17A levels at baseline were significantly associated with a higher improvement in in particular, emotional dysregulation (P = 0.04), opening a door for new (targeted) drug intervention. However, larger prospective studies are warranted to confirm the findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03495375., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Arteaga-Henríquez reported receiving personal fees from Janssen outside the submitted work. Dr. Bitter reported receiving consulting fees from Gedeon Richter and Janssen/Janssen-Cilag; speaker’s honoraria from Gedeon Richter, Hikma Pharmaceuticals, Janssen/Janssen-Cilag, KRKA, Lundbeck, and Medichem Pharmaceuticals Inc. by Unilab; research grant from Gedeon Richter; royalties from Oxford University Press. Dr. Reif reported receiving personal fees from Medice, Shire/Takeda, SAGE/Biogen, Boehringen Ingelheimm, Janssen, and Cyclerion outside the submitted work. Dr. Ramos-Quiroga reported being on the speakers’ bureau and/or having acted as a consultant for Janssen Cilag, Novartis, Shire, Takeda, Bial, Shionogi, Sincrolab, Novartis, BMS, Medice, Rubió, Uriach, Technofarma and Rafo, received travel awards (air tickets + hotel) from Janssen-Cilag, Rubió, Shire, Takeda, Shionogi, Bial and Medice for taking part in psychiatric meetings, outside the submitted work. No other disclosures were reported., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that persists into adulthood in the majority of individuals. While the gut-microbiome seems to be relevant for ADHD, the few publications on gut-microbial alterations in ADHD are inconsistent, in the investigated phenotypes, sequencing method/region, preprocessing, statistical approaches, and findings. To identify gut-microbiome alterations in adult ADHD, robust across studies and statistical approaches, we harmonized bioinformatic pipelines and analyses of raw 16S rRNA sequencing data from four adult ADHD case-control studies (N ADHD =312, N NoADHD =305). We investigated diversity and differential abundance of selected genera (logistic regression and ANOVA-like Differential Expression tool), corrected for age and sex, and meta-analyzed the study results. Converging results were investigated for association with hyperactive/impulsive and inattentive symptoms across all participants. Beta diversity was associated with ADHD diagnosis but showed significant heterogeneity between cohorts, despite harmonized analyses. Several genera were robustly associated with adult ADHD; e.g., Ruminococcus&#95;torques&#95;group (LogOdds=0.17, p fdr =4.42 × 10 -2 ), which was more abundant in adults with ADHD, and Eubacterium&#95;xylanophilum&#95;group (LogOdds= -0.12, p fdr =6.9 × 10 -3 ), which was less abundant in ADHD. Ruminococcus&#95;torques&#95;group was further associated with hyperactivity/impulsivity symptoms and Eisenbergiella with inattention and hyperactivity/impulsivity (p fdr <0.05). The literature points towards a role of these genera in inflammatory processes. Irreproducible results in the field of gut-microbiota research, due to between study heterogeneity and small sample sizes, stress the need for meta-analytic approaches and large sample sizes. While we robustly identified genera associated with adult ADHD, that might overall be considered beneficial or risk-conferring, functional studies are needed to shed light on these properties., Competing Interests: Declaration of competing interest J.A.R.Q was on the speakers’ bureau and/or acted as consultant for Biogen, Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogi, Sincrolab, Novartis, BMS, Medice, Rubió, Uriach, Technofarma and Raffo in the last 3 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Takeda, Shionogi, Bial and Medice. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 3 years: Janssen- Cilag, Shire, Oryzon, Roche, Psious, and Rubió. BF has received educational speaking fees from Medice. IT receives funding from the Dutch organisation of research (ZONMW project numbers 80-86200-98-20006, 80-85200-98-20006, 60-63600-98-903) VR has served as a speaker for Rubió and Shire/Takeda in the last 5 years. She has received travel awards from Shire/Takeda for participating in psychiatric meetings. JKB has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Takeda, Roche, Medice, Angelini, Janssen, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. BJ, PV, DM, PvE, MR, JV, MB, AAV and MH have nothing further to disclose., (Copyright © 2024. Published by Elsevier B.V.)

A significant proportion of individuals with attention-deficit/hyperactivity disorder (ADHD) show persistence into adulthood. The genetic and neural correlates of ADHD in adolescents versus adults remain poorly characterized. We investigated ADHD polygenic risk score (PRS) in relation to previously identified gray matter (GM) patterns, neurocognitive, and symptom findings in the same ADHD sample (462 adolescents & 422 adults from the NeuroIMAGE and IMpACT cohorts). Significant effects of ADHD PRS were found on hyperactivity and impulsivity symptoms in adolescents, hyperactivity symptom in adults, but not GM volume components. A distinct PRS effect between adolescents and adults on individual ADHD symptoms is suggested., (Copyright © 2021. Published by Elsevier B.V.)

Background & Aims: Overall diet quality may partially mediate the detrimental effects of stress and neuroticism on common mental health problems: stressed and/or neurotic individuals may be more prone to unhealthy dietary habits, which in turn may contribute to depression and anxiety. Lifestyle interventions for depressed, anxious or at-risk individuals hinge on this idea, but evidence to support such pathway is missing. Here, we aim to prospectively evaluate the role of overall diet quality in common pathways to developing depression and anxiety., Methods: At baseline, N = 121,008 individuals from the general population (age 18-93) completed an extensive food frequency questionnaire, based on which overall diet quality was estimated. Participants also reported on two established risk factors for mental health problems, i.e. past-year stress exposure (long-term difficulties, stressful life-events) and four neuroticism traits (anger-hostility, self-consciousness, impulsivity, vulnerability). Depression and anxiety were assessed at baseline and follow-up (n = 65,342, +3.6 years). Overall diet quality was modeled as a mediator in logistic regression models predicting the development of depression and anxiety from common risk factors., Results: High stress and high neuroticism scores were - albeit weakly - associated with poorer diet quality. Poor diet quality, in turn, did not predict mental health problems. Overall diet quality did not mediate the relationship between stress/neuroticism and common mental health problems: effects of stress, neuroticism and stress-by-neuroticism interactions on mental health problems at follow-up consisted entirely of direct effects (98.6%-100%)., Conclusions: Diet quality plays no mediating role in two established pathways to common mental health problems. As overall diet quality was reduced in stressed and neurotic individuals, these groups may benefit from dietary interventions. However, such interventions are unlikely to prevent the onset or recurrence of depression and anxiety., Competing Interests: Conflict of interest H Larsson has served as a speaker for Evolan Pharma and Shire and has received research grants from Shire; all outside the submitted work. All other authors certify that they have no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Known comorbidities for Attention-Deficit Hyperactivity Disorder (ADHD) include conduct problems, substance use disorder and gaming. Comorbidity with conduct problems may increase the risk for substance use disorder and gaming in individuals with ADHD. The aim of the study was to build a causal model of the relationships between ADHD and comorbid conduct problems, and alcohol, nicotine, and other substance use, and gaming habits, while accounting for age and sex. We used a state-of-the-art causal discovery algorithm to analyze a case-only sample of 362 ADHD-diagnosed individuals in the ages 12-24 years. We found that conduct problem severity mediates between ADHD severity and nicotine use, but not with more severe alcohol or substance use. More severe ADHD-inattentive symptoms lead to more severe gaming habits. Furthermore, our model suggests that ADHD severity has no influence on severity of alcohol or other drug use. Our findings suggest that ADHD severity is a risk factor for nicotine use, and that this effect is fully mediated by conduct problem severity. Finally, ADHD-inattentive severity was a risk factor for gaming, suggesting that gaming dependence has a different causal pathway than substance dependence and should be treated differently. By identifying these intervention points, our model can aid both researchers and clinicians., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

Gray matter disruptions have been found consistently in Attention-deficit/Hyperactivity Disorder (ADHD). The organization of these alterations into brain structural networks remains largely unexplored. We investigated 508 participants (281 males) with ADHD (N = 210), their unaffected siblings (N = 108), individuals with subthreshold ADHD (N = 49), and unrelated healthy controls (N = 141) with an age range from 7 to 18 years old from 336 families in the Dutch NeuroIMAGE project. Source based morphometry was used to examine structural brain network alterations and their association with symptoms and cognitive performance. Two networks showed significant reductions in individuals with ADHD compared to unrelated healthy controls after False Discovery Rate correction. Component A, mainly located in bilateral Crus I, showed a ADHD/typically developing difference with subthreshold cases being intermediate between ADHD and typically developing controls. The unaffected siblings were similar to controls. After correcting for IQ and medication status, component A showed a negative correlation with inattention symptoms across the entire sample. Component B included a maximum cluster in the bilateral insula, where unaffected siblings, similar to individuals with ADHD, showed significantly reduced loadings compared to controls; but no relationship with individual symptoms or cognitive measures was found for component B. This multivariate approach suggests that areas reflecting genetic liability within ADHD are partly separate from those areas modulating symptom severity., Competing Interests: Declaration of Competing Interest Barbara Franke has received educational speaking fees from Shire and Medice. Other authors report no conflict of interest. All authors critically reviewed the content and approved the final version for publication. No other individuals not listed as authors have made substantial contributions to the paper., (Copyright © 2020. Published by Elsevier Inc.)

Dysregulation of executive function (EF) involves alterations in cognitive flexibility / control and is underscored by learning impairments in neurodevelopmental disorders. Here, we examine cognitive inflexibility in BALB/cJ mice (a mouse model showing diminished sociability, increased anxiety and inattentive behaviour) and closely related "reference" BALB/cByJ mice. We used an appetitive extinction paradigm to investigate if cognitive flexibility measures are different between learning acquisition and extinction. The two BALB/c sub-strains learned to respond to a stimulus in a touchscreen operant chamber, after which the reward was removed and responses should be inhibited. Both mice sub-strains showed a different rate of learning while acquiring the task, in which the BALB/cJ mice were faster learners compared to the BALB/cByJ mice. This was not observed during the extinction phase, in which the BALB/cJ mice were able to extinguish responding to unrewarded stimuli equally. Within the BALB/cJ sub-strain, variation in the ability to inhibit a learnt response was observed when comparing them to similar grouped BALB/cByJ mice: BALB/cJ animals that reached the criterion were more reward driven, while BALB/cJ mice failing to reach the set criterion during extinction processing make more mistakes. Additionally, the changes observed during acquisition, were driven by animals not reaching the extinction criterion. Our results suggest that the BALB/c mice sub-strains may use different strategies to learn during appetitive extinction. This may be useful in the phenotypic dissection of cognitive flexibility in BALB/c sub-strains and their mapping on genetic variance revealed by next-generation sequencing in future studies., (Copyright © 2019. Published by Elsevier B.V.)

While gray matter (GM) anomalies have been reported for attention-deficit/hyperactivity disorder (ADHD), investigating their associations with cognitive deficits and individual symptom domains can help pinpoint the neural underpinnings critical for the pathology of ADHD, particularly the persist form of ADHD. In this work, we performed both independent component analysis and voxel-based morphometry analysis on whole brain GM of 486 adults including 214 patients, 96 unaffected siblings, and 176 healthy controls, in relation to cognition and symptoms. Independent component analysis revealed that higher GM volume in inferior semilunar lobule, inferior frontal gyri, and superior and middle frontal gyri was associated with better working memory performance, and lower GM volume in cerebellar tonsil and culmen was associated with more severe inattention symptoms. Consistently, voxel-based morphometry analysis showed that higher GM volume in multiple regions of frontal lobe, cerebellum and temporal lobe was related to better working memory performance. Focusing on the networks derived from ICA, our results integrated prefrontal regions and cerebellar regions through associations with working memory and inattention symptoms, lending support for the theory of 'cool'-cognition dysfunction being mediated by inferior fronto-striato-cerebellar networks in ADHD. Siblings showed intermediate cognitive impairments between patients and controls but presented GM anomalies in unique focal regions, suggesting they are a separate group potentially affected by the shared genetic and environmental risks with ADHD patients.

Background: Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD., Methods: Genome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks., Results: We found a significant single nucleotide polymorphism-based genetic correlation between ADHD and BPD in the full and age-restricted samples (r Gfull = .64, p = 3.13 × 10 -14 ; r Grestricted = .71, p = 4.09 × 10 -16 ). The meta-analysis between the full BPD sample identified two genome-wide significant (p rs7089973 = 2.47 × 10 -8 ; p rs11756438 = 4.36 × 10 -8 ) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (p rs58502974 = 2.11 × 10 -8 ) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue., Conclusions: The single nucleotide polymorphism-based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The shared genetic basis of attention deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders. One hundred seven methadone maintenance treatment patients, 36 having an ADHD diagnosis, 176 adult patients with ADHD without SUDs, and 500 healthy controls were genotyped for variants in the DRD4 (exon 3 VNTR), DRD5 (upstream VNTR), HTR1B (rs6296), DBH (rs2519152), COMT (rs4680; Val158Met), and OPRM1 (rs1799971; 118A>G) genes. Association with disease was tested using logistic regression models. This pilot study was adequately powered to detect larger genetic effects (OR≥2) of risk alleles with a low frequency. Compared to controls, ADHD patients (with and without SUDs) showed significantly increased frequency of the DBH (rs2519152: OR 1.73; CI 1.15-2.59; P=0.008) and the OPRM1 risk genotypes (rs1799971: OR 1.71; CI 1.17-2.50; P=0.006). The DBH risk genotype was associated with ADHD diagnosis, with the association strongest in the pure ADHD group. The OPRM1 risk genotype increased the risk for the combined ADHD and SUD phenotype. The present study strengthens the evidence for a shared genetic basis for ADHD and addiction. The association of OPRM1 with the ADHD and SUD combination could help to explain the contradictory results of previous studies. The power limitations of the study restrict the significance of these findings: replication in larger samples is warranted., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable disorder and several genes increasing disease risk have been identified. The dopamine transporter gene, SLC6A3/DAT1, has been studied most extensively in ADHD research. Interestingly, a different haplotype of this gene (formed by genetic variants in the 3' untranslated region and intron 8) is associated with childhood ADHD (haplotype 10-6) and adult ADHD (haplotype 9-6). The expression of DAT1 is highest in striatal regions in the brain. This part of the brain is of interest to ADHD because of its role in reward processing is altered in ADHD patients; ADHD patients display decreased striatal activation during reward processing. To better understand how the DAT1 gene exerts effects on ADHD, we studied the effect of this gene on reward-related brain functioning in the area of its highest expression in the brain, the striatum, using functional magnetic resonance imaging. In doing so, we tried to resolve inconsistencies observed in previous studies of healthy individuals and ADHD-affected children. In a sample of 87 adult ADHD patients and 77 healthy comparison subjects, we confirmed the association of the 9-6 haplotype with adult ADHD. Striatal hypoactivation during the reward anticipation phase of a monetary incentive delay task in ADHD patients was again shown, but no significant effects of DAT1 on striatal activity were found. Although the importance of the DAT1 haplotype as a risk factor for adult ADHD was again demonstrated in this study, the mechanism by which this gene increases disease risk remains largely unknown., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

Apolipoprotein E (APOE) is consistently associated with dementia in the general population. Findings on the role of this gene in persons with Down's syndrome (DS) are inconclusive. We studied the effects of APOE on mortality and dementia in a longitudinal prospective study of a large population-based sample of persons with DS (n=425), demented and non-demented. There was evidence that APOE epsilon4 is correlated with the rate of decline in the social competence rating scale (SRZ) (p=0.04). In our population, we found overall a modest but not statistical significant effect on the prevalence of dementia (OR=1.57, 95%CI: 0.87-2.82). We did observed a significant long-term effect on the incidence of dementia (HR=4.66, 95%CI: 1.35-16.14), but for those with a follow-up less than 3 years the risk was not significantly increased: HR=0.83 (95%CI 0.35-1.94). When pooling our data in a meta-analysis, the APOE epsilon4 allele shows a 1.59-fold (95%CI: 1.19-2.12) increase in risk of dementia in persons with DS. We conclude that APOE is influencing the risk of dementia in persons with DS.