Immunophenotyping lymphocyte and acute phase proteins in canine X-linked muscular dystrophy.

Duchenne Muscular Dystrophy (DMD) is the most common X-linked muscular disease affecting humans. The Golden Retriever Muscular Dystrophy model (GRMD) is considerthe most suitable for several studies. This assay aims to quantify lymphocyte subpopulations CD4, CD5, and CD8, and standardize, the serum electrophoretic profile, to understand their contribution to the pathologic process in normal Golden Retriever dogs (GR group) and dystrophic´s (GRMD group), through the umbilical cord blood, in dogs aged from 2 to 3 months (GR II and GRMD II), and in dogs over 1 year of age (GR III and GRMD III). No significant differences were observed between the CD8+ lymphocyte subpopulations of the groups studied. The CD4+ and CD5+ lymphocyte subpopulations were significantly higher in the GRMD III group compared to the GR III group. Twenty-two different proteins in the gel were identified. The serum concentrations of the proteins belonging to the GR I and GRMD I groups were significantly lower than those of the other groups. We show that expression of acute phase proteins are worst during the aging of the dogs. We hope to expand knowledge to better understand the GRMD model and the translational data.

Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric disorder. Despite the high heritability, the unraveling of specific genetic factors related to ADHD is hampered by its considerable genetic complexity. Recent evidence suggests that gene-gene interactions can explain part of this complexity. We examined the impact of strongly supported interaction effects between the LPHN3 gene and the NTAD gene cluster (NCAM1-TTC12-ANKK1-DRD2) in a 7-year follow-up of a clinical sample of adults with ADHD, addressing associations with susceptibility, symptomatology and stability of diagnosis. The sample comprises 548 adults with ADHD and 643 controls. Entropy-based analysis indicated a potential interaction between the LPHN3-rs6551665 and TTC12-rs2303380 SNPs influencing ADHD symptom counts. Further analyses revealed significant interaction effects on ADHD total symptoms (p=0.002), and with hyperactivity/impulsivity symptom counts (p=0.005). In the group composed by predominantly hyperactive/impulsive and combined presentation, the presence of LPHN3-rs6551665 G allele was related to increased ADHD risk only in individuals carrying the TTC12-rs2303380 AA genotype (p=0.026). Also, the same allelic constellation is involved in maintenance of ADHD in a predominantly hyperactive/impulsive or combined presentation after a 7-year follow-up (p=0.008). These observations reinforce and replicate previous evidence suggesting that an interaction effect between the LPHN3 gene and the NTAD cluster may have a role in the genetic substrate associated to ADHD also in adults. Moreover, it is possible that the interactions between LPHN3 and NTAD are specific factors contributing to the development of an ADHD phenotype with increased hyperactivity/impulsivity that is maintained throughout adulthood.

Effects of corticotropin-releasing hormone receptor 1 SNPs on major depressive disorder are influenced by sex and smoking status.

BACKGROUND: The corticotropin-releasing hormone receptor 1 (CRHR1) gene has been repeatedly implicated in Major Depressive Disorder (MDD) in humans and animal models; however, the findings are not absolutely convergent. Since recent evidence from genome-wide association studies suggests that narrowing the phenotypic heterogeneity may be crucial in genetic studies of MDD, the aim of this study was to evaluate the effects of CRHR1 polymorphisms on MDD while addressing the influence of sex and smoking status. METHODS: The association of the CRHR1 SNPs rs12944712, rs110402, and rs878886 with MDD was evaluated in 629 Brazilian adults of European descent recruited from the general population [180 (28.6%) with lifetime MDD]. The sample was subdivided according to sex and smoking status RESULTS: Among nonsmokers, there were nominal associations between MDD and all tested SNPs (rs12944712, P=0.042; rs110402, P=0.031, and rs878886, P=0.040), regardless of sex. In addition, there were significant effects of rs110402 in women (Pcorr=0.034) and rs878886 in men (Pcorr=0.013). Among lifetime smokers, there were no significant associations between CRHR1 SNPs and MDD LIMITATIONS: The lack of a depression rating scale; scarcity of information on the functionality of the CRHR1 SNPs; and relatively small sample sizes in some subgroups. CONCLUSIONS: Our results strengthen the evidence for the role of CRHR1 SNPs in MDD susceptibility and suggest that their effects may be modulated by sex and smoking status. These findings suggest the perspective that reducing phenotypic heterogeneity is warranted in genetic studies of MDD.

Pleiotropic effects of Chr15q25 nicotinic gene cluster and the relationship between smoking, cognition and ADHD.

Polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster (Chr15q25) have been robustly associated with nicotine dependence, including genome-wide studies, as well as with cognitive and neuropsychological measures. In addition, cognitive processes can be influenced by nicotine use through nicotinic acetylcholine receptors (nAChRs). Here, we evaluated the effect of polymorphisms in CHRNA5-CHRNA3-CHRNB4 gene cluster and their interaction with tobacco smoking status on cognition in patients with Attention Deficit/Hyperactivity Disorder (ADHD). Eight SNPs from the CHRNA5-CHRNA3-CHRNB4 gene cluster were evaluated on a clinical sample of 403 adults with ADHD. Cognitive performance was assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Analyses of covariance were used to assess the influence of single markers and their interaction with smoking status in the Vocabulary and Block Design subtests of WAIS-R. Correction for multiple comparisons was applied. Lifetime smoking was associated to Vocabulary subtest. The TT genotypes of CHRNA5 SNPs rs588765 and rs514743 showed a trend towards association with, respectively, higher and lower scores on the Vocabulary subtest. There was a significant interaction between intergenic SNP rs8023462 and smoking on Vocabulary scores. Our results are consistent with an influence of variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on cognitive measures. The overall scenario suggests a pleiotropic role of Chr15q25 nicotinic gene cluster with complex influences in ADHD, tobacco smoking and cognitive performance, characteristics that can be partially interdependent and may share underlying genetic factors.

Predictors of persistence of ADHD into adulthood: a systematic review of the literature and meta-analysis.

Attention-deficit/hyperactivity disorder (ADHD) is traditionally conceptualized as a neurodevelopmental disorder that continues into adulthood in up to half of diagnosed cases. In light of current evidence, factors associated with the course of the disorder remain unknown. We performed a systematic review of the literature searching for risk markers from childhood that predicted the persistence of ADHD into adulthood. We reviewed 26,168 abstracts and selected 72 for full-text review. We identified data from 16 studies, comprising 6 population-based retrospective samples and 10 clinical follow-ups. We performed meta-analyses of factors evaluated by at least three studies. Severity of ADHD (OR 2.33, 95 % CI = 1.6-3.39, p < 0.001), treatment for ADHD (OR 2.09, 95 % CI = 1.04-4.18, p = 0.037), comorbid conduct disorder (OR 1.85, 95 % CI = 1.06-3.24, p = 0.030), and comorbid major depressive disorder (OR 1.8, 95 % CI = 1.1-2.95, p = 0.019) emerged as predictors already presented in childhood for ADHD persistence into adulthood. Further, we suggest that cohort studies should be designed to clarify such an important question for research and clinical practice.

NOS1 and SNAP25 polymorphisms are associated with Attention-Deficit/Hyperactivity Disorder symptoms in adults but not in children.

Several investigations documented that Attention-Deficit/Hyperactivity Disorder (ADHD) is better conceptualized as a dimensional disorder. At the same time, the disorder seems to have different neurobiological underpinnings and phenotypic presentation in children compared to adults. Neurodevelopmental genes could explain, at least partly these differences. The aim of the present study was to examine possible associations between polymorphisms in SNAP25, MAP1B and NOS1 genes and ADHD symptoms in Brazilian samples of children/adolescents and adults with ADHD. The youth sample consisted of 301 patients whereas the adult sample comprises 485 individuals with ADHD. Diagnoses of ADHD and comorbidities were based on the Diagnostic and Statistical Manual of Mental Disorders-4th edition criteria. The Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV) was applied by psychiatrists blinded to genotype. The total SNAP-IV scores were compared between genotypes. Impulsivity SNAP-IV scores were also compared according to NOS1 genotypes. Adult patients homozygous for the C allele at SNAP25 rs8636 showed significantly higher total SNAP-IV scores (F = 11.215; adjusted P-value = 0.004). Impulsivity SNAP-IV scores were also significantly different according to NOS1 rs478597 polymorphisms in adults with ADHD (F = 6.282; adjusted P-value = 0.026). These associations were not observed in children and adolescents with ADHD. These results suggest that SNAP25 and NOS1 genotypes influence ADHD symptoms only in adults with ADHD. Our study corroborates previous evidences for differences in the genetic contribution to adult ADHD compared with childhood ADHD.

NCAM1-TTC12-ANKK1-DRD2 gene cluster and the clinical and genetic heterogeneity of adults with ADHD.

Dysfunctions of the dopaminergic system have been implicated on the etiology of Attention Deficit/Hyperactivity Disorder (ADHD). Meta-analyses addressing the association of the dopamine receptor D2 (DRD2) gene and ADHD were inconclusive due to excessive heterogeneity across studies. Both the great phenotypic heterogeneity of ADHD and the complexity of the genomic region where DRD2 is located could contribute to the inconsistent findings. Most previous DRD2 studies focused on the well-known Taq1A (rs1800497) SNP, which is actually placed in a neighbor gene (ANKK1). These two genes, together with NCAM1 and TTC12, form the NTAD gene cluster on Chr11q22-23. In order to address the reasons for the high heterogeneity previously reported on DRD2 effects on ADHD, this study investigates the role of NTAD variants on ADHD susceptibility in adults and on the modulation of comorbidity and personality profiles in these patients. Functional polymorphisms from NTAD were analyzed, both individually and in haplotypes, on a sample of 520 adults with ADHD and 630 non-ADHD controls. No direct association of NTAD variants with ADHD susceptibility itself was observed. However, different NTAD polymorphisms and haplotypes were associated to various phenotypes relevant to the clinical heterogeneity of ADHD, including Major Depressive Disorder, Generalized Anxiety Disorder, and Harm Avoidance and Persistence temperament scores. Therefore, these findings represent a possible explanation for the multiple conflicting findings regarding polymorphisms in this genomic region in psychiatry. The NTAD cluster may comprise a variety of independent molecular influences on various brain and behavior characteristics eventually associated with ADHD comorbidities and personality traits. © 2015 Wiley Periodicals, Inc.

Severity but not comorbidities predicts response to methylphenidate in adults with attention-deficit/hyperactivity disorder: results from a naturalistic study.

Although the identification of reliable predictors of methylphenidate response in adults with attention-deficit/hyperactivity disorder (ADHD) is necessary to guide treatment decisions, very few data exist on this issue. Here, we assessed the predictors of clinical response to immediate-release methylphenidate hydrochloride (IR-MPH) in a naturalistic setting by analyzing the influence of demographic factors, severity, and a wide range of comorbid psychiatric disorders. Two hundred fifty adult patients with ADHD were evaluated and completed a short-term treatment with IR-MPH. Mental health diagnoses were based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria through the use of standard structured interviews. The Swanson, Nolan, and Pelham Rating Scale, version 4, adapted to adults was used to assess the severity of ADHD. In the linear regression model, only higher severity of ADHD was associated to a better IR-MPH response (b = 0.770; P < 0.001). Treatment of comorbidities in a subsample (n = 62) did not modify this pattern. Our findings suggest that in clinical settings, patients with more severe ADHD symptoms have a good response to treatment independently from the presence of mild or stabilized comorbidities and their treatments. For adults with ADHD, differently from other common psychiatric disorders such as depression and anxiety, higher severity is associated with better treatment response.

Could comorbid bipolar disorder account for a significant share of executive function deficits in adults with attention-deficit hyperactivity disorder?

OBJECTIVE: The frequent comorbidity between attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BD) represents a challenge for disentangling specific impairments of each disorder in adulthood. Their functional impairments seem to be mediated by executive function deficits. However, little is known about the extent to which each executive function deficit might be disorder specific or explained by the comorbidity. The aim of the present study was to determine if comorbid BD could account for a significant share of executive function deficits when measured by the Wisconsin Card Sorting Test (WCST) in adults with ADHD. METHODS: Adult patients with ADHD and healthy subjects were evaluated in the ADHD outpatient Program at the Hospital de Clínicas de Porto Alegre. Psychiatric diagnoses were based on DSM-IV criteria. WCST scores were compared by multivariate analysis of covariance among three groups: ADHD with BD (n = 51), ADHD without BD (n = 278), and healthy subjects (n = 91). RESULTS: When compared to patients without BD and healthy subjects, patients with ADHD and comorbid BD showed lower scores in total correct answers (p = 0.003); higher scores in total errors (p = 0.004) and non-perseverative errors (p = 0.002); and completed fewer categories (p = 0.009). Patients with ADHD without BD did not differ from healthy subjects. CONCLUSIONS: WCST impairments among patients with ADHD seem to be to a large extent attributable to comorbid BD. Although other executive function deficits (e.g., in the inhibitory control domain) have been demonstrated to accompany ADHD, the present findings suggest that set-shifting deficits are strongly related to comorbid BD.

Cognitive deficits in adults with ADHD go beyond comorbidity effects.

OBJECTIVE: This study addresses if deficits in cognitive, attention, and inhibitory control performance in adults with ADHD are better explained by the disorder itself or by comorbid conditions. METHOD: Adult patients with ADHD (n = 352) and controls (n = 94) were evaluated in the ADHD program of a tertiary hospital. The diagnostic process for ADHD and comorbidities was based on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria. Stepwise regression analyses evaluated the effect of ADHD, demographics, and comorbidities on the scores from Wechsler Adult Intelligence Scale-Revised, Continuous Performance Test, and Stroop Color and Word Test. RESULTS: Patients with ADHD of both genders had worse performance on neuropsychological domains, even after adjustment for comorbidities. The presence of comorbid bipolar disorder and specific phobia are associated with more Stroop errors, whereas patients with generalized anxiety disorder present a longer execution time in Stroop. CONCLUSION: Neuropsychological deficits in adults with ADHD go beyond comorbidity. Specific comorbid disorders may influence the neuropsychological functioning in adults with ADHD.

Does age of onset of impairment impact on neuropsychological and personality features of adult ADHD?

The consideration of age of onset of impairment as part of the ADHD diagnosis is controversial and has been a revisited issue with the emergence of the new classifications in Psychiatry. The aim of this study is to compare patients with early and late onset of ADHD impairment in terms of neuropsychological and personality characteristics. Adult patients with ADHD (n = 415) were evaluated in the ADHD outpatient program at Hospital de Clínicas de Porto Alegre, Brazil. The diagnostic process for ADHD and comorbidities was based on DSM-IV criteria. The comparison between the two ages of onset groups (before 7; n = 209 or from 7 to 12 years; n = 206) was performed with ANOVA, followed by Stepwise forward regression analyses to restrict the number of comparisons and access the possible effect of multiple confounders. Patients with early onset ADHD present higher scores in novelty seeking in both analyses (respectively P = 0.016 and P = 0.002), but similar cognitive and attention features as compared with the late onset group. These data add to previous evidence that despite a more externalizing profile of early onset ADHD, the overall performance is similar reinforcing the need for awareness and inclusion of the late onset group in DSM-V diagnostic criteria.

The role of a lifetime history of oppositional defiant and conduct disorders in adults with ADHD: implications for clinical practice.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) are frequently co-occurring disorders in children and adolescents. However, their clinical status among adults is still under discussion. This study analyzes how the current clinical presentation of adult ADHD might be influenced by a lifetime history of CD and ODD. METHODS: We compared three groups of patients: ADHD without history of CD/ODD (n = 178), ADHD + history of ODD (n = 184), and ADHD + history of CD (n = 96). RESULTS: A history of CD (and to a lower extent ODD) is associated with a more severe and externalizing profile. CONCLUSION: Past CD and ODD entail a significant negative mental health impact on persistent ADHD, reinforcing the importance of actively assessing the developmental history of adult ADHD patients.

Adrenergic α2A receptor gene is not associated with methylphenidate response in adults with ADHD.

Adrenergic α2A receptor gene (ADRA2A) is one of the most promising candidate genes for ADHD pharmacogenetics. Thus far, three studies have investigated the association between the ADRA2A -1291 C>G polymorphism and the therapeutic response to methylphenidate (MPH) in children with ADHD, all of them with positive results. The aim of this study is to investigate, for the first time, the association between three ADRA2A polymorphisms (-1291 C>G, -262 G>A, and 1780 C>T) and the response to MPH in adults with ADHD. The sample comprises 165 Brazilians of European descent evaluated in the adult ADHD outpatient clinic of the Hospital de Clínicas de Porto Alegre. The diagnostic procedures followed the DSM-IV criteria. Drug response was assessed by both categorical and dimensional approaches, through the scales Swanson, Nolan, and Pelham Rating scale version IV and the Clinical Global Impression-Severity Scale, applied at the beginning and after the 30th day of treatment. We found no evidence of association between the three ADRA2A polymorphisms and the therapeutic response to MPH treatment. Our findings do not support a significant role for the ADRA2A gene in ADHD pharmacogenetics, at least among adult patients.

Smoking and ADHD: an evaluation of self medication and behavioral disinhibition models based on comorbidity and personality patterns.

OBJECTIVE: The prevalence of smoking is significantly increased among adults with Attention-Deficit/Hyperactivity Disorder (ADHD), and this association has a significant impact in both disorders, ascribed to either self-medication or behavioral disinhibition hypotheses. However, little is known about clinical variables associated with cigarette smoking among patients with ADHD. The present study evaluates comorbidity, demographic and personality profiles of patients with ADHD in relation to smoking status. METHODS: Patients (n422) were evaluated in the adult ADHD outpatient clinic of Hospital de Clínicas de Porto Alegre. Diagnoses were based on DSM-IV criteria and interviews were performed with Portuguese version of K-SADS-E for ADHD and Oppositional-Defiant Disorder. Axis I psychiatric comorbidities were evaluated with the SCID-I and smoking behavior with Fagerström Test for Nicotine Dependence (FTND). Personality was evaluated with Cloninger's Temperament and Character Inventory (TCI). RESULTS: The presence of smoking was strongly associated with externalizing characteristics as antisocial personality disorder (OR4.2) and substance dependence (OR6.5), but not with internalizing disorders. Moreover, smoking was associated with higher novelty seeking and lower harm avoidance scores. CONCLUSIONS: Smoking initiation among patients with ADHD is consistent with a behavioral disinhibition profile beyond the possible role of self-medication in smoking persistence. Smoking in these patients is strongly associated with externalizing comorbid disorders.

Late-onset ADHD in adults: milder, but still dysfunctional.

OBJECTIVE: The requirement in classificatory systems that some impairment from attention-deficit/hyperactivity disorder (ADHD) symptoms starts before 7 years of age (age of onset of impairment criteria - AOC) has been harshly criticized. Although there is evidence that late-onset ADHD is a valid diagnosis, little is known about the role of age of onset of impairment on the clinical profile of adult patients. METHODS: The diagnoses of 349 adults with ADHD followed DSM-IV criteria. ADHD and oppositional defiant disorder (ODD) were evaluated with the K-SADS-E, and other comorbidities with the SCID-IV and the MINI. Subjects were divided in early and late-onset groups (age of onset of impairment between 7 and 12 years old). The effect of age of onset over clinical and demographic characteristics was tested by regression models. RESULTS: Late-onset subjects were diagnosed later (P=0.04), had a lower frequency of problems with authority and discipline (P=0.004), and lower scores in SNAP-IV (P<0.001) and in Barkley's scale for problems in areas of life activities (P=0.03). On the other hand, late-onset patients presented a higher prevalence of comorbid general anxiety disorder (GAD) (P=0.01). Both groups had a similar profile in the remaining comorbidities and sociodemographic characteristics. CONCLUSIONS: This study provides initial evidence that adults with late-onset ADHD have less severity, lower frequency of externalizing symptoms and increased comorbidity with GAD, but similar profile in other comorbidities. In addition, the data suggest that late-onset patients have a higher probability of delayed diagnosis despite the significant impairment of their condition.