Methylation Dynamics on 5'-UTR of DAT1 Gene as a Bio-Marker to Recognize Therapy Success in ADHD Children.

Attention-deficit/hyperactivity disorder (ADHD), a neuropsychiatric condition characterized by inattention, hyperactivity, and impulsivity, afflicts 5% of children worldwide. Each ADHD patient presents with individual cognitive and motivational peculiarities. Furthermore, choice of appropriate therapy is still up to clinicians, who express somewhat qualitative advice on whether a child is being successfully cured or not: it would be more appropriate to use an objective biomarker to indicate whether a treatment led to benefits or not. The aim of our work is to search for such clinical biomarkers. We recruited 60 ADHD kids; psychopathological scales were administered at recruitment and after six weeks of therapy. Out of such a cohort of ADHD children, we rigorously extracted two specific subgroups; regardless of the initial severity of their disease, we compared those who obtained the largest improvement (ΔCGAS > 5) vs. those who were still characterized by a severe condition (CGAS < 40). After such a therapy, methylation levels of DNA extracted from buccal swabs were measured in the 5'-UTR of the DAT1 gene. CpGs 3 and 5 displayed, in relation to the other CpGs, a particular symmetrical pattern; for "improving" ADHD children, they were methylated together with CpG 2 and CpG 6; instead, for "severe" ADHD children, they accompanied a methylated CpG 1. These specific patterns of methylation could be used as objective molecular biomarkers of successful cures, establishing if a certain therapy is akin to a given patient (personalized medicine). Present data support the use of post-therapy molecular data obtained with non-invasive techniques.

The nature and nurture of ADHD and its comorbidities: A narrative review on twin studies.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children worldwide, and also the recognition of its persistence into adulthood is increasing. While ADHD in childhood is highly heritable and mostly driven by familial factors, during adulthood it appears to show a lower heritability, even if there is not total agreement on this yet. This disorder often co-occurs with many other conditions, which also vary across the different stages of development, and several studies have used the twin design to investigate these comorbidities, giving valuable insights into the origins of the observed co-occurrence. This review aims to summarize the main results of twin research, according to the following domains: individual traits, cognitive impairment, behavioral manifestations, clinical conditions and psychosocial risk factors. Individual features seem to play a role in this symptomatology and include personality traits such as negative emotionality, personality disorders and temperamental dimensions with a predominance of novelty seeking. At a lower level, ADHD is associated with both functional and anatomic brain characteristics. ADHD is also associated with some forms of cognitive impairment, such as sluggish cognitive tempo, and learning disabilities, with a specific predisposition to reading disability. In addition, ADHD is strongly associated with externalizing disorders such as conduct disorder and oppositional defiant disorder, and some behavioral outcomes, particularly substance use and abuse both in adolescence and adulthood. Moreover, ADHD symptoms often overlap with other psychological disorders, namely affective and internalizing disorders, as well as autism spectrum disorder and autistic-like traits in a wider sense. Notably, a genetic overlap has been found between asthma and ADHD, particularly with respect to hyperactivity/impulsivity dimensions. ADHD also appears to represent a risk factor for disordered eating, and, more specifically, for binge eating and bulimia nervosa. Finally, among psychosocial factors, an association has been proposed between childhood maltreatment and ADHD symptoms.

Detection of auto-antibodies to DAT in the serum: interactions with DAT genotype and psycho-stimulant therapy for ADHD.

UNLABELLED: Interest is rising for auto-immune contribution in neuro-psychiatry. We evaluated the auto-antibodies against dopamine transporter (DAT aAbs) in 61 children (46 ADHD who met DSM-IV-TR criteria, 15 healthy controls). METHODS: ADHD patients were assigned, according to severity, either to a non-pharmacological therapy (NPT, N=32) or to a pharmacological treatment (PT, N=14) with methylphenidate (MPH). In ADHD children, blood samples were withdrawn twice, at recruitment (T0 basal) and after 6 weeks (T1); following 16 excluded subjects, DAT genotype was characterized (9-repeat or 10-repeat alleles; N=15 each). After 18 months of NPT or PT, some patients (carrying at least one 9-repeat allele) were blood sampled again (T2), for comparison with healthy controls (final n=8) RESULTS: Compared to NPT, basal DAT aAbs titers were higher within most severe patients (then assigned to PT), specifically if carrying a DAT 10/10 genotype. DAT aAbs levels of NPT group resulted highly correlated with distinct subscales of Conners' Parent/Teacher Scales (Rs>0.34), especially within DAT 10/10 genotype (Rs>0.53). While T1 titers were elevated over T0 baseline for NPT children, such an increase was not observed in PT patients carrying at least one 9-repeat allele, who also showed behavioral response to subchronic MPH. After 12-24 months of MPH exposure, DAT aAbs titers in PT subjects were comparable to those of healthy controls, while titers remained significantly elevated in NPT patients. Data warrant further research on serum DAT aAbs, which could be used to confirm ADHD diagnosis and/or to monitor therapeutic efficacy of MPH.

Sleep spindle activity is correlated with reading abilities in developmental dyslexia.

STUDY OBJECTIVES: To analyze sleep architecture of children with dyslexia, by means of conventional parameters and EEG spectral analysis and to correlate sleep parameters and EEG spectra with neuropsychological measures. DESIGN: Cross-sectional study involving validated sleep questionnaires, neuropsychological scales, and polysomnographic recordings. SETTING: Sleep laboratory in academic center. PARTICIPANTS: Sixteen subjects with developmental dyslexia (mean age 10.8 years) and 11 normally reading children (mean age 10.1 years). All the subjects underwent overnight polysomnographic recording; EEG power spectra were computed from the Cz derivation and spindle density was calculated during sleep stages N2. INTERVENTION: N/A. MEASUREMENTS AND RESULTS: Dyslexic children showed an increase in power of frequency bands between 0.5-3 Hz and 11-12 Hz in stage N2 and between 0.5-1 Hz in stage N3; they also showed significantly increased spindle density during N2. The power of the sigma band in N2 was positively correlated with the Word reading and MT reading tests; similarly, spindle density was significantly correlated with the Word reading test. The increased spindle activity and EEG sigma power in dyslexic subjects were found to be correlated with the degree of dyslexic impairment. CONCLUSIONS: The correlation found between sleep spindle activity and reading abilities in developmental dyslexia supports the hypothesis of a role for NREM sleep and spindles in sleep-related neurocognitive processing.

Slow EEG amplitude oscillations during NREM sleep and reading disabilities in children with dyslexia.

STUDY OBJECTIVES: To analyze non-rapid eye movement (NREM) sleep microstructure of children with dyslexia, by means of cyclic alternating pattern (CAP) analysis and to correlate CAP parameters with neuropsychological measures. DESIGN: Cross-sectional study using polysomnographic recordings and neuropsychological assessments. SETTING: Sleep laboratory in academic center. PARTICIPANTS: Sixteen subjects with developmental dyslexia (mean age 10.8 years) and 11 normally reading children (mean age 10.1 years) underwent overnight polysomnographic recording. INTERVENTION: N/A. MEASUREMENTS AND RESULTS: Sleep architecture parameters only showed some statistically significant differences: number of sleep stage shifts per hour of sleep, percentage of N3, and number of R periods were significantly lower in dyslexic children versus controls. CAP analysis revealed a higher total CAP rate and A1 index in stage N3. A2% and A2 index in stage N2 and N3 were lower in dyslexic children while no differences were found for A3 CAP subtypes. The correlation analysis between CAP parameters and cognitive-behavioral measures showed a significant positive correlation between A1 index in N3 with Verbal IQ, full-scale IQ, and Memory and Learning Transfer reading test; while CAP rate in N3 was positively correlated with verbal IQ. CONCLUSIONS: To overcome reading difficulties, dyslexic subjects overactivate thalamocortical and hippocampal circuitry to transfer information between cortical posterior and anterior areas. The overactivation of the ancillary frontal areas could account for the CAP rate modifications and mainly for the increase of CAP rate and of A1 index in N3 that seem to be correlated with IQ and reading abilities.