Sex differences in attention-deficit hyperactivity disorder diagnosis and clinical care: a national study of population healthcare records in Wales.

BACKGROUND: Population-based studies have observed sex biases in the diagnosis and treatment of attention-deficit hyperactivity disorder (ADHD). Females are less likely to be diagnosed or prescribed ADHD medication. This study uses national healthcare records, to investigate sex differences in diagnosis and clinical care in young people with ADHD, particularly regarding recognition and treatment of other mental health conditions. METHODS: The cohort included individuals diagnosed with ADHD, born between 1989 and 2013 and living in Wales between 2000 and 2019. Routine primary and secondary healthcare record data were used to derive diagnoses of ADHD and other neurodevelopmental and mental health conditions, as well as ADHD and antidepressant medications. Demographic variables included ethnicity, socioeconomic deprivation and contact with social services. RESULTS: There were 16,458 individuals diagnosed with ADHD (20.3% females, ages 3-30 years), with a male-to-female ratio of 3.9:1. Higher ratios (4.8:1) were seen in individuals diagnosed younger (<12 years), with the lowest ratio (1.9:1) in those diagnosed as adults (>18). Males were younger at first recorded ADHD diagnosis (mean = 10.9 vs. 12.6 years), more likely to be prescribed ADHD medication and younger at diagnosis of co-occurring neurodevelopmental conditions. In contrast, females were more likely to receive a diagnosis of anxiety, depression or another mental health condition and to be prescribed antidepressant medications, prior to ADHD diagnosis. These sex differences were largely stable across demographic groups. CONCLUSIONS: This study adds to the evidence base that females with ADHD are experiencing later recognition and treatment of ADHD. The results indicate that this may be partly because of diagnostic overshadowing from other mental health conditions, such as anxiety and depression, or initial misdiagnosis. Further research and dissemination of findings to the public are needed to improve awareness, timely diagnosis and treatment of ADHD in females.

Neurological consultation with an autistic patient.

Autism is a neurodevelopmental condition with a very heterogeneous presentation. Autistic people are more likely to have unmet healthcare needs, making it essential that healthcare professionals are 'autism-aware'. In this article, we provide an overview of how autism presents and use case studies to illustrate how a neurological consultation in an outpatient clinic environment could prove challenging for a autistic person. We suggest how to improve communication with autistic patients in clinic and highlight the importance of a patient-centred and flexible approach.

Handgrip and sex-specific cardiometabolic risk factors in Hispanic/Latino migrant farmworkers.

Studies have suggested that handgrip strength might be a marker for cardiometabolic risk (CMR), but it has not been studied in Hispanic/Latino farmworker population. This study aimed to characterize absolute and relative handgrip strength in Hispanic/Latino farmworkers, and investigate the sex-specific association between handgrip strength and CMR factors. CMR factors and seated isometric absolute (the sum of both hands) and relative (absolute handgrip strength divided by body mass index) handgrip strengths were collected in 173 Hispanic/Latino farmworkers (mean age 35.1 ± 0.7 years; 49% female). The absolute and the relative handgrip strengths were 89.2 ± 1.8 kg, 3.3 ± 0.1 kg among males, and 56.5 ± 1.9 kg, 1.9 ± 0.1 kg among females, respectively. Age was correlated with absolute (r = - 0.17, p = 0.03) and relative handgrip strengths (r = - 0.28, p < 0.01). In males, absolute handgrip was related to triglycerides (r = - 0.25, p < 0.05), whereas relative handgrip was related to waist circumference (r = - 0.32, p < 0.01), waist/hip circumference ratio (r = - 0.36, p < 0.01), high-density lipoprotein (r = 0.24, p < 0.05), and triglycerides (r = - 0.35, p < 0.01). In females, absolute handgrip was related to fasting plasma glucose (r = - 0.28, p = 0.03), whereas relative handgrip was related to waist circumference (r = - 0.38, p < 0.01) and fasting plasma glucose (r = - 0.22, p < 0.05). Males had lower absolute handgrip strength when their triglycerides levels were at risk (p = 0.021), and lower relative handgrip strength when their plasma glucose (p = 0.034) and triglycerides (p = 0.002) levels were at risk. Females had lower relative handgrip strength when their plasma glucose (p = 0.001) and blood pressure (p = 0.004) were at risk. This study suggests that handgrip strength may be associated with sex-specific CMR factors in a Hispanic/Latino farmworker population.

The presentation of depression symptoms in attention-deficit/hyperactivity disorder: comparing child and parent reports.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) frequently co-occurs with depression, and outcomes are poor when both are present. Little is known about whether depression symptoms present differently in ADHD compared to the general population, or how reliable young people with ADHD are at reporting these symptoms. This study aimed to describe depression symptoms in a clinical ADHD sample compared to a population sample, and compare self-reports of depression symptoms with parent-reports. METHODS: Two hundred and forty-nine children with ADHD and their parents completed follow-up questionnaires around 5 years after taking part in a Cardiff University ADHD study. Child depression symptoms were measured using parent- and child-reported Mood and Feelings Questionnaires (MFQ) and compared to a population sample with MFQ data (n = 1460). Within both samples, child- and parent-reported depression symptoms were compared. RESULTS: Although the profile of depression symptoms was similar between young people with ADHD and those in the general population, depression symptoms were much more common in the ADHD sample (parent-rated MFQ score = 24.52 vs. 9.39; child-rated = 21.02 vs. 11.86). The most common symptoms in both samples included irritability, restlessness and concentration difficulties, with core depression symptoms such as feeling miserable/unhappy also prominent. Within the ADHD sample, but not the population sample, children reported depression symptoms less frequently than their parents. CONCLUSIONS: Young people with ADHD are at high risk of experiencing symptoms of depression but may under-report the severity of their symptoms. Obtaining parent reports of depression symptoms in this group may be important to avoid missing key indicators of risk.

Investigating late-onset ADHD: a population cohort investigation.

BACKGROUND: Adult ADHD has been assumed to be a continuation of childhood-onset ADHD. However, recent studies have identified individuals with ADHD in adulthood who have not had ADHD in childhood. Whether or not these individuals have a 'typical' neurodevelopmental profile is not clear. METHODS: We tested two explanations for the emergence of apparent late-onset ADHD symptomatology using the ALSPAC epidemiological cohort, by grouping individuals according to their scores on the Strengths and Difficulties Questionnaire (SDQ) hyperactivity subscale at ages 12 and 17 years. First, we tested whether some of those with apparent late-onset ADHD symptoms had been potentially misclassified on the basis of earlier SDQ hyperactivity scores (ages 7, 8 and 9 years) or of subthreshold symptoms at age 12 years. Second, we investigated the possibility that those with 'genuine' late-onset ADHD symptoms had a delayed manifestation of the same liability that underlies childhood-onset symptoms, by investigating whether they had a similar profile of neurodevelopmental impairments (in the domains of autistic symptomatology, language, reading, spelling, executive functioning and IQ) as those with typical childhood-onset ADHD. RESULTS: N = 56/75 (75%) of those with apparent late-onset ADHD had had high ADHD scores at least one point in childhood, suggesting that they may have been misclassified on the basis of their score at age 12 years. The remaining 19 individuals (25%) with genuine late-onset ADHD symptoms did not show a profile of neurodevelopmental impairment typically seen in ADHD, instead showing similar levels of autistic symptoms, language skills, executive functioning ability and IQ to those without ADHD symptoms. The only exceptions were that this group showed reading and spelling problems at age 9 years. CONCLUSIONS: Our work suggests that this small number of individuals with genuine late-onset symptoms may not be most appropriately considered as having a typical neurodevelopmental disorder.

Neurodevelopmental disorders.

Neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder, although most commonly considered in childhood, can be lifelong conditions. In this Personal View that is shaped by clinical experience and research, we adopt a conceptual approach. First, we discuss what disorders are neurodevelopmental and why such a grouping is useful. We conclude that both distinction and grouping are helpful and that it is important to take into account the strong overlap across neurodevelopmental disorders. Then we highlight some challenges in bridging research and clinical practice. We discuss the complexity of clinical phenotypes and the importance of the social context. We also argue the importance of viewing neurodevelopmental disorders as traits but highlight that this is not the only approach to use. Finally, we consider developmental change across the life-span. Overall, we argue strongly for a flexible approach in clinical practice that takes into consideration the high level of heterogeneity and overlap in neurodevelopmental disorders and for research to link more closely to what is observed in real-life practice.

Attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a prevalence of 1·4-3·0%. It is more common in boys than girls. Comorbidity with childhood-onset neurodevelopmental disorders and psychiatric disorders is substantial. ADHD is highly heritable and multifactorial; multiple genes and non-inherited factors contribute to the disorder. Prenatal and perinatal factors have been implicated as risks, but definite causes remain unknown. Most guidelines recommend a stepwise approach to treatment, beginning with non-drug interventions and then moving to pharmacological treatment in those most severely affected. Randomised controlled trials show short-term benefits of stimulant medication and atomoxetine. Meta-analyses of blinded trials of non-drug treatments have not yet proven the efficacy of such interventions. Longitudinal studies of ADHD show heightened risk of multiple mental health and social difficulties as well as premature mortality in adult life.

ADHD severity is associated with white matter microstructure in the subgenual cingulum.

AIMS: This analysis examined hypothesised associations between microstructural attributes in specific white matter (WM) tracts selected a priori and measures of clinical variability in adolescents with a diagnosis of attention deficit hyperactivity disorder (ADHD). Firstly, associations were explored between WM microstructure and ADHD severity in the subgenual cingulum. Secondly, to ensure that tract-specific approaches afforded enhanced rather than differential sensitivity, associations were measured between WM microstructure and autistic traits in the right corticospinal tract based on results of a previously-published voxelwise analysis. METHODS: 40 right-handed males aged 14-18 years (19 with DSM-IV combined type ADHD and 21 healthy controls) underwent a 60 direction diffusion MRI scan. Clinical ADHD and autism variation were assessed by validated questionnaires. Deterministic tractography based on spherical deconvolution methods was used to map the subgenual cingulum and corticospinal tract. RESULTS: Fractional anisotropy was positively correlated and radial diffusivity was negatively correlated with a) ADHD severity in the left subgenual cingulum and b) autistic traits in the inferior segment of the right corticospinal tract. No case-control differences were found. CONCLUSIONS: Results shed light on possible anatomical correlates of ADHD severity and autistic symptoms in pathways which may be involved in the ADHD phenotype. They provide further evidence that tract-specific approaches may a) reveal associations between microstructural metrics and indices of phenotypic variability which would not be detected using voxelwise approaches, and b) provide improved rather than differential sensitivity compared to voxelwise approaches.

Can α-lipoic acid mitigate progression of aging-related decline caused by oxidative stress?

Aging is progressively deteriorating physiological function that leads to increasing risks of illness and death. Increases in life expectancy and the aging of a large segment of the population have made age-related disability and morbidity increasingly important issues. Supplements such as α-lipoic acid may have antiaging effects by positively affecting oxidative stress, cognitive function, and cardiovascular function.

Leptin regulates CD16 expression on human monocytes in a sex-specific manner.

Fat mass is linked mechanistically to the cardiovascular system through leptin, a 16 kDa protein produced primarily by adipocytes. In addition to increasing blood pressure via hypothalamic-sympathetic pathways, leptin stimulates monocyte migration, cytokine secretion, and other functions that contribute to atherosclerotic plaque development. These functions are also characteristics of CD16-positive monocytes that have been implicated in the clinical progression of atherosclerosis. This investigation sought to determine if leptin promoted the development of such CD16-positive monocytes. Cells from 45 healthy men and women with age ranging from 20 to 59 years were analyzed. Circulating numbers of CD14(++)16(++) monocytes, which are primary producers of TNFα, were positively related to plasma leptin concentrations (P < 0.0001), with a stronger correlation in men (P < 0.05 for leptin × sex interaction). In vitro, recombinant human leptin induced CD16 expression in a dose-related manner (P = 0.02), with a stronger influence on monocytes from men (P = 0.03 for leptin × sex interaction). There were no sex-related differences in total leptin receptor expression on any monocyte subtypes, relative expression of long versus short isoforms of the receptor, or soluble leptin receptor concentrations in the plasma. The number of circulating CD14(+)16(++) monocytes, which preferentially migrate into nascent plaques, was positively related to systolic blood pressure (R = 0.56, P = 0.0008) and intima-media thickness (R = 0.37, P = 0.03), and negatively related to carotid compliance (R = -0.39, P = 0.02). These observations indicate that leptin promotes the development of CD16-positive monocyte populations in a sex-specific manner and that these subpopulations are associated with diminished vascular function.

Biological overlap of attention-deficit/hyperactivity disorder and autism spectrum disorder: evidence from copy number variants.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share genetic risks. The aim of this analysis was to determine more broadly whether ADHD and ASD share biological underpinnings. METHOD: We compared copy number variant (CNV) data from 727 children with ADHD and 5,081 population controls to data from 996 individuals with ASD and an independent set of 1,287 controls. Using pathway analyses, we investigated whether CNVs observed in individuals with ADHD have an impact on genes in the same biological pathways as on those observed in individuals with ASD. RESULTS: The results suggest that the biological pathways affected by CNVs in ADHD overlap with those affected by CNVs in ASD more than would be expected by chance. Moreover, this was true even when specific CNV regions common to both disorders were excluded from the analysis. After correction for multiple testing, genes involved in 3 biological processes (nicotinic acetylcholine receptor signalling pathway, cell division, and response to drug) showed significant enrichment for case CNV hits in the combined ADHD and ASD sample. CONCLUSION: The results of this study indicate the presence of significant overlap of shared biological processes disrupted by large rare CNVs in children with these 2 neurodevelopmental conditions.

White matter microstructure predicts autistic traits in attention-deficit/hyperactivity disorder.

Traits of autism spectrum disorder (ASD) in children with attention-deficit/hyperactivity disorder (ADHD) have previously been found to index clinical severity. This study examined the association of ASD traits with diffusion parameters in adolescent males with ADHD (n = 17), and also compared WM microstructure relative to controls (n = 17). Significant associations (p < 0.05, corrected) were found between fractional anisotropy/radial diffusivity and ASD trait severity (positive and negative correlations respectively), mostly in the right posterior limb of the internal capsule/corticospinal tract, right cerebellar peduncle and the midbrain. No case-control differences were found for the diffusion parameters investigated. This is the first report of a WM microstructural signature of autistic traits in ADHD. Thus, even in the absence of full disorder, ASD traits may index a distinctive underlying neurobiology in ADHD.

Autistic traits in children with ADHD index clinical and cognitive problems.

Traits of autistic spectrum disorders (ASD) occur frequently in attention deficit hyperactivity disorder (ADHD), but the significance of their presence in terms of phenotype and underlying neurobiology is not properly understood. This analysis aimed to determine whether higher levels of autistic traits, as measured by the Social Communication Questionnaire (SCQ), index a more severe presentation in a large, rigorously phenotyped sample of children with ADHD (N=711). Regression analyses were used to examine association of SCQ scores with core ADHD features, clinical comorbidities and cognitive and developmental features, with adjustment for putative confounders. For outcomes showing association with total SCQ score, secondary analyses determined levels of differential association of the three ASD sub-domains. Results suggest that increasing ASD symptomatology within ADHD is associated with a more severe phenotype in terms of oppositional, conduct and anxiety symptoms, lower full-scale IQ, working memory deficits and general motor problems. These associations persisted after accounting for ADHD severity, suggesting that autistic symptomatology independently indexes the severity of comorbid impairments in the context of ADHD. Sub-domain scores did not show unique contributions to most outcomes, except that social deficits were independently associated with oppositional symptoms and repetitive behaviours independently predicted hyperactive-impulsive symptoms and motor problems. It would be worthwhile for clinicians to consider levels of socio-communicative and repetitive traits in those with ADHD who do not meet diagnostic criteria for ASD, as they index higher levels of phenotypic complexity, which may have implications for efficacy of interventions.

Soluble TNF and IL-6 receptors: indicators of vascular health in women without cardiovascular disease.

Cytokine receptor subunits are released from cells in a regulated manner and circulate in soluble forms at concentrations that are orders of magnitude greater than the concentrations of the cytokines themselves. The purpose of this study was to determine if the circulating concentrations of soluble receptor subunits for interleukin-1 beta (IL-1ß), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) might serve as early indicators of vascular dysfunction independent of the traditional cardiovascular disease (CVD) risk factors in women. Healthy women, aged 20-50 years (n = 36), were assessed for circulating concentrations of the cytokines IL-1ß, IL-6 and TNFα and the soluble cytokine receptor subunits interleukin-1 receptor type I (sIL-1RI), sIL-1RII, sIL-6Rα, glycoprotein 130 (s-gp130), soluble TNF receptor type 1 (sTNFR1), and sTNFR2, along with traditional CVD risk factors. Cytokine receptor subunit expression on mononuclear cells and the release of these subunits in vitro were also determined. Brachial artery flow-mediated dilation (FMD), carotid intima-media thickness (cIMT) and carotid-femoral pulse wave velocity (cfPWV) were assessed by ultrasonography and Doppler probes. Circulating sIL-6Rα correlated negatively with FMD (r = -0.56, p = 0.007) independent of age and other CVD risk factors. Circulating sTNFR1 correlated positively with cfPWV (r = 0.60, p = 0.002). TNFR1 receptor expression on monocytes correlated positively with cIMT (r = 0.51, p = 0.004). Plasma concentrations of IL-1ß, IL-6 and TNFα were not significantly associated with FMD, cIMT or cfPWV. These data suggest that the receptors for IL-6 and TNFα, rather than the cytokines themselves, may be better indicators of early vascular changes that are associated with CVD.

Role of dietary supplementation in attention-deficit hyperactivity disorder.

Dietary constituents have been increasingly researched as both potential aetiological factors and interventions for attention-deficit hyperactivity disorder (ADHD) symptoms. Although the involvement of dietary factors in ADHD is biologically plausible, the literature to date does not indicate causality and there are no grounds yet for the routine recommendation of dietary manipulation in ADHD.

What have we learnt about the causes of ADHD?

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and its possible causes still attract controversy. Genes, pre and perinatal risks, psychosocial factors and environmental toxins have all been considered as potential risk factors. METHOD: This review (focussing on literature published since 1997, selected from a search of PubMed) critically considers putative risk factors with a focus on genetics and selected environmental risks, examines their relationships with ADHD and discusses the likelihood that these risks are causal as well as some of the main implications. RESULTS: No single risk factor explains ADHD. Both inherited and noninherited factors contribute and their effects are interdependent. ADHD is familial and heritable. Research into the inherited and molecular genetic contributions to ADHD suggest an important overlap with other neurodevelopmental problems, notably, autism spectrum disorders. Having a biological relative with ADHD, large, rare copy number variants, some small effect size candidate gene variants, extreme early adversity, pre and postnatal exposure to lead and low birth weight/prematurity have been most consistently found as risk factors, but none are yet known to be definitely causal. There is a large literature documenting associations between ADHD and a wide variety of putative environmental risks that can, at present, only be regarded as correlates. Findings from research designs that go beyond simply testing for association are beginning to contest the robustness of some environmental exposures previously thought to be ADHD risk factors. CONCLUSIONS: The genetic risks implicated in ADHD generally tend to have small effect sizes or be rare and often increase risk of many other types of psychopathology. Thus, they cannot be used for prediction, genetic testing or diagnostic purposes beyond what is predicted by a family history. There is a need to consider the possibility of parents and siblings being similarly affected and how this might impact on engagement with families, influence interventions and require integration with adult services. Genetic contributions to disorder do not necessarily mean that medications are the treatment of choice. We also consider how findings might influence the conceptualisation of ADHD, public health policy implications and why it is unhelpful and incorrect to dichotomise genetic/biological and environmental explanations. It is essential that practitioners can interpret genetic and aetiological research findings and impart informed explanations to families.