Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and serious neurodevelopmental disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Chronic and childhood stress is involved in ADHD development, and ADHD is highly comorbid with anxiety. Similarly, inflammatory diseases and a pro-inflammatory state have been associated with ADHD. However, while several works have studied the relationship between peripheral inflammation and stress in affective disorders such as depression or bipolar disorder, fewer have explored this association in ADHD. In this narrative review we synthetize evidence showing an interplay between stress, anxiety, and immune dysregulation in ADHD, and we discuss the implications of a potential disrupted neuroendocrine stress response in ADHD. Moreover, we highlight confounding factors and limitations of existing studies on this topic and critically debate multidirectional hypotheses that either suggest inflammation, stress, or anxiety as a cause in ADHD pathophysiology or inflammation as a consequence of this disease. Untangling these relationships will have diagnostic, therapeutic and prognostic implications for ADHD patients.

Inflammation, Anxiety, and Stress in Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is typically a chronic, often lifelong condition. Data suggest that ADHD itself and its treatment may be associated with dysregulated growth, including height and BMI. The reason for this association is yet unknown. The objective of this study was to examine differences in growth hormone (GH) response to exercise between children who had received a diagnosis of ADHD and age- and gender-matched controls. We reasoned that the normal increase in circulating GH seen in response to exercise would be blunted in children with ADHD.We recruited 13 treatment-naïve children with newly diagnosed ADHD and 14 age-matched controls (all male) and measured GH response to an exercise test in which the work was scaled to each subject's physical capability.There was no difference in the peak heart rate achieved during exercise between controls and ADHD participants (196.6 ± 1.5 vs. 196.5 ± 2.1 bpm, respectively) and lactate response to exercise (53.8 ± 5.0 vs. 47.9 ± 3.8 mg/dl, respectively). After exercise, GH increased significantly in the control subjects (p < 0.005), while GH responses were substantially blunted in the ADHD group (p = NS) even though the work performed did not differ from controls.Our data suggest that GH excretion after exercise challenge in children with ADHD is impaired. This can be detected using a minimally invasive, nonpharmacologic challenge and may link ADHD with growth impairment in some children.NCT00945971. 

Reduced exercise-induced growth hormone secretion among children with attention-deficit hyperactivity disorder.

The prevalence of attention deficit hyperactivity disorder (ADHD) in patients with epilepsy was much higher than prevalence in general population, and vice versa. The mechanisms underlying comorbid ADHD and epilepsy remained largely unknown. Here, we systematically analyzed the genetic correlation, causality, shared genetics and specific trait related tissues by using linkage disequilibrium score regression (LDSC), two sample Mendelian randomization (TwoSampleMR), bivariate causal mixture model (MiXeR), conjunctional false discovery rate (conjFDR) and LDSC applied to specifically expressed genes based on genome wide association studies (GWASs) data of ADHD and epilepsy. We found that ADHD had significant positive genetic association with epilepsy. Two-sample Mendelian randomization analysis with genome wide significant single nucleotide polymorphisms (SNPs) as instrument variables suggested a positively causal effect of ADHD on epilepsy. Using MiXeR, which estimates the total amount of shared variants, we observed 1 K causal variants overlapped between ADHD and epilepsy. At conjFDR <0.05, ADHD shared 2 distinct genomic loci with Epilepsy. Further disease-relevant tissues analysis showed that cortex, substantia nigra, amygdala and hippocampus were both associated with ADHD and epilepsy. Our results suggested that ADHD was genetically correlated with epilepsy, which might be due to the fact that they shared common pathogenic sites and tissues origin. 

Shared genetics and causality underlying epilepsy and attention-deficit hyperactivity disorder

Patients who suffer from anorexia nervosa (AN) are characterized by exceedingly lower body weight, micro- and macro-nutrient deficiencies, and hyposalivation as compared to healthy subjects. In addition, AN may predispose to difficulties in oral health maintenance. However, little is known about the relationship between stress-dependent salivary neuro/immunopeptidergic biomarkers such as opiorphin and immunoglobulins (Ig) and AN.The aim of this case-control study was to evaluate salivary opiorphin and immunoglobulins in female children and adolescents diagnosed with AN compared to healthy controls.Adolescent patients with clinically-confirmed severe restrictive subtype AN (Body Mass Index BMI < 15 kg/m2, mean age 15.0 ± 1.8, n = 83) were examined in the first week of hospital admission and compared to healthy matched controls (n = 79). Measurements of salivary opiorphin, IgA, IgG, IgM (ELISA technique), and oral hygiene levels (Plaque Control Record index-PCR) were performed.In the AN group, a significantly higher concentration of opiorphin was evidenced (3.1 ± 4.1 ng/ml) compared to the control group (1.1 ± 1.2 ng/ml), (p < 0.001), contrary to IgM, which was significantly lower (311.0 ± 185.3 ng/ml) than in the control group (421.2 ± 168.1 ng/ml), (p < 0.001). There were no significant differences in the levels of IgA and IgG, despite a higher concentration of IgA in the AN group vs. controls (p = 0.14). Spearman analysis revealed a correlation between opiorphin and age (p < 0.05), but also with all immunoglobulins IgA, IgG, IgM (p = 0.006, p < 0.001, p < 0.001). Similarly a correlation was found between PCR index and immunoglobulins IgG, IgM (respectively p = 0.028, p < 0.001), and between body mass, BMI, IBW% and IgA, IgM (all p < 0.05).In the acute phase of AN, salivary changes in opiorphin and immunoglobulins related to dental plaque suggest an essential role in oral health balance. Changes related to AN may affect the anti-inflammatory and analgesic components of saliva and suggest their use as neurobiological markers in severe malnutrition.The orofacial region is affected by various inflammatory and autoimmune conditions, which might translate into general and regional changes. Saliva is one of the biological fluids where biomarkers of the aforementioned conditions, including sensitivity to pain, could be detected. It is also noteworthy that anorexia nervosa (AN) and malnutrition may change the saliva's analgesic or immune content, but this scientific area is still not satisfactorily explored. The present work related to analgesic (opiorphin peptide) and anti-infectious agents (immunoglobulins Ig A, IgG, IgM) in said body fluid among 83 adolescent patients with severe AN compared to 79 healthy controls. In addition, oral hygiene levels were assessed in the oral cavity via the Plaque Control Record index (PCR). In the AN group, the concentration of opiorphin was significantly higher as compared to the control group, in contrast to IgM, which was significantly lower than in the control group. There were no notable differences in the levels of IgA and IgG between groups, despite a slightly higher concentrations of IgA in the AN group. A correlation was found between opiorphin and all immunoglobulins. A similar correlation was found between PCR index and all immunoglobulins.The present work shows how analgesic opiorphin depends on the oral inflammatory status. This might be a direction for further investigating the immune alterations in patients with AN-related malnutrition. Inclusion of AN patients in intensive oral hygiene care may also be considered. 

https://jeatdisord.biomedcentral.com/counter/pdf/10.1186/s40337-022-00637-3

Expression of salivary immunoglobulins and their association with analgesic neuropeptide opiorphin in anorexia nervosa during adolescence

Endogenous opiates and behavior: 2021

/pdf/salivary-biomarkers-opiorphin-cortisol-amylase-and-iga-46drrsf8l0.pdf

Salivary Biomarkers (Opiorphin, Cortisol, Amylase, and IgA) Related to Age, Sex, and Stress Perception in a Prospective Cohort of Healthy Schoolchildren

Comorbidity studies show that children with ADHD have a higher risk of being overweight and obese than healthy children. This study aimed to assess the genetic alternations that differ between and are shared by ADHD and excessive body weight (EBW). The sample consisted of 743 Polish children aged between 6 and 17 years. We analyzed a unique set of genes and polymorphisms selected for ADHD and/or obesity based on gene prioritization tools. Polymorphisms in the KCNIP1, SLC1A3, MTHFR, ADRA2A, and SLC6A2 genes proved to be associated with the risk of ADHD in the studied population. The COMT gene polymorphism was one that specifically increased the risk of EBW in the ADHD group. Using the whole-exome sequencing technique, we have shown that the ADHD group contains rare and protein-truncating variants in the FBXL17, DBH, MTHFR, PCDH7, RSPH3, SPTBN1, and TNRC6C genes. In turn, variants in the ADRA2A, DYNC1H1, MAP1A, SEMA6D, and ZNF536 genes were specific for ADHD with EBW. In this way, we confirmed, at the molecular level, the existence of genes specifically predisposing to EBW in ADHD patients, which are associated with the biological pathways involved in the regulation of the reward system, intestinal microbiome, and muscle metabolism.

Common and Unique Genetic Background between Attention-Deficit/Hyperactivity Disorder and Excessive Body Weight

Background. This cross-sectional study aimed to evaluate stress and immune biomarkers in saliva samples of attention-deficit/hyperactivity disorder ADHD compared to healthy non-ADHD children. Material and methods. A total of 132 children under 11 years old (8.5 ± 1.1) enrolled in a cross-sectional study: with confirmed ADHD (n = 60) and healthy controls (n = 72). The clinical evaluation included physical measurements (height, waist, hip circumference, body weight, body mass index BMI, BMI z-score) and unstimulated saliva collection and measurements of free cortisol, salivary alpha-amylase (sAA), and secreted immunoglobulins (sIgA, IgG, and IgM) with quantitative assay (ELISA) analysis. Unpaired t-test, Welch test, or Mann-Whitney U test were applied for group comparisons when appropriate, and the correlation between variables was analyzed with Spearman's rank coefficient. Results were considered significant at p 0.05). Significant elevation of the salivary sAA (p = 0.03), sIgA (p = 0.02), and IgM (p ≤ 0.001) biomarkers were detected, without differences in the morning cortisol (p > 0.05). Significant correlations between cortisol and BMI, hip size, and IgA, as well as between IgG and sAA and IgA were obtained. Conclusions. Saliva can be used to monitor ADHD status with regard to biomarkers indicating the hypothalamus-pituitary-adrenal axis, as HPA axis, and sympathetic activity. The results indicate that morning collection of saliva in contrast to unchanged salivary cortisol, may evaluate mentioned above system dysregulations by measurements of sAA and immunoglobulins among ADHD children.

Paula Szczesniewska

Papers

Salivary Biomarkers (Opiorphin, Cortisol, Amylase, and IgA) Related to Age, Sex, and Stress Perception in a Prospective Cohort of Healthy Schoolchildren

Common and Unique Genetic Background between Attention-Deficit/Hyperactivity Disorder and Excessive Body Weight

Stress/Immune Biomarkers in Saliva among Children with ADHD Status