Immunology Profile of Attention-deficit/hyperactivity disorder
Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder with an etiopathogeny not fully understood. According to the prevailing view, the main factors contributing to the disorder are prefrontal dopamine deficiency and central dopaminergic dysfunction, but the factors/mechanisms involved in the brain dysfunction and its consequences are not well known.
Proinflammatory cytokines Interleukin-1, Interleukin-6 (IL-1, IL-6) and tumour necrosis factor alpha (TNFalpha), the key mediators of neuroimmune interactions, are the common pathogenic part of various kinds of the perinatal pathology leading to severe neurological and mental diseases. In the review, features of expression of the proinflammatory cytokines and their receptors in the brain at early age under normal and pathological conditions, their influence on processes of maturing of the CNS cells are described, the data of experimental and clinical researches of disturbances of the mental functions arising in adults owing to elevation of the IL-1, IL-6 levels and TNFalpha in early ontogenesis are cited.
For the past 20 years it has become increasingly evident that cytokines play an important role in both the normal development of the brain, acting as neurotrophic factors, and in brain injuries. Although cytokines and their receptors are synthesized and expressed in the brain (normally at low levels), increased cytokine production levels are now associated with various neurological disorders. T lymphocytes are the cells responsible for coordinating the immune response and a major source of cytokines. Different cytokines induce different subsets of T cells or have different effects on proliferation within a particular subset. Recent studies suggest that the immune response is in fact regulated by the balance between Th1 and Th2 cytokines. These two pathways are often mutually exclusive, the one resulting in protection and the other in progression of disease. Various studies describe the function and production of proinflammatory cytokines in the central nervous system (CNS) and their role in health and disease. Inflammation is upregulated following activation of Th1 cells, whereas Th2 cells may play a significant role in downregulating Th1 proinflammatory responses in those instances in which there is overproduction of Th2 cytokines. Although both Th1 and Th2 cytokines may influence CNS functioning, most studies have so far dealt with proinflammatory cytokines, probably because they directly affect CNS cells and are thought to be implicated in CNS pathology. It is of interest that endogenous glucocorticoids also control Th1-Th2 balance, favoring Th2 cell development. This review presents the evidence that cytokines have important functions in the CNS, both during development and as a part of brain pathology. In particular, the author highlighted recent work that supports a major role for the so-called inflammatory cytokines, Th1, and the anti-inflammatory Th2 cytokines.
Research that has assessed the psychophysiological consequences of caregiver stress in young and middle aged caregivers, that is, in populations not contending with age associated decline of the endocrine and immune systems, has been scarce and yielded inconsistent findings. To extend work in this area, this study assessed the psychosocial, endocrine and immune consequences of caregiver stress in a cross sectional sample of young and middle aged caregivers of children with autism and attention deficit hyperactivity disorder (ADHD) compared against parents of typically developing children.
In one studies that caregivers and parent controls completed measures of psychological distress (perceived stress, anxiety/depression), social support and physical health complaints. To capture important indices of the diurnal cortisol pattern, cortisol was measured at waking, 30 min post waking, 1200 h and 2200 h on two consecutive weekdays. Venous blood was taken to assess systemic concentrations of proinflammatory biomarkers, interleukin-6 (IL-6) and C-reactive protein (CRP). Caregivers scored markedly higher on all measures of psychological distress; scores on social support subscales, however, were significantly lower in this group. Diurnal patterns of cortisol secretion did not differentiate between the groups; however, caregivers displayed elevated systemic concentrations of the proinflammatory biomarker, CRP and reported more frequent episodes of physical ill health. The stress of caregiving exacts a significant psychophysiological toll, that is, even in the absence of HPA dysregulation, caregivers demonstrated elevated concentrations of proinflammatory biomarkers and, therefore, might be at greater risk for diseases fostered by disinhibition of the inflammatory response.
A common variation in a gene for an immune system protein increases a child’s risk of developing Attention Deficit Hyperactivity Disorder (ADHD) by 30 per cent. ADHD affects between four and 10 per cent of school age children and is characterised by inattention, hyperactivity and impulsivity. The causes are unknown. But stimulant drugs such as Ritalin, which boost levels of the neurotransmitter dopamine, have been shown to reduce symptoms in many patients.
Other researchers have also found evidence linking ADHD to variations in certain genes exclusively involved in the dopamine system.
Ronen Segman of the Hadassah–Hebrew University Medical Center in Jerusalem and colleagues studied 86 families with children diagnosed with ADHD. They found a significant association between a variation in the gene for the immune system protein interleukin–1 (IL–1) and ADHD. IL–1 is involved in the immune inflammatory response. But recent work has shown that it also has other roles in the body. IL–1 helps control the release of dopamine and another neurotransmitter called norepinephrine in several brain regions. It also helps promote the growth of dopamine–producing brain cells in the developing embryo.
In contrast to studies of depression and psychosis, the first part of this study showed no major differences in serum levels of cytokines and tryptophan metabolites between healthy children and those with attention-deficit/hyperactivity disorder of the combined type (ADHD). Yet, small decreases of potentially toxic kynurenine metabolites and increases of cytokines were evident in subgroups. Therefore we examined predictions of biochemical associations with the major symptom clusters, measures of attention and response variability.
Total symptom ratings were associated with increases of the interleukins IL-16 and IL-13, where relations of IL-16 (along with decreased S100B) with hyperactivity, and IL-13 with inattention were notable. Opposition ratings were predicted by increased IL-2 in ADHD and IL-6 in control children.
In the CPT, IL-16 related to motor measures and errors of commission, while IL-13 was associated with errors of omission. Increased RT variability related to lower TNF-α, but to higher IFN-γ levels. Tryptophan metabolites were not significantly related to symptoms. But increased tryptophan predicted errors of omission, its breakdown predicted errors of commission and kynurenine levels related to faster RTs.
Many associations were found across diagnostic groups even though they were more marked in one group. This confirms the quantitative trait nature of these features. Conceptually the relationships of the pro- and antiinflammatory cytokines distinguished between behaviours associated more with cognitive or more with motor control respectively. Further study should extend the number of immunological and metabolic markers to confirm or refute the trends reported here and examine their stability from childhood to adolescence in a longitudinal design.
The variability of the expression of these symptoms and of neuropsychological measures in the laboratory is viewed as central to the syndrome and has been proposed as an endophenotype of the disorder. Neuronal firing must be maintained to sustain a behavioural response. A recent hypothesis proposed that an inefficient supply of energy from glial cells (the lactate shuttle: might underlie the intra-individual variability in behaviour and the underlying neuronal activity of children with ADHD.
The cytokine and growth factor S100B is a potential marker of glial function. Serum levels arise largely but not exclusively from astrocytes. Increases have been associated with brain damage, major depression, psychosis and dementia. However, our pilot study of children with ADHD found that levels of S100B were not unusual, although a tendency for levels to decrease in those with internalizing symptoms was noted .
Tryptophan metabolism along the kynurenine pathway takes place primarily in glia. Levels of these metabolites and some cytokines that influence the metabolism as further potential indicators of glial integrity. Relevant to our hypothesis on glial function is that metabolites of kynurenine can be neuroprotective (e.g. kynurenate) or potentially toxic (3-hydroxy-kynurenine, 3-HK) and that the balance between these metabolic routes is modulated by the relative activity of the pro- and anti-inflammatory cytokines.
Our initial analysis reported a modest imbalance of cytokines in children with ADHD. This improved in those treated with methylphenidate, and thus arguably reflected an increased allostatic load. In the kynurenine pathway, we noted lower levels of the potentially toxic 3HK in children with ADHD than controls that could reflect a maturational delay of the neuronal pruning processes seen in typically developing children. [However, an alternative metabolic route for kynurenine over nicotine adenine dinucleotide (NAD(+)) rather than the toxic quinolinic acid cannot be excluded.
The absence of previous work in this field makes precise predictions impractical. We know of only one study of cytokines in ADHD and one relating to kynurenine. The former found no extreme values for type-1 or type-2 interleukins among patients with ADHD, unlike those with schizophrenia or obsessive-compulsive disorder. The latter described a potential increase of kynurenine metabolism (over that for serotonin, 5-HT) in ADHD following stimulant medication. Indeed, there is substantial indirect evidence for considering a role for 5-HT in ADHD, and by implication the availability of its precursor tryptophan. Thus, in the domain of impulsivity, there is evidence for the genetic control in ADHD of the expression of 5-HT receptors,
its synthesis and availability. In the domain of sustained attention, task performance related negatively to 5-HT metabolism, and increased 5-HT metabolism (vs. dopamine metabolism) was inversely related with the signal detection measure, d-prime . In support of a continued consideration of 5-HT metabolism here, we reported moderately increased tryptophan availability in untreated ADHD children.
Thus, this study represents an exploration of the hypothesis that there are potentially functional associations of symptom ratings (e.g. inattention) and continuous performance task measures (CPT: sustained attention, impulsivity and variability) with 8 cytokines, tryptophan and 4 tryptophan metabolites. The cytokines include the interleukins IL-2, IL-6, interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), IL-16, Il-10, IL-13 and S100B. The metabolites include 5-hydroxy-indoleacetic acid (5-HIAA), kynurenine, kynurenate, and 3HK.
Covarying for age and IQ, the CPRS symptom ratings were clearly higher for both ADHD groups than the controls on each scale except anxiety. The anxiety ratings were only a little higher in the ADHD groups than in controls. Similar but less marked differences were shown with the CTRS. There were no differences between the ADHD groups (table (table2).2). Using the same covariates attenuated the group differences on CPT measures, but only that for the errors of commission errors lost significance. Compared to the ADHD groups controls showed less motor activity, a shorter RT with less variability and more errors of omission (table (table3).3). While post-hoc comparisons of the two ADHD groups showed that medication did not significantly reduce RT or errors of omission, the ADHDmed group did show fewer microevents, a shorter duration of activity, less RT variability and fewer errors of commission.
Tryptophan levels and availability were modestly higher and breakdown indices lower in those with a diagnosis of ADHD after controlling for age and gender. But this was not reflected in altered levels of 5-HIAA or kynurenine. Taking account of age and BMI, the ratio of kynurenate to 3HK, was lower in children with ADHD than the comparison groups which showed slightly increased levels of 3HK.
Tryptophan levels increased with age and BMI, but lower SES status facilitated metabolism in the kynurenine pathway. Some proinflammatory cytokine levels decreased (IFN-γ) or increased with BMI (TNF-α, IL-6). Independent of diagnosis, children with allergies tended to show lower levels of 5-HT metabolism. Most children with experience of allergy showed decreases of the proinflammatory TNF-α. However, in contrast to the controls who showed decreases of the anti-inflammatory IL-13, the ADHD group showed increased IL-13 levels.
The changes in oxidative metabolism
The changes in oxidative metabolism and cellular immunity may be involved. There are associations between ADHD and changes in serum levels of nitric oxide synthase (NOS), xanthine oxidase (XO), glutathione S-transferase (GST) and paraoxonase-1 (PON-1) activities, which are important markers of oxidative stress, and adenosine deaminase (ADA) activity, marker of cellular immunity.
NOS, XO and ADA activities of the patients were significantly higher than those of the controls. GST and PON-1 activities of the patients were significantly lower than those of the controls. Changes in oxidative metabolism and cellular immunity may have a role in the etiopathogenesis of ADHD.
Antibodies against glutamic acid decarboxylase 65 (GAD65) have been detected in the serum of patients with several neurological disorders. The presence of antibodies against GAD65 has not yet been examined in the serum of patients with neurodevelopmental disorders such as autism or attention-deficit/hyperactivity disorder (ADHD). GAD65 antibodies and total IgG were assayed in the serum of normal subjects and patients diagnosed with autism or ADHD. GAD65 antibodies were detected in the serum of 15% of children with autism, 27% of children with ADHD and of none of the controls. The serum of 60% of autistic and 53% of ADHD patients reacted with Purkinje neurons in mouse cerebellum. Serum from 20% of ADHD patients reacted also with the cells in the molecular and granule cell layers and cells in the vicinity of the Purkinje neurons.
No association was found between the titer of GAD65 antibodies and total IgG levels, and presence of seizures or mental retardation. None of the ADHD patients were diagnosed with mental retardation. Serum anti-GAD65 antibodies may be a common marker of subgroups of patients with autism and ADHD. Reactions of serum antibodies with the cells in the cerebellum in these patients suggest direct effects on brain function. The subgroup of children with autism and ADHD that tests positive for GAD65 antibodies needs further characterization in a larger study.
Ceylan MF, et al. Changes in oxidative stress and cellular immunity serum markers in attention-deficit/hyperactivity disorder. Psychiatry Clin Neurosci. 2012 Apr;66(3):220-6.
Rout UK, et al. Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. Eur Child Adolesc Psychiatry. 2012 Mar;21(3):141-7.
Zubarev OE, et al. Elevation of proinflammatory cytokines level at early age as the risk factor of neurological and mental pathology development. Ross Fiziol Zh Im I M Sechenova. 2011 Oct;97(10):1048-59.
Robert D Oades,1 Aye-Mu Myint, Maria R Dauvermann, Benno G Schimmelmann, and Markus J Schwarz. Attention-deficit hyperactivity disorder (ADHD) and glial integrity: an exploration of associations of cytokines and kynurenine metabolites with symptoms and attention.
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Lovell B, et al. The psychosocial, endocrine and immune consequences of caring for a child with autism or ADHD. Psychoneuroendocrinology. 2012 Apr;37(4):534-42. doi: 10.1016/j.psyneuen.2011.08.003.
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