Dirk Deboutte

Activation of the inflammatory response system in autism.

Background/Aim: There is now some evidence that autism may be accompanied by abnormalities in the inflammatory response system (IRS). Products of the IRS, such as proinflammatory cytokines, may induce some of the behavioral symptoms of autism, such as social withdrawal, resistance to novelty and sleep disturbances. The main aim of the present study was to examine whether autism is accompanied by an activation of the IRS. Methods: We measured the production of interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1RA), interferon (IFN)-γ and tumor necrosis factor (TNF)-α by whole blood and the serum concentrations of IL-6, the IL-2 receptor (IL-2R) and IL-1RA. Results: This study showed a significantly increased production of IFN-γ and IL-1RA and a trend toward a significantly increased production of IL-6 and TNF-α by whole blood of autistic children. There were no significant differences in the serum concentrations of IL-6, IL-2R and IL-1RA between autistic and normal children. Conclusions: These results suggest that autism may be accompanied by an activation of the monocytic (increased IL-1RA) and Th-1-like (increased IFN-γ) arm of the IRS. It is hypothesized that increased production of proinflammatory cytokines could play a role in the pathophysiology of autism.

Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression

Dysregulation of the hypothalamic-pituitary-adrenal axis, one of the stress-response systems, is one of the key neurobiological features of major depression (MDD). Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in MDD come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone. We examined whether genetic variations in the glucocorticoid receptor gene (Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1) could be associated with increased susceptibility for MDD using a whole gene-based association analysis of single nucleotide polymorphisms (SNPs). Four SNPs were identified in NR3C1 and genotyped in two well-diagnosed samples of patients with MDD ascertained in Belgium and northern Sweden, and matched control samples. In total, 314 MDD patients and 354 control individuals were included in the study. In the Belgian sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with an SNP in the promoter region (NR3C1-1); in the Swedish sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with the R23K SNP. The haplotype association studies showed modest evidence for an involvement of the 5′ region of the NR3C1 gene in the genetic vulnerability for MDD. This study suggests that polymorphisms in the 5′ region of the NR3C1 gene may play a role in the genetic vulnerability for MDD.

Increased serum albumin, γ globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism

BACKGROUND Research on the biological pathophysiology of autism has found some evidence that immune alterations may play a role in the pathophysiology of that illness. As a consequence we expected to find that autism is accompanied by abnormalities in the pattern obtained in serum protein electrophoresis and in the serum immunoglobulin (Ig) and IgG subclass profile. METHOD We examined whether subjects with autism showed changes in total serum protein (TSP) and the serum concentrations of albumin, alpha1 globulin, alpha2 globulin, beta globulin and gamma globulins, IgA, IgM and IgG and the IgG subclasses IgG 1, IgG2, IgG3 and IgG4, compared with normal controls. RESULTS We found significantly increased concentrations of TSP in autistic subjects, which were attributable to increased serum concentrations of albumin and gamma globulin. Serum IgG, IgG2 and IgG4 were also significantly raised. In autism there were significant and positive correlations between social problems and TSP and serum gamma globulin and between withdrawal symptoms and TSP and serum albumin and IgG. CONCLUSIONS The results suggest that autism is characterized by increased TSP, a unique pattern obtained in serum protein electrophoresis, i.e. increased serum albumin and IgG, and by a specific IgG subclass profile, i.e. increased serum IgG2 and IgG4. The increased serum concentrations of IgGs in autism may point towards an underlying autoimmune disorder and/or an enhanced susceptibility to infections resulting in chronic viral infections, whereas the IgG subclass skewing may reflect different cytokine-dependent influences on autoimmune B cells and their products.

Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder.

Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian autistic patients (age 12–18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd values were significantly higher in patients with autism than in healthy volunteers. Plasma concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than in healthy volunteers. There were no significant differences between autistic and normal children in the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of noradrenaline, between both study groups. There were highly significant positive correlations between age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1) serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes significant changes between the ages of 12 and 18 years.

A major SNP haplotype of the arginine vasopressin 1B receptor protects against recurrent major depression

Increasing amounts of data suggest that affective disorders might be related to dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, one of the stress-response systems. Arginine vasopressin (AVP) influences several symptoms, relevant to affective disorders, notable memory processes, pain sensitivity, synchronization of biological rhythms and the timing and quality of REM sleep. We examined whether genetic variations in the AVP receptor 1b gene (AVPR1b) could be associated with increased susceptibility to affective disorders using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). Five SNPs were identified in AVPR1b and genotyped in two well-diagnosed samples of patients with recurrent major depression and matched controls. In the Swedish sample, we observed significant allele (P=0.02) and genotype (P=0.01) association with SNP AVPR1b-s3, and in the Belgian sample, a borderline significant association with SNP AVPR1b-s5 (P=0.04). In both patient–control samples, the haplotype defined by alleles A-T-C-A-G for the AVPR1b-s SNPs s1-s2-s3-s4-s5 was significantly over-represented in controls compared to patients. Our data support a protective effect of this major haplotype for recurrent major depression.

Suicidal behavior and violence in male adolescents: a school-based study.

OBJECTIVE To investigate characteristics of suicidal and violent behavior in a community school sample of adolescents. METHOD Self-report questionnaires were administered to 794 male students (aged 12-18 years) from Antwerp, Belgium. Subjects were classified into four groups: a suicidal-only (n = 40; suicidal ideation and/or self-harming behavior), a violent-only (n = 142), a suicidal-violent (n = 21), and a control group (n = 591). RESULTS Compared with controls, higher levels of internalizing problems, risk-taking behavior (substance use, diminished perception of risk, sensation seeking), and aggression were found in the comparison groups. The suicidal-violent group had the highest levels of depression, somatization, overt and covert aggression, and risk-taking behavior. Compared with the suicidal-only group, the violent-only group had less depression, anxiety, and covert aggression, but higher levels of overt aggression, sensation seeking, diminished perception of risk, and marijuana use. CONCLUSIONS Although adolescent suicidal and violent behavior are both related to internalizing problems, aggression, and risk-taking behavior, marked differences in severity and nature exist in these relationships. Differentiation of suicidal youths based on the presence or absence of violent behavior may add to our understanding of suicidal phenomena and may thus have important clinical consequences.

Differences in hypothalamic-pituitary-adrenal axis functioning among children with ADHD predominantly inattentive and combined types.

Some evidence suggests that the HPA axis may be dysfunctional in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate whether a different pattern of HPA axis activity is found between the inattentive (I) and combined (C) subtypes of ADHD, in comparison with healthy control children. A total of 100 prepubertal subjects [52 children with ADHD combined type (ADHD-C), 23 children with ADHD predominantly inattentive type (ADHD-I), and 25 healthy control subjects] were studied. The effects of stress were studied by comparing cortisol responses to a psychosocial stressor, consisting of a public speaking task. Children with ADHD-I showed an elevated cortisol response to the psychosocial stressor, in contrast to children with ADHD-C who showed a blunted cortisol response to the psychosocial stressor. When a distinction was made between responders and non-responders (a subject was classified as a responder when there was an increase in cortisol reactivity), hyperactivity symptoms were clearly related to a lower cortisol reactivity to stress. The results indicate that a low-cortisol responsivity to stress may be a neurobiological marker for children with ADHD-C, but not for those with ADHD-I. Directions for future research and clinical implications are discussed.

Hypothalamic-pituitary-adrenal reactivity in prepubertal children with social phobia

BACKGROUND The aim of this study was to investigate whether a different pattern of HPA axis activity is found between children with social phobia (SP) and healthy control children. METHODS A total of 50 prepubertal subjects (25 children with SP and 25 healthy control subjects) were studied. The effects of stress were studied by comparing cortisol responses to a psychosocial stressor, consisting of a public speaking task. RESULTS Children with SP showed an elevated cortisol response to the psychosocial stressor as compared with healthy controls. Trait but not state anxiety levels are associated with higher HPA axis activity. LIMITATIONS Limited sample size. CONCLUSIONS The results indicate that a higher cortisol responsivity to stress may be a neurobiological marker for prepubertal children with SP. Directions for future research and clinical implications are discussed.

Neuropsychological characteristics of three subgroups of Flemish delinquent adolescents.

Sixty-three adjudicated adolescents, aged 14-17 years, were followed for 2 years to examine the neuropsychological characteristics of subgroups of delinquents. Nonrecidivistic subjects (n = 29) and late recidivistic subjects (n = 22) differed from early recidivistic subjects (n = 12) on intelligence, self-control functioning, and memory. Late recidivistic subjects, compared with not recidivistic subjects, showed a lower verbal IQ. The differences remained when controlling for the level of substance abuse. This study suggests that neuropsychological assessment may help in differentiating delinquent adolescents, although more research is needed to unravel the mediating influences of substance abuse and early neuropsychological and academic problems.

Exposure to Violence and Suicide Risk in Adolescents: A Community Study

The prevalence of violence exposure is relatively unexplored in adolescents in European communities, and reports on the association between exposure to community violence and suicidal behavior are rare. The aim of this study was to investigate (1) the prevalence of community violence in a European urban adolescent sample, (2) the relationship between exposure to community violence and suicidal ideation/deliberate self-harm, and (3) the influence of depressive symptoms and aggressive behavior on this relationship. Self-report surveys were administered to a representative school-based sample of 1509 adolescents in Antwerp (Belgium). The prevalence rate of violence exposure was still high but lower than that reported in U.S. communities. Suicidal ideation and deliberate self-harm were both related to violence exposure. The gender-specific influence of depressive symptomatology and aggressive behavior on the association between exposure to violence and suicidal behavior suggests the need for further research.