Jan Croonenberghs

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.

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.

Prolyl endopeptidase and dipeptidyl peptidase IV are associated with externalizing and aggressive behaviors in normal and autistic adolescents

AIMS Peptides and a dysregulated immune system play a role in the pathophysiology of autism. Dysfunctions in prolyl endopeptidase (PEP) and dipeptidyl peptidase IV (DPP-IV) may underpin both the peptidergic and immune alterations in autism. The aims of this study are to: (i) delineate serum PEP and DPP-IV enzyme activities in autism, and (ii) examine the associations between both peptidases and behavioral characteristics or immune variables. MAIN METHODS We included 18 autistic patients and 22 healthy controls and measured the Child Behavior Checklist (CBCL), serum PEP and DPP-IV and immune biomarkers, i.e. the serum protein fractions α1, α2 and γ, and immunoglobulins, i.e. IgG1, IgG2, IgG3 and IgG4. Results were adjusted for possible effects of age and body mass index (BMI). KEY FINDINGS There were no significant differences in PEP or DPP-IV between the autistic patients and controls. DPP-IV was significantly and positively associated with the CBCL attention problems, aggressive and externalizing behavior subscales. PEP was significantly and positively associated with the CBCL delinquent, aggressive, externalizing and internalizing behavior subscales. There was a negative correlation between both peptidases and age and Tanner stage. DPP-IV was associated with α2-globulin (positively) and IgG3 (inversely) levels, while PEP activity was correlated with IgG2 levels (inversely). BMI was significantly associated with aggressive and externalizing behaviors. SIGNIFICANCE These findings demonstrate an association between peptidases and aggressive and externalizing behaviors, which may be explained by effects of these peptidases cleaving behavioral neuropeptides. Both peptidases are associated with immune biomarkers suggesting multiple bidirectional effects.

Pathophysiology of autism: current opinions

Research on the neurochemical aspects of the pathophysiology of autism is still increasing and publications are abundant. In this paper we reviewed significant data from the last decade and recent research results from our center. We focused on molecules influencing the central nervous system (CNS) and consecutively responsible for typical autistic behavior. We highlighted the mutual relationship between the serotonergic, immunological and endocrinological system and the interaction of these three pivotal systems with predisposing (genetic)and external (pre-, peri- and postnatal) conditions and xenobiotics. We stressed the influence of age, pubertal stage, sex, race and IQ on biological data. There is growing evidence that the complexity and variability of those interactions might be responsible for the heterogeneity of behavioral phenotypes and biological findings in Autism. Genetic, neuroanatomical and neurophysiological data were mentioned according their relevance to neurochemical opinions.

Risperidone in the treatment of childhood autistic disorder: an open pilot study

Objective: To evaluate the tolerability and efficacy of risperidone in childhood autistic disorder. Methods: A multicenter, open-label, dose-titration study involving seven autistic children (mean age 7.6 years) receiving risperidone for 4 weeks. Results: Mean dose was 0.01 mg/kg/day on day 1, 0.019 mg/kg/day on day 7 (range 0.01–0.041 mg/kg/day) and 0.035 mg/kg/day on day 28 (range 0.014–0.064 mg/kg/day). Over the 4-week period, the Ritvo–Freeman Real Life Rating Scale total score measuring autistic behavior was significantly decreased (P = 0.019), as was the affectual reactions subscale (P = 0.029). Aberrant Behavior Checklist total score was significantly improved (P < 0.001), as were all subscales except inappropriate speech. Visual Analog Scale for individual target symptoms was significantly decreased (P = 0.001), and Clinical Global Impression severity of illness score was significantly improved (P = 0.006). The incidence of adverse effects was low, and no extrapyramidal symptoms were observed. No significant changes or clinically relevant abnormalities occurred in laboratory tests, vital signs or electrocardiograms. Plasma concentrations of the drug were similar to those in adult patients. Conclusions: These favorable results suggest that larger controlled trials of risperidone should be performed in autistic or mentally retarded patients with behavioral disturbances.