Mothers' distress exposure and children's withdrawn behavior - A moderating role for the Interferon Gamma gene (IFNG).

The dysregulation of the inflammatory response, including pro-inflammatory molecules, produces neuropsychiatric symptoms and depression-like behavior, including withdrawal from the physical and social environment. Genetic variants that enhance immune reactivity may thus increase inflammatory and withdrawn reactions to stress. Here we investigated a functional polymorphism of Interferon Gamma gene (IFNG +874 T > A, rs2430561) as moderator of the relationship between mothers' distress exposure and children's withdrawn behavior at preschool age. Participants were 198 Portuguese preschool children (mean age = 57.98 months). Exposure to mother's distress was assessed using the Brief Symptom Inventory, and withdrawn behavior with the Caregiver Teacher Report Form. All children provided saliva samples for genotyping. Contrary to expecations based on prior work, the rs2430561 AA genotype-not the T variant-interacted with (high levels of) mothers' distress exposure, to increase children's withdrawn behavior. No significant main effects were detected. The polymorphism in Interferon Gamma gene showed specific environmental stressor-dependent effects on withdrawn behavior during childhood, ones which are interpreted in light of the "behavioral immune system" hypothesis, and which proved inconsistent with diathesis-stress thinking.

Neuropsychiatric symptoms following sore throat in a young boy.

A previously healthy 6-year-old boy was referred to us by his primary provider, with a history of sudden onset behavioural abnormalities including irritability, sleep disturbance and anxiety. Physical examination revealed no significant findings; further analyses were not suggestive of meningitis, encephalitis, metabolic abnormalities, toxicity or any other obvious cause. On rechecking the patient's history, an episode of throat pain 1 week prior to the symptom onset was noted. Therefore, the possibility of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) was considered. The antistreptolysin O titre was high (1078 IU/mL), and it increased to 1194 IU/mL 4 weeks later, leading to a diagnosis of PANDAS. He was started on ampicillin and administered one dose of intravenous immunoglobulin. His abnormal behaviours subsided and he returned to a normal state within 48 hours of treatment. This report aims to provide insights into the symptomology and diagnosis of PANDAS in children.

The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring.

Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This observation has been modeled in rodents subjected to maternal immune activation (MIA). The immune cell populations critical in the MIA model have not been identified. Using both genetic mutants and blocking antibodies in mice, we show that retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt)-dependent effector T lymphocytes [for example, T helper 17 (TH17) cells] and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes.

Cytokine profiles by peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype?

BACKGROUND: Some children with autism spectrum disorders (ASD) are characterized by fluctuating behavioral symptoms following immune insults, persistent gastrointestinal (GI) symptoms, and a lack of response to the first-line intervention measures. These children have been categorized as the ASD-inflammatory subtype (ASD-IS) for this study. We reported a high prevalence of non-IgE mediated food allergy (NFA) in young ASD children before, but not all ASD/NFA children reveal such clinical features of ASD-IS. This study addressed whether behavioral changes of ASD-IS are associated with innate immune abnormalities manifested in isolated peripheral blood (PB) monocytes (Mo), major innate immune cells in the PB. METHODS: This study includes three groups of ASD subjects (ASD-IS subjects (N = 24), ASD controls with a history of NFA (ASD/NFA (N = 20), and ASD/non-NFA controls (N = 20)) and three groups of non-ASD controls (non-ASD/NFA subjects (N = 16), those diagnosed with pediatric acute onset-neuropsychiatric syndrome (PANS, N = 18), and normal controls without NFA or PANS (N = 16)). Functions of purified PB Mo were assessed by measuring the production of inflammatory and counter-regulatory cytokines with or without stimuli of innate immunity (lipopolysaccharide (LPS), zymosan, CL097, and candida heat extracts as a source of ß-lactam). In ASD-IS and PANS subjects, these assays were done in the state of behavioral exacerbation ('flare') and in the stable ('non-flare') condition. ASD-IS children in the 'flare' state revealed worsening irritability, lethargy and hyperactivity. RESULTS: 'Flare' ASD-IS PB Mo produced higher amounts of inflammatory cytokines (IL-1ß and IL-6) without stimuli than 'non-flare' ASD-IS cells. With zymosan, 'flare' ASD-IS cells produced more IL-1ß than most control cells, despite spontaneous production of large amounts of IL-1ß. Moreover, 'flare' ASD-IS Mo produced less IL-10, a counterregulatory cytokine, in response to stimuli than 'non-flare' cells or other control cells. These changes were not observed in PANS cells. CONCLUSIONS: We observed an imbalance in the production of inflammatory (IL-1ß and IL-6) and counterregulatory (IL-10) cytokines by 'flare' ASD-IS monocytes, which may indicate an association between intrinsic abnormalities of PB Mo and changes in behavioral symptoms in the ASD-IS subjects.

Chronic low-grade inflammation in metabolic disorders: relevance for behavioral symptoms.

The ability of cytokines to influence cerebral functions and to induce the development of behavioral alterations is well established in conditions of acute or chronic high-grade activation of the innate immune system. Recent evidence suggests that the release of these immune mediators during chronic low-grade endogenous inflammatory processes may also contribute to the development of behavioral alterations. Metabolic disorders, including obesity, type 2 diabetes and the metabolic syndrome, represent examples of those conditions which are both characterized by a chronic low-grade inflammatory state and an increased prevalence of behavioral disorders. In metabolic disorders, the increased production of acute-phase proteins and cytokines (e.g. C-reactive protein, interleukin-6 and tumor necrosis factor-α), but at relatively low levels, may promote and contribute to the development of behavioral symptoms, including depressive symptoms, cognitive impairment, fatigue, sleep problems and pain. This hypothesis is supported by a growing literature referring both to experimental and clinical findings that will be reviewed here.

Immunization targeting a minor plaque constituent clears ß-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model.

Although anti-human ß-amyloid (Aß) immunotherapy clears brain ß-amyloid plaques in Alzheimer's disease (AD), targeting additional brain plaque constituents to promote clearance has not been attempted. Endogenous murine Aß is a minor Aß plaque component in amyloid precursor protein (APP) transgenic AD models, which we show is ∼3%-8% of the total accumulated Aß in various human APP transgenic mice. Murine Aß codeposits and colocalizes with human Aß in amyloid plaques, and the two Aß species coimmunoprecipitate together from brain extracts. In the human APP transgenic mouse model Tg2576, passive immunization for 8 weeks with a murine-Aß-specific antibody reduced ß-amyloid plaque pathology, robustly decreasing both murine and human Aß levels. The immunized mice additionally showed improvements in two behavioral assays, odor habituation and nesting behavior. We conclude that passive anti-murine Aß immunization clears Aß plaque pathology--including the major human Aß component--and decreases behavioral deficits, arguing that targeting minor endogenous brain plaque constituents can be beneficial, broadening the range of plaque-associated targets for AD therapeutics.

Neutralization of soluble, synaptotoxic amyloid ß species by antibodies is epitope specific.

Several anti-amyloid ß (Aß) antibodies are under evaluation for the treatment of Alzheimer's disease (AD). Clinical studies using the N-terminal-directed anti-Aß antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals, suggesting the reduction of Aß plaques, and reduced levels of total and phosphorylated tau protein in the CSF of treated AD patients. Preclinical studies using 3D6 (the murine form of bapineuzumab) have demonstrated resolution of Aß plaque and vascular burdens, neuritic dystrophy, and preservation of synaptic density in the transgenic APP mouse models. In contrast, few studies have evaluated the direct interaction of this antibody with synaptotoxic soluble Aß species. In the current report, we demonstrated that 3D6 binds to soluble, synaptotoxic assemblies of Aß(1-42) and prevents multiple downstream functional consequences in rat hippocampal neurons including changes in glutamate AMPA receptor trafficking, AD-type tau phosphorylation, and loss of dendritic spines. In vivo, we further demonstrated that 3D6 prevents synaptic loss and acutely reverses the behavioral deficit in the contextual fear conditioning task in transgenic mouse models of AD, two endpoints thought to be linked to synaptotoxic soluble Aß moieties. Importantly C-terminal anti-Aß antibodies were ineffective on these endpoints. These results, taken with prior studies, suggest that N-terminal anti-Aß antibodies effectively interact with both soluble and insoluble forms of Aß and therefore appear particularly well suited for testing the Aß hypothesis of AD.

Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes.

Innate/adaptive immune responses and transcript profiles of peripheral blood monocytes were studied in ASD children who exhibit fluctuating behavioral symptoms following infection and other immune insults (ASD/Inf, N=30). The ASD/Inf children with persistent gastrointestinal symptoms (ASD/Inf+GI, N=19), revealed less production of proinflammatory and counter-regulatory cytokines with stimuli of innate immunity and marked changes in transcript profiles of monocytes as compared to ASD/no-Inf (N=28) and normal (N=26) controls. This included a 4-5 fold up-regulation of chemokines (CCL2 and CCL7), consistent with the production of more CCL2 by ASD/Inf+GI cells. These results indicate dysregulated innate immune defense in the ASD/Inf+GI children, rendering them more vulnerable to common microbial infection/dysbiosis and possibly subsequent behavioral changes.

Opsoclonus-myoclonus syndrome in anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis has been recently reported as autoimmune/paraneoplastic encephalitis, affecting mostly young females. OBJECTIVE: To describe opsoclonus-myoclonus syndrome in association with anti-NMDAR antibodies. DESIGN: Case report. SETTING: Geneva University Hospital. Patient A 23-year-old woman with opsoclonus-myoclonus syndrome. RESULTS: Two weeks after an episode of gastroenteritis, the patient developed symptoms of depression associated with psychomotor slowing, progressive gait instability, and opsoclonus-myoclonus. Cerebrospinal fluid examination showed mild lymphocytic pleocytosis and intrathecal IgG synthesis with oligoclonal bands. The patient's condition worsened rapidly to an akinetic mutism, followed by a period of agitation, delirium, and hallucinations. These gradually subsided; however, a frontal behavior and executive dysfunction persisted 5 months after symptom presentation. No tumor was found. Anti-NMDAR antibodies were found in the cerebrospinal fluid. CONCLUSIONS: Opsoclonus-myoclonus may occur in patients with anti-NMDAR encephalitis. Prompt diagnosis of this disorder is important because after tumor removal and immunomodulatory therapies it has a relatively good prognosis.

Cytokines and psychopathology: lessons from interferon-alpha.

Interferon-alpha is a potent inducer of the cytokine network and is notorious for causing behavioral alterations. Studies on interferon-alpha-treated patients reveal at least two distinct syndromes: 1) a mood/cognitive syndrome that appears late during interferon-alpha therapy is responsive to antidepressants and is associated with activation of neuroendocrine pathways and altered serotonin metabolism; and 2) a neurovegetative syndrome characterized by psychomotor slowing, and fatigue that appears early during interferon-alpha treatment is antidepressant nonresponsive and may be mediated by alterations in basal ganglia dopamine metabolism. Findings from interferon-alpha may provide important clues regarding the pathophysiology and treatment of cytokine-induced behavioral changes in medically ill patients, while also potentially modeling the development of neuropsychiatric symptoms in patients without medical disorders.

Neurobehavioral, autonomic nervous function and lymphocyte subsets among aluminum electrolytic workers.

The purpose of our study is to determine the alteration of neurobehavioral parameters, autonomic nervous function and lymphocyte subsets in aluminum electrolytic workers of long-term aluminum exposure. 33 men who were 35.16 +/- 2.95 (mean +/- S.D) years old occupationally exposed to aluminum for 14.91 +/- 6.31 (mean +/- S.D) years. Air Al level and urinary aluminum concentration was measured by means of graphite furnace atomic absorption spectrophotometer. Normal reference group were selected from a flour plant. Neurobehavioral core test battery (NCTB) recommended by WHO was utilized. Autonomic nervous function test battery recommended by Ewing DJ was conducted on subjects. FAC SCAN was used to measure the lymphocyte subsets of peripheral blood. The mean air aluminum level in the workshop was 6.36 mg/m3, ranged from 2.90 to 11.38 mg/m3. Urinary aluminum of the Al electrolytic workers (40.08 +/- 9.36 microgram/mg.cre) was obviously higher than that of control group (26.84 +/- 8.93 m/mg.cre). Neurobehavioral results showed that the scores of DSY, PAC and PA in Al electrolytic workers were significantly lower than those of control group, The score of POMSC, POMSF and SRT among Al exposed workers were significantly augmented in relation to those of control group. Autonomic nervous function test results showed that R-R interval variability of maximum ratio of immediately standing up in Al electrolytic workers were decreased compare with the control group, while the BP-IS, HR-V, HR-DB, R30:15 had no significant change. Peripheral blood lymphocyte subsets test showed that CD4-CD8+ T lymphocyte in Al electrolytic workers increased. This study suggests that Al exposure exerts adverse effects on neurobehavioral performance, especially movement coordination and negative mood, and parasympathetic nervous function; moreover it increase CD4-CD8+ T lymphocyte subsets.