Endogenous Retroviruses Activity as a Molecular Signature of Neurodevelopmental Disorders.

Human endogenous retroviruses (HERVs) are genetic elements resulting from relics of ancestral infection of germline cells, now recognized as cofactors in the etiology of several complex diseases. Here we present a review of findings supporting the role of the abnormal HERVs activity in neurodevelopmental disorders. The derailment of brain development underlies numerous neuropsychiatric conditions, likely starting during prenatal life and carrying on during subsequent maturation of the brain. Autism spectrum disorders, attention deficit hyperactivity disorders, and schizophrenia are neurodevelopmental disorders that arise clinically during early childhood or adolescence, currently attributed to the interplay among genetic vulnerability, environmental risk factors, and maternal immune activation. The role of HERVs in human embryogenesis, their intrinsic responsiveness to external stimuli, and the interaction with the immune system support the involvement of HERVs in the derailed neurodevelopmental process. Although definitive proofs that HERVs are involved in neurobehavioral alterations are still lacking, both preclinical models and human studies indicate that the abnormal expression of ERVs could represent a neurodevelopmental disorders-associated biological trait in affected individuals and their parents.

Rates, types and co-occurrence of emotional and behavioural disorders among perinatally HIV-infected youth in Uganda: the CHAKA study.

PURPOSE: To describe the rates, types and comorbidity of emotional and behavioural disorders among perinatally HIV-infected children and adolescents attending care at five HIV youth clinics in Central and Southwestern Uganda. METHODS: 1339 CA-HIV attending care at HIV youth clinics in Uganda were interviewed using the DSM-5-based Child and Adolescent Symptom Inventory-5 (CASI-5; caregiver reported) and the Youth Inventory-4R (YI-4R; youth reported). Prevalence, risk factors and comorbidity for psychiatric disorders were estimated using logistic regression models. RESULTS: According to caregiver or youth report, the prevalence of 'any DSM-5 psychiatric disorder' was 17.4% (95% CI 15.4-19.5%), while that of 'any behavioural disorder' was 9.6% (95% CI 8.1-11.2%) and that of 'any emotional disorder' was 11.5% (95% CI 9.9-13.3%). The most prevalent behavioural disorder was attention deficit hyperactivity disorder (5.3%), while the most prevalent emotional disorder was separation anxiety disorder (4.6%). The statistically significant risk factors were: for behavioural disorders, sex (more among males than females) and age group (more among adolescents than among children); for emotional disorders, age group (more among adolescents than among children) and the caregiver's highest educational attainment (more among CA-HIV with caregivers with secondary education and higher, than among CA-HIV with caregivers with no formal education or only primary level education). About a quarter (24.5%) of CA-HIV with at least one emotional disorder and about a third (33.5%) of the CA-HIV with at least one behavioural disorder had a comorbid psychiatric disorder. CONCLUSION: There was a considerable burden of psychiatric disorders among CA-HIV that spanned a broad spectrum and showed considerable comorbidity.

Human endogenous retroviruses and ADHD.

OBJECTIVES: Several lines of evidences suggest that human endogenous retroviruses (HERVs) are implicated in the development of many complex diseases with a multifactorial aetiology and a strong heritability, such as neurological and psychiatric diseases. Attention deficit hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that results from a complex interaction of environmental, biological and genetic factors. Our aim was to analyse the expression levels of three HERV families (HERV-H, K and W) in patients with ADHD. METHODS: The expression of retroviral mRNAs from the three HERV families was evaluated in peripheral blood mononuclear cells (PBMCs) from 30 patients with ADHD and 30 healthy controls by quantitative RT-PCR. RESULTS: The expression levels of HERV-H are significantly higher in patients with ADHD compared to healthy controls, while there are no differences in the expression levels of HERV-K and W. CONCLUSIONS: Since the ADHD aetiology is due to a complex interaction of environmental, biological and genetic factors, HERVs may represent one link among these factors and clinical phenotype of ADHD. A future confirmation of HERV-H overexpression in a larger number of ADHD patients will make possible to identify it as a new parameter for this clinical condition, also contributing to deepen the study on the role of HERVs in the neurodevelopment diseases.

Prenatal immune activation interacts with genetic Nurr1 deficiency in the development of attentional impairments.

Prenatal exposure to infection has been linked to increased risk of neurodevelopmental brain disorders, and recent evidence implicates altered dopaminergic development in this association. However, since the relative risk size of prenatal infection appears relatively small with respect to long-term neuropsychiatric outcomes, it is likely that this prenatal insult interacts with other factors in shaping the risk of postnatal brain dysfunctions. In the present study, we show that the neuropathological consequences of prenatal viral-like immune activation are exacerbated in offspring with genetic predisposition to dopaminergic abnormalities induced by mutations in Nurr1, a transcription factor highly essential for normal dopaminergic development. We combined a mouse model of heterozygous genetic deletion of Nurr1 with a model of prenatal immune challenge by the viral mimetic poly(I:C) (polyriboinosinic polyribocytidilic acid). In our gene-environment interaction model, we demonstrate that the combination of the genetic and environmental factors not only exerts additive effects on locomotor hyperactivity and sensorimotor gating deficits, but further produces synergistic effects in the development of impaired attentional shifting and sustained attention. We further demonstrate that the combination of the two factors is necessary to trigger maldevelopment of prefrontal cortical and ventral striatal dopamine systems. Our findings provide evidence for specific gene-environment interactions in the emergence of enduring attentional impairments and neuronal abnormalities pertinent to dopamine-associated brain disorders such as schizophrenia and attention deficit/hyperactivity disorder, and further emphasize a critical role of abnormal dopaminergic development in these etiopathological processes.

[Neurologic aspects of HIV infections--follow-up of pediatric patients]. / A HIV-fertózés neurológiai vonatkozásai. Gyermek betegek követésének tapasztalatai.

OBJECTIVES: Before the widespread introduction of combined antiretroviral therapy (1995) complications from HIV and AIDS in the central nervous system had been reported in larger proportion in infants and children than in adults: 80-90% versus 60-70%. Particular clinical manifestations tend to occur at different stages during the evolution of HIV infection. The authors review the neurological aspects of HIV infection. METHOD: First, a summary of the protocol of the neurological examinations and related experience is given. Then authors present the evaluation of neuro-psychological development, prevalence of neurological impairment and neuro-imaging of nine HIV infected children (seven boys, two girls) for the period of ten years (1991-2001). Three/ten children had vertically transmitted HIV six/nine were infected by a nosocomial route in their early childhood. Children were regularly followed up from the diagnosis of HIV. The median follow up time has been 79 month (range: 18-144 month). Four patients died during the study period. The neurological status, the motor and mental development were examined at three month intervals or monthly under one year of age. EEG was performed every six month and CT/MRI once a year. All patients received combined antiretroviral treatment and immunoglobulin therapy continuously. RESULTS: Three/nine children have normal development, one/nine has hyperactive and attention deficit disorder with normal IQ range, two/nine have slight, one/nine moderate and two/nine serious mental retardation. Mild neurological signs were found in two children, various moderate and serious neuro/psychological symptoms were found in four patients, one of them was treated with benign epilepsy too. There was also dose correlation between the clinical symptoms and the results of EEG examination (diffuse background slowing) and results of neuroimaging studies (cortical atrophy, calcification of the basal ganglia, toxoplasma abscesses). According to the results of different examinations three/nine children were found to be symptom-free, one/nine case showed the static form, two/nine patients showed the plateau form, two/nine the rapid progressive form and one/nine the progressive infantile form of AIDS encephalopathy. The majority of the patients suffered from adopting problems and difficulties of socialisation since their families lives were damaged by isolation and rejection from the community. CONCLUSION: The regular neurological and psychological examinations completed with EEG, CT/MRI were very informative to follow the course of neuro-psychological problems of HIV infected children. Symptom-free patients have to face psychosocial problems too, which cause much more damage in their mental progress than HIV itself.

Is decreased blood plasma concentration of the complement C4B protein associated with attention-deficit hyperactivity disorder?

OBJECTIVE: The complement system is a group of blood proteins that play an important role in defending against viral and bacterial infections. The objective of this investigation was to study the plasma levels of the C4B protein in attention-deficit hyperactivity disorder (ADHD) in an attempt to associate infections with the development of some cases of this disorder. METHOD: C4B plasma protein levels were studied using an enzyme-linked immunosorbent assay in a group of 23 subjects meeting DSM-III-R criteria for ADHD and a similar number of age- and sex-matched controls. Also studied were parents of the ADHD subjects. RESULTS: C4B plasma levels (157.0 micrograms/mL) in the ADHD subjects were significantly (p < .01) lower than those (239.3 micrograms/mL) in the normal age-matched subjects. Mothers of the ADHD subjects also had significantly lower C4B values compared with mothers of normal children. On the other hand, C4B values in the fathers were not significantly altered. CONCLUSIONS: Decreased C4B levels in ADHD, if replicated, may represent an important marker for ADHD (or a subgroup of ADHD). It also seems plausible that C4B levels are an important etiological factor for ADHD.