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Autism and Pervasive Developmental Disorders and Infections

Do Viruses, Bacteria, Biotoxins and
Inflammation Chemicals Cause or Increase
Autism, Aspergers or PDD?

It appears that reviews of thousands of articles show infections, toxins from infections, inflammation from chronic infections do cause of increase the risk of autism.

1. Pediatr Dev Pathol. 2011 Oct 10. [Epub ahead of print]

Differential transmission and postnatal outcomes in triplets with intrauterine cytomegalovirus infection.

Kitajima J, Inoue H, Ohga S, Kinjo T, Ochiai M, Yoshida T, Kusuhara K, Hara T.

a Graduate School of Medical Sciences, Kyushu University, Pediatrics.

Abstract We herein present a case of triplets with intrauterine cytomegalovirus (CMV) infection, each of whom showed differential transmission, placental pathology, and postnatal outcome. The first- and second-born infants were both vigorous and asymptomatic at birth, although the first-, but not the second-born triplet, had a high copy-number of CMV DNA in the peripheral blood (1.2{multiply}10(3) copy/mL). The third-born triplet suffered from symptomatic CMV infection with high viral load (6.0{multiply}10(6) copy/mL). The triamniotic-trichorionic placentas were not fused to each other. The histopathological analysis showed that CMV-positive cells were frequently found in the decidua, villi and amnion of the third-born triplet's placenta, but were limited and scattered in the decidua or villi but not amnion of the other two placentas. The third-born triplet underwent ganciclovir therapy. None of the infants had physical or auditory problems at 4 years of age, while the third-born triplet had been diagnosed with an autistic disorder. This observation exemplifies the preventive roles of the individual placentas of triplets with regard to virus infection, thus suggesting that developing CMV disease largely depends on the placental function.

PMID: 21985463 [PubMed - as supplied by publisher]

2. Fetal Diagn Ther. 2011;30(2):141-9. Epub 2011 Sep 29.

Intracranial ultrasound abnormalities and fetal cytomegalovirus infection: report of 8 cases and review of the literature.

Dogan Y, Yuksel A, Kalelioglu IH, Has R, Tatli B, Yildirim A.

Department of Obstetrics and Gynecology, Istanbul Faculty of Medicine, Istanbul University, Turkey.

OBJECTIVES: The aim of this study was to evaluate fetal intracranial and other ultrasonographic findings in cytomegalovirus (CMV) infection. METHODS: Data on amniotic fluid CMV-DNA-PCR-positive pregnancies detected in our institution between January 2006 and June 2009 were reviewed retrospectively. Fetal biometric measurements, fetal anatomy, amniotic fluid volume, placental thickness and texture were analyzed for abnormalities.

RESULTS: Eight fetuses were diagnosed with congenital CMV infection during the study interval. Their mean gestational age at diagnosis was 25.8 weeks (range: 23-29). All fetuses had intracranial abnormalities; increased periventricular echogenicity (n = 7), ventriculomegaly (n = 5), intracranial calcifications (n = 4), intraventricular adhesions (n = 4), thalamic hyperechogenicity (n = 3), mega cisterna magna (n = 3), lissencephaly (n = 2), vermian defect (n = 2) and cerebellar cyst (n = 1). All of them had accompanying extracranial findings, including hyperechogenic bowel (n = 6), cardiomegaly (n = 3), pericardial effusion (n = 2) and hepatosplenomegaly (n = 1). Intrauterine growth retardation was detected in 3 cases. Five pregnancies were terminated, and 1 intrauterine death occurred. The remaining 2 delivered vaginally at term. One of the live-born babies suffers from tetraparesis, mental retardation and autism, and the other has mild hemiplegia.

CONCLUSIONS: The spectrum of sonographic findings may vary widely in patients with congenital CMV infection in the prenatal period. CMV should be kept in mind in differential diagnosis, particularly in fetuses with intracranial sonographic findings such as ventriculomegaly, calcifications, intraventricular adhesions and increased periventricular echogenicity.

2011 S. Karger AG, Basel.

PMID: 21952353 [PubMed - in process]

3. Eur Neuropsychopharmacol. 2011 Aug 31. [Epub ahead of print]

Prenatal exposure to bacterial endotoxin reduces the number of GAD67- and reelin-immunoreactive neurons in the hippocampus of rat offspring.

Nouel D, Burt M, Zhang Y, Harvey L, Boksa P.

Epidemiological studies implicate prenatal infection as a risk factor for the development of schizophrenia and autism. Subjects with schizophrenia and autism are reported to exhibit reduced levels of glutamic acid decarboxylase 67 (GAD67), a marker for GABA neurons, in various brain regions. Reduced levels of reelin, a secretory glycoprotein present in a subpopulation of GABA neurons, have also been found in these disorders. To test if prenatal infection can cause abnormalities in GAD67 and reelin in the brains of offspring, this study used a rat model of prenatal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), and assessed numbers of GAD67-immunoreactive (GAD67+) and reelin-immunoreactive (reelin+) neurons in the hippocampus of offspring. In offspring at postnatal day 14 (PD14), GAD67+ cell counts were reduced in the dentate gyrus of the prenatal LPS group compared to prenatal saline controls, while at PD28, GAD67+ cells counts were reduced in the prenatal LPS group in both the dentate gyrus and the CA1. There was a decrease in the number of reelin+ cells in the prenatal LPS offspring compared to controls in the dentate gyrus at PD14. However using Western blotting, no significant effects of prenatal LPS on levels of GAD67 or reelin protein were observed in various brain regions at PD14. These findings support the idea that prenatal infection can cause reductions in postnatal expression of GAD67 and reelin, and in this way, possibly contribute to the pathophysiology of schizophrenia or autism.

Copyright © 2011 Elsevier B.V. All rights reserved.

PMID: 21889316 [PubMed - as supplied by publisher]

4. Afr J Psychiatry (Johannesbg). 2011 Jul;14(3):208-10. doi:

Autism spectrum disorders (ASD) in Africa: a perspective.

Bakare MO, Munir KM.

Child and Adolescent Unit, Federal Neuro-Psychiatric Hospital, New Haven, Enugu, Enugu State, Nigeria.

BACKGROUND: The universal occurrence of autism spectrum disorders (ASD) was queried about twenty-six years ago. It was thought to occur only in western industrialized countries with high technological development. Over the last decade, knowledge about ASD and its prevalence has been documented as being on the rise in different regions of the world, with most literature coming from the western world - the situation in Africa on aspects of ASD remain unclear.

METHODS: Literature cited in Pubmed over the last decade on aspects of epidemiology, diagnosis, aetiology and knowledge of ASD in the African context were assessed. Keywords: autism, diagnosis, aetiology, knowledge and Africa were variously combined in the literature search.

RESULTS: No study specifically addressed the epidemiology of ASD in Africa. One of the two studies that were relevant addressed epidemiology of ASD in Arab countries, though included two Northern African countries. A higher proportion of non-verbal cases of ASD compared to verbal cases was documented in literature coming from Africa. Associated co-morbid disorders included intellectual disability, epilepsy and oculo-cutaneous albinism. Aetiological factors postulated included post-encephalitic infection, genetic and auto-immune factors, and vitamin D deficiency. Knowledge about ASD in Africa was noted to be low.

CONCLUSION: There is a need for epidemiological studies in Africa to define the magnitude of the problem of ASD and the characteristics of children affected by ASD in this region. This would help in planning and might be helpful in answering the question of aetiology of ASD. Policy making needs to be directed at issues of childhood developmental disorders in Africa.

PMID: 21863205 [PubMed - in process]

5. Med Hypotheses. 2011 Jun;76(6):863-70. Epub 2011 Mar 21.

A proposed mechanism for autism: an aberrant neuroimmune response manifested as a psychiatric disorder.

Buehler MR.

HQ USAFA/DFB, 2355 Faculty Drive, Suite 2P389, USAF Academy, CO 80840, USA.

Autism, an incurable neurodevelopmental brain disorder, is a complex psychopathology in which the affected individual cannot effectively self-regulate their sensory inputs toward coherent and focused motor outputs. There have been many hypotheses as to the etiology of autism - genetics, neurotransmitter imbalances, early childhood immunizations, xenobiotic and teratogenic agents, and maternal infection; the disorder can perhaps be studied best under the field of "Psychoneuroimmunology", which analyzes systemic and psychopathologies from an integrated approach through the combined effects of the nervous, immune, and endocrine systems. Using principles of psychoneuroimmunology along with previously established but yet un-linked scientific principles and observations, this paper proposes a neuroimmune-based mechanistic hypothesis for the etiology of autism that connects elevated levels of maternal pro-inflammatory cytokines to autistic symptoms in her offspring through a logical sequence of events. While both researchers and clinicians often note correlations between pro-inflammatory cytokine levels and autistic symptoms in affected individuals, no specific mechanism has been documented that logically and directly connects the two. I propose that pro-inflammatory cytokines arising from maternal inflammation, infection, and, possibly, autoimmunity, pass through the placenta; enter the fetal circulation; cross the fetal blood-brain barrier (BBB); and cause aberrant neuronal growth and plasticity within the fetal brain via a "cytokine-storm". Microglia and astrocyte stimulation lead to a positive-feedback loop that also facilitates the development of a chronic inflammatory environment within the fetus, pre-disposing it to lifelong comorbid psychiatric and systemic pathologies. Such a mechanism could account for many of the observed symptoms and behaviors of autistic individuals such as hyper-sensitivity to environmental stimuli, object fixation, echolalia, repetitive physical behaviors, chronic enterocolitis, autoimmune disease, and, at the extreme, savantism. The thiazolidinedione pioglitazone (and possibly rosiglitazone), a non-steroidal anti-inflammatory drug (NSAID), which is commonly used to lower blood glucose levels and associated inflammatory markers in patients with diabetes, and histamine receptor blockers, as well as monitoring and limiting sucrose-containing foods, might prove to be effective preventative therapies for the development of autism in the fetus for pregnant women displaying either a cytokine-induced depression or other elevated systemic inflammatory state conditions.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID: 21421290 [PubMed - indexed for MEDLINE]

6. Biol Psychiatry. 2011 Nov 15;70(10):992-9. doi: 10.1016/j.biopsych.2011.01.009. Epub 2011 Mar 5.

Early, time-dependent disturbances of hippocampal synaptic transmission and plasticity after in utero immune challenge.

Escobar M, Crouzin N, Cavalier M, Quentin J, Roussel J, Lanté F, Batista-Novais AR, Cohen-Solal C, De Jesus Ferreira MC, Guiramand J, Barbanel G, Vignes M.

Institut des Biomolécules Max Mousseron, Montpellier, France.

BACKGROUND: Maternal infection during pregnancy is a recognized risk factor for the occurrence of a broad spectrum of psychiatric and neurologic disorders, including schizophrenia, autism, and cerebral palsy. Prenatal exposure of rats to lipopolysaccharide (LPS) leads to impaired learning and psychotic-like behavior in mature offspring, together with an enduring modification of glutamatergic excitatory synaptic transmission. The question that arises is whether any alterations of excitatory transmission and plasticity occurred at early developmental stages after in utero LPS exposure.

METHODS: Electrophysiological experiments were carried out on the CA1 area of hippocampal slices from prenatally LPS-exposed male offspring from 4 to 190 days old to study the developmental profiles of long-term depression (LTD) triggered by delivering 900 shocks either single- or paired-pulse (50-msec interval) at 1 Hz and the N-methyl-D-aspartate receptor (NMDAr) contribution to synaptic transmission.

RESULTS: The age-dependent drop of LTD is accelerated in prenatally LPS-exposed animals, and LTD is transiently converted into a slow-onset long-term potentiation between 16 and 25 days old. This long-term potentiation depends on Group I metabotropic glutamate receptors and protein kinase A activations and is independent of NMDArs. Maternal LPS challenge also leads to a rapid developmental impairment of synaptic NMDArs. This was associated with a concomitant reduced expression of GluN1, without any detectable alteration in the developmental switch of NMDAr GluN2 subunits.

CONCLUSIONS: Aberrant forms of synaptic plasticity can be detected at early developmental stages after prenatal LPS challenge concomitant with a clear hypo-functioning of the NMDAr in the hippocampus. This might result in later-occurring brain dysfunctions.

Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PMID: 21377655 [PubMed - in process]

7. PLoS One. 2011 Feb 23;6(2):e16609.

Lack of infection with XMRV or other MLV-related viruses in blood, post-mortem brains and paternal gametes of autistic individuals.

Lintas C, Guidi F, Manzi B, Mancini A, Curatolo P, Persico AM.

Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy.

BACKGROUND: Autistic spectrum disorder (ASD) is characterized by impaired language, communication and social skills, as well as by repetitive and stereotypic patterns of behavior. Many autistic subjects display a dysregulation of the immune system which is compatible with an unresolved viral infection with prenatal onset, potentially due to vertical viral transmission. Recently, the xenotropic murine leukemia virus-related virus (XMRV) has been implicated in chronic fatigue syndrome (CFS) and in prostate cancer by several, though not all studies.

METHODOLOGY/PRINCIPAL FINDINGS: We assessed whether XMRV or other murine leukemia virus (MLV)-related viruses are involved in autistic disorder. Using nested PCR targeted to gag genomic sequences, we screened DNA samples from: (i) peripheral blood of 102 ASD patients and 97 controls, (ii) post-mortem brain samples of 20 ASD patients and 17 sex- and age-matched controls, (iii) semen samples of 11 fathers of ASD children, 25 infertile individuals and 7 fertile controls. No XMRV gag DNA sequences were detected, whereas peripheral blood samples of 3/97 (3.1%) controls were positive for MLV. CONCLUSIONS|

SIGNIFICANCE: No MLV-related virus was detected in blood, brain, and semen samples of ASD patients or fathers. Hence infection with XMRV or other MLV-related viruses is unlikely to contribute to autism pathogenesis.

PMCID: PMC3043069 PMID: 21373179 [PubMed - indexed for MEDLINE]

8. Behav Brain Res. 2011 May 16;219(1):108-15. Epub 2010 Dec 27.

Brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia.

Willette AA, Lubach GR, Knickmeyer RC, Short SJ, Styner M, Gilmore JH, Coe CL.

Harlow Primate Laboratory, University of Wisconsin, Madison, WI 53715, USA.

Infections and inflammatory conditions during pregnancy can dysregulate neural development and increase the risk for developing autism and schizophrenia. The following research utilized a nonhuman primate model to investigate the potential impact of a mild endotoxemia during pregnancy on brain maturation and behavioral reactivity as well as the infants' hormone and immune physiology. Nine pregnant female rhesus monkeys (Macaca mulatta) were administered nanogram concentrations of lipopolysaccharide (LPS) on two consecutive days, 6 weeks before term, and their offspring were compared to nine control animals. When tested under arousing challenge conditions, infants from the LPS pregnancies were more behaviorally disturbed, including a failure to show a normal attenuation of startle responses on tests of prepulse inhibition. Examination of their brains at 1 year of age with magnetic resonance imaging (MRI) revealed the unexpected finding of a significant 8.8% increase in global white matter volume distributed across many cortical regions compared to controls. More selective changes in regional gray matter volume and cortical thickness were noted in parietal, medial temporal, and frontal areas. While inhibited neural growth has been described previously after prenatal infection and LPS administration at higher doses in rodents, this low dose endotoxemia in the monkey is the first paradigm to produce a neural phenotype associated with augmented gray and white matter growth.

Published by Elsevier B.V.

PMID: 21192986 [PubMed - indexed for MEDLINE]

9. Mol Autism. 2010 Oct 14;1(1):14.

PCR and serology find no association between xenotropic murine leukemia virus-related virus (XMRV) and autism.

Satterfield BC, Garcia RA, Gurrieri F, Schwartz CE.

Cooperative Diagnostics, LLC, Greenwood, SC 29646, USA.

Xenotropic murine leukemia virus-related virus (XMRV) is a retrovirus implicated in prostate cancer and chronic fatigue syndrome (CFS). Press releases have suggested that it could contribute to autism spectrum disorder (ASD). In this study we used two PCR assays and one antibody assay to screen 25 blood samples from autistic children born to mothers with CFS and from 20 mixed controls including family members of the children assayed, people with fibromyalgia and people with chronic Lyme disease. Using a real-time PCR assay, we screened an additional 48 South Carolina autism disorder samples, 96 Italian ASD samples, 61 South Carolina ASD samples and 184 healthy controls. Despite having the ability to detect low copy number XMRV DNA in a large background of cellular DNA, none of the PCR assays found any evidence of XMRV infection in blood cells from patients or controls. Further, no anti-XMRV antibodies were detected, ruling out possible low level or abortive infections in blood or in other reservoirs. These results imply that XMRV is not associated with autism.

PMCID: PMC2964727 PMID: 20946639 [PubMed]

10. Neurosignals. 2010;18(2):113-28. Epub 2010 Oct 2.

Maternal immune activation and autism spectrum disorder: interleukin-6 signaling as a key mechanistic pathway.

Parker-Athill EC, Tan J.

Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, University of South Florida, Tampa, FL 33613, USA.

An emerging area of research in autism spectrum disorder (ASD) is the role of prenatal exposure to inflammatory mediators during critical developmental periods. Epidemiological data has highlighted this relationship showing significant correlations between prenatal exposure to pathogens, including influenza, and the occurrence of ASD. Although there has not been a definitive molecular mechanism established, researchers have begun to investigate this relationship as animal models of maternal infection have support- ed epidemiological findings. Several groups utilizing these animal models have found that activation of the maternal immune system, termed maternal immune activation (MIA), and more specifically the exposure of the developing fetus to maternal cytokines precipitate the neurological, immunological and behavioral abnormalities observed in the offspring of these animals. These abnormalities have correlated with clinical findings of immune dysregulation, neurological and behavioral abnormalities in some autistic individuals. Additionally, researchers have observed genetic variations in these models in genes which regulate neurological and immunological development, similar to what is observed clinically in ASD. Altogether, the role of MIA and cytokine dysregulation, as a key mediator in the neuropathological, behavioral and possibly genetic irregularities observed clinically in autism are important factors that warrant further investigation.

Copyright © 2010 S. Karger AG, Basel.

PMCID: PMC3068755 PMID: 20924155 [PubMed - indexed for MEDLINE]

11. Schizophr Bull. 2010 Aug 30. [Epub ahead of print]

Neonatal Behavioral Changes in Rats With Gestational Exposure to Lipopolysaccharide: A Prenatal Infection Model for Developmental Neuropsychiatric Disorders.

Baharnoori M, Bhardwaj SK, Srivastava LK.

Douglas Mental Health University Institute, Department of Psychiatry, McGill University, 6875 LaSalle Boulevard, Montreal, Quebec, Canada H4H 1R3.

Exposure to prenatal infections has been widely associated with the increased risk for neuropsychiatric disorders of developmental origin such as schizophrenia and autism. Although several behavioral and cognitive deficits have been detected during adulthood in rodent models of prenatal infections, early behavioral changes have not been well characterized. In a prenatal lipopolysaccharide (LPS) model, we have previously observed significant alterations in the neuronal cytoarchitecture during early postnatal life. In the present study, we aimed to investigate the potential effects of prenatal immune activation on early neurophenotypic presentations using a set of behavioral test battery. Female Sprague-Dawley rats were administered with 100 mug/kg LPS (intraperitoneally) at gestational days 15 and 16. During the first postnatal week, we found no significant effect on maternal behavior or mother-pup interaction by this treatment. Also, no major changes in physical developmental milestones of pups were noted from postnatal (P) days P6 to P16. Importantly, prenatal LPS-exposed pups had a significant decrease in the number and duration of ultrasonic vocalization calls at P3 and P5. Prenatal LPS treatment also led to impairments in nest-seeking behavior and odor-stroke associative learning in neonatal rats at P8 and P9. At the molecular level, we detected significant decrease in the expression of cortical 5HT1A and 5HT1B messenger RNA at P3. These data suggest that prenatal exposure to an immune activator can significantly impair the social/communicative behavior in the neonate offspring, which may be relevant to childhood and premorbid abnormalities reported in autism and schizophrenia subjects.

PMID: 20805287 [PubMed - as supplied by publisher]

12. Autism Res. 2010 Aug;3(4):147-52.

Role for antibodies in altering behavior and movement.

Libbey JE, Fujinami RS.

Department of Pathology, University of Utah, Salt Lake City, Utah 84132, USA.

At the past meeting of INSAR, the role of autoimmunity was discussed in an educational session. This article summarizes this discussion. In immune-mediated diseases, antibodies can contribute to the pathogenesis of the disease and are sometimes the force that drives the disease process. This concept has not been established for autism. In autoimmune diseases, such as systemic lupus erythematosus (SLE), antibodies are found to react with double-stranded DNA. These antibodies also cross-react with N-methyl-D aspartate receptors. Many SLE patients suffer neurologic syndromes of the central nervous system (CNS). Similarly individuals infected with Group A streptococcus (GAS) have antibodies against the GAS carbohydrate, which cross-react with tubulin and lysoganglioside GM1 on neurons. During the acute stage of infection, GAS-infected patients develop Syndenham chorea where the disease process is driven in part by these cross-reactive antibodies. As the antibody levels decrease, the clinical features of Syndenham chorea resolve. In these two immune-mediated diseases, antibodies clearly play a role in the pathogenesis of the diseases. There are reports that mothers of individuals with autism have antibodies that react with brain proteins and when these antibodies are passively transferred to pregnant non-human primates or rodents the offspring has behavioral and nervous system changes. It is still not clear whether the antibodies found in mothers of individuals with autism actually play a role in the disease. More studies need to be performed to identify the proteins recognized by the antibodies and to determine how these could affect development, behavior and changes within the CNS.

PMID: 20589715 [PubMed - indexed for MEDLINE]

13. Acta Paediatr. 2010 Sep;99(9):1344-9. doi: 10.1111/j.1651-2227.2010.01852.x.

Congenital cytomegalovirus infection: the impact of cerebral cortical malformations.

Engman ML, Lewensohn-Fuchs I, Mosskin M, Malm G.

Department of Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institutet and Karolinska University Hospital, Huddinge, Stockholm, Sweden.

AIM: Cytomegalovirus has been suggested to have a teratogenous influence during the migration of neural cells from the ventricular zones to the cortex during the gestational period. The aim of this study was to investigate the prevalence of congenital cytomegalovirus infections in a cohort of children with neurological disability and cerebral cortical malformations recognized by neuroimaging.

METHODS: Twenty-six children with neurological disability and cerebral cortical malformations were investigated retrospectively for congenital cytomegalovirus infection by analysing the dried blood spot samples for cytomegalovirus deoxynucleic acid using qualitative polymerase chain reaction.

RESULTS: CMV DNA in the dried blood spot samples was found in four out of 26 children. Two of these four had severe disabilities with mental retardation, autism, spastic cerebral palsy, epilepsy and deafness. A third child had epilepsy and unilateral cerebral palsy, while the fourth had a mild motor coordination dysfunction and hearing deficit.

CONCLUSION: In our study, the number of congenital cytomegalovirus infections in children with cerebral cortical malformations was higher (4/26) than expected with reference to the birth prevalence (0.2-0.5%) of congenital cytomegalovirus infection in Sweden. We thus conclude that congenital cytomegalovirus infection should be considered in children with cortical malformations of unknown origin.

© 2010 The Author(s)/Journal Compilation © 2010 Foundation Acta Paediatrica.

PMID: 20456271 [PubMed - indexed for MEDLINE]

14. Arch Pediatr Adolesc Med. 2010 May;164(5):470-7.

Association of hospitalization for infection in childhood with diagnosis of autism spectrum disorders: a Danish cohort study.

Atladóttir HO, Thorsen P, Schendel DE, Østergaard L, Lemcke S, Parner ET.

Department of Epidemiology, Institute of Public Health, University of Arhus, Bartholin Allé 2, Arhus C, Denmark.

OBJECTIVE: To investigate the association between hospitalization for infection in the perinatal/neonatal period or childhood and the diagnosis of autism spectrum disorders (ASDs).

DESIGN: A population-based cohort study.

SETTING: Denmark.

PARTICIPANTS: All children born in Denmark from January 1, 1980, through December 31, 2002, comprising a total of 1 418 152 children. EXPOSURE: Infection requiring hospitalization.

MAIN OUTCOME MEASURE: The adjusted hazard ratio (HR) for ASDs among children hospitalized for infection compared with other children. RESULTS: A total of 7379 children were diagnosed as having ASDs. Children admitted to the hospital for any infectious disease displayed an increased rate of ASD diagnoses (HR, 1.38 [95% confidence interval, 1.31-1.45]). This association was found to be similar for infectious diseases of bacterial and viral origin. Furthermore, children admitted to the hospital for noninfectious disease also displayed an increased rate of ASD diagnoses (HR, 1.76 [95% confidence interval, 1.68-1.86]), and admissions for infection increased the rate of mental retardation (2.18 [2.06-2.31]).

CONCLUSIONS: The association between hospitalization for infection and ASDs observed in this study does not suggest causality because a general association is observed across different infection groups. Also, the association is not specific for infection or for ASDs. We discuss a number of noncausal explanatory models.

PMID: 20439799 [PubMed - indexed for MEDLINE]

15. J Autism Dev Disord. 2010 Dec;40(12):1423-30.

Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders.

Atladóttir HO, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdallah M, Parner ET.

Department of Epidemiology, Institute of Public Health, University of Aarhus, Bartholins Allé 2, Århus C, Denmark.

Exposure to prenatal infection has been suggested to cause deficiencies in fetal neurodevelopment. In this study we included all children born in Denmark from 1980, through 2005. Diagnoses of autism spectrum disorders (ASDs) and maternal infection were obtained through nationwide registers. Data was analyzed using Cox proportional hazards regression. No association was found between any maternal infection and diagnosis of ASDs in the child when looking at the total period of pregnancy: adjusted hazard ratio = 1.14 (CI: 0.96-1.34). However, admission to hospital due to maternal viral infection in the first trimester and maternal bacterial infection in the second trimester were found to be associated with diagnosis of ASDs in the offspring, adjusted hazard ratio = 2.98 (CI: 1.29-7.15) and adjusted hazard ratio = 1.42 (CI: 1.08-1.87), respectively. Our results support prior hypotheses concerning early prenatal viral infection increasing the risk of ASDs.

PMID: 20414802 [PubMed - indexed for MEDLINE]

16. J Neurovirol. 2010 Mar;16(2):141-9.

Association of autism with polyomavirus infection in postmortem brains.

Lintas C, Altieri L, Lombardi F, Sacco R, Persico AM.

Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy.

Comment in J Neurovirol. 2010 Jul;16(4):330-1; author reply 332-3.

Autism is a highly heritable behavioral disorder. Yet, two decades of genetic investigation have unveiled extremely few cases that can be solely explained on the basis of de novo mutations or cytogenetic abnormalities. Vertical viral transmission represents a nongenetic mechanism of disease compatible with high parent-to-offspring transmission and with low rates of disease-specific genetic abnormalities. Vertically transmitted viruses should be found more frequently in the affected tissues of autistic individuals compared to controls. Our initial step was thus to assess by nested polymerase chain reaction (PCR) and DNA sequence analysis the presence of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), human herpes virus 6 (HHV6), BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) in genomic DNA extracted from postmortem temporocortical tissue (Brodmann areas 41/42) belonging to 15 autistic patients and 13 controls. BKV, JCV, and SV40 combined are significantly more frequent among autistic patients compared to controls (67% versus 23%, respectively; P < .05). The majority of positives yielded archetypal sequences, whereas six patients and two controls unveiled single-base pair changes in two or more sequenced clones. No association is present with the remaining viruses, which are found in relatively few individuals (N

PMID: 20345322 [PubMed - indexed for MEDLINE]

17. Interdiscip Perspect Infect Dis. 2010;2010:273573. Epub 2010 Feb 21.

Chlamydophila pneumoniae Infection and Its Role in Neurological Disorders.

Contini C, Seraceni S, Cultrera R, Castellazzi M, Granieri E, Fainardi E.

Section of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Ferrara, Via Fossato di Mortara, 23, 44100 Ferrara, Italy.

Chlamydophila pneumoniae is an intracellular pathogen responsible for a number of different acute and chronic infections. The recent deepening of knowledge on the biology and the use of increasingly more sensitive and specific molecular techniques has allowed demonstration of C. pneumoniae in a large number of persons suffering from different diseases including cardiovascular (atherosclerosis and stroke) and central nervous system (CNS) disorders. Despite this, many important issues remain unanswered with regard to the role that C. pneumoniae may play in initiating atheroma or in the progression of the disease. A growing body of evidence concerns the involvement of this pathogen in chronic neurological disorders and particularly in Alzheimer's disease (AD) and Multiple Sclerosis (MS). Monocytes may traffic C. pneumoniae across the blood-brain-barrier, shed the organism in the CNS and induce neuroinflammation. The demonstration of C. pneumoniae by histopathological, molecular and culture techniques in the late-onset AD dementia has suggested a relationship between CNS infection with C. pneumoniae and the AD neuropathogenesis. In particular subsets of MS patients, C. pneumoniae could induce a chronic persistent brain infection acting as a cofactor in the development of the disease. The role of Chlamydia in the pathogenesis of mental or neurobehavioral disorders including schizophrenia and autism is uncertain and fragmentary and will require further confirmation.

PMCID: PMC2825657 PMID: 20182626 [PubMed]

18. J Immunol. 2010 Apr 1;184(7):3997-4005. Epub 2010 Feb 24.

IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation.

Girard S, Tremblay L, Lepage M, Sébire G.

Laboratoire de Neurologie Pédiatrique, Département de Pédiatrie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada.

The precise role of maternal bacterial infection and inflammation occurring at the end of gestation is a controversial matter. Although it is recognized as an independent risk factor for neurodevelopmental diseases such as cerebral palsy, mental deficiency, and autism, it remains unclear whether it is causal or simply associated with the diseases. In this study, we demonstrate that IL-1 plays a key role in mediating severe placental damage and neurodevelopmental anomalies in offspring. Our results show that end of gestation exposure of pregnant rats to systemic microbial product (LPS) triggers placental inflammation and massive cell death, fetal mortality, and both forebrain white matter and motor behavioral alterations in the offspring. All these effects are alleviated by the coadministration of IL-1 receptor antagonist with LPS, suggesting a possible protective treatment against human placental and fetal brain damage.

PMID: 20181892 [PubMed - indexed for MEDLINE]

19. J Chin Med Assoc. 2010 Feb;73(2):104-7.

Congenital rubella syndrome with autistic disorder.

Hwang SJ, Chen YS.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Congenital rubella syndrome (CRS) consists of a group of abnormalities that develop in children as a result of maternal infection with rubella virus. CRS may lead to new physical symptoms during adolescence or adulthood, referred to as "late manifestations". Psychiatric disorders are often seen among CRS patients, with an incidence of 4.12-7.3% for autism. We report a case of adolescent CRS with autism. A 20-year-old man had received treatment with antipsychotics and antidepressants since the age of 12 years because of unstable moods, violence, and stereotypic behavior. During follow-up, he developed some insidious-onset physical problems, including hyperlipidemia, dyspnea, constipation, torticollis and a tilted trunk. Under careful survey and evaluation, some physical problems were recognized as side effects of psychotropics, which gradually subsided after adjustment of the medications, and some of the problems were considered partially as manifestations of CRS, such as progressive pulmonary artery stenosis-related dyspnea. We managed some of the patient's physical problems and then he received catheterization for pulmonary artery stenosis. His general physical condition improved and some further improvement in psychiatric status was noted thereafter. Because of a high comorbidity rate for patients with autistic disorder, the clinician should be aware of the possibility of CRS if the patient has multiple congenital physical abnormalities with a history of maternal rubella infection. If patients develop physical symptoms in adolescence, awareness of late manifestations of CRS and differentiation from the adverse effects of psychotropic medications are essential. In addition to psychiatric treatment, management of physical problems associated with CRS would be beneficial for the patients' psychiatric condition.

Copyright 2010 Elsevier. Published by Elsevier B.V. All rights reserved.

PMID: 20171592 [PubMed - indexed for MEDLINE]

20. Neurosci Lett. 2010 Mar 8;471(3):162-5. Epub 2010 Jan 25.

Low-grade endotoxemia in patients with severe autism.

Emanuele E, Orsi P, Boso M, Broglia D, Brondino N, Barale F, di Nemi SU, Politi P.

Department of Health Sciences, Section of Psychiatry, University of Pavia, Via Bassi, 21, I-27100, Pavia, Italy.

The objective of this study was to examine whether levels of endotoxin and other markers of immuno-inflammatory activation are altered in adult patients with severe autism. We determined circulating serum endotoxin levels, its soluble receptor (sCD14), and markers of immuno-inflammatory activation (IL-1beta, IL-6, and IL-10) in 22 adult patients with severe autism and 28 age- and gender-matched healthy controls. Compared with healthy subjects, serum levels of endotoxin were significantly higher in autistic patients and inversely and independently correlated with Socialization scores on the Vineland Adaptive Behavior Scales (VABS) and ADI-R Domain A score (social). Whether increased endotoxin may contribute to the pathophysiology of inflammation and impaired reciprocal social interaction in autism should be further explored in future studies.

PMID: 20097267 [PubMed - indexed for MEDLINE]

21. Invest Clin. 2009 Sep;50(3):315-26.

[Association between HSV-2 infection and serum anti-rat brain antibodies in patients with autism].

[Article in Spanish]

Mora M, Quintero L, Cardenas R, Suárez-Roca H, Zavala M, Montiel N.

Departamento de Biología, Facultad Experimental de Ciencias, Universidad del Zulia, Maracaibo, Venezuela.

Some cases of autism could be linked to viral infections able to induce autoimmune mechanisms directed against the encephalon. Neurothophic virus infections in animals are associated with clinical signs that are similar to those observed in neurodevelopment disorders. Thus, in this study, we determined the co-existence of antibodies against nerve tissue and viruses with neurothophic competence (HSV-1/2, Epstein-Barr-EBV, cytomegalovirus, measles and rubella) in serum of forty autistic children and forty healthy children. The presence of antibodies against nerve tissue was detected in slices of rat encephalic tissue by indirect immunofluorescence. The levels of anti-viral IgG and IgM antibodies were measured by indirect ELISA. The proportion of autistics with anti-encephalon IgG antibodies (77% anti-amygdala, 70% anti-caudate nucleus, 47.5% anti-cerebellum y anti-brain stem, 45% anti-hippocampus, 40% anti-corpus callosum and 17,5% anti-cortex) was significantly greater than that of controls (10% anti- amygdala y 5% anti- cerebellum) and was directly related to the severity of the autism. The proportion of children with positive levels (greater than for anti-HSV IgM antibodies (indicative of acute infection) was significantly greater in autistics (65%) than in healthy children (17.5%). Ninety six percent of the autistics with anti-HSV antibodies also had anti-encephalon antibodies, percentage that was significantly greater than that of autistics negative to the anti-HSV-antibody (43%). In contrast, there were no significant differences for IgG and IgM antibodies for EBV, cytomegalovirus, measles and rubella. This suggests that autoimmunity against encephalic structures elicited by HSV infections could be involved in autism.

PMID: 19961054 [PubMed - indexed for MEDLINE]

22. Eur Neuropsychopharmacol. 2009 Sep;19(9):648-53. Epub 2009 Jun 5.

Prenatal viral infection of mice at E16 causes changes in gene expression in hippocampi of the offspring.

Fatemi SH, Folsom TD, Reutiman TJ, Huang H, Oishi K, Mori S.

Department of Psychiatry, Division of Neuroscience Research, University of Minnesota School of Medicine, Minneapolis 55455, USA.

The hippocampus governs memory formation and emotional regulation, and there is widespread evidence of hippocampal dysfunction in psychiatric disorders, including schizophrenia and autism. There is abundant evidence that prenatal viral infection may play a role in the development of these two disorders. In the current study, we have examined gene expression and structural changes of the hippocampi of exposed neonates following maternal infection at embryonic day (E) 16 (middle second trimester). We observed significant changes in gene expression in the offspring at postnatal day (P) 0 (birth), P14 (childhood), and P56 (adulthood), including a number of candidate genes for autism and schizophrenia. qRT-PCR verified the direction and magnitude of change for 5 of the genes from the microarray data set and revealed mRNA changes for additional genes associated with schizophrenia and autism. MRI revealed a decrease in hippocampal volume at P35 (adolescence). Our results demonstrate altered gene expression and reduced hippocampal volume in the offspring following prenatal viral infection at E16.

PMCID: PMC2716397 PMID: 19501487 [PubMed - indexed for MEDLINE]

23. Schizophr Res. 2009 Jul;112(1-3):46-53. Epub 2009 May 31.

Abnormal expression of myelination genes and alterations in white matter fractional anisotropy following prenatal viral influenza infection at E16 in mice.

Fatemi SH, Folsom TD, Reutiman TJ, Abu-Odeh D, Mori S, Huang H, Oishi K.

Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St. SE, Minneapolis, MN 55455, USA.

Prenatal viral infection has been associated with the development of schizophrenia and autism. Our laboratory has previously shown that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) and late second trimester (E18) administration of influenza virus. We hypothesized that middle second trimester infection (E16) in mice may lead to a different pattern of brain gene expression and structural defects in the developing offspring. C57BL6 mice were infected on E16 with a sublethal dose of human influenza virus or sham-infected using vehicle solution. Male offspring of the infected mice were collected at P0, P14, P35, and P56, their brains removed and cerebella dissected and flash frozen. Microarray, DTI and MRI scanning, as well as qRT-PCR and SDS-PAGE and western blotting analyses were performed to detect differences in gene expression and brain atrophy. Expression of several genes associated with myelination, including Mbp, Mag, and Plp1 were found to be altered, as were protein levels of Mbp, Mag, and DM20. Brain imaging revealed significant atrophy in cerebellum at P14, reduced fractional anisotropy in white matter of the right internal capsule at P0, and increased fractional anisotropy in white matter in corpus callosum at P14 and right middle cerebellar peduncle at P56. We propose that maternal infection in mouse impacts myelination genes.

PMCID: PMC2735410 PMID: 19487109 [PubMed - indexed for MEDLINE]

24. Behav Brain Res. 2009 Dec 7;204(2):313-21. Epub 2008 Dec 24.

Immune involvement in schizophrenia and autism: etiology, pathology and animal models.

Patterson PH.

Biology Division, California Institute of Technology, Pasadena, CA 91125, USA.

There is increasing evidence of immune involvement in both schizophrenia and autism. Of particular interest are striking abnormalities in the expression of immune-related molecules such as cytokines in the brain and cerebral spinal fluid (CSF). It is proposed that this represents a permanent state of brain immune dysregulation, which begins during early development. One possibility is that maternal infection, a known risk factor for schizophrenia and autism, sets this immune activation in motion. Several animal models are being used to investigate this hypothesis. There is also recent evidence that, among schizophrenic subjects, those associated with maternal infection display a distinctive pathology, which suggests that diverse causes for this disorder may explain some of its heterogeneity. The human and animal results related to immune involvement suggest novel therapeutic avenues based on immune interventions.

PMID: 19136031 [PubMed - indexed for MEDLINE]

25. Int J Immunopathol Pharmacol. 2008 Jul-Sep;21(3):553-66.

Antibodies as predictors of complex autoimmune diseases and cancer.

Vojdani A.

Immunosciences Lab., Inc., Beverly Hills, CA, USA.

Erratum in Int J Immunopathol Pharmacol. 2008 Oct-Dec;21(4):following 1051.

The pathologic role of autoantibodies in many autoimmune diseases is widely accepted. An enzyme immunoassay was used for measurement of antibodies against disease-specific antigens and etiologic agents for cross-reactive antigens associated with them. This antibody assay was applied to a panel of antigens for the detection of different neuroautoimmune diseases that included multiple sclerosis, motor peripheral neuropathies, multifocal motor neuropathy, amyotrophic lateral sclerosis, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection. We studied women with pregnancies complicated by neural tube defect, neuroborreliosis, autism and patients with possible somatic hypermutation. Antibodies were also measured against antigens and etiologic agents associated with primary biliary cirrhosis and chronic obstructive pulmonary disease. And, finally, antibodies were measured against several tumor antigens or peptides which are expressed in prostatic, breast and colon tissues. This panel of different autoantibodies was applied to 290 patients with neuroautoimmune disorders, cancer, and possible somatic hypermutation. The levels of these antibodies against different tissue-specific antigens and etiologic agents associated with them were significantly elevated in patients versus controls. We hope that this novel 96 antigen-specific ELISA will be used in additional studies that will prove its clinical efficacy, not only for the early diagnosis of many neuroautoimmune, liver and lung autoimmune disorders, but also for prognosis and the implementation of preventive steps for many complex diseases.

PMID: 18831922 [PubMed - indexed for MEDLINE]

26. Brain Behav Immun. 2009 Jan;23(1):116-23. Epub 2008 Aug 9.

Activation of the maternal immune system alters cerebellar development in the offspring.

Shi L, Smith SE, Malkova N, Tse D, Su Y, Patterson PH.

Biology Division, California Institute of Technology, 391 S. Holliston Avenue, M/C 216-76 Pasadena, CA 91125, USA.

A common pathological finding in autism is a localized deficit in Purkinje cells (PCs). Cerebellar abnormalities have also been reported in schizophrenia. Using a mouse model that exploits a known risk factor for these disorders, maternal infection, we asked if the offspring of pregnant mice given a mid-gestation respiratory infection have cerebellar pathology resembling that seen in these disorders. We also tested the effects of maternal immune activation in the absence of virus by injection of the synthetic dsRNA, poly(I:C). We infected pregnant mice with influenza on embryonic day 9.5 (E9.5), or injected poly(I:C) i.p. on E12.5, and assessed the linear density of PCs in the cerebellum of adult or postnatal day 11 (P11) offspring. To study granule cell migration, we also injected BrdU on P11. Adult offspring of influenza- or poly(I:C)-exposed mice display a localized deficit in PCs in lobule VII of the cerebellum, as do P11 offspring. Coincident with this are heterotopic PCs, as well as delayed migration of granule cells in lobules VI and VII. The cerebellar pathology observed in the offspring of influenza- or poly(I:C)-exposed mice is strikingly similar to that observed in autism. The poly(I:C) findings indicate that deficits are likely caused by the activation of the maternal immune system. Finally, our data suggest that cerebellar abnormalities occur during embryonic development, and may be an early deficit in autism and schizophrenia.

PMCID: PMC2614890 PMID: 18755264 [PubMed - indexed for MEDLINE]

27. Eur Neuropsychopharmacol. 2008 Oct;18(10):712-6. Epub 2008 Aug 6.

Dopamine and serotonin levels following prenatal viral infection in mouse--implications for psychiatric disorders such as schizophrenia and autism.

Winter C, Reutiman TJ, Folsom TD, Sohr R, Wolf RJ, Juckel G, Fatemi SH.

Department of Psychiatry, Charite, Campus Mitte, Berlin, Germany.

Prenatal viral infection has been associated with neurodevelopmental disorders such as schizophrenia and autism. It has previously been demonstrated that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) and middle-late second trimester (E18) administration of influenza virus. Neurochemical analysis following infection on E18 using this model has revealed significantly altered levels of serotonin, 5-hydroxyindoleacetic acid, and taurine, but not dopamine. In order to monitor these different patterns of monoamine expression in exposed offspring in more detail and to see if there are changes in the dopamine system at another time point, pregnant C57BL6J mice were infected with a sublethal dose of human influenza virus or sham-infected using vehicle solution on E16. Male offspring of the infected mice were collected at P0, P14, and P56, their brains removed and cerebellum dissected and flash frozen. Dopamine and serotonin levels were then measured using HPLC-ED technique. When compared to controls, there was a significant decrease in serotonin levels in the cerebella of offspring of virally exposed mice at P14. No differences in levels of dopamine were observed in exposed and control mice, although there was a significant decrease in dopamine at P14 and P56 when compared to P0. The present study shows that the serotonergic system is disrupted following prenatal viral infection, potentially modelling disruptions that occur in patients with schizophrenia and autism.

PMCID: PMC2714699 PMID: 18693086 [PubMed - indexed for MEDLINE]

28. J Child Adolesc Psychopharmacol. 2008 Apr;18(2):221-2.

Abnormal movements with the addition of clindamycin to risperidone in a girl with autism.

Malone RP, Harvey JA.

PMID: 18439121 [PubMed - indexed for MEDLINE]

29. Schizophr Res. 2008 Feb;99(1-3):56-70. Epub 2008 Jan 9.

Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders.

Fatemi SH, Reutiman TJ, Folsom TD, Huang H, Oishi K, Mori S, Smee DF, Pearce DA, Winter C, Sohr R, Juckel G.

Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St. SE, MMC 392, Minneapolis, MN 55455, USA.

Prenatal viral infection has been associated with development of schizophrenia and autism. Our laboratory has previously shown that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) administration of influenza virus. We hypothesized that late second trimester infection (E18) in mice may lead to a different pattern of brain gene expression and structural defects in the developing offspring. C57BL6J mice were infected on E18 with a sublethal dose of human influenza virus or sham-infected using vehicle solution. Male offsping of the infected mice were collected at P0, P14, P35 and P56, their brains removed and prefrontal cortex, hippocampus and cerebellum dissected and flash frozen. Microarray, qRT-PCR, DTI and MRI scanning, western blotting and neurochemical analysis were performed to detect differences in gene expression and brain atrophy. Expression of several genes associated with schizophrenia or autism including Sema3a, Trfr2 and Vldlr were found to be altered as were protein levels of Foxp2. E18 infection of C57BL6J mice with a sublethal dose of human influenza virus led to significant gene alterations in frontal, hippocampal and cerebellar cortices of developing mouse progeny. Brain imaging revealed significant atrophy in several brain areas and white matter thinning in corpus callosum. Finally, neurochemical analysis revealed significantly altered levels of serotonin (P14, P35), 5-Hydroxyindoleacetic acid (P14) and taurine (P35). We propose that maternal infection in mouse provides an heuristic animal model for studying the environmental contributions to genesis of schizophrenia and autism, two important examples of neurodevelopmental disorders.

PMCID: PMC2312390 PMID: 18248790 [PubMed - indexed for MEDLINE]

30. PLoS Pathog. 2007 Nov;3(11):e149.

Congenital viral infections of the brain: lessons learned from lymphocytic choriomeningitis virus in the neonatal rat.

Bonthius DJ, Perlman S.

Department of Pediatrics, Neurology, and Anatomy at the Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.

The fetal brain is highly vulnerable to teratogens, including many infectious agents. As a consequence of prenatal infection, many children suffer severe and permanent brain injury and dysfunction. Because most animal models of congenital brain infection do not strongly mirror human disease, the models are highly limited in their abilities to shed light on the pathogenesis of these diseases. The animal model for congenital lymphocytic choriomeningitis virus (LCMV) infection, however, does not suffer from this limitation. LCMV is a well-known human pathogen. When the infection occurs during pregnancy, the virus can infect the fetus, and the developing brain is particularly vulnerable. Children with congenital LCMV infection often have substantial neurological deficits. The neonatal rat inoculated with LCMV is a superb model system of human congenital LCMV infection. Virtually all of the neuropathologic changes observed in humans congenitally infected with LCMV, including microencephaly, encephalomalacia, chorioretinitis, porencephalic cysts, neuronal migration disturbances, periventricular infection, and cerebellar hypoplasia, are reproduced in the rat model. Within the developing rat brain, LCMV selectively targets mitotically active neuronal precursors. Thus, the targets of infection and sites of pathology depend on host age at the time of infection. The rat model has further shown that the pathogenic changes induced by LCMV infection are both virus-mediated and immune-mediated. Furthermore, different brain regions simultaneously infected with LCMV can undergo widely different pathologic changes, reflecting different brain region-virus-immune system interactions. Because the neonatal rat inoculated with LCMV so faithfully reproduces the diverse neuropathology observed in the human counterpart, the rat model system is a highly valuable tool for the study of congenital LCMV infection and of all prenatal brain infections In addition, because LCMV induces delayed-onset neuronal loss after the virus has been cleared, the neonatal rat infected with LCMV may be an excellent model system to study neurodegenerative or psychiatric diseases whose etiologies are hypothesized to be virus-induced, such as autism, schizophrenia, and temporal lobe epilepsy.

PMCID: PMC2092377 PMID: 18052527 [PubMed - indexed for MEDLINE]

31. Brain Behav Immun. 2008 May;22(4):469-86. Epub 2007 Nov 26.

Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice.

Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J.

Laboratory of Behavioral Neurobiology, ETH Zurich, Schwerzenbach, Switzerland.

Maternal infection during pregnancy increases the risk for neurodevelopmental disorders such as schizophrenia and autism in the offspring. This association appears to be critically dependent on the precise prenatal timing. However, the extent to which distinct adult psychopathological and neuropathological traits may be sensitive to the precise times of prenatal immune activation remains to be further characterized. Here, we evaluated in a mouse model of prenatal immune challenge by the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyIC), whether prenatal immune activation in early/middle and late gestation may influence the susceptibility to some of the critical cognitive, pharmacological, and neuroanatomical dysfunctions implicated in schizophrenia and autism. We revealed that PolyIC-induced prenatal immune challenge on gestation day (GD) 9 but not GD17 significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation specifically in late gestation impaired working memory, potentiated the locomotor reaction to the NMDA-receptor antagonist dizocilpine, and reduced hippocampal NMDA-receptor subunit 1 expression. On the other hand, potentiation of the locomotor reaction to the dopamine-receptor agonist amphetamine and reduction in Reelin- and Parvalbumin-expressing prefrontal neurons emerged independently of the precise times of prenatal immune challenge. Our findings thus highlight that prenatal immune challenge during early/middle and late fetal development in mice leads to distinct brain and behavioral pathological symptom clusters in adulthood. Further examination and evaluation of in utero immune challenge at different times of gestation may provide important new insight into the neuroimmunological and neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders such as schizophrenia and autism.

PMID: 18023140 [PubMed - indexed for MEDLINE]

32. Med Hypotheses. 2008;70(5):967-74. Epub 2007 Nov 5.

The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders.

Bransfield RC, Wulfman JS, Harvey WT, Usman AI.

Department of Psychiatry, Riverview Medical Center, 225 State Route 35, Red Bank, NJ, United States.

Chronic infectious diseases, including tick-borne infections such as Borrelia burgdorferi may have direct effects, promote other infections and create a weakened, sensitized and immunologically vulnerable state during fetal development and infancy leading to increased vulnerability for developing autism spectrum disorders. A dysfunctional synergism with other predisposing and contributing factors may contribute to autism spectrum disorders by provoking innate and adaptive immune reactions to cause and perpetuate effects in susceptible individuals that result in inflammation, molecular mimicry, kynurenine pathway changes, increased quinolinic acid and decreased serotonin, oxidative stress, mitochondrial dysfunction and excitotoxicity that impair the development of the amygdala and other neural structures and neural networks resulting in a partial Klüver-Bucy Syndrome and other deficits resulting in autism spectrum disorders and/or exacerbating autism spectrum disorders from other causes throughout life. Support for this hypothesis includes multiple cases of mothers with Lyme disease and children with autism spectrum disorders; fetal neurological abnormalities associated with tick-borne diseases; similarities between tick-borne diseases and autism spectrum disorder regarding symptoms, pathophysiology, immune reactivity, temporal lobe pathology, and brain imaging data; positive reactivity in several studies with autistic spectrum disorder patients for Borrelia burgdorferi (22%, 26% and 20-30%) and 58% for mycoplasma; similar geographic distribution and improvement in autistic symptoms from antibiotic treatment. It is imperative to research these and all possible causes of autism spectrum disorders in order to prevent every preventable case and treat every treatable case until this disease has been eliminated from humanity.

PMID: 17980971 [PubMed - indexed for MEDLINE]

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