Studies supporting our approach

The role of infections in ASD

The following list consists of scientific studies that have research supporting our approach to treating Autism Spectrum Disorder.

al-Haddad, B., Jacobsson, B., Chabra, S., Modzelewska, D., Olson, E., Bernier, R., Enquobahrie, D., Hagberg, H., Östling, S., Rajagopal, L., Adams Waldorf, K. and Sengpiel, V. (2019). Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero. JAMA Psychiatry.

Angelidou, A., Asadi, S., Alysandratos, K., Karagkouni, A., Kourembanas, S., Theoharides, T. (2012). Perinatal stress, brain inflammation and risk of autism-Review and proposal. BMC Pediatrics, 12(1).

Atladóttir H, Thorsen P, stergaard LO, Schendel D, Lemcke S, Abdallah M, et al. Maternal Infection Requiring Hospitalization During Pregnancy and Autism Spectrum Disorders. Journal Of Autism And Developmental Disorders. 2010;40(12):1423–1430.

Binda S, Bubba L, Pellegrinelli L, Primache V, Gentile I, Zappulo E, et al. DNA detection of herpetic viruses in dried blood spots in children with autism spectrum disorders. Journal of Clinical. 2016 9;Volume 82, Supplement, Pages S137–S138.

Boppana, S. B., Fowler, K. B., Britt, W. J., Stagno, S., Pass, RF. Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics . 1999;104:55–60.

Brun, P., Qesari, M., Marconi, P. C., Kotsafti, A., Porzionato, A., Macchi, V., et al. (2018). Herpes Simplex Virus Type 1 Infects Enteric Neurons and Triggers Gut Dysfunction via Macrophage Recruitment. Front Cell Infect Microbiol, 8(74).

Cannon, M. J., Davis, K. F. (2005). Washing our hands of the congenital cytomegalovirus disease epidemic. BMC PublicHealth, 70(5).

Chess, S. (1977). Follow-up report on autism in congenital rubella. J Autism Child Schizophr, 7:69–74.

Choi, G. B., Yim, Y. S., Wong, H., Kim, S., Kim, H., Kim, S. V., et al. (2016). The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science, 351:933–939.

Elwood, E., Lim, Z., Naveed, H., Galea, I. (2017). The effect of systemic inflammation on human brain barrier function. Brain, Behavior, and Immunity, 62:35–40.

Fatemi, S., Pearce, D. A., Brooks, A. I., Sidwell, R. W. (2005). Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: A potential animal model for schizophrenia and autism. Synapse, 57(2):91–99. Available from: https://doi.org/10.1002/syn.20162.

Garay, P. A., Hsiao, E. Y., Patterson, P. H., McAllister, A. K. (2013). Maternal immune activation causes ageand region-specific changes in brain cytokines in offspring throughout development. Brain, Behavior, and Immunity, 31:54–68.

Garbett, K., Ebert, P., Mitchell, A., Lintas, C., Manzi, B., Mirnics, K., et al. (2008). Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiology Of Disease, 30(3):303–311.

Garbett, K., Hsiao, E., Kálmán, S., Patterson, P., Mirnics, K. (2012). Effects of maternal immune activation on gene expression patterns in the fetal brain. Translational Psychiatry, 2(4):98–98.

Gaytant, M. A., Steegers, E. A., Semmekrot, B. A., Merkus, H. M., Galama, J. M. (2002). Congenital cytomegalovirus infection: review of the epidemiology and outcome. Obstet Gynecol Surv, 57:245–256.

Gee, K., Guzzo, C., Mat, N. C., Ma, W., Kumar, A. (2009). The IL-12 Family of Cytokines in Infection, Inflammation and Autoimmune Disorders. Inflammation & Allergy-Drug Targets, 8(1):40–52.

Ghaziuddin ,M., Al-Khouri, I., Ghaziuddin, N. (2002). Autistic symptoms following herpes encephalitis. European Child & Adolescent Psychiatry, 11(3):142–146.

Greer, M. K., Lyons-Crews, M., Mauldin, L. B. (1989). A case study of the cognitive and behavioral deficits of temporal lobe damage in herpes simplex encephalitis. Autism Dev Disord, 19(2):317–326. Available from: https://doi.org/10.1007/BF02211849.

Hobman, T., Chantler, J. (2007). Rubella virus. In: Knipe D, Howley P, editors. Fields Virology. Philadelphia: Lippincott: Williams & Wilkins; p. 1069–1100.

Hutton, J. (2016).  Does Rubella Cause Autism: A 2015 Reappraisal? Frontiers In Human Neuroscience, 10. Available from: doi:10.3389/fnhum.2016.00025.

Jackson, S., Bartek, J. (2009). The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–1078.

Jay, V., Becker, L. E., Otsubo, H., Cortez, M., Hwang, P., Hoffman, H. J., et al. (1995). Chronic encephalitis and epilepsy (Rasmussen’s encephalitis): Detection of cytomegalovirus and herpes simplex virus 1 by the polymerase chain reaction and in situ hybridization. Neurology, 45.

Jyonouchi, H., Sun, S. N., Le, H. (2001). Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol, 120:170–179.

Kern, J., Geier, D., Sykes, L., Geier, M. (2016). Relevance of Neuroinflammation and Encephalitis in Autism. Frontiers in Cellular Neuroscience, 9.

 

Knuesel, I., Chicha, L., Britschgi, M., Schobel, S. A., Bodmer, M., Hellings, J. A., et al. (2014). Maternal immune activation and abnormal brain development across CNS disorders. Nature Reviews Neurology, 10:643– 660.

Kylat, R. I., Kelly, E. N., Ford-Jones, E. L. (2006). Clinical findings and adverse outcome in neonates with symptomatic congenital cytomegalovirus (SCCMV) infection. Eur J Pediatr. 165:773–778.

Lintas, C., Altieri, L., Lombardi, F., Sacco, R., Persico, A. M. (2010). Association of autism with polyomavirus infection in postmortem brains. J Neurovirol, 16(2):141–9.

Lokensgard, J. R., Hu, S., Sheng, W. (2001). Robust expression of TNF-α, IL-1β, RANTES, and IP-10 by human microglial cells during nonproductive infection with herpes simplex virus. J Neurovirol, 7:208– 219.

Mahic, M., Mjaaland, S., Bovelstad, H. M., Gunnes, N., Susser, E., Bresnahan, M., et al. (2017). Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere, 22(2):16–17. eCollection 2017 Jan-Feb.

 

Meyer, U., Feldon, J., Dammann, O. (2011). Schizophrenia and Autism: Both Shared and Disorder-Specific Pathogenesis Via Perinatal Inflammation? Pediatr Res, 2:26–33.

Nicolson, G. L., Gan, R., Nicolson, N. L., Haier, J. (2007). Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders. Journal of Neuroscience research, 85:1143–1148.

Omura, Y., Lu, D., Jones, M. K., Nihrane, A., Duvvi, H., Shimotsuura, Y., et al. (2015). Early Detection of Autism (ASD) by a Non-invasive Quick Measurement of Markedly Reduced Acetylcholine & DHEA and Increased β-Amyloid (1-42), Asbestos (Chrysotile), Titanium Dioxide, Al, Hg & often Coexisting Virus Infections (CMV, HPV 16 and 18), Bacterial Infections etc. in the Brain and Corresponding Safe Individualized Effective Treatment. Acupunct Electrother Res, 40(3):157–187.

Perry, V., Cunningham, C., Holmes, C. (2007). Systemic infections and inflammation affect chronic neurodegeneration. Nature Reviews Immunology. 7(2):161–167.

Slawinski, B. L., Talge, N., Ingersoll, B., Smith, A., Glazier, A., Kerver, J., et al. (2018). Maternal cytomegalovirus sero-positivity and autism symptoms in children. American Journal of Reproductive Immunilogy. 79(5).

 

Smith, S. E., Li, J., Garbett, K., Mirnics, K., Patterson, P. H. (2007). Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci, 27:10695–10702.

Tabata, T., Petitt, M., Zydek, M., Fang-Hoover, J., Larocque, N., Tsuge, M., et al. (2016). Human cytomegalovirus infection interferes with the maintenance and differentiation of trophoblast progenitor cells of the human placenta. Journal of Virology, 90(2):1108–1115.

Thompson, M. R., Kaminski, J. J., Kurt-Jones, E. A., Fitzgerald, K. A. (2011). Pattern Recognition Receptors and the Innate Immune Response to Viral Infection. Viruses, 3(6):920–940.

Valayi, S., Eftekharian, M. M., Taheri, M., Alikhani, M. Y. (2017). Evaluation of antibodies to cytomegalovirus and Epstein-Barr virus in patients with autism spectrum disorder. Human Antibodies, 26(3):165–169.

Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., Pardo, C. A. (2005). Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol, 57:67–81.

Wang, T., Liu, B., Qin, L., Wilson, B., Hong, J. S. (2004). Protective effect of the SOD/catalase mimetic MnTMPyP on inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuronal-glial cultures. J Neuroimmunol, 147:68–72.

Wang, T., Rumbaugh, J., Nath, A. (2006). Viruses and the brain: from inflammation to dementia. Clinical Science, 110(4):393–407.

Zinkernagel, R. (2001). Maternal Antibodies, Childhood Infections, and Autoimmune Diseases. New England Journal Of Medicine, 345(18):1331–1335.

 

The role of inflammation in ASD

The following list consists of scientific studies that have research supporting our approach to treating Autism Spectrum Disorder.

Anderson, G. M. (2014). Autism Biomarkers: Challenges, Pitfalls and Possibilities. Journal of Autism and Developmental Disorders, 45(4):1103–1113. Available from: 10.1007/s10803-014-2225-4.

 

Angelidou, A., Asadi, S., Alysandratos, K., Karagkouni, A., Kourembanas, S., Theoharides, T. (2012). Perinatal stress, brain inflammation and risk of autism-Review and proposal. BMC Pediatrics, 12(1).

Ashwood, P., Van de Water, J. (2004). Is autism an autoimmune disease? Autoimmunity Reviews, 557–562.

Bauman M, Kemper T. Neuroanatomic observations of the brain in autism: a review and future directions. International Journal Of Developmental Neuroscience. 2005;23(2-3):183–187.

Belmonte M. Autism and Abnormal Development of Brain Connectivity. Journal Of Neuroscience. 2004;24(42):9228–9231.

Choi, G. B., Yim, Y. S., Wong, H., Kim, S., Kim, H., Kim, S. V., et al. (2016). The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science, 351:933–939.

Depino, A. (2013). Peripheral and central inflammation in autism spectrum disorders. Molecular and Cellular Neuroscience, 53:69–76.

Elwood, E., Lim, Z., Naveed, H., Galea, I. (2017). The effect of systemic inflammation on human brain barrier function. Brain, Behavior, and Immunity, 62:35–40.

Fatemi, S., Pearce, D. A., Brooks, A. I., Sidwell, R. W. (2005). Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: A potential animal model for schizophrenia and autism. Synapse, 57(2):91–99. Available from: https://doi.org/10.1002/syn.20162.

Garay, P. A., Hsiao, E. Y., Patterson, P. H., McAllister, A. K. (2013). Maternal immune activation causes ageand region-specific changes in brain cytokines in offspring throughout development. Brain, Behavior, and Immunity, 31:54–68.

Garbett, K., Ebert, P., Mitchell, A., Lintas, C., Manzi, B., Mirnics, K., et al. (2008). Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiology Of Disease, 30(3):303–311.

Garbett, K., Hsiao, E., Kálmán, S., Patterson, P., Mirnics, K. (2012). Effects of maternal immune activation on gene expression patterns in the fetal brain. Translational Psychiatry, 2(4):98–98.

Gesundheit, B., Rosenzweig, J., Naor, D., Lerer, B., Zachor, D., Procházka, V., et al. (2013). Immunological and autoimmune considerations of Autism Spectrum Disorders. Journal of Autoimmunity, 44:1–7.

Ghaziuddin ,M., Al-Khouri, I., Ghaziuddin, N. (2002). Autistic symptoms following herpes encephalitis. European Child & Adolescent Psychiatry, 11(3):142–146.

Goines, P., Van de Water J. (2010). The Immune System’s Role in the Biology of Autism. Curr Opin Neurol, 23(2):111–117.

Greer, M. K., Lyons-Crews, M., Mauldin, L. B. (1989). A case study of the cognitive and behavioral deficits of temporal lobe damage in herpes simplex encephalitis. Autism Dev Disord, 19(2):317–326. Available from: https://doi.org/10.1007/BF02211849.

Gupta, S., Heads, C. (1996). Dysregulated immune system in children with autism: Beneficial effects of intravenous immune globulin on autistic characteristics. Journal of Autism and Developmental Disorders, 26:439–452.

Gupta, S., Lee, T., Aggarval, S. (1998). Alterations in Th1 and Th2 subsets of CD4+ and CD8+ T-cells in autism. J Neuroimmunol, 217:2–14.

Hagberg, H., Gressens, P., Mallard, C. (2012). Inflammation during fetal and neonatal life: Implications for neurologic and neuropsychiatric disease in children and adults. Annuals Of Neurology, 71(4):444– 457.

Han, Y., He, T., Huang, D., Pardo, C. A., Ransohoff, R. M. (2001). TNF-α mediates SDF-1α-induced NF-κB activation and cytotoxic effects in primary astrocytes. J Clin Invest, 108:425–435.

Jackson, S., Bartek, J. (2009). The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–1078.

Jaiswal, M., LaRusso, N. F., Burgart, L. J., Gores, G. J. (2000). Inflammatory Cytokines Induce DNA damage and Inhibit DNA repair in Cholangiocarcinoma Cells by a Nitric Oxide-dependent Mechanism. Cancer Res, 1;p. 184–190.

Jyonouchi, H., Sun, S. N., Le, H. (2001). Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol, 120:170–179.

Kawanishi, S., Hiraku, Y., Pinlaor, S., Ma, N. (2006). Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammationrelated carcinogenesis. Biol Chem. 2006;387:365–372.

Kern, J., Geier, D., Sykes, L., Geier, M. (2016). Relevance of Neuroinflammation and Encephalitis in Autism. Frontiers in Cellular Neuroscience, 9.

Klein, J. A., Ackerman, S. L. (2003). Oxidative stress, cell cycle, and neurodegeneration. J Clin Invest, 111:785–793.

Knuesel, I., Chicha, L., Britschgi, M., Schobel, S. A., Bodmer, M., Hellings, J. A., et al. (2014). Maternal immune activation and abnormal brain development across CNS disorders. Nature Reviews Neurology, 10:643– 660.

Mahic, M., Mjaaland, S., Bovelstad, H. M., Gunnes, N., Susser, E., Bresnahan, M., et al. (2017). Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere, 22(2):16–17. eCollection 2017 Jan-Feb.

Meyer, U., Feldon, J., Dammann, O. (2011). Schizophrenia and Autism: Both Shared and Disorder-Specific Pathogenesis Via Perinatal Inflammation? Pediatr Res, 2:26–33.

Naha, P., Davoren, M., Lyng, F., Byrne, H. (2010). Reactive oxygen species (ROS) induced cytokine production and cytotoxicity of PAMAM dendrimers in J774A.1 cells. Toxicology and Applied Pharmacology, 246(1-2):91–99.

Perry, V., Cunningham, C., Holmes, C. (2007). Systemic infections and inflammation affect chronic neurodegeneration. Nature Reviews Immunology. 7(2):161–167.

Qin, L., Liu, Y., Wang, T. (2004). NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem, 279:1415–1421.

Rose, S., Melnyk, S., Pavliv, O., Bai, S., Nick, T., Frye, R., et al. (2012). Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Translational Psychiatry, 2(7):134–134.

Shpyleva, S., Ivanovsky, S., de Conti, A., Melnyk, S. (2014). Cerebellar oxidative DNA damage and altered DNA methylation in the BTBR T+tf/J mouse model of autism and similarities with human post mortem cerebellum. PLoS One, (9):113712. PMID: 25423485.

Smith, S. E., Li, J., Garbett, K., Mirnics, K., Patterson, P. H. (2007). Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci, 27:10695–10702.

Streit, W. J., Mrak, R. E., Griffin, W. S. (2004). Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation, 1:14.

Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., Pardo, C. A. (2005). Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol, 57:67–81.

Wang, T., Liu, B., Qin, L., Wilson, B., Hong, J. S. (2004). Protective effect of the SOD/catalase mimetic MnTMPyP on inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuronal-glial cultures. J Neuroimmunol, 147:68–72.

Wang, T., Rumbaugh, J., Nath, A. (2006). Viruses and the brain: from inflammation to dementia. Clinical Science, 110(4):393–407.

Wills, S., Cabanlit, M., Bennett, J., Ashwood, P., Amaral, D., Van de Water, J. (2007). Autoantibodies in Autism Spectrum Disorders (ASD). Ann NY Acad Sci, 1107:79–91.

Zimmerman, A., Jyonouchi, H., Comi, A., Connors, S., Milstien, S., Varsou, A., et al. (2005). Cerebrospinal Fluid and Serum. Pediatric Neurology, 33:195–201.

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