Elevation of Tumor Necrosis Factor-Alpha in Cerebrospinal Fluid of Autistic Children
Abstract
Recent reports implicating elevated cytokines in the central nervous system in a small number of patients studied with autism have reported clinical regression. These studies have not focused on tumor necrosis factor-alpha as a possible marker for inflammatory damage. A series of 10 children with autism had clinical evaluation of their serum and spinal fluid for inflammatory changes and possible metabolic disease as part of their neurological evaluation. Elevation of cerebrospinal fluid levels of tumor necrosis factor-alpha was significantly higher (mean = 104.10 pg/mL) than concurrent serum levels (mean = 2.78 pg/mL) in all of the patients studied. The ratio of the cerebrospinal fluid levels to serum levels averaged 53.7:1. This ratio is significantly higher than the elevations reported for other pathological states for which cerebrospinal fluid and serum tumor necrosis factor-alpha levels have been simultaneously measured. This observation may offer a unique insight into central nervous system inflammatory mechanisms that may contribute to the onset of autism and may serve as a potential clinical marker. More controlled study of this potentially important observation may prove valuable.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Increases in many cytokines and chemokines are observed in the brain and cerebrospinal fluid of individuals with autistic disorder, in particular IL-6, TGFβ1, CCL2, and CCL17 in the cerebellum.
“Moreover, increases in many cytokines and chemokines are observed in the brain and cerebrospinal fluid (CSF) of individuals with AD, in particular; interleukin (IL)-6, transforming growth factor beta 1 (TGFβ1), C-C motif ligand 2 (CCL2) and CCL17 in the cerebellum [73–76].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [74]
Children with ASD have elevated levels of pro-inflammatory cytokines including IL-6, TNF-α, and IFN-γ in different tissues.
“Furthermore, evidence suggests that children with ASD have elevated levels of pro-inflammatory cytokines including, interleukin 6 (IL–6), tumour necrosis factor alpha (TNF–α), and interferon gamma (IFN-γ) in different tissues [3,4,5,6,7].”
From Vitamin D and Autism Spectrum Disorder: A Literature Review (2016) · cites this paper as [5]
IFN-γ has been noted as increased in individuals with ASD.
“Similarly, IFN-γ has been noted as increased in individuals with ASD,13, 16, 17, 61 and IFN-γ was increased in ASD and correlated with C disporicum and C tertium.”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [17]
Increased IL6 has been seen in clinical cohorts of ASD.
“Furthermore, increased IL6 has been seen in clinical cohorts of ASD.13, 14, 17, 60”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [17]
Cites
(1943) · The Nervous child · Cited by 8,870 · see citing works
Neuroglial activation and neuroinflammation in the brain of patients with autism
Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., & Pardo, C. A. (2005) · Annals of Neurology · doi:10.1002/ana.20315 · Cited by 2,149 · see citing works
Proinflammatory Cytokines and Early Neurological Worsening in Ischemic Stroke
Vila, N., Castillo, J., Dávalos, A., & Chamorro, Á. (2000) · Stroke · doi:10.1161/01.str.31.10.2325 · Cited by 676 · see citing works
Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation
Nelson, K. B., Grether, J. K., Croen, L., Dambrosia, J. M., Dickens, B. F., Jelliffe‐Pawlowski, L. L., Hansen, R. L., & Phillips, T. M. (2001) · Annals of Neurology · doi:10.1002/ana.1024 · Cited by 435 · see citing works
Actions of TNF‐α on glutamatergic synaptic transmission in the central nervous system
Pickering, M., Cumiskey, D., & O'Connor, J. J. (2005) · Experimental Physiology · doi:10.1113/expphysiol.2005.030734 · Cited by 411 · see citing works
Cerebrospinal Fluid and Serum Markers of Inflammation in Autism
Zimmerman, A. W., Jyonouchi, H., Comi, A. M., Connors, S. L., Milstien, S., Varsou, A., & Heyes, M. P. (2005) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2005.03.014 · Cited by 300 · see citing works
Antibodies to Myelin Basic Protein in Children with Autistic Behavior
Singh, V. K., Warren, R. P., Odell, J. D., Warren, W. L., & Cole, P. (1993) · Brain, Behavior, and Immunity · doi:10.1006/brbi.1993.1010 · Cited by 274 · see citing works
Connolly, A. M., Chez, M. G., Streif, E. M., Keeling, R. M., Golumbek, P. T., Kwon, J. M., Riviello, J. J., Robinson, R., Neuman, R. J., & Deuel, R. K. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.07.004 · Cited by 262 · see citing works
Self-citationSerum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders
Connolly, A. M., Chez, M. G., Pestronk, A., Arnold, S. T., Mehta, S., & Deuel, R. K. (1999) · The Journal of Pediatrics · doi:10.1016/s0022-3476(99)70248-9 · Cited by 236 · see citing works
Self-citationShiozaki, T., Hayakata, T., Tasaki, O., Hosotubo, H., Fuijita, K., Mouri, T., Tajima, G., Kajino, K., Nakae, H., Tanaka, H., et al. (2005) · Shock · doi:10.1097/01.shk.0000161385.62758.24 · Cited by 152 · see citing works
Sjogren, M. (2004) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2003.019422 · Cited by 125 · see citing works
Antibrain antibodies in infantile autism
Todd, R. D., Hickok, J. M., Anderson, G. M., & Cohen, D. J. (1988) · Biological Psychiatry · doi:10.1016/0006-3223(88)90012-1 · Cited by 80 · see citing works
Baraczka, K., Nékám, K., Pozsonyi, T., Szüts, I., & Ormos, G. (2003) · European Journal of Neurology · doi:10.1046/j.1351-5101.2003.00706.x · Cited by 52 · see citing works
(2005) · Annals of Neurology · doi:10.1002/ana.20397 · Cited by 14 · see citing works
Attallah, A. M., & Ibrahim, G. G. (2004) · Journal of Immunoassay and Immunochemistry · doi:10.1081/ias-200033824 · Cited by 6 · see citing works
Monno, L., Zimatore, G. B., Stefano, M. D., Appice, A., Livrea, P., & Angarano, G. (1999) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.67.3.369 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Maternal immune activation and abnormal brain development across CNS disorders
Knuesel, I., Chicha, L., Britschgi, M., Schobel, S. A., Bodmer, M., Hellings, J. A., Toovey, S., & Prinssen, E. P. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.187 · Cited by 880 · see citing works
Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis
Rossignol, D. A., & Frye, R. E. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.136 · Cited by 913 · see citing works
Elevated immune response in the brain of autistic patients
Li, X., Chauhan, A., Sheikh, A. M., Patil, S., Chauhan, V., Li, X.-M., Ji, L., Brown, T., & Malik, M. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.12.002 · Cited by 786 · see citing works
“…reports suggest that a combination of environmental or perhaps in utero risk factors, autoimmune risk factors and localized inflammation of the central nervous system may contribute to the pathogenesis of ASD (Nelson et al., 2001; Vargas et al., 2005; Zimmerman et al., 2005; Chez et al., 2007).”
BackgroundImmune involvement in schizophrenia and autism: Etiology, pathology and animal models
Patterson, P. H. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.12.016 · Cited by 766 · see citing works
“Most important is the recent evidence of dysregulation of immune-related genes in the schizophrenic brain, and striking microglial and astrocyte activation as well as cytokine up-regulation in the autistic brain and CSF [7] [8] [9] [10] [11] [12] [13].”
Consensus Paper: Pathological Role of the Cerebellum in Autism
Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., Chauhan, A., Chauhan, V., Dager, S. R., Dickson, P. E., et al. (2012) · The Cerebellum · doi:10.1007/s12311-012-0355-9 · Cited by 723 · see citing works
Tumor necrosis factor alpha: A link between neuroinflammation and excitotoxicity
Olmos, G., & Lladó, J. (2014) · Mediators of Inflammation · doi:10.1155/2014/861231 · Cited by 730 · see citing works
“Interestingly, it has been proposed that an elevation of this ratio is a major cause of autism spectrum disorder [133, 134]; a pathology in that elevated levels of TNF-α in cerebrospinal fluid has been described [135].”
Maternal infection and immune involvement in autism
Patterson, P. H. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.03.001 · Cited by 520 · see citing works
“Recent results from studies of some of the same postmortem brains and new autism brain samples, as well as CSF, have supported these conclusions (6, 7).”
ResultBlood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders
Fiorentino, M., Sapone, A., Senger, S., Camhi, S. S., Kadzielski, S. M., Buie, T. M., Kelly, D. L., Cascella, N., & Fasano, A. (2016) · Molecular Autism · doi:10.1186/s13229-016-0110-z · Cited by 494 · see citing works
Costa, L. G., Cole, T. B., Dao, K., Chang, Y. C., Coburn, J. L., & Garrick, J. M. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107523 · Cited by 490 · see citing works
Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis
Masi, A., Quintana, D. S., Glozier, N., Lloyd, A. R., Hickie, I. B., & Guastella, A. J. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.59 · Cited by 467 · see citing works
The influence of neuroinflammation in Autism Spectrum Disorder
Matta, S. M., Hill‐Yardin, E. L., & Crack, P. J. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.04.037 · Cited by 414 · see citing works
Activation of the maternal immune system induces endocrine changes in the placenta via IL-6
Hsiao, E. Y., & Patterson, P. H. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2010.12.017 · Cited by 402 · see citing works
“IL-6 is also elevated in sera from living schizophrenic individuals (Maes et al., 2002; Potvin et al., 2008), and many pro-inflammatory cytokines are increased in the cerebrospinal fluid and sera from living autistic individuals (Ashwood et al., 2010; Chez et al., 2007; Pardo et al., 2006).”
BackgroundTargeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease
Decourt, B., Lahiri, D. K., & Sabbagh, M. N. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160930110551 · Cited by 373 · see citing works
Rossignol, D. A., & Frye, R. E. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00150 · Cited by 369 · see citing works
Garay, P. A., Hsiao, E. Y., Patterson, P. H., & McAllister, A. K. (2013) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2012.07.008 · Cited by 366 · see citing works
“It has been suggested that brain cytokines would be altered in MIA offspring based on observations of neural inflammation and cytokine changes in blood, CSF, and postmortem brain tissue from individuals with ASD and SZ (Ashwood et al., 2011a; Ashwood et al., 2011b; Ashwood et al., 2010; Chez et al., 2007; Molloy et al…”
Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation?
MEYER, U., FELDON, J., & DAMMANN, O. (2011) · Pediatric Research · doi:10.1203/pdr.0b013e318212c196 · Cited by 357 · see citing works
“For example, a nearly 50-fold increase in TNF- level was found in the cerebrospinal fluid (CSF) of autistic children (47), and severe inflammation is present in the brains of autistic patients from a broad range of ages (48), characterized by prominent activation of microglia and astroglia cells and enhanced proinflam…”
Understanding the Complexity of the Immune System during Pregnancy
Racicot, K. E., Kwon, J., Aldo, P. B., Silasi, M., & Mor, G. (2014) · American Journal of Reproductive Immunology · doi:10.1111/aji.12289 · Cited by 337 · see citing works
The association of maternal obesity and diabetes with autism and other developmental disabilities
Li, M., Fallin, M. D., Riley, A., Landa, R., Walker, S. O., Silverstein, M., Caruso, D., Pearson, C., Kiang, S., Dahm, J. L., et al. (2016) · PEDIATRICS · doi:10.1542/peds.2015-2206 · Cited by 338 · see citing works
Wei, H., Zou, H., Sheikh, A. M., Malik, M., Dobkin, C., Brown, W. T., & Li, X. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-52 · Cited by 333 · see citing works
ROS and Brain Diseases: The Good, the Bad, and the Ugly
Popa-Wagner, A., Mitran, S., Sivanesan, S., Chang, E., & Buga, A.-M. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/963520 · Cited by 427 · see citing works
“Similarly, in plasma F2dihomo-isoprostanes, a specific component of myelin in the brain of primates, plasma represents an early marker of Rett syndrome, a developmental disorder that almost exclusively affects females but has been found inmale patients, too [106].”
BackgroundLuna, R. A., Oezguen, N., Balderas, M., Venkatachalam, A., Runge, J. K., Versalovic, J., Veenstra-VanderWeele, J., Anderson, G. M., Savidge, T., & Williams, K. C. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2016.11.008 · Cited by 295 · see citing works
“A single study, with a follow-up report, remains the only characterization of the mucosal microbiome in pediatric ASD.23,34 Although focusing mainly on phylum level changes, the key differences associated with the ASD group with FGID were seen as an increase in Clostridiales, particularly in Lachnospiraceae and Rumino…”
BackgroundInfluentialAltered T cell responses in children with autism
Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I. N., & Van de Water, J. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2010.09.002 · Cited by 281 · see citing works
An in vivo neuroimmune organoid model to study human microglia phenotypes
Schafer, S. T., Mansour, A. A., Schlachetzki, J. C. M., Pena, M., Ghassemzadeh, S. S., Mitchell, L. E., Mar, A., Quang, D., Stumpf, S., Ortiz, I. S., et al. (2023) · Cell · doi:10.1016/j.cell.2023.04.022 · Cited by 269 · see citing works
The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder
Masi, A., Glozier, N., Dale, R. C., & Guastella, A. J. (2017) · Neuroscience Bulletin · doi:10.1007/s12264-017-0103-8 · Cited by 260 · see citing works
Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors
Wei, H., Chadman, K. K., McCloskey, D. P., Sheikh, A. M., Malik, M. N., Brown, W. T., & Li, X. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.01.011 · Cited by 257 · see citing works
“A number of recent studies have demonstrated that various inflammatory cytokines were elevated in blood mononuclear cells, serum, plasma and cerebrospinal fluid of autistic subjects [7-13].”
BackgroundPribiag, H., & Stellwagen, D. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0530-13.2013 · Cited by 249 · see citing works
“Deficits in GABAergic neurotransmission are also implicated in ASD (Chao et al., 2010; Han et al., 2012), which is often accompanied by immune dysregulation and elevated levels of TNF (Chez et al., 2007; Malik et al., 2011).”
BackgroundInnate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders
Zengeler, K. E., & Lukens, J. R. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-020-00487-7 · Cited by 254 · see citing works
The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders
Morris, G., & Berk, M. (2015) · BMC Medicine · doi:10.1186/s12916-015-0310-y · Cited by 245 · see citing works
“The observations relating to elevated levels of PICs extend to TNF-α [107,108] and INF-γ, which are once again elevated in the brain [92] and the peripheral circulation, interestingly, correlated with the levels of other inflammatory mediators such as NO [109,110].”
BackgroundInflammation in Children and Adolescents With Neuropsychiatric Disorders: A Systematic Review
Mitchell, R. H. B., & Goldstein, B. I. (2013) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2013.11.013 · Cited by 241 · see citing works
CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: A systematic review
Kothur, K., Wienholt, L. A., Brilot, F., & Dale, R. C. (2015) · Cytokine · doi:10.1016/j.cyto.2015.10.001 · Cited by 240 · see citing works
Evidence for a Dysregulated Immune System in the Etiology of Psychiatric Disorders
Gibney, S. M., & Drexhage, H. A. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9462-8 · Cited by 237 · see citing works
Preterm or Early Term Birth and Risk of Autism
Crump, C., Sundquist, J., & Sundquist, K. (2021) · PEDIATRICS · doi:10.1542/peds.2020-032300 · Cited by 223 · see citing works
Inflammatory Cytokines: Potential Biomarkers of Immunologic Dysfunction in Autism Spectrum Disorders
Xu, N., Li, X., & Zhong, Y. (2015) · Mediators of Inflammation · doi:10.1155/2015/531518 · Cited by 223 · see citing works
“(2007) detected elevated TNF-α in the cerebrospinal fluid of autistic children [4].”
BackgroundGaray, P. (2010) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2010.00136 · Cited by 217 · see citing works
“In another study, TNFα was elevated in CSF from 10 autistic children with a history of regression (Chez et al., 2007).”
BackgroundFrye, R. E., & Rossignol, D. A. (2011) · Pediatric Research · doi:10.1203/pdr.0b013e318212f16b · Cited by 217 · see citing works
“This has changed our view of ASD from a primary CNS disorder to a disorder that affects multiple physiological systems.”
InfluentialEvidence of microglial activation in autism and its possible role in brain underconnectivity
Rodriguez, J. I., & Kern, J. K. (2011) · Neuron Glia Biology · doi:10.1017/s1740925x12000142 · Cited by 205 · see citing works
“As mentioned earlier, there is evidence of proinflammatory cytokine profiles in the brain and cerebrospinal fluid of children with ASD (Vargas et al. , 2005; Zimmerman et al. , 2005; Chez et al. , 2007).”
Major histocompatibility complex class I proteins in brain development and plasticity
Elmer, B. M., & McAllister, A. K. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.08.001 · Cited by 196 · see citing works
Tsilioni, I., Taliou, A., Francis, K., & Theoharides, T. C. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.142 · Cited by 199 · see citing works
Peripheral and central inflammation in autism spectrum disorders
Depino, A. M. (2013) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.10.003 · Cited by 189 · see citing works
Abdallah, M. W., Larsen, N., Grove, J., Nørgaard-Pedersen, B., Thorsen, P., Mortensen, E. L., & Hougaard, D. M. (2013) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2011.639803 · Cited by 186 · see citing works
“Several studies have suggested an association between elevated levels of TNF- α and ASD: elevated levels of TNF- α in cerebrospinal fl uid (Chez et al. 2007), peripheral blood mononuclear cells (Jyonouchi et al. 2005, 2001), whole blood samples (Croonenberghs et al. 2002) and post mortem brain…”
BackgroundPsychiatric Symptoms in Systemic Lupus Erythematosus
Meszaros, Z. S., Perl, A., & Faraone, S. V. (2012) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.11r07425 · Cited by 179 · see citing works
Maternal immune activation in neurodevelopmental disorders
Solek, C. M., Farooqi, N., Verly, M., Lim, T. K., & Ruthazer, E. S. (2018) · Developmental Dynamics · doi:10.1002/dvdy.24612 · Cited by 168 · see citing works
“A marked upregulation of tumor necrosis factor alpha (TNF-a) was observed in the CSF of autistic children (Chez et al., 2007), as were lowered D E V E L O P M E N T A L D Y N A M IC S immunoglobulin (IgG and IgM) plasma levels (Heuer et al., 2008), corroborating previous findings suggesting a…”
BackgroundResultKang, S. S., Kurti, A., Fair, D. A., & Fryer, J. D. (2014) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0156-9 · Cited by 167 · see citing works
“Pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)α, have been associated with increased anxiety, altered cognitive function [35-38], and are elevated in ASD patients [39-41].”
BackgroundThe Neuroprotective Effects of Astaxanthin: Therapeutic Targets and Clinical Perspective
Fakhri, S., Aneva, I. Y., Farzaei, M. H., & Sobarzo‐Sánchez, E. (2019) · Molecules · doi:10.3390/molecules24142640 · Cited by 166 · see citing works
“There is also a close link between autism and the release of proinflammatory cytokines [122,123].”
BackgroundNovel and Emerging Treatments for Autism Spectrum Disorders: A Systematic Review
Rossignol, D. A. (2009) · Annals of Clinical Psychiatry · doi:10.1177/104012370902100404 · Cited by 162 · see citing works
Pagnozzi, A. M., Conti, E., Calderoni, S., Fripp, J., & Rose, S. (2018) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2018.08.010 · Cited by 162 · see citing works
“Although it is not yet understood how CSF relates to the aetiology of ASD, it may be an early structural sign of improper fi ltering and draining of waste particles, potentially leading to neuro-in fl ammation and autism (Chez et al., 2007; Zimmerman et al., 2005).”
BackgroundAutism spectrum disorder: insights into convergent mechanisms from transcriptomics
Quesnel-Vallières, M., Weatheritt, R. J., Cordes, S. P., & Blencowe, B. J. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0066-2 · Cited by 160 · see citing works
Perinatal stress, brain inflammation and risk of autism-Review and proposal
Angelidou, A., Asadi, S., Alysandratos, K., Karagkouni, A., Kourembanas, S., & Theoharides, T. C. (2012) · BMC Pediatrics · doi:10.1186/1471-2431-12-89 · Cited by 153 · see citing works
“A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells.”
InfluentialNutritional interventions for autism spectrum disorder
Karhu, E., Zukerman, R. J., Eshraghi, R. S., Mittal, J., Deth, R. C., Castejon, A. M., Trivedi, M. S., Mittal, R., & Eshraghi, A. A. (2019) · Nutrition Reviews · doi:10.1093/nutrit/nuz092 · Cited by 145 · see citing works
“Young patients with ASD have decreased brain levels of cystathionine,(130) consistent with premature CSE expression induced by TNF-a, cerebrospinal fluid levels of which are higher in patients with ASD.(133) CBS and CSE also convert HCY and CYS to hydrogen sulfide (H2S), which inhibits mitochondrial respiration and de…”
BackgroundThe Impact of Neuroimmune Alterations in Autism Spectrum Disorder
Gottfried, C., Bambini-Junior, V., Francis, F., Riesgo, R., & Savino, W. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2015.00121 · Cited by 143 · see citing works
“Also, increased level of TNF-α was found in cerebrospinal fluid of children with ASD (122).”
BackgroundAutism, Alzheimer disease, and fragile X
Sokol, D. K., Maloney, B., Long, J. M., Ray, B., & Lahiri, D. K. (2011) · Neurology · doi:10.1212/wnl.0b013e3182166dc7 · Cited by 141 · see citing works
Cytokines and the neurodevelopmental basis of mental illness
Ratnayake, U., Quinn, T., Walker, D. W., & Dickinson, H. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00180 · Cited by 136 · see citing works
“…immunological factors also appear to be involved, in that chronically increased levels of IL-1β, IL6, IL-8 and TNF-α are positively associated with the severity of the schizophrenia or autism that eventually develops (Maes et al., 2002; Chez et al., 2007; Potvin et al., 2008; Ashwood et al., 2011).”
BackgroundThe relationship between mercury and autism: A comprehensive review and discussion
Kern, J. K., Geier, D. A., Sykes, L. K., Haley, B. E., & Geier, M. R. (2016) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2016.06.002 · Cited by 136 · see citing works
Wei, H., Alberts, I. L., & Li, X. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.08.025 · Cited by 133 · see citing works
“Chez et al. has also reported the elevation of tumor necrosis factor (TNF)-a in the cerebrospinal fluid of autistic subjects (Chez et al., 2007).”
BackgroundMast cell activation and autism
Theoharides, T. C., Angelidou, A., Alysandratos, K.-D., Zhang, B., Asadi, S., Francis, K., Toniato, E., & Kalogeromitros, D. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.12.017 · Cited by 125 · see citing works
“Biochimica et Biophysica Acta xxx (2011) xxx–xxx BBADIS-63219; No. of pages: 8; 4C: 3, 4, 5, 6 Contents lists available at ScienceDirect Biochimica et Biophysica Acta j ourna l homepage: www.e lsev ie r.com/ locate /bbad is Review Mast cell activation and autism☆ Theoharis C. Theoharides a,b,c,d,e,⁎, Asimenia Angelido…”
BackgroundInfluentialImmune Abnormalities in Autism Spectrum Disorder—Could They Hold Promise for Causative Treatment?
Gładysz, D., Krzywdzińska, A., & Hozyasz, K. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0822-x · Cited by 130 · see citing works
“Only three studies [213, 227, 232] focused on both CSF and peripheral blood and did not confirm any correlation between the same proteins in those two samples.”
BackgroundRecent Updates in the Treatment of Neurodegenerative Disorders Using Natural Compounds
Rasool, M., Malik, A., Qureshi, M. S., Manan, A., Pushparaj, P. N., Asif, M., Qazi, M. H., Qazi, A. M., Kamal, M. A., Gan, S. H., et al. (2014) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2014/979730 · Cited by 124 · see citing works
“Multiple biochemical andmolecular features could be observed for the neurodegeneration in the brain of ASD [35, 36] including oxidative stress [37, 38], activated astrocytes and microglia [39, 40], neuronal loss [35, 40], elevated levels of 8-oxo-guanosine [41], and development of proinflammatory cytokines [40, 42].”
BackgroundBiomarkers in autism spectrum disorders: Current progress
Shen, L., Liu, X., Zhang, H., Lin, J., Feng, C., & Iqbal, J. (2019) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.12.009 · Cited by 124 · see citing works
A Case Series of a Luteolin Formulation (Neuroprotek®) in Children with Autism Spectrum Disorders
Theoharides, T. C., Asadi, S., & Panagiotidou, S. (2012) · International Journal of Immunopathology and Pharmacology · doi:10.1177/039463201202500201 · Cited by 120 · see citing works
“CSF levels ofTNF were significantly increased in autistic children (17), while brains ofASD patients had elevated expression of IL-6 (18).”
BackgroundEhninger, D., Sano, Y., de Vries, P. J., Dies, K., Franz, D., Geschwind, D. H., Kaur, M., Lee, Y.-S., Li, W., Lowe, J. K., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2010.115 · Cited by 120 · see citing works
Cattane, N., Richetto, J., & Cattaneo, A. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.07.001 · Cited by 118 · see citing works
The Neurobiology of Lipid Metabolism in Autism Spectrum Disorders
Tamiji, J., & Crawford, D. A. (2010) · Neurosignals · doi:10.1159/000323189 · Cited by 114 · see citing works
Vitamin D and Autism Spectrum Disorder: A Literature Review
Mazahery, H., Camargo, C., Conlon, C., Beck, K., Kruger, M., & Von Hurst, P. (2016) · Nutrients · doi:10.3390/nu8040236 · Cited by 110 · see citing works
“Furthermore, evidence suggests that children with ASD have elevated levels of pro-inflammatory cytokines including, interleukin 6 (IL–6), tumour necrosis factor alpha (TNF–α), and interferon gamma (IFN-γ) in different tissues [3–7].”
BackgroundRelevance of Neuroinflammation and Encephalitis in Autism
Kern, J. K., Geier, D. A., Sykes, L. K., & Geier, M. R. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00519 · Cited by 111 · see citing works
“…suggestive of ongoing neuroinflammation or encephalitis (encephalitis is defined as brain inflammation) in different regions of the brain (Enstrom et al., 2005; Pardo et al., 2005; Vargas et al., 2005; Zimmerman et al., 2005; Chez et al., 2007; Morgan et al., 2010, 2012; Tetreault et al., 2012).”
BackgroundResultInfluentialGustafsson, H., Sullivan, E. L., Nousen, E. K., Sullivan, C. A., Huang, E., Rincon, M. P., Nigg, J. T., & Loftis, J. M. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.06.011 · Cited by 109 · see citing works
Coiro, P., Padmashri, R., Suresh, A., Spartz, E., Pendyala, G., Chou, S., Jung, Y., Meays, B., Roy, S., Gautam, N., et al. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.07.022 · Cited by 105 · see citing works
“…both disorders; inflammation is present in postmortem brains, and cytokine levels are altered in the blood, brain, and cerebrospinal fluid in ASD and SZ (Vargas et al., 2005; Chez et al., 2007; Patterson, 2009; Morgan et al., 2010; Watanabe et al., 2010; Ashwood et al., 2011; Wei et al., 2011).”
Bar, E., & Barak, B. (2019) · Glia · doi:10.1002/glia.23637 · Cited by 103 · see citing works
Zimmerman, A. W., Singh, K., Connors, S. L., Liu, H., Panjwani, A. A., Lee, L.-C., Diggins, E., Foley, A., Melnyk, S., Singh, I. N., et al. (2021) · Molecular Autism · doi:10.1186/s13229-021-00447-5 · Cited by 103 · see citing works
The neurobiology of autism spectrum disorders
Parellada, M., Penzol, M. J., Pina‐Camacho, L., Moreno, C., González‐Vioque, E., Zalsman, G., & Arango, C. (2013) · European Psychiatry · doi:10.1016/j.eurpsy.2013.02.005 · Cited by 101 · see citing works
“shown to be increased in the cerebral spinal fluid (CSF) of autistic patients [121,20].”
BackgroundEvidence of parallels between mercury intoxication and the brain pathology in autism
Kern, J. K., Geier, D. A., AUDHYA, T. K., King, P. G., Sykes, L. K., & Geier, M. R. (2012) · Acta Neurobiologiae Experimentalis · doi:10.55782/ane-2012-1887 · Cited by 100 · see citing works
Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders
Bhandari, R., & Kuhad, A. (2016) · Neurochemistry International · doi:10.1016/j.neuint.2016.12.012 · Cited by 100 · see citing works
Pendyala, G., Chou, S., Jung, Y., Coiro, P., Spartz, E., Padmashri, R., Li, M., & Dunaevsky, A. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2017.7 · Cited by 99 · see citing works
“…in biofluids such as blood, cerebrospinal fluid as well as the brain in ASD patients suggesting a neuroinflammatory condition to contribute to the symptoms and pathology of ASD (Ashwood et al, 2011a; Ashwood et al, 2011b; Chez et al, 2007; Molloy et al, 2006; Pardo et al, 2005; Vargas et al, 2005).”
BackgroundRossignol, D. A., Rossignol, L. W., Smith, S. A., Schneider, C., Logerquist, S., Usman, A., Neubrander, J., Madren, E. M., Hintz, G., Grushkin, B., et al. (2009) · BMC Pediatrics · doi:10.1186/1471-2431-9-21 · Cited by 97 · see citing works
“Multiple studies have reported that these problems are relatively common in children with autism [26-34].”
Saresella, M., Marventano, I., Guerini, F. R., Mancuso, R., Ceresa, L., Zanzottera, M., Rusconi, B., Maggioni, E., Tinelli, C., & Clerici, M. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.06.020 · Cited by 98 · see citing works
Frye, R. E., & Rossignol, D. A. (2016) · Clinical Medicine Insights Pediatrics · doi:10.4137/cmped.s38337 · Cited by 96 · see citing works
Baj, J., Flieger, W., Flieger, M., Forma, A., Sitarz, R., Skórzyńska-Dziduszko, K., Grochowski, C., Maciejewski, R., & Karakuła‐Juchnowicz, H. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.07.029 · Cited by 100 · see citing works
“Numerous studies confirm increased neuroinflammatory reactivity and neuronal damage in the brain of ASD patients (Chez et al., 2007; Enstrom et al., 2005; Fatemi et al., 2008; Laurence and Fatemi, 2005; Morgan et al., 2012, 2010; Pardo et al., 2005; Tetreault et al., 2012; Vargas et al., 2005;…”
BackgroundEissa, N., Sadeq, A. S., Sasse, A., & Sadek, B. S. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00886 · Cited by 97 · see citing works
Tartaglione, A. M., Villani, A., Ajmone‐Cat, M. A., Minghetti, L., Ricceri, L., Pazienza, V., Simone, R. D., & Calamandrei, G. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02149-9 · Cited by 94 · see citing works
Evidence of neurodegeneration in autism spectrum disorder
Kern, J., Geier, D., Sykes, L. K., & Geier, M. (2013) · Translational Neurodegeneration · doi:10.1186/2047-9158-2-17 · Cited by 89 · see citing works
“Chez et al [46] also observed that there was a significant increase in TNF-α in the CSF of individuals diagnosed was an ASD in comparison to the concurrent serum levels and that the magnitude of the difference was significantly higher than that observed for other diseases.”
ResultNg, M., de Montigny, J., Ofner, M., & Do, M. (2017) · Health Promotion and Chronic Disease Prevention in Canada · doi:10.24095/hpcdp.37.1.01 · Cited by 90 · see citing works
Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism
Costa, L. G., Chang, Y. C., & Cole, T. B. (2017) · Current Environmental Health Reports · doi:10.1007/s40572-017-0135-2 · Cited by 91 · see citing works
A Study of Nuclear Transcription Factor-Kappa B in Childhood Autism
Naik, U., Gangadharan, C., Abbagani, K., Balakrishna, N., Dasari, N., & Manna, S. K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019488 · Cited by 86 · see citing works
Bhandari, R., & Kuhad, A. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.09.012 · Cited by 84 · see citing works
Cytokine profile in autistic patients
Eftekharian, M. M., Ghafouri‐Fard, S., Noroozi, R., Omrani, M. D., Arsang‐Jang, S., Ganji, M., Gharzi, V., Noroozi, H., Komaki, A., Mazdeh, M., et al. (2018) · Cytokine · doi:10.1016/j.cyto.2018.03.034 · Cited by 82 · see citing works
Mandal, M., Marzouk, A. C., DONNELLY, R. J., & Ponzio, N. M. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.09.011 · Cited by 82 · see citing works
Chen, M., Su, T., Chen, Y.-S., Hsu, J.-W., Huang, K., Chang, W.-H., Chen, T., & Bai, Y. (2012) · Research in Autism · doi:10.1016/j.rasd.2012.08.008 · Cited by 81 · see citing works
Novel therapeutic targets for autism
Theoharides, T. C., Doyle, R., Francis, K., Conti, P., & Kalogeromitros, D. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.06.002 · Cited by 81 · see citing works
Autism: an emerging ‘neuroimmune disorder’ in search of therapy
Theoharides, T. C., Kempuraj, D., & Redwood, L. (2009) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656560903107789 · Cited by 79 · see citing works
“Cerebrospinal fluid (CSF) levels of tumor necrosis factor (TNF) were significantly higher than corresponding serum levels in ten autistic children [50] .”
BackgroundAutism Spectrum Disorders and Mastocytosis
Theoharides, T. C. (2009) · International Journal of Immunopathology and Pharmacology · doi:10.1177/039463200902200401 · Cited by 79 · see citing works
Griffiths, K. K., & Levy, R. J. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/4314025 · Cited by 77 · see citing works
A review of recent reports on autism: 1000 studies published in 2007
Hughes, J. R. (2008) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2008.06.015 · Cited by 76 · see citing works
“[96] showed an elevation of cerebral spinal fluid tumor necro-”
BackgroundAssociation between Viral Infections and Risk of Autistic Disorder: An Overview
Shuid, A. N., Jayusman, P. A., Shuid, N., Ismail, J., Nor, N. K., & Mohamed, I. N. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18062817 · Cited by 77 · see citing works
Cieślik, M., Gąssowska-Dobrowolska, M., Jęśko, H. M., Czapski, G. A., Wilkaniec, A., Zawadzka, A., Dominiak, A., Polowy, R., Filipkowski, R. K., Boguszewski, P. M., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21114097 · Cited by 73 · see citing works
Carroll, L., Braeutigam, S., Dawes, J. M., Krsnik, Ž., Kostović, I., Coutinho, E., Dewing, J. M., Horton, C. A., Gómez‐Nicola, D., & Menassa, D. A. (2020) · The Neuroscientist · doi:10.1177/1073858420921378 · Cited by 75 · see citing works
Ahmad, S. F., Ansari, M. A., Nadeem, A., Bakheet, S. A., Alzahrani, M. Z., Alshammari, M. A., Alanazi, W. A., Alasmari, A. F., & Attia, S. M. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.04.008 · Cited by 73 · see citing works
Neurotensin is increased in serum of young children with autistic disorder
Angelidou, A., Francis, K., Vasiadi, M., Alysandratos, K., Zhang, B., Theoharides, A., Lykouras, L., Sideri, K., Kalogeromitros, D. C., & Theoharides, T. C. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-48 · Cited by 73 · see citing works
“Another study reported that TNF-a levels in CSF of patients with ASD (n = 10) were significantly higher than concurrent serum levels [40].”
BackgroundMicroglia Ontology and Signaling
ElAli, A., & Rivest, S. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00072 · Cited by 73 · see citing works
“However, recent lessons from macrophages suggested that the same cell has the potential to adopt M1 or M2 phenotype based on either the nature of the stimuli and/or on the original activation status of the cell before being exposed to the stimuli (Mosser and Edwards, 2008).”
BackgroundMuratore, C., Hodgson, N., Trivedi, M. S., Abdolmaleky, H. M., Persico, A. M., Lintas, C., de la Monte, S. M., & Deth, R. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056927 · Cited by 71 · see citing works
“Moreover, levels of inflammation-associated cytokines such as tumor necrosis factor-alpha (TNF-a) are significantly elevated in CSF and postmortem brain samples from autistic subjects [30,31,54], which suggests that cortical MS status might be altered by oxidative stress in autism.”
BackgroundBradstreet, J. J., Smith, S. A., Baral, M., & Rossignol, D. A. (2010) · PubMed · Cited by 71 · see citing works
Chez, M. G., Lepage, C., Parise, C. A., Dang-Chu, A., Hankins, A. I., & Carroll, M. P. (2018) · Stem Cells Translational Medicine · doi:10.1002/sctm.17-0042 · Cited by 70 · see citing works
Self-citation
- Authors
- Chez, M. G., Dowling, T., Patel, P. B., Khanna, P., & Kominsky, M.
- Affiliations
- Sutter Health (US)
- Illinois State University (US)
- Rosalind Franklin University of Medicine and Science (US)
- Corresponding author
- Chez, Michael G.
- ORCID
- Chez, Michael G.
- Venue
- Pediatric Neurology
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 36
- Issue
- 6
- Pages
- 361-365
- ISSN
- 0887-8994 (ISSN-L)
- OpenAlex
- W2063547860
- Cited by
- 317
- References
- 16
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 20 · 2023: 10 · 2022: 21 · 2021: 22 · 2020: 19 · 2019: 16 · 2018: 24 · 2017: 15 · 2016: 21 · 2015: 17 · 2014: 15 · 2013: 21 · 2012: 18
- FWCI
- 7.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pediatric Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- TNF-α, cerebrospinal fluid, autism spectrum disorder, cytokines, neuroinflammation, biomarkers
- MeSH terms
- Autistic Disorder, Central Nervous System, Child, Child, Preschool, Encephalitis, Female, Humans, Infant, Male, Tumor Necrosis Factor-alpha, Biomarkers, Early Diagnosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
