Plasmatic and salivary biomarkers for early diagnosis of Autism Spectrum Disorder: a systematic review

Authors

DOI:

https://doi.org/10.33448/rsd-v10i10.18924

Keywords:

Biomarkers; Autism Spectrum Disorder; Diagnosis; Plasma; Saliva.

Abstract

Autistic Spectrum Disorder (ASD) is considered a neurological development disorder characterized by different degrees of deficit in communication, social interaction, and learning, accompanied by repetitive and stereotyped patterns of behavior. ASD diagnosis is extremely complex due to the still unknown etiopathology, the diversity of symptoms presented by the individuals, and it is carried out solely from clinical observations of the individual's behavior. This study aims to review the main plasma and salivary biomarkers currently studied for the early diagnosis of ASD. For this systematic literature review, we used the online data directory and database “Google Scholar” and “Publish Medliner” (PubMed), respectively, with the descriptors: “Autism”, “Biomarker”, “Diagnostic”, “Saliva”, and “Plasma”. We selected 564 studies in PubMed and 185 in Google Scholar, by screening the titles. After reading the abstracts, we excluded 647 studies, either due to irrelevance or because they were review articles, genetics studies or did not use plasma or saliva samples. The remaining 102 original studies were evaluated in full, and 83 were excluded. Thus, nineteen complete articles that met the inclusion criteria were included in the qualitative analysis. Results identified Cortisol, glutamate/GABA, glutathione, Lipid peroxidation, markers of oxidative stress, mitochondrial dysfunction, and pro-inflammatory cytokines, especially IL-6, as the main plasma and salivary biomarkers currently studied for the early diagnosis of ASD. However, considering that several results were controversial and inconclusive, further studies are needed to validate specific biomarkers as diagnostic tools. The current findings encourage studies that are controlled, multicentric, prospective, and of greater diagnostic precision.

References

Aita, C., Mizoguchi, Y., Yamamoto, M., SeguchI, Y., Yatsuga, C., Nishimura, T., & Monji, A. (2019). Oxytocin levels and sex differences in autism spectrum disorder with severe intellectual disabilities. Psychiatry Research, 273(May 2018), 67–74. https://doi.org/10.1016/j.psychres.2018.12.139

Al-Gadani, Y., El-Ansary, A., Attas, O., & Al-Ayadhi, L. (2009). Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clinical Biochemistry, 42(10–11), 1032–1040. https://doi.org/10.1016/j.clinbiochem.2009.03.011

Alzghoul, L., Abdelhamid, S. S., Yanis, A. H., Qwaider, Y. Z., Aldahabi, M., & Albdour, S. A. (2019). The association between levels of inflammatory markers in autistic children compared to their unaffected siblings and unrelated healthy controls. Turkish Journal of Medical Sciences, 49(4), 1047–1053. https://doi.org/10.3906/sag-1812-167

American Psychiatric Association. (2014). DSM-5: Diagnostic and statistical manual of mental disorders. Artmed Editora (5th ed.). http://www.niip.com.br/wp-content/uploads/2018/06/Manual-Diagnosico-e-Estatistico-de-Transtornos-Mentais-DSM-5-1-pdf.pdf

Anderson, G. M. (2015). Autism Biomarkers: Challenges, Pitfalls and Possibilities. Journal of Autism and Developmental Disorders, 45(4), 1103–1113. https://doi.org/10.1007/s10803-014-2225-4

Assumpção. F., Jr., & Kuczynski, E. (2011). Psicofarmacoterapia nos transtornos globais do desenvolvimento. In J. Schwartzman & C. Araújo (Eds.), Transtornos do Espectro do Autismo (pp. 215-226). São Paulo: Memmon.

Bakker-Huvenaars, M. J., Greven, C. U., Herpers, P., Wiegers, E., Jansen, A., van der Steen, R., & Buitelaar, J. K. (2018). Saliva oxytocin, cortisol, and testosterone levels in adolescent boys with autism spectrum disorder, oppositional defiant disorder/conduct disorder and typically developing individuals. European Neuropsychopharmacology, 30, 87–101. https://doi.org/10.1016/j.euroneuro.2018.07.097

Bjørklund, G., Meguid, N. A., El-Ansary, A., El-Bana, M. A., Dadar, M., Aaseth, J., & Chirumbolo, S. (2018). Diagnostic and Severity-Tracking Biomarkers for Autism Spectrum Disorder. Journal of Molecular Neuroscience, 66(4), 492–511. https://doi.org/10.1007/s12031-018-1192-1

Boris, M., Kaiser, C. C., Goldblatt, A., Elice, M. W., Edelson, S. M., Adams, J. B., & Feinstein, D. L. (2007). Effect of pioglitazone treatment on behavioral symptoms in autistic children. Journal of Neuroinflammation, 4, 1–7. https://doi.org/10.1186/1742-2094-4-3

Brentani, H., De Paula, C. S., Bordini, D., Rolim, D., Sato, F., Portolese, J., & McCracken, J. T. (2013). Autism spectrum disorders: An overview on diagnosis and treatment. Revista Brasileira de Psiquiatria, 35(SUPPL. 1), 62–72. https://doi.org/10.1590/1516-4446-2013-S104

Buemo, B., Alli, F., Iracet, J. V., Ribas, L., Pereira, R., Kruel, C. S., & Carlesso, J. P. P. (2019). Autismo no Contexto Escolar: A Importância da Inserção Social. Research, Society and Development, 8(3), 1–13. https://doi.org/10.33448/rsd-v8i3.822

Caetano Júnior, P. C., Castilho, M. L., & Raniero, L. (2017). Salivary Cortisol Responses and Session Ratings of Perceived Exertion to a Rugby Match and Fatigue Test. Perceptual and Motor Skills, 124(3), 649–661. https://doi.org/10.1177/0031512517704340

Cai, J., Ding, L., Zhang, J. S., Xue, J., & Wang, L. Z. (2016). Elevated plasma levels of glutamate in children with autism spectrum disorders. NeuroReport, 27(4), 272–276. https://doi.org/10.1097/WNR.0000000000000532

Carter, C. S., Pournajafi-Nazarloo, H., Kramer, K. M., Ziegler, T. E., White-Traut, R., Bello, D., & Schwertz, D. (2007). Oxytocin: Behavioral associations and potential as a salivary biomarker. Annals of the New York Academy of Sciences, 1098, 312–322. https://doi.org/10.1196/annals.1384.006

Cochran, D. M., Fallon, D., Hill, M., & Frazier, J. A. (2013). The role of oxytocin in psychiatric disorders: A review of biological and therapeutic research findings. Harvard Review of Psychiatry, 21(5), 219–247. https://doi.org/10.1097/HRP.0b013e3182a75b7d

Cohly, H. H. P., & Panja, A. (2005). Immunological Findings in Autism. International Review of Neurobiology, 71(05), 317–341. https://doi.org/10.1016/S0074-7742(05)71013-8

Cortelazzo, A., De Felice, C., Guerranti, R., Signorini, C., Leoncini, S., Zollo, G., & Hayek, J. (2016). Expression and oxidative modifications of plasma proteins in autism spectrum disorders: interplay between inflammatory response and lipid peroxidation. Proteomics - Clinical Applications, 10(11), 1103–1112. https://doi.org/10.1002/prca.201500076

Costa, L. C., Carvalho, L. M. de F., & Bezerra, K. C. B. (2020). Avaliações de distúrbios gastrointestinais nutricionais no transtorno do espectro autista: uma revisão integrativa Evaluations. Research, Society and Development, 9(11), 1–15. http://dx.doi.org/10.33448/rsd-v9i11.9498

Croonenberghs, J., Van Grieken, S., Wauters, A., Van West, D., Brouw, L., Maes, M., & Deboutte, D. (2010). Serum testosterone concentration in male autistic youngsters. Activitas Nervosa Superior Rediviva, 52(2), 163–168. http://rediviva.sav.sk/52i2/163.pdf

Deshpande, R. R., Dungarwal, P. P., Bagde K. K., Thakur P. S., Gajjar, P. M., & Kamath, A. P. (2019). Comparative evaluation of salivary zinc concentration in autistic and healthy children in mixed dentition age group-pilot study. Indian Journal of Dental Research, 30(1), 43–46. https://www.ijdr.in/text.asp?2019/30/1/43/254528

Dhossche, D., Applegate, H., Abraham, A., Maertens, P., Bland, L., Bencsath, A., & Martinez, J. (2002). Elevated plasma gamma-aminobutyric acid (GABA) levels in autistic youngsters: Stimulus for a GABA hypothesis of autism. Medical Science Monitor, 8(8), 1–7. PR1-PR6.

El-Ansary, A., & Al-Ayadhi, L. (2014). GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders. Journal of Neuroinflammation, 11(1), 1–9. https://doi.org/10.1186/s12974-014-0189-0

El-Meshad, G. M., El-Nabi, S. A. A., Moharam, N. M., & El-Khair, M. S. A. (2017). The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Menoufia Medical Journal, 30(3), 727–733. https://doi.org/10.1080/13547500902783747

Eldevik, S., Hastings, R. P., Hughes, J. C., Jahr, E., Eikeseth, S., & Cross, S. (2009). Meta-analysis of Early Intensive Behavioral Intervention for children with autism. Journal of Clinical Child and Adolescent Psychology, 38(3), 439–450. https://doi.org/10.1080/15374410902851739

Frye, R. E., Vassall, S., Kaur, G., Lewis, C., Karim, M., & Rossignol, D. (2019). Emerging biomarkers in autism spectrum disorder: a systematic review. Annals of Translational Medicine, 7(23), 792–792. https://doi.org/10.21037/atm.2019.11.53

Frustaci, A., Neri, M., Cesario, A., Adams, J. B., Domenici, E., Dalla Bernardina, B., & Bonassi, S. (2012). Oxidative stress-related biomarkers in autism: Systematic review and meta-analyses. Free Radical Biology and Medicine, 52(10), 2128–2141. https://doi.org/10.1016/j.freeradbiomed.2012.03.011

Furlano, R. I., Anthony, A., Day, R., Brown, A., McGarvey, L., Thomson, M. A., & Murch, S. H. (2001). Colonic CD8 and γδ T-cel infiltration with epithelial damage in children with autism. Journal of Pediatrics, 138(3), 366–372. https://doi.org/10.1067/mpd.2001.111323

Gabriele, S., Sacco, R., & Persico, A. M. (2014). Blood serotonin levels in autism spectrum disorder: A systematic review and meta-analysis. European Neuropsychopharmacology, 24(6), 919–929. https://doi.org/10.1016/j.euroneuro.2014.02.004

Gadia, C. A., Tuchman, R., & Rotta, N. T. (2004). Autismo e doenças invasivas de desenvolvimento. Jornal de Pediatria, 80(2), 83–94. https://doi.org/10.1590/s0021-75572004000300011

Gadient, R. A., & Otten, U. H. (1997). Interleukin-6 (IL-6) - A molecule with both beneficial and destructive potentials. Progress in Neurobiology, 52(5), 379–390. https://doi.org/10.1016/S0301-0082(97)00021-X

Geier, D. A., Kern, J. K., Garver, C. R., Adams, J. B., Audhya, T., & Geier, M. R. (2009). A prospective study of transsulfuration biomarkers in autistic disorders. Neurochemical Research, 34(2), 386–393. https://doi.org/10.1007/s11064-008-9782-x

Ghaleiha, A., Rasa, S. M., Nikoo, M., Farokhnia, M., Mohammadi, M. R., & Akhondzadeh, S. (2015). A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism. Psychiatry Research, 229(1–2), 181–187. https://doi.org/10.1016/j.psychres.2015.07.043

Gruol, D. L., & Nelson, T. E. (1997). Physiological and pathological roles of interleukin-6 in the central nervous system. Molecular Neurobiology, 15(3), 307–339. https://doi.org/10.1007/BF02740665

Guedes, N. P. da S., & Tada, I. N. C. (2015). A produção científica brasileira sobre autismo na psicologia e na educação. Psicologia: Teoria e Pesquisa, 31(3), 303–309. https://doi.org/10.1590/0102-37722015032188303309

Hewitson, L., Mathews, J. A., Devlin, M., Schutte, C., Lee, J., & German, D. C. (2021). Blood biomarker discovery for autism spectrum disorder: A proteomic analysis. PLoS ONE, 16(2), 1–15. https://doi.org/10.1371/journal.pone.0246581

Hyman, S. L., Levy, S. E., & Myers, S. M. (2020). Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics, 145(1). https://doi.org/10.1542/peds.2019-3447

Jarquin, V. G., Wiggins, L. D., Schieve, L. A., & Van Naarden-Braun, K. (2011). Racial disparities in community identification of autism spectrum disorders over time; Metropolitan Atlanta, Georgia, 2000-2006. Journal of Developmental and Behavioral Pediatrics, 32(3), 179–187. https://doi.org/10.1097/DBP.0b013e31820b4260

Kern, J. K., & Jones, A. M. (2006). Evidence of toxicity, oxidative stress, and neuronal insult in autism. Journal of Toxicology and Environmental Health - Part B: Critical Reviews, 9(6), 485–499. https://doi.org/10.1080/10937400600882079

Khemakhem, A. M., Frye, R. E., El-Ansary, A., Al-Ayadhi, L., & Bacha, A. Ben. (2017). Novel biomarkers of metabolic dysfunction is autism spectrum disorder: potential for biological diagnostic markers. Metabolic Brain Disease, 32(6), 1983–1997. https://doi.org/10.1007/s11011-017-0085-2

Magalhães, J. M., Silva, T. M. da, Silva, F. da C., Alencar, M. de F. B. de, Neta, M. M. R., Alencar, D. de C., & Arisawa, E. A. L. S. (2021). Perfil de crianças com transtorno do espectro autista. Research, Society and Development, 10(4), 1–12. http://dx.doi.org/10.33448/rsd-v10i4.13880

Marchezan, J., Dos Santos, E. G. A.W., Deckmann, I., & Riesgo, R. D. S. (2019). Immunological dysfunction in autism spectrum disorder: A potential target for therapy. NeuroImmunoModulation, 25(5–6), 300–319. https://doi.org/10.1159/000492225

Marí, M., Morales, A., Colell, A., García-Ruiz, C., Kaplowitz, N., & Fernández-Checa, J. C. (2013). Mitochondrial Glutathione: Features, regulation and role in disease. Biochimica et Biophysica Acta (BBA)-General Subjects, 1830(5), 3317–3328. https://doi.org/10.1016/j.bbagen.2012.10.018

Modahl, C., Green, L. A., Fein, D., Morris, M., Waterhouse, L., Feinstein, C., & Levin, H. (1998). Plasma oxytocin levels in autistic children. Biological Psychiatry, 43(4), 270–277. https://doi.org/10.1016/S0006-3223(97)00439-3

Naushad, S. M., Jain, J. M. N., Prasad, C. K., Naik, U., & Akella, R. R. D. (2013). Autistic children exhibit distinct plasma amino acid profile. Indian Journal of Biochemistry and Biophysics, 50(5), 474–478.

Ngounou Wetie, A. G., Wormwood, K. L., Russell, S., Ryan, J. P., Darie, C. C., & Woods, A. G. (2015). A Pilot Proteomic Analysis of Salivary Biomarkers in Autism Spectrum Disorder. Autism Research, 8(3), 338–350. https://doi.org/10.1002/aur.1450

Pandey, V., Upadhayaya, V., Tripathi, J., Pandey, S., & Sidhu, G. K. (2014). Saliva - A Diagnostic Fluid: A Review. International Journal of Dental and Medical Research, 1(3), 149–154. http://www.ijohmr.com/upload/27_Saliva-%20A%20Diagnostic%20Fluid.pdf

Putnam, S. K., Lopata, C., Fox, J. D., Thomeer, M. L., Rodgers, J. D., Volker, M. A., & Werth, J. (2012). Comparison of saliva collection methods in children with high-functioning Autism Spectrum disorders: Acceptability and recovery of cortisol. Child Psychiatry and Human Development, 43(4), 560–573. https://doi.org/10.1007/s10578-012-0284-3

Ratajczak, H. V., & Sothern, R. B. (2015). Measurement in saliva from neurotypical adults of biomarkers pertinent to autism spectrum disorders. Future Science OA, 1(4). https://doi.org/10.4155/fso.15.70

Samaranayake, L. (2007). Saliva as a diagnostic fluid. International Dental Journal, 57(5), 295–299. https://doi.org/10.1111/j.1875-595X.2007.tb00135.x

Schwichtenberg, A. J., & Malow, B. A. (2015). Melatonin treatment in children with developmental disabilities. Sleep Medicine Clinics, 10(2), 181–187. https://doi.org/10.1016/j.jsmc.2015.02.008

Sen, C. K. (1997). Nutritional biochemistry of cellular glutathione. Journal of Nutritional Biochemistry, 8(12), 660–672. https://doi.org/10.1016/S0955-2863(97)00113-7

Shomrat, T., & Nesher, N. (2019). Updated view on the relation of the pineal gland to autism spectrum disorders. Frontiers in Endocrinology, 10(FEB), 1–8. https://doi.org/10.3389/fendo.2019.00037

Tilford, J. M., Payakachat, N., Kuhlthau, K. A., Pyne, J. M., Kovacs, E., Bellando, J., & Frye, R. E. (2015). Treatment for Sleep Problems in Children with Autism and Caregiver Spillover Effects. Journal of Autism and Developmental Disorders, 45(11), 3613–3623. https://doi.org/10.1007/s10803-015-2507-5

Walsh, P., Elsabbagh, M., Bolton, P., & Singh, I. (2011). In search of biomarkers for autism: Scientific, social and ethical challenges. Nature Reviews Neuroscience, 12(10), 603–612. https://doi.org/10.1038/nrn3113

Warren, R. P., Burger, R. A., Odell, D., Torres, A. R., & Warren, W. L. (1994). Decreased Plasma Concentrations of the C4B Complement Protein in Autism. Archives of Pediatrics & Adolescent Medicine, 148(2), 180–183. https://doi.org/10.1001/archpedi.1994.02170020066011

Wei, H., Zou, H., Sheikh, A. M., Malik, M., Dobkin, C., Brown, W. T., & Li, X. (2011). IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. Journal of Neuroinflammation, 8(1), 52. https://doi.org/10.1186/1742-2094-8-52

World Health Organization, W. H. O. (2019). Autism spectrum disorders (ASD). https://www.who.int/news-room/q-a-detail/autism-spectrum-disorders-(asd)

Yang, C. J., Liu, C. L., Sang, B., Zhu, X. M., & Du, Y. J. (2015). The combined role of serotonin and interleukin-6 as biomarker for autism. Neuroscience, 284, 290–296. https://doi.org/10.1016/j.neuroscience.2014.10.011

Yang, C. J., Tan, H. P., Yang, F. Y., Liu, C. L., Sang, B., Zhu, X. M., & Du, Y. J. (2015). The roles of cortisol and pro-inflammatory cytokines in assisting the diagnosis of autism spectrum disorder. Research in Autism Spectrum Disorders, 9, 174–181. https://doi.org/10.1016/j.rasd.2014.10.012

Zhang, C. Z., Cheng, X. Q., Li, J. Y., Zhang, P., Yi, P., Xu, X., & Zhou, X. D. (2016). Saliva in the diagnosis of diseases. International Journal of Oral Science, 8(3), 133–137. https://doi.org/10.1038/ijos.2016.38

Zhou, Y., & Danbolt, N. C. (2014). Glutamate as a neurotransmitter in the healthy brain. Journal of Neural Transmission, 121(8), 799–817. https://doi.org/10.1007/s00702-014-1180-8

Published

15/08/2021

How to Cite

PINTO, M. M. V.; ARISAWA, E. A. L. S.; MARTINS, R. A. B. L.; RANIERO, L. J. Plasmatic and salivary biomarkers for early diagnosis of Autism Spectrum Disorder: a systematic review. Research, Society and Development, [S. l.], v. 10, n. 10, p. e412101018924, 2021. DOI: 10.33448/rsd-v10i10.18924. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/18924. Acesso em: 18 oct. 2021.

Issue

Section

Health Sciences