Biomarcadores plasmáticos y salivales para el diagnóstico temprano del Trastorno del Espectro Autista: revisión sistemática
DOI:
https://doi.org/10.33448/rsd-v10i10.18924Palabras clave:
Biomarcadores; Trastorno del Espectro Autista; Diagnóstico; Plasma; Saliva.Resumen
El Trastorno del Espectro Autista (TEA) es un trastorno del desarrollo neurológico que se caracteriza por diferentes grados de déficit en la comunicación, la interacción social, el aprendizaje, acompañado de patrones de comportamiento repetitivos y estereotipados. El diagnóstico de TEA es sumamente complejo debido a la etiopatología aún desconocida y la diversidad de síntomas que presentan los individuos, siendo realizado únicamente a partir de observaciones clínicas del comportamiento del individuo. Este estudio tiene como objetivo revisar los principales biomarcadores plasmáticos y salivales actualmente estudiados para el diagnóstico precoz de los TEA. Para esta revisión sistemática de la literatura se utilizó el directorio y la base de datos en línea "Google Scholar" y "Publish Medliner" (PubMed), respectivamente, con los descriptores: "Autismo", "Biomarcador", "Diagnóstico", "Saliva" y "Plasma". Se seleccionaron 564 estudios en PubMed y 185 en Google Scholar, mediante la selección de los títulos. Después de leer los resúmenes, 647 estudios fueron excluidos, ya sea por irrelevancia o porque eran artículos de revisión, estudios genéticos o no utilizaron muestras de plasma o saliva. Los 102 estudios originales restantes se evaluaron en su totalidad y se excluyeron 83. Así, se utilizaron en el análisis cualitativo diecinueve artículos completos que cumplieron con los criterios de inclusión. Los resultados identificaron cortisol, glutamato/GABA, glutatión, peroxidación lipídica, marcadores de estrés oxidativo, disfunción mitocondrial y citocinas proinflamatorias, especialmente IL-6, como los principales biomarcadores plasmáticos y salivales actualmente estudiados para el diagnóstico precoz de TEA. Sin embargo, considerando que varios resultados fueron controvertidos y no concluyentes, se necesitan más estudios para validar biomarcadores específicos como herramientas de diagnóstico. Los hallazgos actuales fomentan estudios de mayor precisión diagnóstica, controlados, multicéntricos y prospectivos.
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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
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