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Serum Biomarkers to Mild Cognitive Deficits in Children and Adolescents

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Abstract

Intellectual disability (ID) is a condition characterized by significant limitations in both cognitive development and adaptive behavior. The diagnosis is made through clinical assessment, standardized tests, and intelligence quotient (IQ). Genetic, inflammation, oxidative stress, and diet have been suggested to contribute to ID, and biomarkers could potentially aid in diagnosis and treatment. Study included children and adolescents aged 6–16 years. The ID group (n = 16) and the control group (n = 18) underwent the Wechsler Intelligence Scale for Children (WISC-IV) test, and blood samples were collected. Correlations between biomarker levels and WISC-IV test scores were analyzed. The ID group had an IQ score below 75, and the values of four domains (IQ, IOP, IMO, and IVP) were lower compared to the control group. Serum levels of FKN, NGF-β, and vitamin B12 were decreased in the ID group, while DCFH and nitrite levels were increased. Positive correlations were found between FKN and the QIT and IOP domains, NGF and the QIT and IMO domains, and vitamin B12 and the ICV domain. TNF-α showed a negative correlation with the ICV domain. Our study identified FKN, NGF-β, and vitamin B12 as potential biomarkers specific to ID, which could aid in the diagnosis and treatment of ID. TNF-α and oxidative stress biomarkers suggest that ID has a complex etiology, and further research is needed to better understand this condition and develop effective treatments. Future studies could explore the potential implications of these biomarkers and develop targeted interventions based on their findings.

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Data Availability

Data supporting this study are not publicly available due to privacy of subjects. Please contact alexandrep.muller@gmail.com to access the data.

References

  1. Amor DJ (2018) Investigating the child with intellectual disability. J Paediatr Child Health 54(10):1154–58. https://doi.org/10.1093/pch/pxy093

    Article  PubMed  Google Scholar 

  2. American Psychiatric Association (APA) (2000) Diagnostic and statistical manual of mental disorders. APA, Washington, DC

    Google Scholar 

  3. Vissers LE, Gilissen C, Veltman JA (2016) Genetic studies in intellectual disability and related disorders. Nat Rev Genet 17(1):9–18. https://doi.org/10.1038/nrg3999

    Article  PubMed  CAS  Google Scholar 

  4. Merikangas KR, Nakamura EF, Kessler RC (2009) Epidemiology of mental disorders in children and adolescents. Dialogues Clin Neurosci 11(1):7–20. https://doi.org/10.31887/DCNS.2009.11.1/krmerikangas

    Article  PubMed  PubMed Central  Google Scholar 

  5. Moeschler JB, Shevell M (2014) Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 134(3):903–18. https://doi.org/10.1542/peds.2014-1839

    Article  Google Scholar 

  6. Ganguly P, Brenhouse HC (2015) Broken or maladaptive? Altered trajectories in neuroinflammation and behavior after early life adversity. Dev Cogn Neurosci 11:18–30. https://doi.org/10.1016/j.dcn.2014.07.001

    Article  PubMed  Google Scholar 

  7. Patel DR, Greydanus DE, Calles JL, Pratt HD (2010) Developmental disabilities across the lifespan. Disease-a-Month 56(6):305–397. https://doi.org/10.1016/j.disamonth.2010.02.001

    Article  Google Scholar 

  8. Cortese S, Solmi M, Michelini G, et al. (2023) Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review. World Psychiatry. 129–149. https://doi.org/10.1002/wps.21037

  9. Jagadapillai R, Qiu X, Ojha K et al (2022) Potential cross talk between autism risk genes and neurovascular molecules: a pilot study on impact of blood brain barrier integrity. Cells 11(14):2211. https://doi.org/10.3390/cells1114221. 15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Lyman M, Lloyd DG, Ji X et al (2014) Neuroinflammation: the role and consequences. Neurosci Res 79:1–12. https://doi.org/10.1016/j.neures.2013.10.004

    Article  PubMed  CAS  Google Scholar 

  11. Patlola SR, Donohoe G, McKernan DP (2023) The relationship between inflammatory biomarkers and cognitive dysfunction in patients with schizophrenia: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 121:110668. https://doi.org/10.1016/j.pnpbp.2022.110668

    Article  PubMed  CAS  Google Scholar 

  12. Chukaew P, Bunmak N, Auampradit N et al (2022) Correlation of BDNF, VEGF, TNF-α, and S100B with cognitive impairments in chronic, medicated schizophrenia patients. Neuropsychopharmacol Rep 42(3):281–287. https://doi.org/10.1002/npr2.12261

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Meshkat S, Alnefeesi Y, Jawad MY et al (2022) Brain-derived neurotrophic factor (BDNF) as a biomarker of treatment response in patients with treatment resistant depression (TRD): a systematic review & meta-analysis. Psychiatry Res 317:114857. https://doi.org/10.1016/j.psychres.2022.114857

    Article  PubMed  CAS  Google Scholar 

  14. Lenz KM, Nelson LH (2018) Microglia and beyond: innate immune cells as regulators of brain development and behavioral function. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.00698

  15. Yamada K, Mizuno M, Nabeshima T (2002) Role for brain-derived neurotrophic factor in learning and memory. Life Sci 70(7):735–44. https://doi.org/10.1016/s0024-3205(01)01461-8

    Article  PubMed  CAS  Google Scholar 

  16. Lu B, Nagappan G, Lu Y (2014) BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol 220:223–50. https://doi.org/10.1007/978-3-642-45106-5_9

    Article  PubMed  CAS  Google Scholar 

  17. Sheridan GK, Wdowicz A, Pickering M et al (2014) CX3CL1 is up-regulated in the rat hippocampus during memory-associated synaptic plasticity. Front Cell Neurosci 8:233. https://doi.org/10.3389/fncel.2014.00233. 12

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lauro C, Catalano M, Trettel F, Limatola C (2015) Fractalkine in the nervous system: neuroprotective or neurotoxic molecule? Ann N Y Acad Sci 1351:141–8. https://doi.org/10.1111/nyas.12805

    Article  PubMed  CAS  Google Scholar 

  19. Liu W, Jiang L, Bian C et al (2016) Role of CX3CL1 in diseases. Arch Immunol Ther Exp 64(5):141–8. https://doi.org/10.1007/s00005-016-0395-9

    Article  CAS  Google Scholar 

  20. Jiang NM, Cowan M, Moonah SN, Petri WA (2018) The impact of systemic inflammation on neurodevelopment. Trends Mol Med 24(9):794–804. https://doi.org/10.1016/j.molmed.2018.06.008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Adler V, Yin Z, Tew KD, Ronai Z (1999) Role of redox potential and reactive oxygen species in stress signaling. Oncogene 18(45):6104–11. https://doi.org/10.1038/sj.onc.1203128

    Article  PubMed  CAS  Google Scholar 

  22. Mangialasche F, Polidori MC, Monastero R et al (2009) Biomarkers of oxidative and nitrosative damage in Alzheimer’s disease and mild cognitive impairment. Ageing Res Rev 8(4):285–305. https://doi.org/10.1016/j.arr.2009.04.002

    Article  PubMed  CAS  Google Scholar 

  23. Manzanero S, Santro T, Arumugam TV (2013) Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury. Neurochem Int 62(5):712–8. https://doi.org/10.1016/j.neuint.2012.11.009

    Article  PubMed  CAS  Google Scholar 

  24. Chauhan A, Audhya T, Chauhan V (2012) Brain region-specific glutathione redox imbalance in autism. Neurochem Res 37(8):1681–9. https://doi.org/10.1007/s11064-012-0775

    Article  PubMed  CAS  Google Scholar 

  25. Rathod R, Kale A, Joshi S (2016) Novel insights into the effect of vitamin B12 andomega-3 fatty acids on brain function. J Biomed Sci 23:17. https://doi.org/10.1186/s12929-016-0241-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Abdel Ghany EA, Alsharany W, Ali AA, Youness ER, Hussein JS (2016) Anti-oxidant profiles and markers of oxidative stress in preterm neonates. Paediatr Int Child Health 36(2):134–40. https://doi.org/10.1179/2046905515Y.0000000017

    Article  PubMed  Google Scholar 

  27. Ozsurekci Y, Aykac K (2016) Oxidative stress related diseases in newborns. Oxid Med Cell Longev 2016:2768365. https://doi.org/10.1155/2016/2768365

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Nerhus M, Berg AO, Simonsen C et al (2017) Vitamin D deficiency associated with cognitive functioning in psychotic disorders. J Clin Psychiatry 78(7):750–57. https://doi.org/10.4088/JCP.16m10880

    Article  Google Scholar 

  29. AlJohri R, AlOkail M, Haq SH (2019) Neuroprotective role of vitamin D in primary neuronal cortical culture. eNeurologicalSci 14:43–8. https://doi.org/10.1016/j.ensci.2018.12.004

    Article  PubMed  Google Scholar 

  30. Styck KM, Watkins MW (2017) Structural validity of the WISC-IV for students with ADHD. J Atten Disord 21(11):921–928. https://doi.org/10.1177/1087054714553052

    Article  PubMed  Google Scholar 

  31. de Farias JM, Dos Santos Tramontin N, Pereira EV et al (2021) Physical exercise training improves judgment and problem-solving and modulates serum biomarkers in patients with Alzheimer’s disease. Mol Neurobiol. 58(9):4217–4225. https://doi.org/10.1007/s12035-021-02411-z

    Article  PubMed  CAS  Google Scholar 

  32. Perea JR, Lleó A, Alcolea D, Fortea J, Ávila J, Bolós M (2018) Decreased CX3CL1 levels in the cerebrospinal fluid of patients with Alzheimer’s disease. Front Neurosci 7(12):609. https://doi.org/10.3389/fnins.2018.00609

    Article  Google Scholar 

  33. Pawelec P, Ziemka-Nalecz M, Sypecka J, Zalewska T (2020) The impact of the CX3CL1/CX3CR1 axis in neurological disorders. Cells 9(10):2277. https://doi.org/10.3390/cells9102277. 13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Garré JM, Silva HM, Lafaille JJ, Yang G (2017) CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-α. Nat Med 23(6):714–722. https://doi.org/10.1038/nm.4340

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Rogers JT, Morganti JM, Bachstetter AD et al (2011) CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci 31(45):16241–50. https://doi.org/10.1523/JNEUROSCI.3667-11.2011. 9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Kawamura N, Katsuura G, Yamada-Goto N et al (2021) Impaired brain fractalkine-CX3CR1 signaling is implicated in cognitive dysfunction in diet-induced obese mice. BMJ Open Diabetes Res Care 9(1):e001492. https://doi.org/10.1136/bmjdrc-2020-001492

    Article  PubMed  PubMed Central  Google Scholar 

  37. Guney E, Ceylan MF, Kara M et al (2014) Serum nerve growth factor (NGF) levels in children with attention deficit/hyperactivity disorder (ADHD). Neurosci Lett 560:107–11. https://doi.org/10.1016/j.neulet.2013.12.026

    Article  PubMed  CAS  Google Scholar 

  38. Yang C, Liu Y, Ni X et al (2014) Enhancement of the nonamyloidogenic pathway by exogenous NGF in an Alzheimer transgenic mouse model. Neuropeptides 48(4):233–8. https://doi.org/10.1016/j.npep.2014.04.005

    Article  PubMed  CAS  Google Scholar 

  39. Budni J, Bellettini-Santos T, Mina F et al (2015) The involvement of BDNF, NGF and GDNF in aging and Alzheimer’s disease. Aging Dis 6(5):331–41. https://doi.org/10.14336/AD.2015.0825

    Article  PubMed  PubMed Central  Google Scholar 

  40. Schwab ME, Otten U, Agid Y et al (1979) Nerve growth factor (NGF) in the rat CNS: absence of specific retrograde axonal transport and tyrosine hydroxylase induction in locus coeruleus and substantia nigra. Brain Res 168(3):473–483. https://doi.org/10.1016/0006-8993(79)90303-2

    Article  PubMed  CAS  Google Scholar 

  41. Klyushnik TP, Sergienko NS, Danilovskaya EV et al (2001) Autoantibodies to nerve growth factor in disorders of mental development in infants. Neurosci Behav Physiol 31:165–7. https://doi.org/10.1023/a:1005208206719

    Article  PubMed  CAS  Google Scholar 

  42. Cortesi M, Alfei E, Barale F, Fusar-Poli P (2007) Linking autism, regression and Landau-Kleffner syndrome: integrative role of nerve growth factor. Med Hypotheses 68:1178–9. https://doi.org/10.1016/j.mehy.2006.10.029

    Article  PubMed  CAS  Google Scholar 

  43. Dinçel N, Ünalp A, Kutlu A et al (2013) Serum nerve growth factor levels in autistic children in Turkish population: a preliminary study. Indian J Med Res 138:900–3

    PubMed  PubMed Central  Google Scholar 

  44. Nelson KB, Grether JK, Croen LA et al (2001) Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol 49(5):597–606. https://doi.org/10.1002/ana.1024

    Article  PubMed  CAS  Google Scholar 

  45. Dou SH, Cui Y, Huang SM, Zhang B (2022) The role of brain-derived neurotrophic factor signaling in central nervous system disease pathogenesis. Front Hum Neurosci 16:924155. https://doi.org/10.3389/fnhum.2022.924155. 24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Langan RC, Faafp MD, Goodbred AJMD (2017) Vitamin B12 deficiency: recognition and management. Am Fam Physician 96(6):384–389

    PubMed  Google Scholar 

  47. Winje BA, Kvestad I, Krishnamachari S et al (2018) Does early vitamin B12 supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow-ups from randomised controlled trials in India and Tanzania. BMJ Open. https://doi.org/10.1136/bmjopen-2017-018962

    Article  PubMed  PubMed Central  Google Scholar 

  48. Venkatramanan S, Armata IE, Strupp BJ, Finkelstein JL (2016) Vitamin B-12 and cognition in children. Adv Nutr 7(5):879–88. https://doi.org/10.3945/an.115.012021. 5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454(7203):428–435. https://doi.org/10.1038/nature07201

    Article  PubMed  CAS  Google Scholar 

  50. Haas CB, Carvalho AK, Muller AP et al (2020) Insulin activates microglia and increases COX-2/IL-1β expression in young but not in aged hippocampus. Brain Res 1741:146884. https://doi.org/10.1016/j.brainres.2020.146884. 15

    Article  PubMed  CAS  Google Scholar 

  51. Miller AA, Spencer SJ (2014) Obesity and neuroinflammation: a pathway to cognitive impairment. Brain Behav Immun 42:10–21. https://doi.org/10.1016/j.bbi.2014.04.001

    Article  PubMed  CAS  Google Scholar 

  52. Kim YS, Lee KJ, Kim H (2017) Serum tumour necrosis factor-α and interleukin-6 levels in Alzheimer’s disease and mild cognitive impairment. Psychogeriatrics 17(4):224–230. https://doi.org/10.1111/psyg.12218

    Article  PubMed  Google Scholar 

  53. Baumeister D, Aakhtar R, Ciufolini S et al (2016) Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry 21(5):642–649. https://doi.org/10.1038/mp.2015.67

    Article  PubMed  CAS  Google Scholar 

  54. Scheuer T, Endesfelder S, Auf dem Brinke E et al (2022) Neonatal oxidative stress impairs cortical synapse formation and GABA homeostasis in parvalbumin-expressing interneurons. Oxid Med Cell Longev 25(2022):8469756. https://doi.org/10.1155/2022/8469756

    Article  CAS  Google Scholar 

  55. Steullet P, Cabungcal JH, Coyle J et al (2017) Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia. Mol Psychiatry 22(7):936–43. https://doi.org/10.1038/mp.2017.47

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Hajjar I, Hayek SS, Goldstein FC et al (2018) Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study. J Neuroinflammation. https://doi.org/10.1186/s12974-017-1026-z

    Article  PubMed  PubMed Central  Google Scholar 

  57. Garlet TR, Parisotto EB, de Medeiros GDS et al (2013) Systemic oxidative stress in children and teenagers with Down syndrome. Life Sci 93(16):558–63. https://doi.org/10.1016/j.lfs.2013.08.017

    Article  PubMed  CAS  Google Scholar 

  58. Parisotto EB, Giaretta AG, Zamoner A et al (2015) Persistence of the benefit of an antioxidant therapy in children and teenagers with Down syndrome. Res Dev Disabil 14–20:45–46. https://doi.org/10.1016/j.ridd.2015.07.010

    Article  Google Scholar 

  59. Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R (2003) Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 329(1–2):23–38. https://doi.org/10.1016/s0009-8981(03)00003-2

    Article  PubMed  CAS  Google Scholar 

  60. Zitnanová I, Korytár P, Sobotová H et al (2006) Markers of oxidative stress in children with Down syndrome. Clin Chem Lab Med 44(3):306–10. https://doi.org/10.1515/CCLM.2006.053

    Article  PubMed  CAS  Google Scholar 

  61. Ordonez FJ, Rosety I, Rosety MA et al (2012) Aerobic training at moderate intensity reduced protein oxidation in adolescents with Down syndrome. Scand J Med Sci Sports 22(1):91–4. https://doi.org/10.1111/j.1600-0838.2010.01153.x

    Article  PubMed  CAS  Google Scholar 

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Funding

This work was supported by grants from FAPESC-PPSUS 2016, CNPq-Universal 2018, and UNESC.

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Lisiane Tuon, conceptualized and designed the study, performed the WISC-IV and wrote the manuscript; Natalia Santos Tramontin, organization of experiments, blood analysis and data analysis, critically reviewed and revised the manuscript for important intellectual content; Isis Custódio, data analysis and wrote the manuscript; Vitor Hugo Comim, data analysis and wrote the manuscript; Barbara Costa blood analysis and data analysis, critically reviewed and revised the manuscript for important intellectual content; Lariani Tamires Witt Tietbohl, blood analysis and data analysis, critically reviewed and revised the manuscript for important intellectual content; Alexandre Pastoris Muller, conceptualized and designed the study, blood and data analysis, and wrote the manuscript.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Correspondence to Alexandre Pastoris Muller.

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Tuon, L., Tramontin, N.S., Custódio, I. et al. Serum Biomarkers to Mild Cognitive Deficits in Children and Adolescents. Mol Neurobiol 60, 7080–7087 (2023). https://doi.org/10.1007/s12035-023-03536-z

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