Evaluation of structural variations in the pituitary gland, hormonal status and laboratory markers of the central nervous system functioning in patients with chronic disorders of consciousness

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Abstract

BACKGROUND: Consciousness is the state of being awake and aware of oneself and the environment. The disorders of consciousness result from pathologies that impair awareness. The development of effective comprehensive personalized interventions contributing to the recovery of consciousness in patients with chronic disorders of consciousness is one of the most pressing and challenging tasks in modern rehabilitation.

AIM: The aim of this study was to understand structural problems of the pituitary gland, blood levels of gonadotropins and melatonin as well as brain damage markers in the blood and cerebrospinal fluid in patients with chronic disorders of consciousness and to analyze the levels of the above markers among different groups of patients depending on the level of impaired consciousness.

MATERIALS AND METHODS: We examined 61 chronic disorders of consciousness patients and identified three groups depending on the level of consciousness including 24 patients with unresponsive wakefulness syndrome, 24 patients with a minus minimally conscious state, and 13 patients with minimally conscious state plus. We performed magnetic resonance imaging of chiasmatic-sellar region and determined blood serum levels of follicle-stimulating and luteinizing hormones and melatonin, as well as urinary level of 6-sulfatoxymelatonin and the content of brain derived neurotrophic factor (BDNF), apoptosis antigen (APO-1), FasL, glutamate, and S100 protein in the blood serum and cerebrospinal fluid.

RESULTS: The patients were examined in the age ranging from 15 to 61 years old. Patient groups were homogeneous by the level of consciousness in terms of age and duration of chronic disorders of consciousness by the time of examination. The patients did not differ in the pituitary volume regardless of the level of consciousness. No significant differences were found between the groups with different levels of consciousness when studying the levels of melatonin in the blood serum and its metabolite in the urine. A peak in melatonin secretion was detected at 3 a.m. in 54.5 % of the patients, which can be considered as a favorable prognostic marker for further recovery of consciousness. Hypogonadotropic ovarian failure was found in 34 % of the patients, with normogonadotropic ovarian failure in the remaining patients. Serum APO-1 and BDNF levels were significantly higher in patients with minimally conscious state relative to those with unresponsive wakefulness syndrome. Significantly lower levels of glutamate in the cerebrospinal fluid were detected in women with unresponsive wakefulness syndrome compared to patients with minimally conscious state.

CONCLUSIONS: Further in-depth examination and accumulation of data on patients with chronic disorders of consciousness may provide an opportunity to identify highly informative markers for predicting outcomes and to develop new effective approaches to rehabilitation of consciousness in this category of patients.

About the authors

Ekaterina A. Kondratyeva

Polenov Neurosurgical Institute, Almazov National Medical Research Center

Email: eak2003@mail.ru
ORCID iD: 0000-0001-6362-6543
SPIN-code: 6966-3270
Scopus Author ID: 57191545581

MD, Dr. Sci. (Med.)

Russian Federation, Saint Petersburg

Alina O. Ivanova

Research Institute of Obstetrics, Gynecology, and Reproductology named after D.O. Ott

Author for correspondence.
Email: ivanova_ao93@mail.ru
ORCID iD: 0000-0003-0792-3337
SPIN-code: 5573-6990
Scopus Author ID: 1045544
ResearcherId: AAL-4500-2020

MD

Russian Federation, Saint Petersburg

Maria I. Yarmolinskaya

Research Institute of Obstetrics, Gynecology, and Reproductology named after D.O. Ott; North-Western State Medical University named after I.I. Mechnikov

Email: m.yarmolinskaya@gmail.com
ORCID iD: 0000-0002-6551-4147
SPIN-code: 3686-3605
Scopus Author ID: 7801562649
ResearcherId: P-2183-2014

MD, Dr. Sci. (Med.), Professor, Professor of the Russian Academy of Sciences

Russian Federation, Saint Petersburg

Elena G. Potyomkina

Polenov Neurosurgical Institute, Almazov National Medical Research Center

Email: potemkina25@rambler.ru
ORCID iD: 0000-0003-0449-9163
SPIN-code: 1422-2553
Scopus Author ID: 703392

MD, Dr. Sci. (Med.)

Russian Federation, Saint Petersburg

Natalya V. Dryagina

Polenov Neurosurgical Institute, Almazov National Medical Research Center

Email: nvdryagina@mail.ru
ORCID iD: 0000-0001-8595-6666
SPIN-code: 1916-2139
Scopus Author ID: 35773283500

MD, Cand. Sci. (Med.)

Russian Federation, Saint Petersburg

Natalya N. Zybina

Nikiforov Russian Center of Emergency and Radiation Medicine

Email: zybinan@inbox.ru
ORCID iD: 0000-0002-5422-2878
SPIN-code: 5164-2969
Scopus Author ID: 97381

MD, Dr. Sci. (Med.), Professor

Russian Federation, Saint Petersburg

Nelly Yu. Andreeva

Research Institute of Obstetrics, Gynecology, and Reproductology named after D.O. Ott

Email: nelly8352@yahoo.com
ORCID iD: 0000-0002-1928-1266
SPIN-code: 3355-2646
Scopus Author ID: 1053801

MD

Russian Federation, Saint Petersburg

Anatoly N. Kondratyev

Polenov Neurosurgical Institute, Almazov National Medical Research Center

Email: eak2003@mail.ru
ORCID iD: 0000-0002-7648-2208

MD, Dr. Sci. (Med.), Professor

Russian Federation, Saint Petersburg

References

  1. Posner JB, Saper CB, Schiff N, Plum F. Plum and Posner’s diagnosis of stupor and coma. 4th ed. Oxford: Oxford University Press; 2007. [cited 23 Aug 2021]. Available from: https://medicinainternaelsalvador.com/wp-content/uploads/2018/10/Plum-and-Posners-Diagnosis-of-Stupor-and-Coma.pdf
  2. Jennett B. Thirty years of the vegetative state: clinical, ethical and legal problems. Prog Brain Res. 2005;150:537−543. doi: 10.1016/S0079-6123(05)50037-2
  3. Bakulin IS, Kremneva EI, Kuznecov AV, et al. Hronicheskie narusheniya soznaniya. Ed. by MA Piradov. 2nd ed. Moscow: Goryachaya liniya – Telekom; 2020. (In Russ.)
  4. Piradov MA, Suponeva NA, Voznyuk IA, et al. Russian workgroup on chronic disorders of consciousness. [Chronic disorders of consciousness: terminology and diagnostic criteria. The results of the first meeting of the Russian Working Group for Chronic Disorders of Consciousness]. Annals of clinical and experimental neurology. 2020;14(1):5–16. (In Russ.). doi: 10.25692/ACEN.2020.1.1
  5. Kondrat’eva EA, Voznyuk IA. Rukovodstvo po nevrologicheskomu osmotru pacienta s dlitel’nym narusheniem soznaniya. Saint Petersburg: Foliant, 2019. (In Russ.)
  6. Yoshimoto H, Uozumi T. Anterior pituitary function in the vegetative state. Neurol Med Chir (Tokyo). 1989;29(6):490−495. doi: 10.2176/nmc.29.490
  7. Klose M, Juul A, Struck J, et al. Acute and long-term pituitary insufficiency in traumatic brain injury: a prospective single-centre study. Clin Endocrinol (Oxf). 2007;67(4):598−606. doi: 10.1111/j.1365-2265.2007.02931.x
  8. Olivecrona Z, Dahlqvist P, Koskinen LO. Acute neuro-endocrine profile and prediction of outcome after severe brain injury. Scand J Trauma Resusc Emerg Med. 2013;21:33. doi: 10.1186/1757-7241-21-33
  9. Wagner J, Dusick JR, McArthur DL, et al. Acute gonadotroph and somatotroph hormonal suppression after traumatic brain injury. J Neurotrauma. 2010;27(6):1007−1019. doi: 10.1089/neu.2009.1092
  10. Tanriverdi F, Senyurek H, Unluhizarci K, et al. High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma. J Clin Endocrinol Metab. 2006;91(6):2105−2111. doi: 10.1210/jc.2005-2476
  11. Kleindienst A, Brabant G, Bock C, et al. Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: a prospective longitudinal evaluation. J Neurotrauma. 2009;26(9):1435−1446. doi: 10.1089/neu.2008.0601
  12. Kondrat’eva EA, Dryagina NV, Ajbazova MI, et al. Prognoz iskhoda hronicheskogo narusheniya soznaniya na osnovanii opredeleniya nekotoryh gormonov i natrijureticheskogo peptida. Vestnik anesteziologii i reanimatologii. 2019;16(6):16−22. (In Russ.). doi: 10.21292/2078-5658-2019-16-6-16-22
  13. Ivanova AO, Kondrat’eva EA, YArmolinskaya MI, et al. Sluchai hronicheskogo narusheniya soznaniya v akushersko ginekologicheskoj praktike. ZHurnal akusherstva i zhenskih boleznej. 2020;69(6):31–42. (In Russ.). doi: 10.17816/JOWD69631-42
  14. Fernández A, Ordóñez R, Reiter RJ, et al. Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis. J Pineal Res. 2015;59(3):292–307. doi: 10.1111/jpi.12264
  15. Light and biological rhythms in man / ed. Wetterberg L. N.-Y.: Elsevier; 2014.
  16. Bekinschtein TA, Golombek DA, Simonetta SH, et al. Circadian rhythms in the vegetative state. Brain Inj. 2009;23(11):915–919. doi: 10.1080/02699050903283197
  17. Guaraldi P, Sancisi E, La Morgia C, et al. Nocturnal melatonin regulation in post-traumatic vegetative state: a possible role for melatonin supplementation? Chronobiol Int. 2014;31(5):741–745. doi: 10.3109/07420528.2014.901972
  18. Belkin AA, Alekseeva EV, Alasheev AM, et al. Ocenka cirkadnosti dlya prognoza iskhoda vegetativnogo sostoyaniya. Consilium Medicum. 2017;19(2):19–23. (In Russ.)
  19. Kanarskii M, Nekrasova J, Vitkovskaya S, et al. Effect of retinohypothalamic tract dysfunction on melatonin level in patients with chronic disorders of consciousness. Brain Sci. 2021;11(5):559. doi: 10.3390/brainsci11050559
  20. Gobert F, Luauté J, Raverot V, et al. Is circadian rhythmicity a prerequisite to coma recovery? Circadian recovery concomitant to cognitive improvement in two comatose patients. J Pineal Res. 2019;66(3):e12555. doi: 10.1111/jpi.12555
  21. Popova NK, Morozova MV. Nejrotroficheskij faktor mozga: vliyanie na geneticheski i epigeneticheski determinirovannye narusheniya povedeniya. Rossijskij fiziologicheskij zhurnal im. I.M. Sechenova. 2013;99(10):1125−1137. (In Russ.)
  22. Hung PL, Huang CC, Huang HM, et al. Thyroxin treatment protects against white matter injury in the immature brain via brain-derived neurotrophic factor. Stroke. 2013;44(8):2275−2283. doi: 10.1161/STROKEAHA.113.001552
  23. Numakawa T, Odaka H, Adachi N. Actions of brain-derived neurotrophin factor in the neurogenesis and neuronal function, and its involvement in the pathophysiology of brain diseases. Int J Mol Sci. 2018;19(11):3650. doi: 10.3390/ijms19113650
  24. Pearn ML, Hu Y, Niesman IR, et al. Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation. Anesthesiology. 2012;116(2):352−361. doi: 10.1097/ALN.0b013e318242a48c
  25. Leitas C, Piñol-Ripoll G, Marfull P, et al. proBDNF is modified by advanced glycation end products in Alzheimer’s disease and causes neuronal apoptosis by inducing p75 neurotrophin receptor processing. Mol Brain. 2018;11(1):68. doi: 10.1186/s13041-018-0411-6
  26. Lanni C, Stanga S, Racchi M, Govoni S. The expanding universe of neurotrophic factors: therapeutic potential in aging and age-associated disorders. Curr Pharm Des. 2010;16(6):698−717. doi: 10.2174/138161210790883741
  27. Eyileten C, Sharif L, Wicik Z, et al. The relation of the brain-derived neurotrophic factor with microRNAs in neurodegenerative diseases and ischemic stroke. Mol Neurobiol. 2021;58(1):329−347. doi: 10.1007/s12035-020-02101-2
  28. Mohammadi A, Amooeian VG, Rashidi E. Dysfunction in brain-derived neurotrophic factor signaling pathway and susceptibility to schizophrenia, Parkinson’s and Alzheimer’s diseases. Curr Gene Ther. 2018;18(1):45−63. doi: 10.2174/1566523218666180302163029
  29. Betti L, Palego L, Unti E, et al. Brain-derived neurotrophic factor (BDNF) and serotonin transporter (SERT) in platelets of patients with mild huntington’s disease: Relationships with social cognition symptoms. Arch Ital Biol. 2018;156(1−2):27−39. doi: 10.12871/00039829201813
  30. Jiang L, Zhang H, Wang C, et al. Serum level of brain-derived neurotrophic factor in Parkinson’s disease: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2019;88:168−174. doi: 10.1016/j.pnpbp.2018.07.010
  31. Zhang H, Qian YL, Li C, et al. Brain-derived neurotrophic factor in the mesolimbic reward circuitry mediates nociception in chronic neuropathic pain. Biol Psychiatry. 2017;82(8):608−618. doi: 10.1016/j.biopsych.2017.02.1180
  32. Di Carlo P, Punzi G, Ursini G. Brain-derived neurotrophic factor and schizophrenia. Psychiatr Genet. 2019;29(5):200−210. doi: 10.1097/YPG.0000000000000237
  33. Koo JW, Chaudhury D, Han MH, Nestler EJ. Role of mesolimbic brain-derived neurotrophic factor in depression. Biol Psychiatry. 2019;86(10):738−748. doi: 10.1016/j.biopsych.2019.05.020
  34. Bayazit H, Dulgeroglu D, Selek S. Brain-derived neurotrophic factor and oxidative stress in cannabis dependence. Neuropsychobiology. 2020;79(3):186−190. doi: 10.1159/000504626
  35. Oyesiku NM, Evans CO, Houston S, et al. Regional changes in the expression of neurotrophic factors and their receptors following acute traumatic brain injury in the adult rat brain. Brain Res. 1999;833(2):161−172. doi: 10.1016/s0006-8993(99)01501-2
  36. Kobori N, Clifton GL, Dash P. Altered expression of novel genes in the cerebral cortex following experimental brain injury. Brain Res Mol Brain Res. 2002;104(2):148−158. doi: 10.1016/s0169-328x(02)00331-5
  37. Korley FK, Diaz-Arrastia R, Wu AH, et al. Circulating brain-derived neurotrophic factor has diagnostic and prognostic value in traumatic brain injury. J Neurotrauma. 2016;33(2):215−225. doi: 10.1089/neu.2015.3949
  38. Kalish H, Phillips TM. Analysis of neurotrophins in human serum by immunoaffinity capillary electrophoresis (ICE) following traumatic head injury. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878(2):194−200. doi: 10.1016/j.jchromb.2009.10.022
  39. Bagnato S, Galardi G, Ribaudo F, et al. Serum BDNF levels are reduced in patients with disorders of consciousness and are not modified by verticalization with robot-assisted lower-limb training. Neural Plast. 2020;2020:5608145. doi: 10.1155/2020/5608145
  40. Iazeva EG, Legostaeva LA, Bakulin IS, et al. Effect of neuromodulation on neurotrophic factors in patients with chronic disorders of consciousness. Bulletin of RSMU. 2020;(5):40−47. (In Russ.). doi: 10.24075/vrgmu.2020.056
  41. Lenzlinger PM, Marx A, Trentz O, et al. Prolonged intrathecal release of soluble Fas following severe traumatic brain injury in humans. J Neuroimmunol. 2002;122(1−2):167−174. doi: 10.1016/s0165-5728(01)00466-0
  42. Solodeev I, Meilik B, Volovitz I, et al. Fas-L promotes the stem cell potency of adipose-derived mesenchymal cells. Cell Death Dis. 2018;9(6):695. doi: 10.1038/s41419-018-0702-y
  43. Dorsett CR, McGuire JL, DePasquale EA, et al. Glutamate neurotransmission in rodent models of traumatic brain injury. J Neurotrauma. 2017;34(2):263−272. doi: 10.1089/neu.2015.4373
  44. Khatri N, Thakur M, Pareek V, et al. Oxidative stress: Major threat in traumatic brain injury. CNS Neurol Disord Drug Targets. 2018;17(9):689−695. doi: 10.2174/1871527317666180627120501
  45. O’Neil DA, Nicholas MA, Lajud N, et al. Preclinical models of traumatic brain injury: emerging role of glutamate in the pathophysiology of depression. Front Pharmacol. 2018;9:579. doi: 10.3389/fphar.2018.00579
  46. Yasen AL, Smith J, Christie AD. Glutamate and GABA concentrations following mild traumatic brain injury: a pilot study. J Neurophysiol. 2018;120(3):1318−1322. doi: 10.1152/jn.00896.2017
  47. Gonzalez LL, Garrie K, Turner MD. Role of S100 proteins in health and disease. Biochim Biophys Acta Mol Cell Res. 2020;1867(6):118677. doi: 10.1016/j.bbamcr.2020.118677
  48. Selinfreund RH, Barger SW, Pledger WJ, Van Eldik LJ. Neurotrophic protein S100 beta stimulates glial cell proliferation. Proc Natl Acad Sci USA. 1991;88(9):3554−3558. doi: 10.1073/pnas.88.9.3554
  49. Winningham-Major F, Staecker JL, Barger SW, et al. Neurite extension and neuronal survival activities of recombinant S100 beta proteins that differ in the content and position of cysteine residues. J Cell Biol. 1989;109(6 Pt 1):3063−3071. doi: 10.1083/jcb.109.6.3063
  50. Oris C, Pereira B, Durif J, et al. The biomarker S100B and mild traumatic brain injury: A meta-analysis. Pediatrics. 2018;141(6):e20180037. doi: 10.1542/peds.2018-0037
  51. Michetti F, Corvino V, Geloso MC, et al. The S100B protein in biological fluids: more than a lifelong biomarker of brain distress. J Neurochem. 2012;120(5):644−659. doi: 10.1111/j.1471-4159.2011.07612.x
  52. Neher MD, Keene CN, Rich MC, et al. Serum biomarkers for traumatic brain injury. South Med J. 2014;107(4):248−255. doi: 10.1097/SMJ.0000000000000086
  53. Metting Z, Wilczak N, Rodiger LA, et al. GFAP and S100B in the acute phase of mild traumatic brain injury. Neurology. 2012;78(18):1428−1433. doi: 10.1212/WNL.0b013e318253d5c7

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