Effects of tumor necrosis factor α on the structure of brain networks and cognitive functions in patients with chronic cerebral ischemia

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Abstract

Introduction. The processes of cognitive decline, which are typical for elderly and senile people, as well as for patients with chronic cerebral circulation insufficiency, involve pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-6, etc.

The aim of this work was to study the association of TNF-α with brain network structure and cognitive functions in patients with chronic cerebral ischemia (CCI).

Materials and methods. We examined 101 patients with CCI (50–85 years old, men and women) who were assessed for the saliva levels of TNF-α during cognitive testing. The status of resting-state networks was analyzed in 55 patients using functional magnetic resonance therapy.

Results. After cognitive tasks, the saliva level of TNF-α increased by 17.6 ± 6.2 pg/mL. Half of the CCI patients older than 60 years showed a significant increase in the level of TNF-α. This cytokine correlated with delayed word recall and the ratio of delayed recall to their performance on the Luria Memory Words Test. The change in TNF-α saliva levels correlated with the status of the resting-state network, mainly with the salience network. An increase in TNF-α levels was associated with a higher frequency of negative correlations than at lower values of TNF-α (less than 80 pg/mL). TNF-α-sensitive connectivities correlated with cognitive tasks, not only memory tests, but also with the Montreal Cognitive Assessment Scale, verbal fluency test scores, etc.

Discussion. The study revealed two significant facts: an increase in the TNF-α saliva level during cognitive performance and a lower success rate of cognitive performance associated with an increase in the levels of this cytokine. The central mechanism for the implementation of this relationship includes the restructuring of the salience network, namely the additional increase of negative correlations within the connective structure of the salience neural network of the right hemisphere.

Conclusions. A change in the saliva level of TNF-α affects the connectivity of resting-state networks, mainly the salience network

About the authors

Vitaliy F. Fokin

Research Center of Neurology

Author for correspondence.
Email: fvf@mail.ru
ORCID iD: 0000-0003-2915-9384

D. Sci. (Biol.), Prof., principal researcher, Laboratory of age-related physiology of the brain and neurocybernetics, Brain Research Institute

Russian Federation, Moscow

Аlla A. Shabalina

Research Center of Neurology

Email: ashabalina@yandex.ru
ORCID iD: 0000-0001-9604-7775

D. Sci. (Med.), leading researcher, Head, Department of laboratory diagnostics, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Natalia V. Ponomareva

Research Center of Neurology

Email: ponomare@yandex.ru
ORCID iD: 0000-0002-9771-0775

D. Sci. (Med.), principal researcher, Head, Laboratory of age-related physiology of the brain and neurocybernetics, Brain Research Institute

Russian Federation, Moscow

Rodion N. Konovalov

Research Center of Neurology

Email: krn_74@mail.ru
ORCID iD: 0000-0001-5539-245X

Cand. Sci. (Med.), senior researcher, Department of radiation diagnostics, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Roman B. Medvedev

Research Center of Neurology

Email: medvedev-roman@yandex.ru
ORCID iD: 0000-0003-3887-0418

Cand. Sci. (Med.), researcher, 1st Neurological department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Olga V. Lagoda

Research Center of Neurology

Email: olga.lagoda@gmail.com
ORCID iD: 0000-0001-7562-4991

Cand. Sci. (Med.), senior researcher, 1st Neurological department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Marina V. Krotenkova

Research Center of Neurology

Email: krotenkova_mrt@mail.ru
ORCID iD: 0000-0003-3820-4554

D. Sci. (Med.), Head, Department of radiation diagnostics, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Marine M. Tanashyan

Research Center of Neurology

Email: m_tanashyan2004@mail.ru
ORCID iD: 0000-0002-5883-8119

Dr. Sci. (Med.), Professor, Corr. Member of the Russian Academy of Sciences, Deputy director of science, Head, 1st Neurology department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

References

  1. Суслина З.А., Иллариошкин С.Н., Пирадов М.А. Неврология и нейронауки — прогноз развития. Анналы клинической и экспериментальной неврологии. 2007; 1(1): 5–9. Suslina Z.A., Illarioshkin S.N., Piradov M.A. Neurology and neurosciences — development forecast. Annals of Clinical and Experimental Neurology. 2007; 1(1): 5–9. (In Russ.)
  2. Page M.J., Bester J., Pretorius E. The inflammatory effects of TNF-α and complement component 3 on coagulation. Sci Rep8. 2018; 8(1): 1812. doi: 10.1038/s41598-018-20220-8
  3. Popa C., Netea M.G., van Riel P.L.C.M. et al. The role of TNF-α in chro-nic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J. Lipid Res. 2007; 48(4): 751–762. doi: 10.1194/jlr.R600021-JLR200
  4. Vlahopoulos S., Boldogh I., Casola A., Brasier A.R. Nuclear factor-kappa B-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation. Blood. 1999; 94(6): 1878–1789.
  5. Johnson J.D., Barnard D.F., Kulp A.C., Mehta D.M. Neuroendocrine regu- lation of brain cytokines after psychological stress. J. Endocr. Soc. 2019; 3(7): 1302–1320. doi: 10.1210/js.2019-00053
  6. Kim Y.K., Maes M. The role of the cytokine network in psychological stress. The role of the cytokine network in psychological stress. Acta Neuropyschiatr. 2003; 15(3): 148–155. doi: 10.1034/j.1601-5215.2003.00026.x
  7. Pan W., Kastin A.J. Tumor necrosis factor and stroke: role of the blood-brain barrier. Prog. Neurobiol. 2007; 83(6): 363–374. doi: 10.1016/j.pneurobio. 2007.07.008
  8. Steensberg A., Dalsgaard M.K., Secher N.H., Pedersen B.K. Cerebrospinal fluid IL-6, HSP72, and TNF-alpha in exercising humans. Brain Behav. Immun. 2006; 20(6): 585–589. doi: 10.1016/j.bbi.2006.03.002
  9. Bourgognon JM, Cavanagh J. The role of cytokines in modulating learning and memory and brain plasticity. Brain Neurosci. Adv. 2020; 4: 2398212820979802. doi: 10.1177/2398212820979802
  10. McAfoose J., Baune B.T. Evidence for a cytokine model of cognitive function. Neurosci. Biobehav. Rev. 2009; 33(3): 355–366. doi: 10.1016/j.neubiorev.2008.10.005
  11. Фокин В.Ф., Шабалина А.А., Пономарева Н.В. и др. Изменчивость интерлейкинов при когнитивной нагрузке у больных с хронической ишемией мозга. Вестник РГМУ. 2020; (6): 94–100. Fokin V.F., Shabalina A.A., Ponomareva N.V. et al. Interleukin dynamics during cognitive stress in patients with chronic cerebral ischemia. Vestnik RGMU. 2020; (6): 94–100. (In Russ.) doi: 10.24075/vrgmu.2020.085
  12. Танашян М.М., Максимова М.Ю., Домашенко М.А. Дисциркуляторная энцефалопатия. Путеводитель врачебных назначений. 2015; 2: 1–25. Tanashyan M.M., Maksimova M.Yu., Domashenko M.A. Encephalopathy. Guide to medical appointments. 2015; 2: 1–25. (In Russ.)
  13. Батышева Т.Т., Артемова И.Ю., Вдовиченко Т.В. Хроническая ишемия мозга: механизмы развития и современное комплексное лечение. Consilium medicum. 2004; 3 (4). Batysheva T.T., Artemova I.Yu., Vdovichenko T.V. Hronicheskaya ishemiya mozga: mekhanizmy razvitiya I sovremennoe kompleksnoe lechenie. Consilium medicum. 2004; 3 (4). (In Russ.)
  14. Захаров В.В., Локшина А.Б. Когнитивные нарушения при дисциркуляторной энцефалопатии. РМЖ. 2009; (20): 1325–1331. Zakharov V.V., Lokshina A.B. Cognitive impairment in dyscirculatory encephalopathy. RMZh. 2009; (20): 1325–1331. (In Russ.)
  15. Morris J.C. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int. Psychogeriatric. 1997; (9 Suppl 1): 173–176. doi: 10.1017/s1041610297004870
  16. Whitfield-Gabrieli S., Nieto-Castanon A. Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect. 2012; 2(3): 125–141. doi: 10.1089/brain.2012.0073.
  17. Лурия А.Р. Лекции по общей психологии. СПб.; 2006; 320 с. Luriya A.R. Lectures on General Psychology. St. Petersburg; 2006; 320 p. (In Russ.)
  18. La Fratta I., Tatangelo R., Campagna G. et al. The plasmatic and salivary levels of IL-1β, IL-18 and IL-6 are associated to emotional difference during stress in young male. Sci. Rep. 2018; 8(1): 3031. doi: 10.1038/s41598-018-21474-y
  19. Seeley W.W. The salience network: a neural system for perceiving and responding to homeostatic demands. J. Neurosci. 2019; 39(50): 9878–9882. doi: 10.1523/JNEUROSCI.1138-17.2019
  20. Cunningham A.J., Murray C.A., O’Neill L.A. et al. Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci. Lett. 1996; 203(1): 17–20. doi: 10.1016/0304-3940(95)12252-4
  21. Pickering M., Cumiskey D., O’Connor J.J. Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp. Physiol. 2005; 90(5): 663–670. doi: 10.1113/expphysiol.2005.030734
  22. Lindbergh C.A., Casaletto K.B., Staffaroni A.M. et al. Systemic tumor necrosis factor-alpha trajectories relate to brain health in typically aging older adults. J. Gerontol. A BiolSci. Med. Sci. 2020; 75(8): 1558–1565. doi: 10.1093/gerona/glz209
  23. Aruldass A.R., Kitzbichler M.G., Morgan S.E. et al. Dysconnectivity of a brain functional network was associated with blood inflammatory markers in depression. Brain Behav. Immun. 2021; 98: 299–309. doi: 10.1016/j.bbi.2021.08.226

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2. Fig. 1. Correlation between TNF-α levels and the age of patients with CCI. A — age distribution of TNF-α levels; B — difference between the mean values of TNF-α in patients of different age groups. n — number of examined patients; F — Fisher's exact test; p — significance level.

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3. Fig. 2. The ratio of delayed word recall to immediate recall (R/M) in the Luria test in two groups of CCI patients older than 60 years with TNF-α saliva levels below and above 80 pg/mL. n — number of examined patients; F — Fisher's exact test; p — significance level.

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4. Fig. 3. Significantly different connectivity parameters in the groups of CCI patients with low and high levels of TNF-α. Salience.AInsula (anterior insula) — salience network in the anterior insula; iLOC (inferior lateral occipital cortex) — the lower part of the lateral occipital cortex; sLOC (superior lateral occipital cortex) — the superior part of the lateral occipital cortex; VisualLateral — lateral visual network; TOFusC (temporal occipital fusiform cortex) — temporal-occipital fusiform cortex; SubCalC (subcallosal cortex) — subcallosal cortex; IFGtri (inferior frontal gyrus pars triangularis) — the triangular part of the inferior frontal gyrus; r and l — right and left hemispheres.

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5. Fig. 4. Connectivity of the right salience network at low — < 80 pg/mL (A) and high — ≥ 80 pg/mL (B) saliva levels of TNF-α. Red circle (right hemisphere) — the area of the salience network in the anterior part of the insula. In the upper part of the figure, the color of positive (pink lines) and negative (blue lines) connections is indicated. All connectivities were significantly different from zero (pFDR < 0.05).

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Copyright (c) 2022 Fokin V.F., Shabalina А.A., Ponomareva N.V., Konovalov R.N., Medvedev R.B., Lagoda O.V., Krotenkova M.V., Tanashyan M.M.

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This work is licensed under a Creative Commons Attribution 4.0 International License.

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