THE RELATIONSHIP BETWEEN DECREASED COGNITIVE FUNCTIONS AND THE LEVEL OF PROINFLAMMATORY CYTOKINES IN PATIENTS WITH ALZHEIMER’S DISEASE, VASCULAR DEMENTIA, AND MILD COGNITIVE DISORDER

Keywords: Alzheimer’s disease, vascular dementia, mild cognitive disorder, neurocognitive domains, interleukins 17 and 23

Abstract

Introduction. Alzheimer's disease (AD) is a degenerative disease that leads to dementia symptoms [1, 2]. Histopathological signs of AD are amyloid plaques in the brain, mainly consisting of fibrillary forms of amyloid β-peptide-40 (Aβ-40) and amyloid β-peptide-42 (Aβ-42). Neutrophils are the main targets for IL-17 in the central nervous system (CNS) that promote inflammation and damage to CNS tissues, and may play an important role in the development of AD pathology. Interleukin 23 (IL‑23) synergizes with IL-6, IL-1 and is involved in the differentiation of Th17 cells in a pro-inflammatory context.

The aim of the study was to analyze the relationship between interleukin levels of IL-17, IL-23 and neurocognitive scales in patients with AD, vascular dementia (VD) and mild cognitive disorder (MCD).

Materials and methods: The study involved 89 patients, of which 59 patients had cognitive impairment (32 men and 27 women, mean age 66.8±8.4 years); among them, 29 had major neurocognitive impairment (NCD), including 15 patients with AD, 14 – with VD, 30 patients – with MCD and 30 people in the control group had no cognitive deficit.

All patients were tested with comprehensive neuropsychological examination using the following tests and scales: Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Alzheimer Disease Assessment Scale-cognitive (ADAScog).

Serum levels of cytokines of IL-17 and IL-23 were assayed using sandwich ELISA on «Chem Well 2900» immunoanalyzer (Awareness Technology, USA). Test systems using Bender Medsystems, Australia (IL-17 and IL-23) were used in accordance with the manufactures instructions.

Discussion. Levels of detectable interleukins (IL-17 and IL-23) were significantly higher in patients with AD vs. patients with VD and MCD. The correlations between the two cytokines and the MMSE scales, MoCA, ADAS-cog and FAB were examined. Our results showed a significant positive correlation between the serum concentration of IL-23 and neurocognitive scales in all patients with AD. The most relevant correlations in the AD group were linked with the scales: ADAS-cog (r = 0.760; р = 0.001), namely with the sections «tasks for repeating words» (r = 0.775; p ˂ 0.001), «constructive praxis» (r = 0.651; p = 0.010), «orientation» (r = 0.684; p = 0.01), as well as «word recognition tasks» (r = 0.616; p = 0.020); and with MoCA scale (r = −0.592; p = 0.020), namely with the section «delayed recall» (r = −0.641; p = 0.010). A significant positive correlation was established between IL-23 and individual sections of the ADAS-cog scale in patients with MCD (r = 0.423; p = 0.020), namely with «word recognition tasks» (r = 0.466; p = 0.030), «understanding» (r = 0.306; p = 0.059) as well as «strike out numbers» (r = 0.301; p = 0.061). A weak positive correlation was found between the serum concentration of IL-23 and ADAS-cog scores in patients with VD (r = 0.497; p = 0.045). Moderate positive correlation was observed for IL-23 with «concentration and distraction» (r = 0.558; p = 0.040). An inverse correlation was established between the serum levels of IL-23 and MoCA scores in patients with VD (r = −0.510; р = 0.060), especially with «language» (r = −0.538; p = 0.047) and «executive functioning» (r = −0.485; p = 0.079). However, no other significant correlations were found between the serum concentration of IL-17 and neurocognitive domains in patients with MCD and VD.

Correlation analysis confirmed the relationship between the severity of cognitive impairment and the level of proinflammatory markers, suggesting that inflammation can lead to cognitive decline in AD patients. The results of the study indicated that IL-23 may have a more complex relationship with the progression of this disease which gives reason to consider IL-23 as a marker of inflammatory activity.

Levels of detectable proinflammatory cytokines (IL-17 and IL-23) were significantly higher in patients with AD vs. patients with VD and MCD. Such more pronounced changes in the production of interleukin 23 in patients with AD may indicate the activity of the inflammatory process. The level of IL-23 in all examined patients with Alzheimer's disease had high correlations with indicators of neurocognitive scales, which indicated its important role in the pathogenesis of this disease. There were no other significant correlations between the serum concentration of IL-17 and neurocognitive domains in patients with MCD and VD.

Author Biographies

Olha S. Chyniak, Department of Neurosurgery and Neurology, Medical institute, Sumy State University, Sumy , Ukraine

Assistant of Department of Neurosurgery and Neurology, Medical institute, Sumy State University, Sumy, Ukraine.

ORCID: 0000-0002-6008-1039, e-mail: o.chinyak@med.sumdu.edu.ua

Address for correspondence: 2 Rymskogo-Korsakova st., Sumy, Ukraine 40007

Telefone: +38 095 063 01 71 (mobile)

Olga Ye. Dubenko, Department of Neurology and Neurosurgery, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine

MD, PhD, Professor of Department of Neurology and Neurosurgery, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine.

ORCID: 0000-0002-4911-5613 e-mail: olgadubenko05@gmail.com

Address for correspondence: 58 Amosova str., Kharkiv, Ukraine 61176

Telefone: +38 050 660 14 42 (mobile)

Olexander О. Potapov, Department of Neurosurgery and Neurology, Medical institute, Sumy State University, Sumy , Ukraine

MD, PhD, Professor, Head of Department the Neurosurgery and Neurology, Medical institute, Sumy State University, Sumy, Ukraine.

ORSID: 0000-0002-9683-3685 e-mail: neiro@med.sumdu.edu.ua

Address for correspondence: 2 Rymskogo-Korsakova st., Sumy, Ukraine 40007

Telefone: +38 050 577 50 00 (mobile)

References

1. Lai P, Liu S, Rau A, Lanctôt L, Köhler A, Pakosh M, et al. Peripheral inflammatory markers in Alzheimer's disease: a systematic review and meta-analysis of 175 studies. J. Neurol. Neurosurg. Psychiatry. 2017;88:876-882. Doi: 10.1136/jnnp-2017-316201
2. Kinney J, Bemiller S, Murtishaw A, Leisgang A, Salazar A, Lamb B. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y). 2018;4:575-590. Doi: 10.1016/j.trci.2018.06.014
3. Ahmad, M, Fatima, M, Mondal, A. Influence of microglia and astrocyte activation in the neuroinflammatory pathogenesis of Alzheimer’s disease: Rational insights for the therapeutic approaches. Journal Of Clinical Neuroscience. 2019;59:6-11. Doi: 10.1016/j.jocn.2018.10.034
4. Tahmasebinia F, Pourgholaminejad A. The role of Th17 cells in auto-inflammatory neurological disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2017;3(79):408-416. Doi: 10.1016/j.pnpbp.2017.07.023
5. Milovanovic J, Arsenijevic A, Stojanovic B, Kanjevac T, Arsenijevic D, Radosavljevic G, Milovanovic M, Arsenijevic N. Interleukin-17 in Chronic Inflammatory Neurological Diseases. Front. Immunol. 2020;11:947. Doi: 10.3389/fimmu.2020.00947
6. Park JC, Han SH, Mook-Jung I. Peripheral inflammatory biomarkers in Alzheimer’s disease: a brief review. BMB Reports. 2020;53(1):10-19. Doi: 10.5483/BMBRep.2020.53.1.309
7. Chen J, Jiang G, Li Q, Zhou Z, Cheng Q. Increased Serum Levels of Interleukin-18, -23 and -17 in Chinese Patients with Alzheimer's Disease. Dement Geriatr Cogn Disord. 2014;38:321-329. Doi: 10.1159/000360606
8. McKhaann M, Knopman, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institue on Aging- Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263-269. Doi: 10.1016/j.jalz.2011.03.005
9. Sachdev P, Lipnicki D, Crawford J, Brodaty H. The Vascular Behavioral and Cognitive Disorders criteria for vascular cognitive disorders: a validation study. Eur J Neurol. 2019;9:1161-1167. Doi: 10.1111/ene.13960
10. Shen X, Niu L, Wang Y, Cao X, Liu Q, Tan L, Zhang C, Yu J. Inflammatory markers in Alzheimer's disease and mild cognitive impairment: A meta-analysis and systematic review of 170 studies. Alzheimer’s Dement. 2020;16(4):e041476. Doi: 10.1002/alz.041476
11. Wang W, Tan M, Yu J, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med. 2015; 3(10)136. Doi: 10.3978/j.issn.2305-5839.2015.03.49
12. Domingues, C, da Cruz E Silva, O, Henriques G. Impact of Cytokines and Chemokines on Alzheimer's Disease Neuropathological Hallmarks. Current Alzheimer research. 2017;14(8):870-882. Doi: 10.2174/1567205014666170317113606
13. Zhu Y , Chai Y , Hilal S. Serum IL-8 is a marker of white-matter hyperintensities in patients with Alzheimer's disease. Alzheimers Dement. 2017;7:41–7. Doi: 10.1016/j.dadm.2017.01.001
14. Wennberg M, Hagen C, Mary M, Machulda M, Knopman D, Petersen R, Michelle M, Mielke M. The Cross-sectional and Longitudinal Associations Between IL-6, IL-10, and TNFα and Cognitive Outcomes in the Mayo Clinic Study of Aging, The Journals of Gerontology: Series A. 2019;74(8):1289-1295. Doi: 10.1093/gerona/gly217
15. Balldin VH , Hall JR , Barber RC , et al The Relation between Inflammation and Neuropsychological Test Performance. Int J Alzheimers Dis. 2012;2012:1–6. Doi: 10.1155/2012/703871
16. Uslu S , Akarkarasu Z , Ozbabalik D , et al. Levels of amyloid beta-42, interleukin-6 and tumor necrosis factor-alpha in Alzheimer's disease and vascular dementia. Neurochem Res.2012;37:1554–9. Doi: 10.1007/s11064-012-0750-0
17. Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Alberoni M, Nemni R, Clerici M. Increased activity of Th-17 and Th-9 lymphocytes and a skewing of the post-thymic differentiation pathway are seen in Alzheimer’s disease. Brain Behav Immun. 2011;25:539-547. Doi: 10.1016/j.bbi.2010.12.004
18. Chen, J, Liu, X, Zhong, Y. Interleukin-17A: The Key Cytokine in Neurodegenerative Diseases. Front Aging Neurosci. 2020;12:307. Doi: 10.3389/fnagi.2020.566922
19. Pastor-Fernández G, Mariblanca IR, Navarro MN. Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities. Cells. 2020; 9(9):2044. Doi: 10.3390/cells9092044.
Published
2021-09-29
How to Cite
Olha S. Chyniak, Olga Ye. Dubenko, & Olexander О. Potapov. (2021). THE RELATIONSHIP BETWEEN DECREASED COGNITIVE FUNCTIONS AND THE LEVEL OF PROINFLAMMATORY CYTOKINES IN PATIENTS WITH ALZHEIMER’S DISEASE, VASCULAR DEMENTIA, AND MILD COGNITIVE DISORDER. Eastern Ukrainian Medical Journal, 9(3), 247-255. https://doi.org/10.21272/eumj.2021;9(3):247-255