بررسی ارتباط سایتوکین‌های التهابی و عامل نورون‌زایی مشتق از مغز با کارکردهای شناختی در بیماران مبتلا به مولتیپل اسکلروزیس

عرب مقدم, نرگس; عسگری, کریم; دریابر, غلامرضا; پورصادق فرد, مریم

doi:10.22059/japr.2024.99090

بررسی ارتباط سایتوکین‌های التهابی و عامل نورون‌زایی مشتق از مغز با کارکردهای شناختی در بیماران مبتلا به مولتیپل اسکلروزیس

نوع مقاله : مقاله پژوهشی

نویسندگان

¹ دانشجوی دکتری روانشناسی، گروه روان‌شناسی، دانشکدۀ علوم تربیتی و روان‌شناسی، دانشگاه اصفهان، اصفهان، ایران.

² دانشیار، گروه روان‌شناسی، دانشکدۀ علوم تربیتی و روان‌شناسی دانشگاه اصفهان، اصفهان، ایران.

³ استادیار، گروه ایمونولوژی، مرکز تحقیقات بیماری های خودایمنی، دانشگاه علوم پزشکی شیراز، شیراز ، ایران.

⁴ دانشیار، گروه نورولوژی، مرکز تحقیقات نورولوژی بالینی. دانشگاه علوم پزشکی شیراز، شیراز، ایران.

10.22059/japr.2024.99090

چکیده

هدف این پژوهش، بررسی رابطۀ عوامل ایمونولوژیک با کارکردهای شناختی در بیماران مولتیپل اسکلروزیس بود. طرح تحقیق همبستگی و روش پژوهش به‌لحاظ هدف بنیادی بود. جامعۀ پژوهش شامل بیماران مبتلا به مولتیپل اسکلروزیس در شهر شیراز و در سال 1401 بودند. 68 بیمار در سه گروه شامل 23 بیمار تازه تشخیص داده‌شده (ND)، 23 بیمار مبتلا به نوع عودکننده-بهبودیابنده (RRMS) و 22 بیمار مبتلا به نوع پیش‌روندۀ ثانویه (SPMS) شامل 55 زن و 13 مرد از طریق نمونه‌گیری دردسترس انتخاب شدند. همچنین 22 نفر (17 زن و 5 مرد) از افراد سالم همتاشده از نظر سن، جنس و تحصیلات در گروه کنترل قرار گرفتند. سطوح سرمی سایتوکین‌های اینترفرون گاما (IFN-γ)، اینترلوکین 6 (IL-6)، عامل نکروزدهندۀ تومور آلفا (TNF-α) و اینترلوکین 17 (IL-17) و نیز عامل نورون‌زایی مشتق از مغز (BDNF) بیماران و گروه کنترل به روش الایزا سنجش شد. برای ارزیابی کارکردهای شناختی از آزمون‌های یادگیری کلامی کالیفرنیا (CVLT-11)، حافظۀ فضایی مختصر-تجدیدنظرشده (BVMT-R)، جایگزینی نماد-ارقام (SDMT)، سیالی کلامی (COWAT) و عملکردهای اجرایی (D-KEFS) استفاده شد. داده‌ها با نرم‌افزار SPSS-26 به روش رگرسیون تجزیه و تحلیل شدند. تفاوت معناداری در کارکردهای شناختی و سطوح سرمی اینترفرون گاماواینترلوکین 17 و عامل نورون‌زایی مشتق از مغز در بیماران در مقایسه با گروه کنترل مشاهده شد. عامل نورون‌زایی مشتق از مغز پیش‌بینی‌کنندۀ مثبت حافظۀ دیداری-فضایی و عملکرد اجرایی در بیماران نوع عودکننده-بهبودیابنده و بیماران تازه تشخیص داده‌شده، اینترفرون گاما پیش‌بینی‌کنندۀ منفی عملکرد اجرایی در بیماران تازه تشخیص داده‌شده و عامل نکروزدهندۀ تومور آلفا پیش‌بینی‌کنندۀ منفی سرعت پردازش اطلاعات در بیماران مبتلا به نوع پیش‌روندۀ ثانویه بود. عامل نورون‌زایی مشتق از مغز و سایتوکین‌های اینترفرون گاما و اینترلوکین 17 نشانگرهای بالقوه‌ای برای ارزیابی برخی از کارکردهای شناختی در بیماران مولتیپل اسکلروزیس هستند.

کلیدواژه‌ها

عنوان مقاله [English]

Investigating the Relationship of Inflammatory Cytokines and Brain-Derived Neurotrophic Factor with Cognitive Functions in Multiple Sclerosis Patients

نویسندگان [English]

Narges َArab-Moghaddam ¹
Karim Asgari Mobarakeh ²
Gholamreza Daryabor ³
Maryam Poursadeghfard ⁴

¹ Department of Psychology, Faculty of Education and Psychology, Isfahan University, Isfahan, Iran.

² Department of Psychology, Faculty of Education and Psychology, University of Isfahan Isfahan, Iran.

³ Department of Immunology, Autoimmune Disease Research Center, Shiraz University of Medical Sciences, Shiraz, Iran,

⁴ Department of Neurology, Clinical Neurology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran.

چکیده [English]

The aim of this study was to investigate the relationship between immunological factors and cognitive functions in patients with multiple sclerosis (MS). The methodology was fundamental in nature, and the research design was correlational. Patients diagnosed with multiple sclerosis comprised the research population. 68 patients with multiple sclerosis (MS) were selected through convenience sampling. These patients were divided into three groups: 23 newly diagnosed patients (ND), 23 patients with relapsing-remitting MS (RRMS), and 22 patients with secondary progressive types (SPMS). The patients were 55 women and 13 men. Additionally, the control group consisted of 22 healthy individuals (17 women and 5 men) who were matched based on their age, gender, and educational background. The ELISA method was used to measure the serum levels of cytokines IFN-γ, IL-6, TNF-α, and IL-17, as well as brain-derived neurogenesis factor (BDNF) in the control group and the patients. California Verbal Learning Tests (CVLT-11), Brief Spatial Memory-Revised (BVMT-R), Symbol Digit Substitution (SDMT), Verbal Fluency (COWAT), and Executive Functions (D-KEFS) were implemented to assess cognitive functions. SPSS-26 software was employed to analyze the data that was obtained using the regression method. Compared to the control group, patients exhibited substantial variations in cognitive functions and serum levels of cytokines IFN-γ, IL-17, and BDNF. In RRMS and ND patients, BDNF was a positive predictor of visual-spatial memory and executive function. In ND patients, IFN-γ was a negative predictor of executive function, and TNF-α was a negative predictor of information processing speed in SPMS patients. Neurotrophic factor BDNF and cytokines IFN-γ and IL-17 are potential biomarkers for the assessment of certain cognitive functions in patients with multiple sclerosis.

کلیدواژه‌ها [English]

Autoimmunity
Brain-Derived Neurogenesis Factor
Cognitive Functions
Inflammatory Cytokines
Multiple Sclerosis

مراجع

پیرویان، ف. (1394). بررسی مقایسه‌ای پروفایل سایتوکاین ها در افراد طبیعی و بیماران اسکلروز منتشر در استان فارس. رسالۀ دکتری فارماکولوژی، دانشکدۀ پزشکی، دانشگاه علوم پزشکی شیراز.

References

Amato, M. P., Ponziani, G., Siracusa, G., & Sorbi, S. (2001). Cognitive dysfunction in early-onset multiple sclerosis: A reappraisal after 10 years. Archives of Neurology, 58(10), 1602-1606. https://doi.org/10.1001/archneur.58.10.1602

Ashtari, F., Madanian, R., Shaygannejad, V., Zarkesh, S. H., & Ghadimi, K. (2019). Serum levels of IL-6 and IL-17 in multiple sclerosis, neuromyelitis optica patients and healthy subjects. International Journal of Physiology, Pathophysiology, and Pharmacolog, 11(6), 267-273. http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6971496/

Azoulay, D., Urshansky, N., & Karni, A. (2008). Low and dysregulated BDNF secretion from immune cells of MS patients is related to reduced neuroprotection. Journal of Neuroimmunology, 195(1-2), 186-193. https://doi.org/10.1016/j.jneuroim.2008.01.010

Azoulay, D., Vachapova, V., Shihman, B., Miler, A., & Karni, A. (2005). Lower brain-derived neurotrophic factor in serum of relapsing remitting MS: reversal by glatiramer acetate. Journal of Neuroimmunology, 167(1-2), 215-218. https://doi.org/10.1016/j.jneuroim.2005.07.001

Babaloo, Z., Babaie, F., Farhoodi, M., Aliparasti, M., Baradaran, B., Almasi, S., & Hoseini, A. (2010). Interleukin-17A and interleukin-17F mRNA expressions in peripheral blood mononuclear cells of patients with multiple sclerosis. Iranian Journal of Immunology, 7(4), 202-209. https://iji.sums.ac.ir/article_17059.html

Babaloo, Z., Khajir Yeganeh, R., Farhoodi, M., Baradaran, B., Bonyadi, M., & Aghebati, L. (2013). Increased IL-17A but decreased IL-27 serum levels in patients with multiple sclerosis. Iranian Journal of Immunology, 10(1), 47-54. https://pubmed.ncbi.nlm.nih.gov/23502338/

Benedict, R. H. (2005). Effects of using same-versus alternate-form memory tests during short-interval repeated assessments in multiple sclerosis. Journal of the International Neuropsychological Society, 11(6), 727-736. https://doi.org/10.1017/S1355617705050782

Benedict, R. H., Fischer, J. S., Archibald, C. J., Arnett, P. A., Beatty, W. W., Bobholz, J., ... & Munschauer, F. (2002). Minimal neuropsychological assessment of MS patients: a consensus approach. The Clinical Neuropsychologist, 16(3), 381-397. https://doi.org/10.1076/clin.16.3.381.13859

Bjartmar, C., & Trapp, B. D. (2001). Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Current Opinion in Neurology, 14(3), 271-278. https://doi.org/10.1097/00019052-200106000-00003

Carotenuto, A., Costabile, T., Moccia, M., Falco, F., Scala, M. R., Russo, C. V., ... & Morra, V. B. (2019). Olfactory function and cognition in relapsing–remitting and secondary-progressive multiple sclerosis. Multiple Sclerosis and Related Disorders, 27, 1-6. https://doi.org/10.1016/j.msard.2018.09.024

Christensen, J. R., Börnsen, L., Ratzer, R., Piehl, F., Khademi, M., Olsson, T., ... & Sellebjerg, F. (2013). Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17-and activated B-cells and correlates with progression. PloS One, 8(3), e57820. https://doi.org/10.1371/journal.pone.0057820

DiGiuseppe, G., Blair, M., & Morrow, S. A. (2018). Prevalence of cognitive impairment in newly diagnosed relapsing-remitting multiple sclerosis. International Journal of MS Care, 20(4), 153-157. https://doi.org/10.7224/1537-2073.2017-029

Diker, S., Has, A. C., Kurne, A., Göçmen, R., Oğuz, K. K., & Karabudak, R. (2016). The association of cognitive impairment with gray matter atrophy and cortical lesion load in clinically isolated syndrome. Multiple Sclerosis and Related Disorders, 10, 14-21. https://doi.org/10.1016/j.msard.2016.08.008

Eshaghi, A., Riyahi-Alam, S., Roostaei, T., Haeri, G., Aghsaei, A., Aidi, M. R., ... & Sahraian, M. A. (2012) Validity and reliability of a Persian translation of the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS). Clinical Neuropsychology, 26, 975- 984. https://doi.org/10.1080/13854046.2012.694912

Farrokhi, M., Etemadifar, M., Jafary Alavi, M. S., Zarkesh-Esfahani, S. H., Behjati, M., Rezaei, A., & Amani-Beni, A. (2015). TNF-alpha production by peripheral blood monocytes in multiple sclerosis patients and healthy controls. Immunological Investigations, 44(6), 590-601. https://doi.org/10.3109/08820139.2015.1059851

Fitzner, B., Hecker, M., & Zettl, U. K. (2015). Molecular biomarkers in cerebrospinal fluid of multiple sclerosis patients. Autoimmunity Reviews, 14(10), 903-913. https://doi.org/10.1016/j.autrev.2015.06.001

Frota, E. R. C., Rodrigues, D. H., Donadi, E. A., Brum, D. G., Maciel, D. R. K., & Teixeira, A. L. (2009). Increased plasma levels of brain derived neurotrophic factor (BDNF) after multiple sclerosis relapse. Neuroscience Letters, 460(2), 130-132. https://doi.org/10.1016/j.neulet.2009.05.057

Gajewski, P. D., Hengstler, J. G., Golka, K., Falkenstein, M., & Beste, C. (2011). The Met-allele of the BDNF Val66Met polymorphism enhances task switching in elderly. Neurobiology of Aging, 32(12), 2327e7-2327e19. https://doi.org/10.1016/j.neurobiolaging.2011.06.010

Hasheminia, S. J., Tolouei, S., Zarkesh, E. S. H., Shaygannejad, V., Shirzad, H., Torabi, R., & Hashem, Z. C. M. (2015). Cytokine gene expression in newly diagnosed multiple sclerosis patients. Iran Journal Allergy Asthma Immunology, 14(2), 208-2016. https://pubmed.ncbi.nlm.nih.gov/25780887/

Heesen, C., Schulz, K. H., Fiehler, J., Von der Mark, U., Otte, C., Jung, R., ... & Gold, S. M. (2010). Correlates of cognitive dysfunction in multiple sclerosis. Brain, Behavior, and Immunity, 24(7), 1148–1155. https://doi.org/10.1016/j.bbi.2010.05.006

Howitt, D., & Cramer, D. (2011). Introduction to SPSS Statistics in Psychology: For version 19 and earlier (5^th Ed.). Prentice Hall. ‌

Johnen, A., Landmeyer, N. C., Bürkner, P. C., Wiendl, H., Meuth, S. G., & Holling, H. (2017). Distinct cognitive impairments in different disease courses of multiple sclerosis- A systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews, 83, 568-578. https://doi.org/10.1016/j.neubiorev.2017.09.005

Kallaur, A. P., Oliveira, S. R., Simão, A. N. C., de Almeida, E. R. D., Morimoto, H. K., Lopes, J., ... & Reiche, E. M. V. (2013). Cytokine profile in relapsing‑remitting multiple sclerosis patients and the association between progression and activity of the disease. Molecular Medicine Reports, 7(3), 1010-1020. https://doi.org/10.3892/mmr.2013.1256

Kolls, J. K., & Lindén, A. (2004). Interleukin-17 family members and inflammation. Immunity. 21(4), 467-476. https://doi.org/10.1016/j.immuni.2004.08.018

Koven, N. S., & Collins, L. R. (2014). Urinary brain-derived neurotrophic factor as a biomarker of executive functioning. Neuropsychobiology, 69(4), 227-234. https://doi.org/10.1159/000362242

Kurtzke, J. F. (1983). Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology, 33(11), 1444-1452. https://doi.org/10.1212/WNL.33.11.1444

Larocca, N. G., & King, M. (2016). Managing Cognitive Problems in MS, National MS Society. https://ncrgea.com/wp-content/uploads/2024/04/Brochure-Managing-Cognitive-Problems.pdf

Liu, M., Hu, X., Wang, Y., Peng, F., Yang, Y., Chen, X., Lu, Z., & Zheng, X. (2009). Effect of high‐dose methylprednisolone treatment on Th17 cells in patients with multiple sclerosis in relapse. Acta Neurologica Scandinavica, 120(4), 235-241. https://doi.org/10.1111/j.1600-0404.2009.01158.x

Martins, T. B., Rose, J. W., Jaskowski, T. D., Wilson, A. R., Husebye, D., Seraj, H. S., & Hill, H. R. (2011). Analysis of proinflammatory and anti-inflammatory cytokine serum concentrations in patients with multiple sclerosis by using a multiplexed immunoassay. American Journal of Clinical Pathology, 136(5), 696-704. https://doi.org/10.1309/AJCP7UBK8IBVMVNR

Migliore, S., Ghazaryan, A., Simonelli, I., Pasqualetti, P., Squitieri, F., Curcio, G., ... & Vernieri, F. (2017). Cognitive impairment in relapsing-remitting multiple sclerosis patients with very mild clinical disability. Behavioral Neurology, 2017, 7404289. https://doi.org/10.1155/2017/7404289

Naegelin, Y., Saeuberli, K., Schaedelin, S., Dingsdale, H., Magon, S., Baranzini, S., ... & Barde, Y. A. (2020). Levels of brain-derived neurotrophic factor in patients with multiple sclerosis. Annals of Clinical and Translational Neurology, 7(11), 2251-2261. https://doi.org/10.1002/acn3.51215

Nakae, S., Saijo, S., Horai, R., Sudo, K., Mori, S., & Iwakura, Y. (2003). IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proceedings of the National Academy of Sciences, 100(10), 5986-5990. https://doi.org/10.1073/pnas.1035999100

Oraby, M. I., El Masry, H. A., Abd El Shafy, S. S., & Galil, E. M. A. (2021). Serum level of brain-derived neurotrophic factor in patients with relapsing–remitting multiple sclerosis: a potential biomarker for disease activity. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery, 57(1), 1-8. https://doi.org/10.1186/s41983-021-00296-2

Pirkhaefi, A. (2018). Evaluation of Cognitive Abilities of Different Groups of Sclerosis Patients and Its Comparison with Healthy People. Journal of Practice in Clinical Psychology, 6(2), 111-118. http://dx.doi.org/10.29252/nirp.jpcp.6.2.111

Prokopova, B., Hlavacova, N., Vlcek, M., Penesova, A., Grunnerova, L., Garafova, A., ... & Jezova, D. (2016). Early cognitive impairment along with decreased stress-induced BDNF in male and female patients with newly diagnosed multiple sclerosis. Journal of Neuroimmunology, 302, 34–40. https://doi.org/10.1016/j.jneuroim.2016.11.007

Rasi Marzabadi, L., Sadigh-Eteghad, S., & Talebi, M. (2021). Circulating inflammatory cytokine levels correlates with cognitive impairment. Clinical and Experimental Neuroimmunology, 12(1), 66-71. https://doi.org/10.1111/cen3.12613

Rostami, A., & Ciric, B. (2013). Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination. Journal of the Neurological Sciences, 333(1-2), 76-87. https://doi.org/10.1016/j.jns.2013.03.002

Segal, B. M. (2019). Multiple sclerosis, In Robert R. Rich, Thomas A. Fleisher, William T. Shearer, Harry W. Schroeder, Jr., Anthony J. Frew, & Cornelia M. Weyand (Eds), Clinical Immunology (Fifth Edition): Principles and Practice (pp. 891-902), Fifth Edition, Elsevier Inc.

Şen, M., Akbayır, E., Mercan, Ö., Arsoy, E., Gencer, M., Yılmaz, V., ... & Türkoğlu, R. (2021). Cytokine–chemokine and cognitive profile of multiple sclerosis patients with predominant optic nerve and spinal cord involvement. The Journal of Spinal Cord Medicine, 44(3), 411-417. https://doi.org/10.1080/10790268.2019.1666238

Serre-Miranda, C., Roque, S., Santos, N. C., Portugal-Nunes, C., Costa, P., Palha, J. A., ... & Correia-Neves, M. (2015). Effector memory CD4+ T cells are associated with cognitive performance in a senior population. Neurology-Neuroimmunology & Neuroinflammation, 2(1), e54. https://doi.org/10.1212/NXI.0000000000000054

Silakarma, D., & Sudewi, A. A. R. (2019). The role of brain-derived neurotrophic factor (BDNF) in cognitive functions. Bali Medical Journal, 8(2), 427- 434. Link

Sosa, R. A., Murphey, C., Robinson, R. R., & Forsthuber, T. G. (2015). IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation. Proceedings of the National Academy of Sciences, 112(36), E5038-E5047. https://doi.org/10.1073/pnas.1505955112

Sundgren, M. (2016). Cognitive function and neurophysiological correlates in relapsing-remitting multiple sclerosis. PhD Dissertation, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. https://openarchive.ki.se/xmlui/handle/10616/45030

Tauil, C. B., da Rocha Lima, A. D., Ferrari, B. B., da Silva, V. A., Moraes, A. S., da Silva, F. M., ... & dos Santos-Neto, L. L. (2020). Depression and anxiety in patients with multiple sclerosis treated with interferon-beta or fingolimod: Role of indoleamine 2, 3-dioxygenase and pro-inflammatory cytokines. Brain, Behavior, & Immunity Health, 9, 100162. https://doi.org/10.1016/j.bbih.2020.100162

Thomas, A. J., Hamilton, C. A., Donaghy, P. C., Martin‐Ruiz, C., Morris, C. M., Barnett, N., ... & O'Brien, J. T. (2020). Prospective longitudinal evaluation of cytokines in mild cognitive impairment due to AD and Lewy body disease. International Journal of Geriatric Psychiatry, 35(10), 1250-1259. https://doi.org/10.1002/gps.5365

Thöne, J., Ellrichmann, G., Seubert, S., Peruga, I., Lee, D. H., Conrad, R., ... & Gold, R. (2012). Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. The American Journal of Pathology, 180(1), 267-274. https://doi.org/10.1016/j.ajpath.2011.09.037

Vollmer, T., Huynh, L., Kelley, C., Galebach, P., Signorovitch, J., DiBernardo, A., & Sasane, R., (2016). Relationship between brain volume loss and cognitive outcomes among patients with multiple sclerosis: a systematic literature review. Neurological Sciences, 37(2), 165-179. https://doi.org/10.1007/s10072-015-2400-1

Yoshimura, S., Ochi, H., Isobe, N., Matsushita, T., Motomura, K., Matsuoka, T., Minohara, M., & Kira, J. I. (2010). Altered production of brain-derived neurotrophic factor by peripheral blood immune cells in multiple sclerosis. Multiple Sclerosis Journal, 16(10), 1178-1188. https://doi.org/10.1177/1352458510375706