r-n-jРоссийский неврологический журналRussian neurological journal2658-79472686-7192МИА10.30629/2658-7947-2024-29-2-24-33r-n-j-548Research ArticleИССЛЕДОВАНИЯ И КЛИНИЧЕСКИЕ НАБЛЮДЕНИЯCLINICAL RESEARCHES AND CASE REPORTSИммунологические маркеры ранней когнитивной дисфункции в остром периоде ишемического инсультаEarly cognitive dysfunction development immunological predictors in the ischemic stroke acute periodhttps://orcid.org/0000-0003-1743-4713ТынтероваА. М.TynterovaA. M.

Калининград

Kaliningrad

antynterova@mail.ruФедеральный университет имени Иммануила КантаРоссияImmanuel Kant Baltic Federal UniversityRussian Federation2024230520242922433Copyright © Тынтерова А.М., 20242024Тынтерова А.М.Tynterova A.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.r-n-j.com/jour/article/view/548

Целью исследования являлось определение активности цитокинов семейства CXC у пациентов с когнитивными нарушениями в остром периоде ишемического инсульта

Материал и методы

Материал и методы. Обследовано 78 пациентов с диагнозом «Ишемический инсульт». В зависимости от состояния когнитивных функций, оценивавшихся с применением шкалы Montreal Cognitive Assessment (МоСА), пациенты разделены на две группы: 1-я группа — 58 пациентов, имеющих когнитивное снижение (≤ 25 баллов по MoCA); 2-я группа — 20 пациентов без когнитивного снижения. Нейропсихологическое обследование проводилось на 2-й день госпитализации и включало исследование эпизодической памяти, управляющих функций, речи, гнозиса, праксиса, параметров опросника родственников о когнитивном снижении у пожилого человека (IQCODE). Лабораторная диагностика включала оценку уровня хемокинов семейства CXC (CXCL10, CXCL11, CXCL9, CXCL1, CXCL8) и цитокина TNF-α в плазме крови пациентов на 2-й день госпитализации. Статистический анализ проводился с использованием языка программирования Python, библиотеки Pandas и SciPy.

Результаты

Результаты. Статистический анализ выявил более высокий уровень хемокинов IP-10/CXCL10 (р = 0,002) и Gro-a/CXCL1 (р = 0,044) у пациентов 1-й группы, статистически значимые корреляции показателей МоСА и IQCODE с концентрациями IP-10/CXCL10 и Gro-a/CXCL1, корреляции концентрации IP-10/CXCL10 с функциями семантической обработки информации (r = –0,512), предметного гнозиса (r = –0,211), памяти (r = 0,275) речи (r = –0,400), уровня Gro-a/CXCL1 — с семантической обработкой информации (r = –0,418).

Заключение

Заключение. Исследование хемокинов кластера CXC представляет собой актуальное и многообещающее направление в диагностике и оценке прогрессирования ранних постинсультных когнитивных нарушений смешанного генеза в силу минимальной инвазивности и высокой специфичности. Необходимо дальнейшее проведение исследований, направленных на верификацию хемокинов CXCL, в частности IP-10/CXCL10 и Gro-a/CXCL1, как потенциальных молекулярных маркеров неврологического повреждения при нейродегенеративных и воспалительных заболеваниях центральной нервной системы.

The purpose of the study is activity identification CXC family cytokines in patients with cognitive impairments in the acute period of ischemic stroke.

Material and methods

Material and methods. 78 patients with diagnosis “Ischemic stroke” were examined. Depending on cognitive impairment (Montreal Cognitive Assessment (MoCA)) patients were divided into two groups: the 1st group — 58 patients with cognitive decline (MoCA ≤ 25 points); the 2nd group — 20 patients without cognitive decline. Neuropsychologic testing was performed on the second day of hospitalisation and included episodic memory, executive function, speech, gnosis, praxis and IQCODE parameters examination. Laboratory diagnosis consisted of level assessing of CXC family chemokines (CXCL10, CXCL11, CXCL9, CXCL1, CXCL8) and TNF-α cytokine in patients’ plasma on the second day of hospitalisation. Statistical analysis was employed using the Python programing language and its libraries Pandas and SciPy.

Results

Results. Statistical analysis revealed the highest level of IP-10/CXCL10 chemokines (p = 0.002) and Gro-a/CXCL1 (p = 0.044) in patients of the 1st group, statistically significant correlations of MoCA and IQCODE with IP-10/CXCL10 and Gro-a/CXCL1 concentrations, correlations of IP-10/CXCL10 concentrations with semantic information processing functions (r = –0.512), subject gnosis (r = –0.211), memory (r = 0.275), speech (r = –0.400), and Gro-a/ CXCL1 level with semantic information processing (r = –0.418).

Conclusion

Conclusion. The study of chemokines of the CXC cluster represents a relevant and promising direction in the diagnosis and assessment of progression of early post-stroke cognitive impairment of mixed genesis due to minimal invasiveness and high specificity. Further studies are needed to verify CXCL chemokines, particularly IP-10/CXCL10 and Gro-a/CXCL1 as potential molecular markers of neurological damage in neurodegenerative and inflammatory diseases of the central nervous system.

ишемический инсульткогнитивная функцияцитокиныIP-10/CXCL10 и Gro-a/CXCL1ischemic strokecognitive functioncytokinesIP-10/CXCL10Gro-a/CXCL1Исследование было проведено в рамках проекта «Приоритет 2030» БФУ им. И. Канта.This work was performed within the scope of the Agreement #FZWM-2020-0013, «Priority 2030» Program.ReferencesКлочихина О.А., Шпрах В.В., Стаховская Л.В., Полунина О.С., Полунина Е.А. Динамика показателей заболеваемости инсультом и смертности от него за восьмилетний период на территориях, вошедших в федеральную программу реорганизации помощи пациентам с инсультом. Acta Biomedica Scientifica. 2021;6(1):75–80. doi: 10.29413/ABS.2021-6.1.10Klochikhina O.., Shprach V.V., Stakhovskaya L.V., Polunina O.S, Polunina E.A. Dynamics of stroke morbidity and mortality over an eight-year period in the territories included in the Federal program for the reorganization of care for stroke patients. Acta Biomedica Scientifica. 2021;6(1):75–80. (In Russ.). doi: 10.29413/ABS.2021-6.1.10Lim J.S, Lee J.J, Woo C.W. Post-Stroke Cognitive Impairment: Pathophysiological Insights into Brain Disconnectome from Advanced Neuroimaging Analysis Techniques. J Stroke. 2021;23(3):297–311. doi: 10.5853/jos.2021.02376Lim J.S, Lee J.J, Woo C.W. Post-Stroke Cognitive Impairment: Pathophysiological Insights into Brain Disconnectome from Advanced Neuroimaging Analysis Techniques. J Stroke. 2021;23(3):297–311. doi: 10.5853/jos.2021.02376Gottesman R.F., Schneider A.L., Zhou Y., Coresh J., Green E., Gupta N. et al. Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition. JAMA. 2017;317(14):1443–1450. doi: 10.1001/jama.2017.3090Gottesman R.F., Schneider A.L., Zhou Y., Coresh J., Green E., Gupta N. et al. Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition. JAMA. 2017;317(14):1443–1450. doi: 10.1001/jama.2017.3090Román G.C., Tatemichi T.K., Erkinjuntti T., Cummings J.L., Masdeu J.C., Garcia J.H. et al. Vascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurol. 1993;43(2):250–260. doi: 10.1212/wnl.43.2.250.Román G.C., Tatemichi T.K., Erkinjuntti T., Cummings J.L., Masdeu J.C., Garcia J.H. et al. Vascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurol. 1993;43(2):250–260. doi: 10.1212/wnl.43.2.250.Табеева Г.Р. Смешанная деменция: роль цереброваскулярной патологии. Журнал неврологии и психиатрии им. С.С. Корсакова. 2018;118(9):111–116. doi: 10.17116/jnevro2018118091111Tabeeva G.R. Mixed dementia: the role of cerebrovascular pathology. S.S. Korsakov Journal of Neurology and Psychiatry. 2018;118(9):111–116. (In Russ.). doi: 10.17116/jnevro2018118091111Pinho J., Quintas-Neves M., Dogan I., Reetz K., Reich A., Costa A.S. Incident stroke in patients with Alzheimer’s disease: systematic review and meta-analysis. Sci Rep. 2021;11:16385. doi: 10.1038/s41598-021-95821-xPinho J., Quintas-Neves M., Dogan I., Reetz K., Reich A., Costa A.S. Incident stroke in patients with Alzheimer’s disease: systematic review and meta-analysis. Sci Rep. 2021;11:16385. doi: 10.1038/s41598-021-95821-xLoeffler D.A. Modifiable, Non-Modifiable, and Clinical Factors Associated with Progression of Alzheimer’s Disease. J Alzheimers Dis. 2021;80(1):1–27. doi: 10.3233/JAD-201182.Loeffler D.A. Modifiable, Non-Modifiable, and Clinical Factors Associated with Progression of Alzheimer’s Disease. J Alzheimers Dis. 2021;80(1):1–27. doi: 10.3233/JAD-201182.Быкова А.Ю., Кулеш А.А., Кайлева Н.А., Куклина Е.М., Шестаков В.В. Взаимосвязь динамики сывороточных концентраций интерлейкина-1β, интерлейкина-6 и интерлейкина-10 с клиническими данными в остром периоде ишемического инсульта в зависимости от стратегии реперфузионной терапии. Бюллетень сибирской медицины. 2019;18(4):16–25. doi: 10.20538/1682-0363-2019-4-16–25Bykova A.Yu., Kulesh A.A., Kayleva N.A., Kuklina E.M., Shestakov V.V. Interrelation of the dynamics of serum concentrations of interleukin-1β, interleukin-6 and interleukin-10 with clinical data in acute ischemic stroke and the strategy of reperfusion therapy. Bulletin of Siberian Medicine. 2019;18(4):16–25. (In Russ.). doi: 10.20538/1682-0363-2019-4-16–25Прилуцкая И.А., Крюк Ю.Я. Уровни фактора некроза опухолей α у больных ишемическим инсультом. Медицинская иммунология. 2019;21(4):755–764. doi: 10.15789/1563-0625-2019-4-755-764Prilutskaya I.A., Kryuk Yu.Ya. Levels of tumor necrosis factor alpha in patients with ischemic stroke. Medical Immunology (Russia). 2019;21(4):755–764. (In Russ.). doi: 10.15789/1563-0625-2019-4-755-764Hughes C.E, Nibbs R.J.B. A guide to chemokines and their receptors. FEBS J. 2018;285(16):2944–2971. doi: 10.1111/febs.14466.Hughes C.E, Nibbs R.J.B. A guide to chemokines and their receptors. FEBS J. 2018;285(16):2944–2971. doi: 10.1111/febs.14466.Zhou F., Sun Y., Xie X., Zhao Y. Blood and CSF chemokines in Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis. Alzheimers Res Ther. 2023;15(1):107. doi: 10.1186/s13195-023-01254-1Zhou F., Sun Y., Xie X., Zhao Y. Blood and CSF chemokines in Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis. Alzheimers Res Ther. 2023;15(1):107. doi: 10.1186/s13195-023-01254-1Tang E.Y.H., Price C.I., Robinson L., Exley C., Desmond D.W., Köhler S. et al. Assessing the Predictive Validity of Simple Dementia Risk Models in Harmonized Stroke Cohorts. Stroke. 202051(7):2095–2102. doi: 10.1161/STROKEAHA.120.027473Tang E.Y.H., Price C.I., Robinson L., Exley C., Desmond D.W., Köhler S. et al. Assessing the Predictive Validity of Simple Dementia Risk Models in Harmonized Stroke Cohorts. Stroke. 202051(7):2095–2102. doi: 10.1161/STROKEAHA.120.027473Парфенов В.А. Когнитивные нарушения после инсульта. Неврология, нейропсихиатрия, психосоматика. 2019;11(4):22–27. doi: 0.14412/2074-2711-2019-4-22-27Parfenov V.A. Poststroke cognitive impairment. Neurology, Neuropsychiatry, Psychosomatics. 2019;11(4):22–27. (In Russ.). doi: 0.14412/2074-2711-2019-4-22-27Desai RH, Reilly M, van Dam W. The multifaceted abstract brain. Philos Trans R Soc Lond B Biol Sci. 2018;373(1752):20170122. doi: 10.1098/rstb.2017.0122Desai RH, Reilly M, van Dam W. The multifaceted abstract brain. Philos Trans R Soc Lond B Biol Sci. 2018;373(1752):20170122. doi: 10.1098/rstb.2017.0122Weaver N.A., Kuijf H.J., Aben H.P., Abrigo J., Bae H.J., Barbay M. et al. Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts. Lancet Neurol. 2021;20(6):448–459. doi: 10.1016/S1474-4422(21)00060-0Weaver N.A., Kuijf H.J., Aben H.P., Abrigo J., Bae H.J., Barbay M. et al. Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts. Lancet Neurol. 2021;20(6):448–459. doi: 10.1016/S1474-4422(21)00060-0Cole R.H., Clark C.N., Poole N.A. Semantic dementia: a complex and culturally influenced presentation. BJPsych Bull. 2023Jan 31:1–7. doi: 10.1192/bjb.2022.100Cole R.H., Clark C.N., Poole N.A. Semantic dementia: a complex and culturally influenced presentation. BJPsych Bull. 2023Jan 31:1–7. doi: 10.1192/bjb.2022.100Васенина Е.Е., Левин О.С. Нарушение речи при нейродегенеративных заболеваниях как проявление дисфазии. Журнал неврологии и психиатрии им. С.С. Корсакова. 2020;120(5):50–59. doi: 10.17116/jnevro202012005150Vasenina EE, Levin OS. Speech disorders in neurodegenerative diseases as dysphasia manifestation. S.S. Korsakov Journal of Neurology and Psychiatry. 2020;120(5):50–59. (In Russ.). doi: 10.17116/jnevro202012005150Тихомиров Г.В, Григорьева В.Н. Зрительная предметная агнозия сложных форм у больных с острым ишемическим инсультом. Практическая медицина. 2019;17(7):107–110. doi: 10.32000/2072-1757-2019-7-107-110Tikhomirov G.V, Grigoryeva V.N. Visual object agnosia for complex shapes in patients with acute ischemic stroke. Practical Medicine. 2019;17 (7):107–110. (In Russ.). doi: 10.32000/2072-1757-2019-7-107-110Rost N.S., Brodtmann A., Pase M.P., van Veluw S.J., Biffi A., Duering M. et al. Post-Stroke Cognitive Impairment and Dementia. Circ Res. 2022;130(8):1252–1271. doi: 10.1161/CIRCRESAHA.122.319951Rost N.S., Brodtmann A., Pase M.P., van Veluw S.J., Biffi A., Duering M. et al. Post-Stroke Cognitive Impairment and Dementia. Circ Res. 2022;130(8):1252–1271. doi: 10.1161/CIRCRESAHA.122.319951Doyle K.P., Buckwalter M.S. Immunological mechanisms in poststroke dementia. Curr Opin Neurol. 2020;33(1):30–36. doi: 10.1097/WCO.0000000000000783Doyle K.P., Buckwalter M.S. Immunological mechanisms in poststroke dementia. Curr Opin Neurol. 2020;33(1):30–36. doi: 10.1097/WCO.0000000000000783Berchiche Y.A., Sakmar T.P. CXC Chemokine Receptor 3 Alternative Splice Variants Selectively Activate Different Signaling Pathways. Mol Pharmacol. 2016;90(4):483–95. doi: 10.1124/mol.116.105502Berchiche Y.A., Sakmar T.P. CXC Chemokine Receptor 3 Alternative Splice Variants Selectively Activate Different Signaling Pathways. Mol Pharmacol. 2016;90(4):483–95. doi: 10.1124/mol.116.105502Phares T.W., Stohlman S.A., Hinton D.R., Bergmann C.C. Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis. J Virol. 2013;87(6):3382–92. doi: 10.1128/JVI.03307-12Phares T.W., Stohlman S.A., Hinton D.R., Bergmann C.C. Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis. J Virol. 2013;87(6):3382–92. doi: 10.1128/JVI.03307-12Liu C.Y., Yang Y., Ju W.N., Wang X., Zhang H.L. Emerging Roles of Astrocytes in Neuro-Vascular Unit and the Tripartite Synapse With Emphasis on Reactive Gliosis in the Context of Alzheimer’s Disease. Front Cell Neurosci. 2018;12:193. doi: 10.3389/fncel.2018.00193Liu C.Y., Yang Y., Ju W.N., Wang X., Zhang H.L. Emerging Roles of Astrocytes in Neuro-Vascular Unit and the Tripartite Synapse With Emphasis on Reactive Gliosis in the Context of Alzheimer’s Disease. Front Cell Neurosci. 2018;12:193. doi: 10.3389/fncel.2018.00193Amin M., Vakilian A., Mahmoodi M.H., Hassanshahi G., Falahati-Pour S.K., Dolatabadi M.R., Nadimi A.E. Circulatory Levels of C-X-C Motif Chemokine Ligands 1, 9, and 10 Are Elevated in Patients with Ischemic Stroke. Eurasian J Med. 2017;49(2):92–96. doi: 10.5152/eurasianjmed.2017.17022Amin M., Vakilian A., Mahmoodi M.H., Hassanshahi G., Falahati-Pour S.K., Dolatabadi M.R., Nadimi A.E. Circulatory Levels of C-X-C Motif Chemokine Ligands 1, 9, and 10 Are Elevated in Patients with Ischemic Stroke. Eurasian J Med. 2017;49(2):92–96. doi: 10.5152/eurasianjmed.2017.17022Wojcieszak J., Kuczyńska K., Zawilska J.B. Role of Chemokines in the Development and Progression of Alzheimer’s Disease. J Mol Neurosci. 2022;72(9):1929–1951. doi: 10.1007/s12031-022-02047-1Wojcieszak J., Kuczyńska K., Zawilska J.B. Role of Chemokines in the Development and Progression of Alzheimer’s Disease. J Mol Neurosci. 2022;72(9):1929–1951. doi: 10.1007/s12031-022-02047-1Gill D., Sivakumaran P., Wilding P., Love M., Veltkamp R., KarA. Trends in C-reactive protein levels are associated with neurological change twenty-four hours after thrombolysis for acute ischemic stroke. J. Stroke Cerebrovasc. Dis. 2016;25(8):1966–1999. doi: 10.1016/J.JSTROKECEREBROVASDIS.2016.05.003Gill D., Sivakumaran P., Wilding P., Love M., Veltkamp R., KarA. Trends in C-reactive protein levels are associated with neurological change twenty-four hours after thrombolysis for acute ischemic stroke. J. Stroke Cerebrovasc. Dis. 2016;25(8):1966–1999. doi: 10.1016/J.JSTROKECEREBROVASDIS.2016.05.003Boro M., Balaji K.N. CXCL1 and CXCL2 Regulate NLRP3 Inflammasome Activation via G-Protein-Coupled Receptor CXCR2. J Immunol. 2017;199(5):1660–1671. doi: 10.4049/jimmunol.1700129Boro M., Balaji K.N. CXCL1 and CXCL2 Regulate NLRP3 Inflammasome Activation via G-Protein-Coupled Receptor CXCR2. J Immunol. 2017;199(5):1660–1671. doi: 10.4049/jimmunol.1700129Huang F., Lan Y., Qin L., Dong H., Shi H., Wu H. et al. Astragaloside IV Promotes Adult Neurogenesis in Hippocampal Dentate Gyrus of Mouse through CXCL1/CXCR2 Signaling. Molecules. 2018;23(9):2178. doi: 10.3390/molecules23092178Huang F., Lan Y., Qin L., Dong H., Shi H., Wu H. et al. Astragaloside IV Promotes Adult Neurogenesis in Hippocampal Dentate Gyrus of Mouse through CXCL1/CXCR2 Signaling. Molecules. 2018;23(9):2178. doi: 10.3390/molecules23092178Korbecki J., Gąssowska-Dobrowolska M., Wójcik J., Szatkowska I., Barczak K., Chlubek M., Baranowska-Bosiacka I. The Importance of CXCL1 in Physiology and Noncancerous Diseases of Bone, Bone Marrow, Muscle and the Nervous System. Int J Mol Sci. 2022;23(8):4205. doi: 10.3390/ijms23084205Korbecki J., Gąssowska-Dobrowolska M., Wójcik J., Szatkowska I., Barczak K., Chlubek M., Baranowska-Bosiacka I. The Importance of CXCL1 in Physiology and Noncancerous Diseases of Bone, Bone Marrow, Muscle and the Nervous System. Int J Mol Sci. 2022;23(8):4205. doi: 10.3390/ijms23084205Sanchez E., Wilkinson T., Coughlan G., Mirza S., Baril A.A., Ramirez J. et al. Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative. Alzheimers Dement. 2023 Dec 17. doi: 10.1002/alz.13560. Epub ahead of print. PMID:38105605.Sanchez E., Wilkinson T., Coughlan G., Mirza S., Baril A.A., Ramirez J. et al. Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative. Alzheimers Dement. 2023 Dec 17. doi: 10.1002/alz.13560. Epub ahead of print. PMID:38105605.

The authors declare that there are no conflicts of interest present.