炎症生物标记物与脑小血管病的研究进展
Research Progress on Inflammatory Biomarkers and Cerebral Small Vessel Disease
DOI: 10.12677/acm.2025.152530, PDF,   
作者: 周惠敏:济宁医学院临床医学院(附属医院),山东 济宁;闫中瑞*:济宁市第一人民医院神经内科,山东 济宁
关键词: 脑小血管病生物标记物炎症标记物影像学特征Cerebral Small Vessel Disease Biomarkers Inflammatory Markers Imaging Features
摘要: 脑小血管病是指各种病因导致大脑小动脉、小静脉和毛细血管的病变所致的一系列临床影像病理综合征。它是脑血管疾病最常见的亚型之一,与卒中的发生和复发、认知障碍、步态障碍、心理障碍和排尿困难有关。尽管脑小血管病对人们生活造成重大负担,但对其潜在病理生理机制的了解并不完全。目前,CSVD的诊断主要依靠神经影像学指标,但不能完全反映疾病的全貌。近年来,人们研究发现一些炎症标志物与CSVD有关,但其潜在机制尚不完全清楚。本文旨在系统地回顾和总结CSVD发病机制及相关炎症标志物,以期为CSVD的诊断和治疗提供思路。
Abstract: Cerebral small vessel disease is a series of clinico-imaging pathological syndromes resulting from various etiological factors causing lesions in the small arteries, veins and capillaries of the brain. It is one of the most common subtypes of cerebrovascular disease and is associated with the development and recurrence of stroke, cognitive impairment, gait disturbance, psychological disturbances, and urinary difficulties. Despite the significant burden of cerebral small vessel disease on people’s lives, the underlying pathophysiological mechanisms are incompletely understood. Currently, the diagnosis of CSVD relies on neuroimaging indices, which do not fully reflect the full picture of the disease. In recent years, some inflammatory markers have been investigated and found to be associated with CSVD, but the underlying mechanisms are still unclear. The aim of this paper is to systematically review and summarise the inflammatory markers related to the pathogenesis of CSVD, with a view to providing ideas for the diagnosis and treatment of CSVD.
文章引用:周惠敏, 闫中瑞. 炎症生物标记物与脑小血管病的研究进展[J]. 临床医学进展, 2025, 15(2): 1725-1733. https://doi.org/10.12677/acm.2025.152530

参考文献

[1] 陈玮琪, 徐佳洁, 陆瑶, 等. 中国脑小血管病的神经影像学诊断标准及名词标准化定义——来自中国卒中学会的专家共识[J]. 中国卒中杂志, 2024, 19(4): 376-404.
[2] 周惠敏, 王艳, 宋芳星, 等. 脑小血管病的发病机制[J]. 国际脑血管病杂志, 2023(2): 146-150.
[3] da Silva, P.H.R., Paschoal, A.M., Secchinatto, K.F., Zotin, M.C.Z., dos Santos, A.C., Viswanathan, A., et al. (2022) Contrast Agent‐Free State‐of‐the‐Art Magnetic Resonance Imaging on Cerebral Small Vessel Disease. Part 2: Diffusion Tensor Imaging and Functional Magnetic Resonance Imaging. NMR in Biomedicine, 35, e4743. [Google Scholar] [CrossRef] [PubMed]
[4] Zwartbol, M.H., van der Kolk, A.G., Kuijf, H.J., Witkamp, T.D., Ghaznawi, R., Hendrikse, J., et al. (2020) Intracranial Vessel Wall Lesions on 7T MRI and MRI Features of Cerebral Small Vessel Disease: The SMART-MR Study. Journal of Cerebral Blood Flow & Metabolism, 41, 1219-1228. [Google Scholar] [CrossRef] [PubMed]
[5] Sproston, N.R. and Ashworth, J.J. (2018) Role of C-Reactive Protein at Sites of Inflammation and Infection. Frontiers in Immunology, 9, Article No. 754. [Google Scholar] [CrossRef] [PubMed]
[6] Soeki, T. and Sata, M. (2016) Inflammatory Biomarkers and Atherosclerosis. International Heart Journal, 57, 134-139. [Google Scholar] [CrossRef] [PubMed]
[7] Kuppa, A., Tripathi, H., Al-Darraji, A., Tarhuni, W.M. and Abdel-Latif, A. (2023) C-Reactive Protein Levels and Risk of Cardiovascular Diseases: A Two-Sample Bidirectional Mendelian Randomization Study. International Journal of Molecular Sciences, 24, Article No. 9129. [Google Scholar] [CrossRef] [PubMed]
[8] Jaime Garcia, D., Chagnot, A., Wardlaw, J.M. and Montagne, A. (2023) A Scoping Review on Biomarkers of Endothelial Dysfunction in Small Vessel Disease: Molecular Insights from Human Studies. International Journal of Molecular Sciences, 24, Article No. 13114. [Google Scholar] [CrossRef] [PubMed]
[9] Moutachakkir, M., Lamrani Hanchi, A., Baraou, A., Boukhira, A. and Chellak, S. (2017) Immunoanalytical Characteristics of C-Reactive Protein and High Sensitivity C-Reactive Protein. Annales de Biologie Clinique, 75, 225-229. [Google Scholar] [CrossRef] [PubMed]
[10] Webb, N.R. (2021) High-Density Lipoproteins and Serum Amyloid a (SAA). Current Atherosclerosis Reports, 23, Article No. 7. [Google Scholar] [CrossRef] [PubMed]
[11] De Buck, M., Gouwy, M., Struyf, S., Opdenakker, G. and Van Damme, J. (2019) The Ectoenzyme-Side of Matrix Metalloproteinases (MMPs) Makes Inflammation by Serum Amyloid a (SAA) and Chemokines Go Round. Immunology Letters, 205, 1-8. [Google Scholar] [CrossRef] [PubMed]
[12] Sack, G.H. (2020) Serum Amyloid A (SAA) Proteins. In: Subcellular Biochemistry, Springer International Publishing, 421-436. [Google Scholar] [CrossRef] [PubMed]
[13] Luyendyk, J.P., Schoenecker, J.G. and Flick, M.J. (2019) The Multifaceted Role of Fibrinogen in Tissue Injury and Inflammation. Blood, 133, 511-520. [Google Scholar] [CrossRef] [PubMed]
[14] Wolberg, A.S. (2023) Fibrinogen and Fibrin: Synthesis, Structure, and Function in Health and Disease. Journal of Thrombosis and Haemostasis, 21, 3005-3015. [Google Scholar] [CrossRef] [PubMed]
[15] Held, C., White, H.D., Stewart, R.A.H., Budaj, A., Cannon, C.P., Hochman, J.S., et al. (2017) Inflammatory Biomarkers Interleukin‐6 and C‐Reactive Protein and Outcomes in Stable Coronary Heart Disease: Experiences from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial. Journal of the American Heart Association, 6, e005077. [Google Scholar] [CrossRef] [PubMed]
[16] van Loo, G. and Bertrand, M.J.M. (2022) Death by TNF: A Road to Inflammation. Nature Reviews Immunology, 23, 289-303. [Google Scholar] [CrossRef] [PubMed]
[17] Pan, L., Cheng, Y., Yang, W., Wu, X., Zhu, H., Hu, M., et al. (2023) Nintedanib Ameliorates Bleomycin-Induced Pulmonary Fibrosis, Inflammation, Apoptosis, and Oxidative Stress by Modulating PI3K/Akt/mTOR Pathway in Mice. Inflammation, 46, 1531-1542. [Google Scholar] [CrossRef] [PubMed]
[18] Bui, T.M., Wiesolek, H.L. and Sumagin, R. (2020) ICAM-1: A Master Regulator of Cellular Responses in Inflammation, Injury Resolution, and Tumorigenesis. Journal of Leukocyte Biology, 108, 787-799. [Google Scholar] [CrossRef] [PubMed]
[19] Guieu, R., Ruf, J. and Mottola, G. (2022) Hyperhomocysteinemia and Cardiovascular Diseases. Annales de Biologie Clinique, 80, 7-14. [Google Scholar] [CrossRef] [PubMed]
[20] Tawfik, A., Elsherbiny, N.M., Zaidi, Y. and Rajpurohit, P. (2021) Homocysteine and Age-Related Central Nervous System Diseases: Role of Inflammation. International Journal of Molecular Sciences, 22, Article No. 6259. [Google Scholar] [CrossRef] [PubMed]
[21] Conway, E.M. (2011) Thrombomodulin and Its Role in Inflammation. Seminars in Immunopathology, 34, 107-125. [Google Scholar] [CrossRef] [PubMed]
[22] Ozaki, Y., Suzuki-Inoue, K. and Inoue, O. (2013) Platelet Receptors Activated via Mulitmerization: Glycoprotein VI, Gpib-ix-v, and Clec-2. Journal of Thrombosis and Haemostasis, 11, 330-339. [Google Scholar] [CrossRef] [PubMed]
[23] Suidan, G.L., Brill, A., De Meyer, S.F., Voorhees, J.R., Cifuni, S.M., Cabral, J.E., et al. (2013) Endothelial Von Willebrand Factor Promotes Blood-Brain Barrier Flexibility and Provides Protection from Hypoxia and Seizures in Mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 33, 2112-2120. [Google Scholar] [CrossRef] [PubMed]
[24] Yao, H., Mizoguchi, Y., Monji, A., Yakushiji, Y., Takashima, Y., Uchino, A., et al. (2019) Low-Grade Inflammation Is Associated with Apathy Indirectly via Deep White Matter Lesions in Community-Dwelling Older Adults: The Sefuri Study. International Journal of Molecular Sciences, 20, Article No. 1905. [Google Scholar] [CrossRef] [PubMed]
[25] Elkind, M.S.V., Luna, J.M., McClure, L.A., Zhang, Y., Coffey, C.S., Roldan, A., et al. (2014) C-Reactive Protein as a Prognostic Marker after Lacunar Stroke: Levels of Inflammatory Markers in the Treatment of Stroke Study. Stroke, 45, 707-716. [Google Scholar] [CrossRef] [PubMed]
[26] Gu, Y., Gutierrez, J., Meier, I.B., Guzman, V.A., Manly, J.J., Schupf, N., et al. (2019) Circulating Inflammatory Biomarkers Are Related to Cerebrovascular Disease in Older Adults. Neurology Neuroimmunology & Neuroinflammation, 6, e521. [Google Scholar] [CrossRef] [PubMed]
[27] Schweizer, J., Bustamante, A., Lapierre-Fétaud, V., Faura, J., Scherrer, N., Azurmendi Gil, L., et al. (2020) SAA (Serum Amyloid A): A Novel Predictor of Stroke-Associated Infections. Stroke, 51, 3523-3530. [Google Scholar] [CrossRef] [PubMed]
[28] Shridas, P. and Tannock, L.R. (2019) Role of Serum Amyloid A in Atherosclerosis. Current Opinion in Lipidology, 30, 320-325. [Google Scholar] [CrossRef] [PubMed]
[29] Xu, W., Wang, J. and Yang, H. (2022) Correlation and Prognostic Action of SAA, Hcy, and BNP Levels with the Condition of Patients with Spontaneous Intracerebral Hemorrhage. Evidence-Based Complementary and Alternative Medicine, 2022, Article ID: 1126611. [Google Scholar] [CrossRef] [PubMed]
[30] Guo, X., Deng, B., Zhong, L., Xie, F., Qiu, Q., Wei, X., et al. (2021) Fibrinogen Is an Independent Risk Factor for White Matter Hyperintensities in CADASIL but Not in Sporadic Cerebral Small Vessel Disease Patients. Aging and Disease, 12, 801-811. [Google Scholar] [CrossRef] [PubMed]
[31] Xu, M., Li, J., Xu, B., Zheng, Q. and Sun, W. (2024) Association of Coagulation Markers with the Severity of White Matter Hyperintensities in Cerebral Small Vessel Disease. Frontiers in Neurology, 15, Article ID: 1331733. [Google Scholar] [CrossRef] [PubMed]
[32] Shen, M., Wei, G., Cheng, M. and Jiang, H. (2020) Association between Enlarged Perivascular Spaces and Internal Carotid Artery Stenosis: A Study in Patients Diagnosed by Digital Subtraction Angiography. Journal of Stroke and Cerebrovascular Diseases, 29, Article ID: 104635. [Google Scholar] [CrossRef] [PubMed]
[33] Liu, J., Wang, D., Xiong, Y., Liu, B., Lin, J., Zhang, S., et al. (2017) Association between Coagulation Function and Cerebral Microbleeds in Ischemic Stroke Patients with Atrial Fibrillation And/or Rheumatic Heart Disease. Aging and disease, 8, 131-135. [Google Scholar] [CrossRef] [PubMed]
[34] Georgakis, M.K., Malik, R., Gill, D., et al. (2020) Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study. Circulation: Genomic and Precision Medicine, 13, e002872.
[35] Palta, P., Xue, Q., Deal, J.A., Fried, L.P., Walston, J.D. and Carlson, M.C. (2014) Interleukin-6 and C-Reactive Protein Levels and 9-Year Cognitive Decline in Community-Dwelling Older Women: The Women’s Health and Aging Study Ii. The Journals of Gerontology: Series A, 70, 873-878. [Google Scholar] [CrossRef] [PubMed]
[36] Noz, M.P., ter Telgte, A., Wiegertjes, K., Joosten, L.A.B., Netea, M.G., de Leeuw, F., et al. (2018) Trained Immunity Characteristics Are Associated with Progressive Cerebral Small Vessel Disease. Stroke, 49, 2910-2917. [Google Scholar] [CrossRef] [PubMed]
[37] Satizabal, C.L., Zhu, Y.C., Mazoyer, B., Dufouil, C. and Tzourio, C. (2012) Circulating IL-6 and CRP Are Associated with MRI Findings in the Elderly: The 3C-Dijon Study. Neurology, 78, 720-727. [Google Scholar] [CrossRef] [PubMed]
[38] Hervella, P., Alonso-Alonso, M.L., Sampedro-Viana, A., Rodríguez-Yáñez, M., López-Dequidt, I., Pumar, J.M., et al. (2024) Differential Blood-Based Biomarkers of Subcortical and Deep Brain Small Vessel Disease. Therapeutic Advances in Neurological Disorders, 17, Article ID: 61442934. [Google Scholar] [CrossRef] [PubMed]
[39] Shoamanesh, A., Preis, S.R., Beiser, A.S., Vasan, R.S., Benjamin, E.J., Kase, C.S., et al. (2015) Inflammatory Biomarkers, Cerebral Microbleeds, and Small Vessel Disease: Framingham Heart Study. Neurology, 84, 825-832. [Google Scholar] [CrossRef] [PubMed]
[40] Manukjan, N., Majcher, D., Leenders, P., Caiment, F., van Herwijnen, M., Smeets, H.J., et al. (2023) Hypoxic Oligodendrocyte Precursor Cell-Derived VEGFA Is Associated with Blood–brain Barrier Impairment. Acta Neuropathologica Communications, 11, Article No. 128. [Google Scholar] [CrossRef] [PubMed]
[41] Zhang, J.B., Li, M.F., Zhang, H.X., Li, Z.G., Sun, H.R., Zhang, J.S., et al. (2016) Association of Serum Vascular Endothelial Growth Factor Levels and Cerebral Microbleeds in Patients with Alzheimer’s Disease. European Journal of Neurology, 23, 1337-1342. [Google Scholar] [CrossRef] [PubMed]
[42] Ma, C., Yang, L. and Wang, L. (2022) Correlation of Serum C‐Peptide, Soluble Intercellular Adhesion Molecule‐1, and NLRP3 Inflammasome‐Related Inflammatory Factor Interleukin‐1β after Brain Magnetic Resonance Imaging Examination with Cerebral Small Vessel Disease. Contrast Media & Molecular Imaging, 2022, Article ID: 4379847. [Google Scholar] [CrossRef] [PubMed]
[43] Han, J.H., Wong, K.S., Wang, Y.Y., Fu, J.H., Ding, D. and Hong, Z. (2009) Plasma Level of Sicam-1 Is Associated with the Extent of White Matter Lesion among Asymptomatic Elderly Subjects. Clinical Neurology and Neurosurgery, 111, 847-851. [Google Scholar] [CrossRef] [PubMed]
[44] Ji, Y., Li, X., Teng, Z., Li, X., Jin, W. and Lv, P.Y. (2020) Homocysteine Is Associated with the Development of Cerebral Small Vessel Disease: Retrospective Analyses from Neuroimaging and Cognitive Outcomes. Journal of Stroke and Cerebrovascular Diseases, 29, Article ID: 105393. [Google Scholar] [CrossRef] [PubMed]
[45] Staszewski, J., Piusińska-Macoch, R., Brodacki, B., Skrobowska, E. and Stepien, A. (2018) IL-6, PF-4, Scd40 L, and Homocysteine Are Associated with the Radiological Progression of Cerebral Small-Vessel Disease: A 2-Year Follow-Up Study. Clinical Interventions in Aging, 13, 1135-1141. [Google Scholar] [CrossRef] [PubMed]
[46] Hassan, A. (2003) Markers of Endothelial Dysfunction in Lacunar Infarction and Ischaemic Leukoaraiosis. Brain, 126, 424-432. [Google Scholar] [CrossRef] [PubMed]
[47] Wang, X., Chappell, F.M., Valdes Hernandez, M., Lowe, G., Rumley, A., Shuler, K., et al. (2016) Endothelial Function, Inflammation, Thrombosis, and Basal Ganglia Perivascular Spaces in Patients with Stroke. Journal of Stroke and Cerebrovascular Diseases, 25, 2925-2931. [Google Scholar] [CrossRef] [PubMed]
[48] Gottesman, R.F., Cummiskey, C., Chambless, L., Wu, K.K., Aleksic, N., Folsom, A.R., et al. (2009) Hemostatic Factors and Subclinical Brain Infarction in a Community-Based Sample: The ARIC Study. Cerebrovascular Diseases, 28, 589-594. [Google Scholar] [CrossRef] [PubMed]
[49] Rouhl, R.P.W., Damoiseaux, J.G.M.C., Lodder, J., Theunissen, R.O., Knottnerus, I.L.H., Staals, J., et al. (2012) Vascular Inflammation in Cerebral Small Vessel Disease. Neurobiology of Aging, 33, 1800-1806. [Google Scholar] [CrossRef] [PubMed]
[50] Zhang, C.E., Wong, S.M., Uiterwijk, R., Backes, W.H., Jansen, J.F.A., Jeukens, C.R.L.P.N., et al. (2018) Blood-Brain Barrier Leakage in Relation to White Matter Hyperintensity Volume and Cognition in Small Vessel Disease and Normal Aging. Brain Imaging and Behavior, 13, 389-395. [Google Scholar] [CrossRef] [PubMed]
[51] Wardlaw, J.M., Benveniste, H., Nedergaard, M., Zlokovic, B.V., Mestre, H., Lee, H., et al. (2020) Perivascular Spaces in the Brain: Anatomy, Physiology and Pathology. Nature Reviews Neurology, 16, 137-153. [Google Scholar] [CrossRef] [PubMed]
[52] Wei, C., Cui, P., Li, H., Lang, W., Liu, G. and Ma, X. (2019) Shared Genes between Alzheimer’s Disease and Ischemic Stroke. CNS Neuroscience & Therapeutics, 25, 855-864. [Google Scholar] [CrossRef] [PubMed]
[53] Cuadrado-Godia, E., Dwivedi, P., Sharma, S., Ois Santiago, A., Roquer Gonzalez, J., Balcells, M., et al. (2018) Cerebral Small Vessel Disease: A Review Focusing on Pathophysiology, Biomarkers, and Machine Learning Strategies. Journal of Stroke, 20, 302-320. [Google Scholar] [CrossRef] [PubMed]