Association between Serum Innate Immunity-related Inflammatory Markers and MRI Features of Cerebral Small Vessel Disease: A Systematic Review and Meta-analysis
Abstract
Cerebral small vessel disease (CSVD) is a microvascular disorder associated with endothelial dysfunction, blood–brain barrier disruption, and chronic immune inflammation. However, the relationships between circulating inflammatory markers and magnetic resonance imaging (MRI) features of CSVD remain unclear.
A systematic search of PubMed, Embase, Web of Science, Cochrane Library, CNKI, and Wanfang databases was conducted from inception to December 2025. Observational studies evaluating associations between serum inflammatory markers and MRI-defined CSVD features, including white matter hyperintensities (WMH), lacunar infarction (LI), and cerebral microbleeds (CMB), were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models.
Eighteen studies were included. Elevated interleukin-6 (IL-6) levels were significantly associated with LI (OR=1.53, 95% CI: 1.11–2.11) and CMB (OR=1.28, 95% CI: 1.06–1.55). Increased high-sensitivity C-reactive protein (hs-CRP) levels were significantly associated with WMH (OR=2.19, 95% CI: 1.18–4.07), LI (OR=1.97, 95% CI: 1.21–3.20), and CMB (OR=1.67, 95% CI: 1.37–2.04). Elevated fibrinogen (FIB) levels were significantly associated with WMH (OR=1.48, 95% CI: 1.21–1.80). In contrast, conventional C-reactive protein showed no significant association with CSVD imaging markers.
This meta-analysis demonstrates that elevated IL-6, hs-CRP, and FIB levels are associated with MRI features of CSVD, supporting the involvement of innate immune inflammation in CSVD pathophysiology. These markers may reflect chronic cerebral microvascular injury and endothelial dysfunction. However, causal relationships cannot be established, and further prospective studies are required.
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2. Wang Y, Liu Z. Research progress on the correlation between MRI and impairment caused by cerebral small vessel disease: A review. Medicine 2023;102(40):e35389.
3. Bennett J, van Dinther M, Voorter P, Backes W, Barnes J, Barkhof F, et al. Assessment of Microvascular Disease in Heart and Brain by MRI: Application in Heart Failure with Preserved Ejection Fraction and Cerebral Small Vessel Disease. Medicina. 2023;59(9):1596.
4. Zhang H,Zhang Ch Y,LI J,He M L. Role of immunoinflammation in cerebral small vessel disease. International Journal of Cerebrovascular Diseases 2024;32(3):202-208.
5. Low A, Mak E, Rowe B J. Inflammation and cerebral small vessel disease: A systematic review. Ageing Res Rev. 2019;53100916.
6. Zhang H B, Guo Y J. Research progress of cerebral small vessel disease associated with immunoinflammatory mechanisms. Chinese J Contemporary Neurol Neurosurgery. 2021;21(05): 345-9.
7. Rascle L, Nighoghossian N, Cho T, Bochaton T, Paccalet A, Crola Da Silva C, et al. Inflammatory profile and white matter hyperintensity burden in acute ischemic stroke patients. J Neuroimmunol. 2022;371:577934.
8. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987(21);9:1-30.
9. Staszewski J, Piusińska-Macoch R, Brodacki B, Skrobowska E, Stępień A. Association between hemostatic markers, serum lipid fractions and progression of cerebral small vessel disease: A 2-year follow-up study. Neurol Neurochir Pol. 2018;52(1):54-63.
10. Van Dijk EJ, Prins ND, Vermeer SE, Vrooman HA, Hofman A, Koudstaal PJ, et al. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation. 2005;112(6):900-5.
11. Yao H, Mizoguchi Y, Monji A, Yakushiji Y, Takashima Y, Uchino A, et al. Low-Grade Inflammation Is Associated with Apathy Indirectly via Deep White Matter Lesions in Community-Dwelling Older Adults: The Sefuri Study. Int J Mol Sci. 2019;20(8):1905.
12. Staszewski J, Piusińska-Macoch R, Brodacki B, Skrobowska E, Stępień A. 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. Clin Interv Aging. 2018;13:1135-41.
13. Li X, Wu Zh X, Zhang DP, Zhang YH, Zhang HL. Relationship of vertebrobasilar dolichoectasia and three vascular endothelial injury factors to white matter hyperintensity and lacunar infarction in patients with cerebral small vessel disease. Chinese J Cerebrovascular Dis. 2025;22(03):188-98.
14. Lu QL, Li CH, Jia ZR. Study on correlation between levels of hs-CRP, IL-6 and MMP-9 with cerebral microbleeding. Chongqing Med. 2017;46(26):3629-31.
15. Lu QL, Li C, Song Y, Jia ZR. Association between risk factors for cerebral microbleeds and inflammatory markers. Chinese J Geriatric Heart Brain Vessel Dis. 2016;18(10):1066-9.
16. Wada M, Takahashi Y, Iseki C, Kawanami T, Daimon M, Kato T. Plasma fibrinogen, global cognitive function, and cerebral small vessel disease: results of a cross-sectional study in community-dwelling Japanese elderly. Int Med Tokyo, Japan. 2011;50(9):999-1007.
17. Fornage M, Chiang YA, O'Meara ES, Psaty BM, Reiner AP, Siscovick DS, et al. Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study. Stroke. 2008;39(7):1952-9.
18. Hervella P, Alonso-Alonso ML, Sampedro-Viana A, Rodríguez-Yáñez M, López-Dequidt I, Pumar JM, et al. Differential blood-based biomarkers of subcortical and deep brain small vessel disease. Ther Adv Neurol Diso. 2024;17:17562864241243274.
19. Hoshi T, Kitagawa K, Yamagami H, Furukado S, Hougaku H, Hori M. Relations of serum high-sensitivity C-reactive protein and interleukin-6 levels with silent brain infarction. Stroke. 2005;36(4):768-72.
20. Guo X, Deng B, Zhong L, Xie F, Qiu Q, Wei X, et al. Fibrinogen is an Independent Risk Factor for White Matter Hyperintensities in CADASIL but not in Sporadic Cerebral Small Vessel Disease Patients. Aging Dis. 2021;12(3):801-11.
21. Gu Y, Gutierrez J, Meier IB, Guzman VA, Manly JJ, Schupf N, et al. Circulating inflammatory biomarkers are related to cerebrovascular disease in older adults. Neurol Neuroimmunol. 2018;6(1):e521.
22. Qiao Y, Zhao L, Cong C, Li Y, Tian S, Zhu X, et al. Association of systemic inflammatory markers with white matter hyperintensities and microstructural injury: an analysis of UK Biobank data. J Psychiatry Neurosci. 2025;50(1):E45-56.
23. Liu H, Sun F, Xu QQ, Gao YJ, Ma Z, Dou ZJ. Relationship between plasma D-D, LPA, FIB and brain white matter high signal in type 2 diabetes patients combined with cerebral small vessel disease. Chinese J Gerontol. 2021;41(4):702-4.
24. You C, Liu D, Liu L, Liu Q, Li G. Correlation between Fibrinogen and White Matter Hyperintensities among Nondiabetic Individuals with Noncardiogenic Ischemic Stroke. J Stroke Cerebrovascular Dis. 2018;27(9):2360-6.
25. Wei C, Zhang S, Liu J, Lin J, Yang T, Zhang S, et al. Association between Fibrinogen and Leukoaraiosis in Patients with Ischemic Stroke and Atrial Fibrillation. J Stroke Cerebrovascular Dis. 2017;26(11):2630-7.
26. Mitaki S, Nagai A, Oguro H, Yamaguchi S. C-reactive protein levels are associated with cerebral small vessel-related lesions. Acta Neurol Scand. 2016;133(1):68-74.
27. Backhouse EV, Boardman JP, Wardlaw JM. Cerebral Small Vessel Disease: Early-Life Antecedents and Long-Term Implications for the Brain, Aging, Stroke, and Dementia. Hypertension. 2024;81(1):54-74.
28. Noz MP, Ter Telgte A, Wiegertjes K, Joosten LAB, Netea MG, de Leeuw F, et al. Trained Immunity Characteristics Are Associated With Progressive Cerebral Small Vessel Disease. Stroke. 2018;49(12):2910-7.
29. Walker KA, Windham BG, Power MC, Hoogeveen RC, Folsom AR, Ballantyne CM, et al. The association of mid-to late-life systemic inflammation with white matter structure in older adults: The Atherosclerosis Risk in Communities Study. Neurobiol Aging. 2018;68:26-33.
30. Chen Y, Lu B, Shu Y, Sun Y. Spatiotemporal Dynamics of Cerebral Vascular Permeability in Type 2 Diabetes-Related Cerebral Microangiopathy. Front Endocrinol. 2022;12(4):805637.
31. HaiLing W, ChunLin Z, YanMei Q. Dysfunction of the Blood-brain Barrier in Cerebral Microbleeds: from Bedside to Bench.Aging and disease 2021;12(8):1898-919.
32. Grebenciucova E, VanHaerents S. Interleukin 6: at the interface of human health and disease. Front Immunol. 2023;14(5):1255533.
33. Voirin A, Perek N, Roche F. Inflammatory stress induced by a combination of cytokines (IL-6, IL-17, TNF-α) leads to a loss of integrity on bEnd.3 endothelial cells in vitro BBB model. Brain Res. 2020;1730(C):146647.
34. Lee S, Song I, Na S, Jeong D, Chung S. Association Between Long-term Functional Outcome and Change in hs-CRP Level in Patients With Acute Ischemic Stroke. Neurologist. 2020;25(5):122-5.
35. Zhang J, Liu C, Hu Y, Yang A, Zhang Y, Hong Y. The trend of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in spontaneous intracerebral hemorrhage and the predictive value of short-term postoperative prognosis in patients. Front Neurol. 2023;14:1189898.
36. Zhao Y, Wang X, Ren H, Yao Y. Systemic inflammation response index (SIRI) on the 3rd postoperative day are associated with severe pneumonia in cerebral hemorrhage patients: A single-center retrospective study. Medicine. 2023;102(43):e35587.
37. Li J, Xu LN, Li M, Song Y, Zhang J, Jia L. Correlations between serum BDNF, IL-18 and hs-CRP levels in patients with acute cerebral infarction and vascular cognitive impairment. Beijing Da Xue Xue Bao. Yi Xue Ban = Journal of Peking University. Health Sciences. 2024;56(4):708-14.
38. Hiba A, Nina M. Interleukin-6 promotes a sustained loss of endothelial barrier function via Janus kinase-mediated STAT3 phosphorylation and de novo protein synthesis.American journal of physiology. Cell physiology. 2018;314(5):C589-C602.
39. M P R. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. Circul Res. 2016;118(1):145-56.
40. Wolberg AS. Fibrinogen and fibrin: synthesis, structure, and function in health and disease. J Thrombosis Haemost. 2023;21(11):3005-15.
41. Kryczka KE, Kruk M, Demkow M, Lubiszewska B. Fibrinogen and a Triad of Thrombosis, Inflammation, and the Renin-Angiotensin System in Premature Coronary Artery Disease in Women: A New Insight into Sex-Related Differences in the Pathogenesis of the Disease. Biomolecules. 2021;11(7):1036.
42. Valcovici M, Iacob S M, Sharma A.The Junction of Allergic Inflammation and Atherosclerosis: Pathways and Clinical Implications-A Review. Life 2025;15(6):964.
2. Wang Y, Liu Z. Research progress on the correlation between MRI and impairment caused by cerebral small vessel disease: A review. Medicine 2023;102(40):e35389.
3. Bennett J, van Dinther M, Voorter P, Backes W, Barnes J, Barkhof F, et al. Assessment of Microvascular Disease in Heart and Brain by MRI: Application in Heart Failure with Preserved Ejection Fraction and Cerebral Small Vessel Disease. Medicina. 2023;59(9):1596.
4. Zhang H,Zhang Ch Y,LI J,He M L. Role of immunoinflammation in cerebral small vessel disease. International Journal of Cerebrovascular Diseases 2024;32(3):202-208.
5. Low A, Mak E, Rowe B J. Inflammation and cerebral small vessel disease: A systematic review. Ageing Res Rev. 2019;53100916.
6. Zhang H B, Guo Y J. Research progress of cerebral small vessel disease associated with immunoinflammatory mechanisms. Chinese J Contemporary Neurol Neurosurgery. 2021;21(05): 345-9.
7. Rascle L, Nighoghossian N, Cho T, Bochaton T, Paccalet A, Crola Da Silva C, et al. Inflammatory profile and white matter hyperintensity burden in acute ischemic stroke patients. J Neuroimmunol. 2022;371:577934.
8. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987(21);9:1-30.
9. Staszewski J, Piusińska-Macoch R, Brodacki B, Skrobowska E, Stępień A. Association between hemostatic markers, serum lipid fractions and progression of cerebral small vessel disease: A 2-year follow-up study. Neurol Neurochir Pol. 2018;52(1):54-63.
10. Van Dijk EJ, Prins ND, Vermeer SE, Vrooman HA, Hofman A, Koudstaal PJ, et al. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation. 2005;112(6):900-5.
11. Yao H, Mizoguchi Y, Monji A, Yakushiji Y, Takashima Y, Uchino A, et al. Low-Grade Inflammation Is Associated with Apathy Indirectly via Deep White Matter Lesions in Community-Dwelling Older Adults: The Sefuri Study. Int J Mol Sci. 2019;20(8):1905.
12. Staszewski J, Piusińska-Macoch R, Brodacki B, Skrobowska E, Stępień A. 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. Clin Interv Aging. 2018;13:1135-41.
13. Li X, Wu Zh X, Zhang DP, Zhang YH, Zhang HL. Relationship of vertebrobasilar dolichoectasia and three vascular endothelial injury factors to white matter hyperintensity and lacunar infarction in patients with cerebral small vessel disease. Chinese J Cerebrovascular Dis. 2025;22(03):188-98.
14. Lu QL, Li CH, Jia ZR. Study on correlation between levels of hs-CRP, IL-6 and MMP-9 with cerebral microbleeding. Chongqing Med. 2017;46(26):3629-31.
15. Lu QL, Li C, Song Y, Jia ZR. Association between risk factors for cerebral microbleeds and inflammatory markers. Chinese J Geriatric Heart Brain Vessel Dis. 2016;18(10):1066-9.
16. Wada M, Takahashi Y, Iseki C, Kawanami T, Daimon M, Kato T. Plasma fibrinogen, global cognitive function, and cerebral small vessel disease: results of a cross-sectional study in community-dwelling Japanese elderly. Int Med Tokyo, Japan. 2011;50(9):999-1007.
17. Fornage M, Chiang YA, O'Meara ES, Psaty BM, Reiner AP, Siscovick DS, et al. Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study. Stroke. 2008;39(7):1952-9.
18. Hervella P, Alonso-Alonso ML, Sampedro-Viana A, Rodríguez-Yáñez M, López-Dequidt I, Pumar JM, et al. Differential blood-based biomarkers of subcortical and deep brain small vessel disease. Ther Adv Neurol Diso. 2024;17:17562864241243274.
19. Hoshi T, Kitagawa K, Yamagami H, Furukado S, Hougaku H, Hori M. Relations of serum high-sensitivity C-reactive protein and interleukin-6 levels with silent brain infarction. Stroke. 2005;36(4):768-72.
20. Guo X, Deng B, Zhong L, Xie F, Qiu Q, Wei X, et al. Fibrinogen is an Independent Risk Factor for White Matter Hyperintensities in CADASIL but not in Sporadic Cerebral Small Vessel Disease Patients. Aging Dis. 2021;12(3):801-11.
21. Gu Y, Gutierrez J, Meier IB, Guzman VA, Manly JJ, Schupf N, et al. Circulating inflammatory biomarkers are related to cerebrovascular disease in older adults. Neurol Neuroimmunol. 2018;6(1):e521.
22. Qiao Y, Zhao L, Cong C, Li Y, Tian S, Zhu X, et al. Association of systemic inflammatory markers with white matter hyperintensities and microstructural injury: an analysis of UK Biobank data. J Psychiatry Neurosci. 2025;50(1):E45-56.
23. Liu H, Sun F, Xu QQ, Gao YJ, Ma Z, Dou ZJ. Relationship between plasma D-D, LPA, FIB and brain white matter high signal in type 2 diabetes patients combined with cerebral small vessel disease. Chinese J Gerontol. 2021;41(4):702-4.
24. You C, Liu D, Liu L, Liu Q, Li G. Correlation between Fibrinogen and White Matter Hyperintensities among Nondiabetic Individuals with Noncardiogenic Ischemic Stroke. J Stroke Cerebrovascular Dis. 2018;27(9):2360-6.
25. Wei C, Zhang S, Liu J, Lin J, Yang T, Zhang S, et al. Association between Fibrinogen and Leukoaraiosis in Patients with Ischemic Stroke and Atrial Fibrillation. J Stroke Cerebrovascular Dis. 2017;26(11):2630-7.
26. Mitaki S, Nagai A, Oguro H, Yamaguchi S. C-reactive protein levels are associated with cerebral small vessel-related lesions. Acta Neurol Scand. 2016;133(1):68-74.
27. Backhouse EV, Boardman JP, Wardlaw JM. Cerebral Small Vessel Disease: Early-Life Antecedents and Long-Term Implications for the Brain, Aging, Stroke, and Dementia. Hypertension. 2024;81(1):54-74.
28. Noz MP, Ter Telgte A, Wiegertjes K, Joosten LAB, Netea MG, de Leeuw F, et al. Trained Immunity Characteristics Are Associated With Progressive Cerebral Small Vessel Disease. Stroke. 2018;49(12):2910-7.
29. Walker KA, Windham BG, Power MC, Hoogeveen RC, Folsom AR, Ballantyne CM, et al. The association of mid-to late-life systemic inflammation with white matter structure in older adults: The Atherosclerosis Risk in Communities Study. Neurobiol Aging. 2018;68:26-33.
30. Chen Y, Lu B, Shu Y, Sun Y. Spatiotemporal Dynamics of Cerebral Vascular Permeability in Type 2 Diabetes-Related Cerebral Microangiopathy. Front Endocrinol. 2022;12(4):805637.
31. HaiLing W, ChunLin Z, YanMei Q. Dysfunction of the Blood-brain Barrier in Cerebral Microbleeds: from Bedside to Bench.Aging and disease 2021;12(8):1898-919.
32. Grebenciucova E, VanHaerents S. Interleukin 6: at the interface of human health and disease. Front Immunol. 2023;14(5):1255533.
33. Voirin A, Perek N, Roche F. Inflammatory stress induced by a combination of cytokines (IL-6, IL-17, TNF-α) leads to a loss of integrity on bEnd.3 endothelial cells in vitro BBB model. Brain Res. 2020;1730(C):146647.
34. Lee S, Song I, Na S, Jeong D, Chung S. Association Between Long-term Functional Outcome and Change in hs-CRP Level in Patients With Acute Ischemic Stroke. Neurologist. 2020;25(5):122-5.
35. Zhang J, Liu C, Hu Y, Yang A, Zhang Y, Hong Y. The trend of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in spontaneous intracerebral hemorrhage and the predictive value of short-term postoperative prognosis in patients. Front Neurol. 2023;14:1189898.
36. Zhao Y, Wang X, Ren H, Yao Y. Systemic inflammation response index (SIRI) on the 3rd postoperative day are associated with severe pneumonia in cerebral hemorrhage patients: A single-center retrospective study. Medicine. 2023;102(43):e35587.
37. Li J, Xu LN, Li M, Song Y, Zhang J, Jia L. Correlations between serum BDNF, IL-18 and hs-CRP levels in patients with acute cerebral infarction and vascular cognitive impairment. Beijing Da Xue Xue Bao. Yi Xue Ban = Journal of Peking University. Health Sciences. 2024;56(4):708-14.
38. Hiba A, Nina M. Interleukin-6 promotes a sustained loss of endothelial barrier function via Janus kinase-mediated STAT3 phosphorylation and de novo protein synthesis.American journal of physiology. Cell physiology. 2018;314(5):C589-C602.
39. M P R. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. Circul Res. 2016;118(1):145-56.
40. Wolberg AS. Fibrinogen and fibrin: synthesis, structure, and function in health and disease. J Thrombosis Haemost. 2023;21(11):3005-15.
41. Kryczka KE, Kruk M, Demkow M, Lubiszewska B. Fibrinogen and a Triad of Thrombosis, Inflammation, and the Renin-Angiotensin System in Premature Coronary Artery Disease in Women: A New Insight into Sex-Related Differences in the Pathogenesis of the Disease. Biomolecules. 2021;11(7):1036.
42. Valcovici M, Iacob S M, Sharma A.The Junction of Allergic Inflammation and Atherosclerosis: Pathways and Clinical Implications-A Review. Life 2025;15(6):964.
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| Issue | Vol 25 No 5 (2026) | |
| Section | Original Article(s) | |
| Keywords | ||
| Cerebral small vessel disease Inflammatory factors MRI characteristics Meta-analysis Systematic review | ||
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How to Cite
1.
Wu S, Zhu B. Association between Serum Innate Immunity-related Inflammatory Markers and MRI Features of Cerebral Small Vessel Disease: A Systematic Review and Meta-analysis. Iran J Allergy Asthma Immunol. 2026;25(5):663-680.
