Correlations of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 with white matter hyperintensities in patients with cerebral small vessel disease_West China Medical Journal

Authors：

LUO Beilin ^1,2 , ZHANG Yifen ^1,2 , HE Shunpo ² , ZHU Renjing ² ,  YANG Qingwei ^1,2 , ZHENG Yuqin ² , HUANG Fuzhi ² , SU Huamei ²

1. The Graduate School of Fujian Medical University, Fuzhou, Fujian 350000, P. R. China;
2. Department of Neurology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361000, P. R. China;

Corresponding author：

YANG Qingwei, Email: yiheng66@126.com

Keywords：

Matrix metalloproteinase; tissue inhibitor of metalloproteinase; cerebral small vessel disease; white matter hyperintensity; cranial magnetic resonance imaging

DOI：

10.7507/1002-0179.202404251

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Objective To explore the correlations of serum levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and their ratios, with the severity of white matter hyperintensities (WMH) in patients with cerebral small vessel disease (CSVD). Methods This prospective study included patients with CSVD who were treated at Zhongshan Hospital, Xiamen University between January 2022 and February 2024. Qualitative and quantitative analyses of WMH were performed using the Fazekas scale and lesion prediction algorithm. Biomarkers such as MMP-2, MMP-9, and TIMP-1 were measured to explore their correlations with the severity of WMH. Results A total of 144 patients with CSVD were included in this study, comprising 63 males and 81 females, with an average age of (67.60±8.73) years. There were 83 (57.6%), 41 (28.5%), and 20 (13.9%) patients were categorized as Fazekas grade 1, 2, and 3 for WMH, respectively, with an median total WMH volume of 4.31 mL. Multinomial logistic regression analysis for Fazekas grade (grade 1 as the reference level) showed that MMP-2 [grade 2: odds ratio (OR)=1.059, 95% confidence interval (CI) (1.016, 1.105); grade 3: OR=1.463, 95%CI (1.124, 1.905)], TIMP-1 [grade 2: OR=1.019, 95%CI (1.006, 1.032); grade 3: OR=1.048, 95%CI (1.008, 1.090)], and MMP-9/TIMP-1 [grade 3: OR=2.650, 95%CI (1.393, 5.039)] were independently associated with Fazekas grade (P<0.05). Multinomial logistic regression analysis for the quartile group of total WMH volume (group Q₁ as the reference level) showed that MMP-2 [group Q₂: OR=1.160, 95%CI (1.021, 1.318); group Q₃: OR=1.238, 95%CI (1.086, 1.412); group Q₄: OR=1.313, 95%CI (1.140, 1.512)] and TIMP-1 [group Q₂: OR=1.095, 95%CI (1.054, 1.138); group Q₃: OR=1.084, 95%CI (1.045, 1.125); group Q₄: OR=1.102, 95%CI (1.057, 1.149)] were independently associated with the quartile group of total WMH volume (P<0.05). Conclusions Serum levels of MMP-2 and TIMP-1 demonstrate significant independent associations with both the Fazekas grade and the total volume of WMH in patients with CSVD. These correlations underscore the potential utility of MMP-2 and TIMP-1 as critical biomarkers for assessing the severity of WMH in CSVD, highlighting their prospective roles in clinical diagnostics and therapeutic monitoring.

Citation： LUO Beilin, ZHANG Yifen, HE Shunpo, ZHU Renjing, YANG Qingwei, ZHENG Yuqin, HUANG Fuzhi, SU Huamei. Correlations of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 with white matter hyperintensities in patients with cerebral small vessel disease. West China Medical Journal, 2024, 39(5): 723-731. doi: 10.7507/1002-0179.202404251 Copy

1.	Solé-Guardia G, Custers E, de Lange A, et al. Association between hypertension and neurovascular inflammation in both normal-appearing white matter and white matter hyperintensities. Acta Neuropathol Commun, 2023, 11(1): 2.
2.	Duering M, Biessels GJ, Brodtmann A, et al. Neuroimaging standards for research into small vessel disease-advances since 2013. Lancet Neurol, 2023, 22(7): 602-618.
3.	Grosu S, Rospleszcz S, Hartmann F, et al. Associated factors of white matter hyperintensity volume: a machine-learning approach. Sci Rep, 2021, 11(1): 2325.
4.	Ottavi TP, Pepper E, Bateman G, et al. Consensus statement for the management of incidentally found brain white matter hyperintensities in general medical practice. Med J Aust, 2023, 219(6): 278-284.
5.	Zhang DD, Cao Y, Mu JY, et al. Inflammatory biomarkers and cerebral small vessel disease: a community-based cohort study. Stroke Vasc Neurol, 2022, 7(4): 302-309.
6.	Jiang L, Cai X, Yao D, et al. Association of inflammatory markers with cerebral small vessel disease in community-based population. J Neuroinflammation, 2022, 19(1): 106.
7.	Ahmadighadykolaei H, Lambert JA, Raeeszadeh-Sarmazdeh M. TIMP-1 protects tight junctions of brain endothelial cells from MMP-mediated degradation. Pharm Res, 2023, 40(9): 2121-2131.
8.	Jiménez-Balado J, Pizarro J, Riba-Llena I, et al. New candidate blood biomarkers potentially associated with white matter hyperintensities progression. Sci Rep, 2021, 11(1): 14324.
9.	Zhang DP, Peng YF, Zhang HL, et al. Basilar artery tortuosity is associated with white matter hyperintensities by TIMP-1. Front Neurosci, 2019, 13: 836.
10.	Boumiza S, Chahed K, Tabka Z, et al. MMPs and TIMPs levels are correlated with anthropometric parameters, blood pressure, and endothelial function in obesity. Sci Rep, 2021, 11(1): 20052.
11.	Kim Y, Kim YK, Kim NK, et al. Circulating matrix metalloproteinase-9 level is associated with cerebral white matter hyperintensities in non-stroke individuals. Eur Neurol, 2014, 72(3/4): 234-240.
12.	Zhang M, Zhu W, Yun W, et al. Correlation of matrix metalloproteinase-2 single nucleotide polymorphisms with the risk of small vessel disease (SVD). J Neurol Sci, 2015, 356(1/2): 61-64.
13.	《中国高血压防治指南》修订委员会. 中国高血压防治指南 2018 年修订版. 心脑血管病防治, 2019, 19(1): 1-44.
14.	American Diabetes Association Professional Practice Committee. 2. Diagnosis and classification of diabetes: Standards of Care in Diabetes-2024. Diabetes Care, 2024, 47(Suppl 1): S20-S42.
15.	中国血脂管理指南修订联合专家委员会. 中国血脂管理指南(2023 年). 中华心血管病杂志, 2023, 51(3): 221-255.
16.	李东晓, 张尧, 张宏武, 等. 高同型半胱氨酸血症的诊断、治疗与预防专家共识. 罕少疾病杂志, 2022, 29(6): 1-4.
17.	中华医学会内分泌学分会. 中国高尿酸血症与痛风诊疗指南(2019). 中华内分泌代谢杂志, 2020, 36(1): 1-13.
18.	中华医学会心血管病学分会介入心脏病学组, 中华医学会心血管病学分会动脉粥样硬化与冠心病学组, 中国医师协会心血管内科医师分会血栓防治专业委员会, 等. 稳定性冠心病诊断与治疗指南. 中华心血管病杂志, 2018, 46(9): 680-694.
19.	倪其泓, 张岚. 重视外周血管疾病的早期识别与综合防治. 中华全科医师杂志, 2019, 18(10): 909-912.
20.	中国医师协会睡眠医学专业委员会. 成人阻塞性睡眠呼吸暂停多学科诊疗指南. 中华医学杂志, 2018, 98(24): 1902-1914.
21.	Rossing P, Caramori ML, Chan JCN, et al. Executive summary of the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease: an update based on rapidly emerging new evidence. Kidney Int, 2022, 102(5): 990-999.
22.	Zeng W, Chen Y, Zhu Z, et al. Severity of white matter hyperintensities: lesion patterns, cognition, and microstructural changes. J Cereb Blood Flow Metab, 2020, 40(12): 2454-2463.
23.	Fazekas F, Chawluk JB, Alavi A, et al. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol, 1987, 149(2): 351-356.
24.	Kynast J, Lampe L, Luck T, et al. White matter hyperintensities associated with small vessel disease impair social cognition beside attention and memory. J Cereb Blood Flow Metab, 2018, 38(6): 996-1009.
25.	de Leeuw FE, de Groot JC, Achten E, et al. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry, 2001, 70(1): 9-14.
26.	Wallin A, Kapaki E, Boban M, et al. Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - a consensus report. BMC Neurol, 2017, 17(1): 102.
27.	de Almeida LGN, Thode H, Eslambolchi Y, et al. Matrix metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacol Rev, 2022, 74(3): 712-768.
28.	Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci, 2020, 21(24): 9739.
29.	Alber J, Alladi S, Bae HJ, et al. White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): knowledge gaps and opportunities. Alzheimers Dement (N Y), 2019, 5: 107-117.
30.	闫少净, 朴翔宇, 赵洁, 等. 血清基质金属蛋白酶-2 在脑白质病变患者头颅 MRI 各分级中的表达水平. 临床神经病学杂志, 2017, 30(6): 435-438.
31.	Ihara M, Tomimoto H, Kinoshita M, et al. Chronic cerebral hypoperfusion induces MMP-2 but not MMP-9 expression in the microglia and vascular endothelium of white matter. J Cereb Blood Flow Metab, 2001, 21(7): 828-834.
32.	Rost NS, Cougo P, Lorenzano S, et al. Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke. J Cereb Blood Flow Metab, 2018, 38(1): 75-86.
33.	Yang Y, Rosenberg GA. Matrix metalloproteinases as therapeutic targets for stroke. Brain Res, 2015, 1623: 30-38.
34.	Romero JR, Vasan RS, Beiser AS, et al. Association of matrix metalloproteinases with MRI indices of brain ischemia and aging. Neurobiol Aging, 2010, 31(12): 2128-2135.
35.	Bugno M, Graeve L, Gatsios P, et al. Identification of the interleukin-6/oncostatin M response element in the rat tissue inhibitor of metalloproteinases-1 (TIMP-1) promoter. Nucleic Acids Res, 1995, 23(24): 5041-5047.
36.	Schoeps B, Frädrich J, Krüger A. Cut loose TIMP-1: an emerging cytokine in inflammation. Trends Cell Biol, 2023, 33(5): 413-426.
37.	Low A, Mak E, Rowe JB, et al. Inflammation and cerebral small vessel disease: a systematic review. Ageing Res Rev, 2019, 53: 100916.
38.	孟江涛, 杨思宇, 赵晓霞. 新型血栓标志物与脑白质病变程度的相关性分析. 中风与神经疾病杂志, 2023, 40(8): 730-734.
39.	Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol, 2014, 6(10): a016295.
40.	Yuan CL, Yi R, Dong Q, et al. The relationship between diabetes-related cognitive dysfunction and leukoaraiosis. Acta Neurol Belg, 2021, 121(5): 1101-1110.
41.	Liu X, Lam DC, Mak HK, et al. Associations of sleep apnea risk and oxygen desaturation indices with cerebral small vessel disease burden in patients with stroke. Front Neurol, 2022, 13: 956208.
42.	Song TJ, Park JH, Choi KH, et al. Moderate-to-severe obstructive sleep apnea is associated with cerebral small vessel disease. Sleep Med, 2017, 30: 36-42.
43.	Ölmez B, Togay Işikay C, Peker E, et al. The relationship between renal function and imaging markers and total burden of cerebral small vessel disease. Neurologist, 2022, 27(4): 157-163.

1. Solé-Guardia G, Custers E, de Lange A, et al. Association between hypertension and neurovascular inflammation in both normal-appearing white matter and white matter hyperintensities. Acta Neuropathol Commun, 2023, 11(1): 2.
2. Duering M, Biessels GJ, Brodtmann A, et al. Neuroimaging standards for research into small vessel disease-advances since 2013. Lancet Neurol, 2023, 22(7): 602-618.
3. Grosu S, Rospleszcz S, Hartmann F, et al. Associated factors of white matter hyperintensity volume: a machine-learning approach. Sci Rep, 2021, 11(1): 2325.
4. Ottavi TP, Pepper E, Bateman G, et al. Consensus statement for the management of incidentally found brain white matter hyperintensities in general medical practice. Med J Aust, 2023, 219(6): 278-284.
5. Zhang DD, Cao Y, Mu JY, et al. Inflammatory biomarkers and cerebral small vessel disease: a community-based cohort study. Stroke Vasc Neurol, 2022, 7(4): 302-309.
6. Jiang L, Cai X, Yao D, et al. Association of inflammatory markers with cerebral small vessel disease in community-based population. J Neuroinflammation, 2022, 19(1): 106.
7. Ahmadighadykolaei H, Lambert JA, Raeeszadeh-Sarmazdeh M. TIMP-1 protects tight junctions of brain endothelial cells from MMP-mediated degradation. Pharm Res, 2023, 40(9): 2121-2131.
8. Jiménez-Balado J, Pizarro J, Riba-Llena I, et al. New candidate blood biomarkers potentially associated with white matter hyperintensities progression. Sci Rep, 2021, 11(1): 14324.
9. Zhang DP, Peng YF, Zhang HL, et al. Basilar artery tortuosity is associated with white matter hyperintensities by TIMP-1. Front Neurosci, 2019, 13: 836.
10. Boumiza S, Chahed K, Tabka Z, et al. MMPs and TIMPs levels are correlated with anthropometric parameters, blood pressure, and endothelial function in obesity. Sci Rep, 2021, 11(1): 20052.
11. Kim Y, Kim YK, Kim NK, et al. Circulating matrix metalloproteinase-9 level is associated with cerebral white matter hyperintensities in non-stroke individuals. Eur Neurol, 2014, 72(3/4): 234-240.
12. Zhang M, Zhu W, Yun W, et al. Correlation of matrix metalloproteinase-2 single nucleotide polymorphisms with the risk of small vessel disease (SVD). J Neurol Sci, 2015, 356(1/2): 61-64.
13. 《中国高血压防治指南》修订委员会. 中国高血压防治指南 2018 年修订版. 心脑血管病防治, 2019, 19(1): 1-44.
14. American Diabetes Association Professional Practice Committee. 2. Diagnosis and classification of diabetes: Standards of Care in Diabetes-2024. Diabetes Care, 2024, 47(Suppl 1): S20-S42.
15. 中国血脂管理指南修订联合专家委员会. 中国血脂管理指南(2023 年). 中华心血管病杂志, 2023, 51(3): 221-255.
16. 李东晓, 张尧, 张宏武, 等. 高同型半胱氨酸血症的诊断、治疗与预防专家共识. 罕少疾病杂志, 2022, 29(6): 1-4.
17. 中华医学会内分泌学分会. 中国高尿酸血症与痛风诊疗指南(2019). 中华内分泌代谢杂志, 2020, 36(1): 1-13.
18. 中华医学会心血管病学分会介入心脏病学组, 中华医学会心血管病学分会动脉粥样硬化与冠心病学组, 中国医师协会心血管内科医师分会血栓防治专业委员会, 等. 稳定性冠心病诊断与治疗指南. 中华心血管病杂志, 2018, 46(9): 680-694.
19. 倪其泓, 张岚. 重视外周血管疾病的早期识别与综合防治. 中华全科医师杂志, 2019, 18(10): 909-912.
20. 中国医师协会睡眠医学专业委员会. 成人阻塞性睡眠呼吸暂停多学科诊疗指南. 中华医学杂志, 2018, 98(24): 1902-1914.
21. Rossing P, Caramori ML, Chan JCN, et al. Executive summary of the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease: an update based on rapidly emerging new evidence. Kidney Int, 2022, 102(5): 990-999.
22. Zeng W, Chen Y, Zhu Z, et al. Severity of white matter hyperintensities: lesion patterns, cognition, and microstructural changes. J Cereb Blood Flow Metab, 2020, 40(12): 2454-2463.
23. Fazekas F, Chawluk JB, Alavi A, et al. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol, 1987, 149(2): 351-356.
24. Kynast J, Lampe L, Luck T, et al. White matter hyperintensities associated with small vessel disease impair social cognition beside attention and memory. J Cereb Blood Flow Metab, 2018, 38(6): 996-1009.
25. de Leeuw FE, de Groot JC, Achten E, et al. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry, 2001, 70(1): 9-14.
26. Wallin A, Kapaki E, Boban M, et al. Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - a consensus report. BMC Neurol, 2017, 17(1): 102.
27. de Almeida LGN, Thode H, Eslambolchi Y, et al. Matrix metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacol Rev, 2022, 74(3): 712-768.
28. Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci, 2020, 21(24): 9739.
29. Alber J, Alladi S, Bae HJ, et al. White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): knowledge gaps and opportunities. Alzheimers Dement (N Y), 2019, 5: 107-117.
30. 闫少净, 朴翔宇, 赵洁, 等. 血清基质金属蛋白酶-2 在脑白质病变患者头颅 MRI 各分级中的表达水平. 临床神经病学杂志, 2017, 30(6): 435-438.
31. Ihara M, Tomimoto H, Kinoshita M, et al. Chronic cerebral hypoperfusion induces MMP-2 but not MMP-9 expression in the microglia and vascular endothelium of white matter. J Cereb Blood Flow Metab, 2001, 21(7): 828-834.
32. Rost NS, Cougo P, Lorenzano S, et al. Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke. J Cereb Blood Flow Metab, 2018, 38(1): 75-86.
33. Yang Y, Rosenberg GA. Matrix metalloproteinases as therapeutic targets for stroke. Brain Res, 2015, 1623: 30-38.
34. Romero JR, Vasan RS, Beiser AS, et al. Association of matrix metalloproteinases with MRI indices of brain ischemia and aging. Neurobiol Aging, 2010, 31(12): 2128-2135.
35. Bugno M, Graeve L, Gatsios P, et al. Identification of the interleukin-6/oncostatin M response element in the rat tissue inhibitor of metalloproteinases-1 (TIMP-1) promoter. Nucleic Acids Res, 1995, 23(24): 5041-5047.
36. Schoeps B, Frädrich J, Krüger A. Cut loose TIMP-1: an emerging cytokine in inflammation. Trends Cell Biol, 2023, 33(5): 413-426.
37. Low A, Mak E, Rowe JB, et al. Inflammation and cerebral small vessel disease: a systematic review. Ageing Res Rev, 2019, 53: 100916.
38. 孟江涛, 杨思宇, 赵晓霞. 新型血栓标志物与脑白质病变程度的相关性分析. 中风与神经疾病杂志, 2023, 40(8): 730-734.
39. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol, 2014, 6(10): a016295.
40. Yuan CL, Yi R, Dong Q, et al. The relationship between diabetes-related cognitive dysfunction and leukoaraiosis. Acta Neurol Belg, 2021, 121(5): 1101-1110.
41. Liu X, Lam DC, Mak HK, et al. Associations of sleep apnea risk and oxygen desaturation indices with cerebral small vessel disease burden in patients with stroke. Front Neurol, 2022, 13: 956208.
42. Song TJ, Park JH, Choi KH, et al. Moderate-to-severe obstructive sleep apnea is associated with cerebral small vessel disease. Sleep Med, 2017, 30: 36-42.
43. Ölmez B, Togay Işikay C, Peker E, et al. The relationship between renal function and imaging markers and total burden of cerebral small vessel disease. Neurologist, 2022, 27(4): 157-163.

West China Medical Journal

Correlations of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 with white matter hyperintensities in patients with cerebral small vessel disease

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