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

Video：

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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.	《中國高血壓防治指南》修訂委員會. 中國高血壓防治指南 2018 年修訂版. 心腦血管病防治, 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.	中國血脂管理指南修訂聯合專家委員會. 中國血脂管理指南(2023 年). 中華心血管病雜志, 2023, 51(3): 221-255.
16.	李東曉, 張堯, 張宏武, 等. 高同型半胱氨酸血癥的診斷、治療與預防專家共識. 罕少疾病雜志, 2022, 29(6): 1-4.
17.	中華醫學會內分泌學分會. 中國高尿酸血癥與痛風診療指南(2019). 中華內分泌代謝雜志, 2020, 36(1): 1-13.
18.	中華醫學會心血管病學分會介入心臟病學組, 中華醫學會心血管病學分會動脈粥樣硬化與冠心病學組, 中國醫師協會心血管內科醫師分會血栓防治專業委員會, 等. 穩定性冠心病診斷與治療指南. 中華心血管病雜志, 2018, 46(9): 680-694.
19.	倪其泓, 張嵐. 重視外周血管疾病的早期識別與綜合防治. 中華全科醫師雜志, 2019, 18(10): 909-912.
20.	中國醫師協會睡眠醫學專業委員會. 成人阻塞性睡眠呼吸暫停多學科診療指南. 中華醫學雜志, 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.	閆少凈, 樸翔宇, 趙潔, 等. 血清基質金屬蛋白酶-2 在腦白質病變患者頭顱 MRI 各分級中的表達水平. 臨床神經病學雜志, 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, Fr?drich 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.	孟江濤, 楊思宇, 趙曉霞. 新型血栓標志物與腦白質病變程度的相關性分析. 中風與神經疾病雜志, 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.	?lmez B, Togay I?ikay 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. 《中國高血壓防治指南》修訂委員會. 中國高血壓防治指南 2018 年修訂版. 心腦血管病防治, 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. 中國血脂管理指南修訂聯合專家委員會. 中國血脂管理指南(2023 年). 中華心血管病雜志, 2023, 51(3): 221-255.
16. 李東曉, 張堯, 張宏武, 等. 高同型半胱氨酸血癥的診斷、治療與預防專家共識. 罕少疾病雜志, 2022, 29(6): 1-4.
17. 中華醫學會內分泌學分會. 中國高尿酸血癥與痛風診療指南(2019). 中華內分泌代謝雜志, 2020, 36(1): 1-13.
18. 中華醫學會心血管病學分會介入心臟病學組, 中華醫學會心血管病學分會動脈粥樣硬化與冠心病學組, 中國醫師協會心血管內科醫師分會血栓防治專業委員會, 等. 穩定性冠心病診斷與治療指南. 中華心血管病雜志, 2018, 46(9): 680-694.
19. 倪其泓, 張嵐. 重視外周血管疾病的早期識別與綜合防治. 中華全科醫師雜志, 2019, 18(10): 909-912.
20. 中國醫師協會睡眠醫學專業委員會. 成人阻塞性睡眠呼吸暫停多學科診療指南. 中華醫學雜志, 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. 閆少凈, 樸翔宇, 趙潔, 等. 血清基質金屬蛋白酶-2 在腦白質病變患者頭顱 MRI 各分級中的表達水平. 臨床神經病學雜志, 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, Fr?drich 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. 孟江濤, 楊思宇, 趙曉霞. 新型血栓標志物與腦白質病變程度的相關性分析. 中風與神經疾病雜志, 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. ?lmez B, Togay I?ikay 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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