Research progress on the regression of white matter hyperintensity of presumed vascular origin_West China Medical Journal

Authors：

REN Siyi ,  WU Bo ,  CHENG Yajun

Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding?author：

WU Bo, Email: dr.bowu@hotmail.com; CHENG Yajun, Email: chengyajun1234@163.com

Keywords：

Cerebral small vessel disease; white matter hyperintensity of presumed vascular origin; regression; cognitive function

DOI：

10.7507/1002-0179.202604102

Video：

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Abstract Full text Figures/Tables Video References Cited by

White matter hyperintensity (WMH) of presumed vascular origin is a common neuroimaging feature of cerebral small vessel disease. WMH regression has attracted increasing attention in recent years. In this review, we systematically summarize the incidence, influencing factors, pathological mechanisms, and clinical implications of WMH regression. The reported incidence of WMH regression varies widely across studies due to differences in study populations and measurement methods. However, neuroimaging evidence suggests that WMH regression has true biological significance rather than a simple measurement error. Many studies suggest that WMH regression has a protective effect on cognitive function. It holds promise as a surrogate imaging outcome for evaluating treatments for cerebral small vessel disease. Future studies are needed to better understand the underlying mechanisms, thus providing new insights into the treatment of cerebral small vessel disease.

Citation： REN Siyi, WU Bo, CHENG Yajun. Research progress on the regression of white matter hyperintensity of presumed vascular origin. West China Medical Journal, 2026, 41(5): 717-722. doi: 10.7507/1002-0179.202604102 Copy

1.	中華醫學會神經病學分會, 中華醫學會神經病學分會腦血管病學組. 中國腦小血管病診治指南 2020. 中華神經科雜志, 2022, 55(8): 807-818.
2.	Markus HS, de Leeuw FE. Cerebral small vessel disease: recent advances and future directions. Int J Stroke, 2023, 18(1): 4-14.
3.	Markus HS, Joutel A. The pathogenesis of cerebral small vessel disease and vascular cognitive impairment. Physiol Rev, 2025, 105(3): 1075-1171.
4.	徐芒芒, 劉鳴. 應當對無卒中癥狀的腔隙性腦梗死病灶或白質脫髓鞘進行恰當診治. 華西醫學, 2022, 37(6): 801-805.
5.	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.
6.	Das AS, Regenhardt RW, Vernooij MW, et al. Asymptomatic cerebral small vessel disease: insights from population-based studies. J Stroke, 2019, 21(2): 121-138.
7.	Han F, Zhai FF, Wang Q, et al. Prevalence and risk factors of cerebral small vessel disease in a Chinese population-based sample. J Stroke, 2018, 20(2): 239-246.
8.	van Dijk EJ, Prins ND, Vrooman HA, et al. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke, 2008, 39(10): 2712-2719.
9.	Sachdev P, Wen W, Chen X, et al. Progression of white matter hyperintensities in elderly individuals over 3 years. Neurology, 2007, 68(3): 214-222.
10.	Schmidt R, Enzinger C, Ropele S, et al. Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. Lancet, 2003, 361(9374): 2046-2048.
11.	Cho AH, Kim HR, Kim W, et al. White matter hyperintensity in ischemic stroke patients: it may regress over time. J Stroke, 2015, 17(1): 60-66.
12.	Al-Janabi OM, Bauer CE, Goldstein LB, et al. White matter hyperintensity regression: comparison of brain atrophy and cognitive profiles with progression and stable groups. Brain Sci, 2019, 9(7): 170.
13.	van Leijsen EMC, van Uden IWM, Ghafoorian M, et al. Nonlinear temporal dynamics of cerebral small vessel disease: the RUN DMC study. Neurology, 2017, 89(15): 1569-1577.
14.	van Leijsen EM, Bergkamp MI, van Uden IW, et al. Cognitive consequences of regression of cerebral small vessel disease. Eur Stroke J, 2019, 4(1): 85-89.
15.	Brown RB, Tozer DJ, Egle M, et al. How often does white matter hyperintensity volume regress in cerebral small vessel disease?. Int J Stroke, 2023, 18(8): 937-947.
16.	van den Heuvel DM, ten Dam VH, de Craen AJ, et al. Measuring longitudinal white matter changes: comparison of a visual rating scale with a volumetric measurement. AJNR Am J Neuroradiol, 2006, 27(4): 875-878.
17.	Jochems ACC, Arteaga C, Chappell F, et al. Longitudinal changes of white matter hyperintensities in sporadic small vessel disease: a systematic review and meta-analysis. Neurology, 2022, 99(22): e2454-e2463.
18.	Bahrani AA, Nelson PT, Abner EL, et al. White matter hyperintensity regression: fact or artifact?. Neurobiol Aging, 2026, 159: 33-46.
19.	Busby N, Newman-Norlund R, Wilmskoetter J, et al. Longitudinal progression of white matter hyperintensity severity in chronic stroke aphasia. Arch Rehabil Res Clin Transl, 2023, 5(4): 100302.
20.	Clancy U, Makin SDJ, Mchutchison CA, et al. Impact of small vessel disease progression on long-term cognitive and functional changes after stroke. Neurology, 2022, 98(14): e1459-e1469.
21.	Wang X, Valdés Hernández MC, Doubal F, et al. How much do focal infarcts distort white matter lesions and global cerebral atrophy measures?. Cerebrovasc Dis, 2012, 34(5/6): 336-342.
22.	Jochems ACC, Mu?oz Maniega S, Clancy U, et al. Longitudinal cognitive changes in cerebral small vessel disease: the effect of white matter hyperintensity regression and progression. Neurology, 2025, 104(4): e213323.
23.	Jochems ACC, Mu?oz Maniega S, Clancy U, et al. Definitions of white matter hyperintensity change: impact on estimates of progression and regression. Stroke Vasc Neurol, 2025, 10(3): 411-414.
24.	Bahrani AA, Smith CD, Barber JM, et al. Development of a protocol to assess within-subject, regional white matter hyperintensity changes in aging and dementia. J Neurosci Methods, 2021, 360: 109270.
25.	曹瑾怡, 仲偉逸, 夏憶瑋, 等. 血管源性腦白質高信號消退與認知功能的關聯: 一項基于社區人群的縱向研究. 中國臨床神經科學, 2025, 33(2): 200-209, 220.
26.	Zhang J, Jia X, Li H, et al. Associations of white matter hyperintensity regression and progression with cognitive and structural brain changes: a population-based cohort study. Alzheimers Res Ther, 2026, 18(1): 64.
27.	Bernal J, Menze I, Yakupov R, et al. Longitudinal evidence for a mutually reinforcing relationship between white matter hyperintensities and cortical thickness in cognitively unimpaired older adults. Alzheimers Res Ther, 2024, 16(1): 240.
28.	Kim SJ, Lee DK, Jang YK, et al. The effects of longitudinal white matter hyperintensity change on cognitive decline and cortical thinning over three years. J Clin Med, 2020, 9(8): 2663.
29.	de Havenon A, Majersik JJ, Tirschwell DL, et al. Blood pressure, glycemic control, and white matter hyperintensity progression in type 2 diabetics. Neurology, 2019, 92(11): e1168-e1175.
30.	Wardlaw JM, Chappell FM, Valdés Hernández MDC, et al. White matter hyperintensity reduction and outcomes after minor stroke. Neurology, 2017, 89(10): 1003-1010.
31.	Jiang J, Yao K, Huang X, et al. Longitudinal white matter hyperintensity changes and cognitive decline in patients with minor stroke. Aging Clin Exp Res, 2022, 34(5): 1047-1054.
32.	Xu Y, Huang D, Zhang H, et al. White matter hyperintensities regress at a high rate at three months after minor ischemic stroke or transient ischemic attack. J Neuroradiol, 2025, 52(1): 101239.
33.	Cai M, Jacob MA, van Loenen MR, et al. Determinants and temporal dynamics of cerebral small vessel disease: 14-year follow-up. Stroke, 2022, 53(9): 2789-2798.
34.	Jiaerken Y, Luo X, Yu X, et al. Microstructural and metabolic changes in the longitudinal progression of white matter hyperintensities. J Cereb Blood Flow Metab, 2019, 39(8): 1613-1622.
35.	Rachmadi MF, Valdés-Hernández MDC, Makin S, et al. Automatic spatial estimation of white matter hyperintensities evolution in brain MRI using disease evolution predictor deep neural networks. Med Image Anal, 2020, 63: 101712.
36.	Rachmadi MF, Valdés-Hernández MDC, MakinS, et al. Prediction of white matter hyperintensities evolution one-year post-stroke from a single-point brain MRI and stroke lesions information. Sci Rep, 2025, 15(1): 1208.
37.	Jochems ACC, Mu?oz Maniega S, Clancy U, et al. Magnetic resonance imaging tissue signatures associated with white matter changes due to sporadic cerebral small vessel disease indicate that white matter hyperintensities can regress. J Am Heart Assoc, 2024, 13(3): e032259.
38.	Ramirez J, McNeely AA, Berezuk C, et al. Dynamic progression of white matter hyperintensities in Alzheimer’s disease and normal aging: results from the sunnybrook dementia study. Front Aging Neurosci, 2016, 8: 62.
39.	Bahrani AA, Abner EL, DeCarli CS, et al. Multi-site cross-site inter-rater and test-retest reliability and construct validity of the MarkVCID white matter hyperintensity growth and regression protocol. J Alzheimers Dis, 2023, 96(2): 683-693.
40.	Wardlaw JM, Valdés Hernández MC, Mu?oz-Maniega S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J Am Heart Assoc, 2015, 4(6): 001140.
41.	Jochems ACC, Mu?oz Maniega S, Del CVHM, et al. Contribution of white matter hyperintensities to ventricular enlargement in older adults. Neuroimage Clin, 2022, 34: 103019.
42.	Inoue Y, Nakajima M, Inatomi Y, et al. Reversible periventricular hyperintensity lesions in cerebral amyloid angiopathy: a case mimicking cerebral amyloid angiopathy-related Inflammation. Intern Med, 2022, 61(23): 3581-3584.
43.	Lindland ES, R?vang MS, Solheim AM, et al. Are white matter hyperintensities associated with neuroborreliosis? The answer is twofold. Neuroradiology, 2025, 67(1): 37-48.
44.	Raja R, Rosenberg G, Caprihan A. Review of diffusion MRI studies in chronic white matter diseases. Neurosci Lett, 2019, 694: 198-207.
45.	Wardlaw JM, Debette S, Jokinen H, et al. ESO Guideline on covert cerebral small vessel disease. Eur Stroke J, 2021, 6(2): CXI-CLXII.
46.	Rajani RM, Quick S, Ruigrok SR, et al. Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. Sci Transl Med, 2018, 10(448): eaam9507.
47.	Wardlaw JM, Woodhouse LJ, Mhlanga, Ii, et al. Isosorbide mononitrate and cilostazol treatment in patients with symptomatic cerebral small vessel disease: the Lacunar Intervention Trial-2 (LACI-2) randomized clinical trial. JAMA Neurol, 2023, 80(7): 682-692.

1. 中華醫學會神經病學分會, 中華醫學會神經病學分會腦血管病學組. 中國腦小血管病診治指南 2020. 中華神經科雜志, 2022, 55(8): 807-818.
2. Markus HS, de Leeuw FE. Cerebral small vessel disease: recent advances and future directions. Int J Stroke, 2023, 18(1): 4-14.
3. Markus HS, Joutel A. The pathogenesis of cerebral small vessel disease and vascular cognitive impairment. Physiol Rev, 2025, 105(3): 1075-1171.
4. 徐芒芒, 劉鳴. 應當對無卒中癥狀的腔隙性腦梗死病灶或白質脫髓鞘進行恰當診治. 華西醫學, 2022, 37(6): 801-805.
5. 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.
6. Das AS, Regenhardt RW, Vernooij MW, et al. Asymptomatic cerebral small vessel disease: insights from population-based studies. J Stroke, 2019, 21(2): 121-138.
7. Han F, Zhai FF, Wang Q, et al. Prevalence and risk factors of cerebral small vessel disease in a Chinese population-based sample. J Stroke, 2018, 20(2): 239-246.
8. van Dijk EJ, Prins ND, Vrooman HA, et al. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke, 2008, 39(10): 2712-2719.
9. Sachdev P, Wen W, Chen X, et al. Progression of white matter hyperintensities in elderly individuals over 3 years. Neurology, 2007, 68(3): 214-222.
10. Schmidt R, Enzinger C, Ropele S, et al. Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. Lancet, 2003, 361(9374): 2046-2048.
11. Cho AH, Kim HR, Kim W, et al. White matter hyperintensity in ischemic stroke patients: it may regress over time. J Stroke, 2015, 17(1): 60-66.
12. Al-Janabi OM, Bauer CE, Goldstein LB, et al. White matter hyperintensity regression: comparison of brain atrophy and cognitive profiles with progression and stable groups. Brain Sci, 2019, 9(7): 170.
13. van Leijsen EMC, van Uden IWM, Ghafoorian M, et al. Nonlinear temporal dynamics of cerebral small vessel disease: the RUN DMC study. Neurology, 2017, 89(15): 1569-1577.
14. van Leijsen EM, Bergkamp MI, van Uden IW, et al. Cognitive consequences of regression of cerebral small vessel disease. Eur Stroke J, 2019, 4(1): 85-89.
15. Brown RB, Tozer DJ, Egle M, et al. How often does white matter hyperintensity volume regress in cerebral small vessel disease?. Int J Stroke, 2023, 18(8): 937-947.
16. van den Heuvel DM, ten Dam VH, de Craen AJ, et al. Measuring longitudinal white matter changes: comparison of a visual rating scale with a volumetric measurement. AJNR Am J Neuroradiol, 2006, 27(4): 875-878.
17. Jochems ACC, Arteaga C, Chappell F, et al. Longitudinal changes of white matter hyperintensities in sporadic small vessel disease: a systematic review and meta-analysis. Neurology, 2022, 99(22): e2454-e2463.
18. Bahrani AA, Nelson PT, Abner EL, et al. White matter hyperintensity regression: fact or artifact?. Neurobiol Aging, 2026, 159: 33-46.
19. Busby N, Newman-Norlund R, Wilmskoetter J, et al. Longitudinal progression of white matter hyperintensity severity in chronic stroke aphasia. Arch Rehabil Res Clin Transl, 2023, 5(4): 100302.
20. Clancy U, Makin SDJ, Mchutchison CA, et al. Impact of small vessel disease progression on long-term cognitive and functional changes after stroke. Neurology, 2022, 98(14): e1459-e1469.
21. Wang X, Valdés Hernández MC, Doubal F, et al. How much do focal infarcts distort white matter lesions and global cerebral atrophy measures?. Cerebrovasc Dis, 2012, 34(5/6): 336-342.
22. Jochems ACC, Mu?oz Maniega S, Clancy U, et al. Longitudinal cognitive changes in cerebral small vessel disease: the effect of white matter hyperintensity regression and progression. Neurology, 2025, 104(4): e213323.
23. Jochems ACC, Mu?oz Maniega S, Clancy U, et al. Definitions of white matter hyperintensity change: impact on estimates of progression and regression. Stroke Vasc Neurol, 2025, 10(3): 411-414.
24. Bahrani AA, Smith CD, Barber JM, et al. Development of a protocol to assess within-subject, regional white matter hyperintensity changes in aging and dementia. J Neurosci Methods, 2021, 360: 109270.
25. 曹瑾怡, 仲偉逸, 夏憶瑋, 等. 血管源性腦白質高信號消退與認知功能的關聯: 一項基于社區人群的縱向研究. 中國臨床神經科學, 2025, 33(2): 200-209, 220.
26. Zhang J, Jia X, Li H, et al. Associations of white matter hyperintensity regression and progression with cognitive and structural brain changes: a population-based cohort study. Alzheimers Res Ther, 2026, 18(1): 64.
27. Bernal J, Menze I, Yakupov R, et al. Longitudinal evidence for a mutually reinforcing relationship between white matter hyperintensities and cortical thickness in cognitively unimpaired older adults. Alzheimers Res Ther, 2024, 16(1): 240.
28. Kim SJ, Lee DK, Jang YK, et al. The effects of longitudinal white matter hyperintensity change on cognitive decline and cortical thinning over three years. J Clin Med, 2020, 9(8): 2663.
29. de Havenon A, Majersik JJ, Tirschwell DL, et al. Blood pressure, glycemic control, and white matter hyperintensity progression in type 2 diabetics. Neurology, 2019, 92(11): e1168-e1175.
30. Wardlaw JM, Chappell FM, Valdés Hernández MDC, et al. White matter hyperintensity reduction and outcomes after minor stroke. Neurology, 2017, 89(10): 1003-1010.
31. Jiang J, Yao K, Huang X, et al. Longitudinal white matter hyperintensity changes and cognitive decline in patients with minor stroke. Aging Clin Exp Res, 2022, 34(5): 1047-1054.
32. Xu Y, Huang D, Zhang H, et al. White matter hyperintensities regress at a high rate at three months after minor ischemic stroke or transient ischemic attack. J Neuroradiol, 2025, 52(1): 101239.
33. Cai M, Jacob MA, van Loenen MR, et al. Determinants and temporal dynamics of cerebral small vessel disease: 14-year follow-up. Stroke, 2022, 53(9): 2789-2798.
34. Jiaerken Y, Luo X, Yu X, et al. Microstructural and metabolic changes in the longitudinal progression of white matter hyperintensities. J Cereb Blood Flow Metab, 2019, 39(8): 1613-1622.
35. Rachmadi MF, Valdés-Hernández MDC, Makin S, et al. Automatic spatial estimation of white matter hyperintensities evolution in brain MRI using disease evolution predictor deep neural networks. Med Image Anal, 2020, 63: 101712.
36. Rachmadi MF, Valdés-Hernández MDC, MakinS, et al. Prediction of white matter hyperintensities evolution one-year post-stroke from a single-point brain MRI and stroke lesions information. Sci Rep, 2025, 15(1): 1208.
37. Jochems ACC, Mu?oz Maniega S, Clancy U, et al. Magnetic resonance imaging tissue signatures associated with white matter changes due to sporadic cerebral small vessel disease indicate that white matter hyperintensities can regress. J Am Heart Assoc, 2024, 13(3): e032259.
38. Ramirez J, McNeely AA, Berezuk C, et al. Dynamic progression of white matter hyperintensities in Alzheimer’s disease and normal aging: results from the sunnybrook dementia study. Front Aging Neurosci, 2016, 8: 62.
39. Bahrani AA, Abner EL, DeCarli CS, et al. Multi-site cross-site inter-rater and test-retest reliability and construct validity of the MarkVCID white matter hyperintensity growth and regression protocol. J Alzheimers Dis, 2023, 96(2): 683-693.
40. Wardlaw JM, Valdés Hernández MC, Mu?oz-Maniega S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J Am Heart Assoc, 2015, 4(6): 001140.
41. Jochems ACC, Mu?oz Maniega S, Del CVHM, et al. Contribution of white matter hyperintensities to ventricular enlargement in older adults. Neuroimage Clin, 2022, 34: 103019.
42. Inoue Y, Nakajima M, Inatomi Y, et al. Reversible periventricular hyperintensity lesions in cerebral amyloid angiopathy: a case mimicking cerebral amyloid angiopathy-related Inflammation. Intern Med, 2022, 61(23): 3581-3584.
43. Lindland ES, R?vang MS, Solheim AM, et al. Are white matter hyperintensities associated with neuroborreliosis? The answer is twofold. Neuroradiology, 2025, 67(1): 37-48.
44. Raja R, Rosenberg G, Caprihan A. Review of diffusion MRI studies in chronic white matter diseases. Neurosci Lett, 2019, 694: 198-207.
45. Wardlaw JM, Debette S, Jokinen H, et al. ESO Guideline on covert cerebral small vessel disease. Eur Stroke J, 2021, 6(2): CXI-CLXII.
46. Rajani RM, Quick S, Ruigrok SR, et al. Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. Sci Transl Med, 2018, 10(448): eaam9507.
47. Wardlaw JM, Woodhouse LJ, Mhlanga, Ii, et al. Isosorbide mononitrate and cilostazol treatment in patients with symptomatic cerebral small vessel disease: the Lacunar Intervention Trial-2 (LACI-2) randomized clinical trial. JAMA Neurol, 2023, 80(7): 682-692.

West China Medical Journal

Research progress on the regression of white matter hyperintensity of presumed vascular origin

Abstract Full text Figures/Tables Video References Cited by

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