Correlation between White Matter Hyperintensities and Glymphatic System Function in Patients with Recent Small Subcortical Infarcts

doi:10.3969/j.issn.1673-5765.2025.11.009

Abstract

Abstract: Objective To investigate the correlation between different regions and severities of white matter hyperintensities (WMH) and glymphatic system (GS) function in patients with recent small subcortical infarct (RSSI).
Methods Patients with RSSI admitted consecutively to the Third Affiliated Hospital of Nanjing Medical University (Changzhou Second People’s Hospital), from December 2023 to December 2024 were retrospectively enrolled. All patients completed cranial MRI examination within 3 days after admission, including diffusion tensor imaging sequences. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) technique was used to calculate the DTI-ALPS index for evaluating GS function. The volumes of total white matter hyperintensity (WMH), periventricular white matter hyperintensity (PWMH), and deep white matter hyperintensity (DWMH) were measured. WMH was scored and grouped using the Fazekas scale. According to the Fazekas scale scores, patients with PWMH or DWMH scores of 0-1 points were classified as the none-to-mild group, while those with scores of 2-3 points were classified as the moderate-to-severe group for the corresponding region. The total WMH grade was determined by summing the scores of the two regions, and patients were further grouped accordingly: grade 0-1 (0-2 points) were defined as the none-to-mild WMH group, and grade 2-3 (3-6 points) as the moderate-to-severe WMH group. Univariate analysis was performed to compare clinical data and the DTI-ALPS index among different groups. Multivariate logistic regression analysis was used to identify independent influencing factors of WMH in different regions. Spearman correlation analysis was conducted to assess the relationship between WMH volume and the DTI-ALPS index, and mediation analysis was performed to examine the mediating effect of the DTI-ALPS index on the relationship between age and WMH volume.
Results Univariate analysis showed that in the comparisons of WMH, PWMH, and DWMH groups, significant differences in the DTI-ALPS index and age were observed between the moderate-to-severe and none-to-mild groups. The moderate-to-severe groups had lower DTI-ALPS indices and were older than the none-to-mild groups (both P<0.05). Multivariate logistic regression analysis indicated that the DTI-ALPS index was a independent influencing factor for WMH severity in different regions. In the WMH, PWMH, and DWMH groups, the OR of the DTI-ALPS index were 0.002 (95%CI 0.000-0.243, P=0.012), 0.009 (95%CI 0.000-0.779, P=0.038), and 0.002 (95%CI 0.000-0.223, P=0.011), respectively. Spearman correlation analysis further revealed that WMH volume was negatively correlated with the DTI-ALPS index in RSSI patients (WMH: rs=−0.479, P<0.001; PWMH: rs=−0.355, P=0.004; DWMH: rs=−0.460, P<0.001). Mediation analysis demonstrated that age indirectly affected WMH volume through the DTI-ALPS index, with a significant indirect effect accounting for 35.629% of the total effect.
Conclusions In RSSI patients, the DTI-ALPS index was an independent influencing factor for WMH severity, showed negative correlations with WMH volumes in all regions, and mediated the relationship between age and WMH volume.

Key words: Recent small subcortical infarct; White matter hyperintensity; Glymphatic system; Diffusion tensor image analysis along the perivascular space

摘要： 目的探讨近期皮质下小梗死（recent small subcortical infarct，RSSI）患者不同部位、不同严重程度白质高信号（white matter hyperintensity，WMH）与脑类淋巴系统（glymphatic system，GS）功能的相关性。
方法回顾性连续纳入南京医科大学第三附属医院（常州市第二人民医院）2023年12月—2024年12月收治的RSSI患者，其均于入院后3 d内完善头颅MRI检查（包含弥散张量成像序列）。利用沿血管周围间隙弥散张量成像分析（diffusion tensor image analysis along the perivascular space，DTI-ALPS）技术计算DTI-ALPS指数评估GS功能，测量全脑WMH、脑室旁白质高信号（periventricular white matter hyperintensity，PWMH）和深部白质高信号（deep white matter hyperintensity，DWMH）的体积，采用Fazekas量表对WMH进行评分并分组。根据Fazekas量表评分，PWMH或DWMH评分为0～1分者归入相应部位的无-轻度组，2～3分者归入相应部位的中重度组；两部位评分相加后进行总体WMH分级并分组，0～1级（总分0～2分）定义为WMH无-轻度组，2～3级（总分3～6分）定义为WMH中重度组。采用单因素分析比较各组RSSI患者的临床资料及DTI-ALPS指数。采用多因素logistic回归分析探讨不同部位WMH的独立影响因素，采用Spearman相关性分析评估WMH体积与DTI-ALPS指数的关系，并通过中介分析检验DTI-ALPS指数在年龄与WMH体积间的中介效应。
结果单因素分析显示，在WMH、PWMH及DWMH分组比较中，DTI-ALPS指数和年龄在无-轻度组与中重度组间的差异均具有统计学意义。其中，中重度组的DTI-ALPS指数更低、年龄更大（均P<0.05）。多因素logistic回归分析显示，DTI-ALPS指数是不同部位WMH严重程度的独立影响因素：在WMH、PWMH及DWMH分组中，DTI-ALPS指数的OR值分别为0.002（95%CI 0.000～0.243，P=0.012）、0.009（95%CI 0.000～0.779，P=0.038）和0.002（95%CI 0.000～0.223，P=0.011）。Spearman相关性分析进一步显示，RSSI患者的WMH体积与DTI-ALPS指数呈负相关（WMH：rs=-0.479，P<0.001；PWMH：rs=-0.355，P=0.004；DWMH：rs=-0.460，P<0.001）。中介分析结果显示，年龄通过DTI-ALPS指数间接影响WMH体积，间接效应显著，占总效应的35.629%。
结论在RSSI患者中，DTI-ALPS指数为WMH严重程度的独立影响因素，与各部位WMH体积均呈负相关，并在年龄与WMH体积间具有中介作用。

关键词: 近期皮质下小梗死; 白质高信号; 类淋巴系统; 沿血管周围间隙弥散张量成像分析

CLC Number:

ZHANG Xue, ZHANG Min, WU Peng, YUN Wenwei. Correlation between White Matter Hyperintensities and Glymphatic System Function in Patients with Recent Small Subcortical Infarcts[J]. Chinese Journal of Stroke, 2025, 20(11): 1402-1410.

张雪, 张敏, 吴鹏, 恽文伟. 近期皮质下小梗死患者白质高信号与脑类淋巴系统功能的相关性研究[J]. 中国卒中杂志, 2025, 20(11): 1402-1410.

References

[1] JIANG S，CAO T，YAN Y Y，et al. Lenticulostriate artery combined with neuroimaging markers of cerebral small vessel disease differentiate the pathogenesis of recent subcortical infarction[J]. J Cereb Blood Flow Metab，2021，41（8）：2105-2115.
[2] DUERING M，BIESSELS G J，BRODTMANN A，et al. Neuroimaging standards for research into small vessel disease—advances since 2013[J]. Lancet Neurol，2023，22（7）：602-618.
[3] WARDLAW J M，SMITH C，DICHGANS M. Small vessel disease：mechanisms and clinical implications[J]. Lancet Neurol，2019，18（7）：684-696.
[4] LEE D H，LEE E C，PARK S W，et al. Pathogenesis of cerebral small vessel disease：role of the glymphatic system dysfunction[J/OL]. Int J Mol Sci，2024，25（16）：8752[2025-06-20]. https://doi.org/10.3390/ijms25168752.
[5] WARDLAW J M，BENVENISTE H，NEDERGAARD M，et al. Perivascular spaces in the brain：anatomy，physiology and pathology[J]. Nat Rev Neurol，2020，16（3）：137-153.
[6] RASMUSSEN M K，MESTRE H，NEDERGAARD M. The glymphatic pathway in neurological disorders[J]. Lancet Neurol，2018，17（11）：1016-1024.
[7] CHESEBRO A G，MELGAREJO J D，LEENDERTZ R，et al. White matter hyperintensities mediate the association of nocturnal blood pressure with cognition[J/OL]. Neurology，2020，94（17）：e1803-e1810[2025-06-20]. https://doi.org/10.1212/WNL.0000000000009316.
[8] TAOKA T，MASUTANI Y，KAWAI H，et al. Evaluation of glymphatic system activity with the diffusion MR technique：diffusion tensor image analysis along the perivascular space（DTI-ALPS）in Alzheimer’s disease cases[J]. Jpn J Radiol，2017，35（4）：172-178.
[9] TIAN Y，CAI X L，ZHOU Y J，et al. Impaired glymphatic system as evidenced by low diffusivity along perivascular spaces is associated with cerebral small vessel disease：a population-based study[J]. Stroke Vasc Neurol，2023，8（5）：413-423.
[10] HARRISON I F，ISMAIL O，MACHHADA A，et al. Impaired glymphatic function and clearance of tau in an Alzheimer’s disease model[J]. Brain，2020，143（8）：2576-2593.
[11] HONG H，HONG L W，LUO X，et al. The relationship between amyloid pathology，cerebral small vessel disease，glymphatic dysfunction，and cognition：a study based on Alzheimer’s disease continuum participants[J/OL]. Alzheimers Res Ther，2024，16（1）：43[2025-06-20]. https://doi.org/10.1186/s13195-024-01407-w.
[12] 孙凌辰，张敏，马翼，等. 近期皮质下小梗死患者的深髓静脉可见性与认知障碍的相关性研究[J]. 中华神经医学杂志，2024，23（8）：785-791.
SUN L C，ZHANG M，MA Y，et al. Correlation between deep medullary veins visibility and cognitive impairment in patients with recent subcortical small infarction[J]. Chin J Neuromed，2024，23（8）：785-791.
[13] FAZEKAS F，CHAWLUK J B，ALAVI A，et al. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging[J]. AJR Am J Roentgenol，1987，149（2）：351-356.
[14] LIU X D，BARISANO G，SHAO X F，et al. Cross-vendor test-retest validation of diffusion tensor image analysis along the perivascular space（DTI-ALPS）for evaluating glymphatic system function[J]. Aging Dis，2024，15（4）：1885-1898.
[15] ZHANG X，WANG W，ZHANG X Y，et al. Normal glymphatic system function in patients with new daily persistent headache using diffusion tensor image analysis along the perivascular space[J]. Headache，2023，63（5）：663-671.
[16] ZHANG J，LIU S W，WU Y Q，et al. Enlarged perivascular space and index for diffusivity along the perivascular space as emerging neuroimaging biomarkers of neurological diseases[J/OL]. Cell Mol Neurobiol，2023，44（1）：14[2025-06-20]. https://doi.org/10.1007/s10571-023-01440-7.
[17] SHEN T，YUE Y M，BA F，et al. Diffusion along perivascular spaces as marker for impairment of glymphatic system in Parkinson’s disease[J/OL]. NPJ Parkinsons Dis，2022，8（1）：174[2025-06-20]. https://doi.org/10.1038/s41531-022-00437-1.
[18] CHANG H I，HUANG C W，HSU S W，et al. Gray matter reserve determines glymphatic system function in young-onset Alzheimer’s disease：evidenced by DTI-ALPS and compared with age-matched controls[J]. Psychiatry Clin Neurosci，2023，77（7）：401-409.
[19] YANG Y J，KNOL M J，WANG R Q，et al. Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI[J]. Brain，2023，146（2）：492-506.
[20] WASSENARR T M，YAFFE K，VAN DER WERF Y D，et al. Associations between modifiable risk factors and white matter of the aging brain：insights from diffusion tensor imaging studies[J/OL]. Neurobiol Aging，2019，80：56-70[2025-06-20]. https://doi.org/10.1016/j.neurobiolaging.2019.04.006.
[21] OUIN E，DIMITROVIC A，GROSSET L，et al. White matter hyperintensities of the corpus callosum are associated with clinical severity in CADASIL[J/OL]. Stroke，2023，54（4）：e138-e141[2025-06-20]. https://doi.org/10.1161/STROKEAHA.122.040938.
[22] XU J J，SU Y，FU J Y，et al. Glymphatic dysfunction correlates with severity of small vessel disease and cognitive impairment in cerebral amyloid angiopathy[J]. Eur J Neurol，2022，29（10）：2895-2904.
[23] PURKAYASTHA S，FADAR O，MEHREGAN A，et al. Impaired cerebrovascular hemodynamics are associated with cerebral white matter damage[J]. J Cereb Blood Flow Metab，2014，34（2）：228-234.
[24] YANKOVA G，BOGOMYAKOVA O，TULUPOV A. The glymphatic system and meningeal lymphatics of the brain：new understanding of brain clearance[J]. Rev Neurosci，2021，32（7）：693-705.
[25] GROH J，SIMONS M. White matter aging and its impact on brain function[J]. Neuron，2025，113（1）：127-139.
[26] LI Y F，ZHOU Y，ZHONG W S，et al. Choroid plexus enlargement exacerbates white matter hyperintensity growth through glymphatic impairment[J]. Ann Neurol，2023，94（1）：182-195.
[27] SIMON M，WANG M X，ISMAIL O，et al. Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid β plaque formation in mice[J/OL]. Alzheimers Res Ther，2022，14：59[2025-06-20]. https://doi.org/10.1186/s13195-022-00999-5.
[28] 中国研究型医院学会脑小血管病专业委员会《中国脑小血管病诊治专家共识》编写组. 中国脑小血管病诊治专家共识2021[J]. 中国卒中杂志，2021，16（7）：716-726.
Cerebral Small Vessel Disease Professional Committee Consensus Writing Group，Chinese Research Hospital Association. Chinese consensus on diagnosis and therapy of cerebral small vessel disease 2021[J]. Chin J Stroke，2021，16（7）：716-726.
[29] CHONG P L H，GARIC D，SHEN M D，et al. Sleep，cerebrospinal fluid，and the glymphatic system：a systematic review[J/OL]. Sleep Med Rev，2022，61：101572[2025-06-20]. https://doi.org/10.1016/j.smrv.2021.101572.
[30] PLOG B A，NEDERGAARD M. The glymphatic system in central nervous system health and disease：past，present，and future[J/OL]. Annu Rev Pathol，2018，13：379-394[2025-06-20]. https://doi.org/10.1146/annurev-pathol-051217-111018.