Disruptions of deep medullary veins (DMV) have been associated with the radiological severity and cognitive impairment observed in cerebral small vessel disease (SVD). Glymphatic dysfunction may serve as a potential mechanism underlying these associations.
Objective
We aimed to clarify the associations between DMV disruptions, MRI indices previously hypothesized as related to glymphatic function, white matter hyperintensities (WMH), and cognitive impairment in SVD.
Methods
This cross-sectional study included 133 SVD participants. DMV disruptions were visually rated on susceptibility-weighted imaging (SWI). Five MRI indices related to glymphatic function were measured: the diffusion tensor imaging along the perivascular space (DTI-ALPS), free water (FW) fraction, choroid plexus (Cp) volumes, perivascular spaces in basal ganglia (BG-PVS) and white matter (WM-PVS).
Results
Higher DMV scores were associated with higher WMH volumes (β = 0.55, p < 0.001) and lower Montreal Cognitive Assessment (MoCA) scores (β = −0.24, p = 0.003). Higher DMV scores were correlated with lower DTI-ALPS values, higher FW fraction, higher volumes in Cp, BG-PVS, and WM-PVS (all p < 0.001). DTI-ALPS values and BG-PVS volumes mediated the associations between DMV scores and WMH volumes, with only BG-PVS volumes mediating the associations between DMV scores and MoCA scores.
Conclusions
Our results suggested that DMV disruptions contribute to WMH burden and cognitive impairment in SVD. This effect could be mediated by MRI markers indicative of glymphatic dysfunction, particularly the enlargement of BG-PVS.
DueringMBiesselsGJBrodtmannA, et al.Neuroimaging standards for research into small vessel disease-advances since 2013. Lancet Neurol2023; 22: 602–618.
2.
FulopGATarantiniSYabluchanskiyA, et al.Role of age-related alterations of the cerebral venous circulation in the pathogenesis of vascular cognitive impairment. Am J Physiol Heart Circ Physiol2019; 316: H1124–H1140.
3.
NanDChengYFengL, et al.Potential mechanism of venous system for leukoaraiosis: from post-mortem to in vivo research. Neurodegener Dis2019; 19: 101–108.
4.
AoDHZhangDDZhaiFF, et al.Brain deep medullary veins on 3-T MRI in a population-based cohort. J Cereb Blood Flow Metab2021; 41: 561–568.
5.
LiaoMWangMLiH, et al.Discontinuity of deep medullary veins in SWI is associated with deep white matter hyperintensity volume and cognitive impairment in cerebral small vessel disease. J Affect Disord2024; 350: 600–607.
6.
ZhangRHuangPJiaerkenY, et al.Venous disruption affects white matter integrity through increased interstitial fluid in cerebral small vessel disease. J Cereb Blood Flow Metab2021; 41: 157–165.
7.
LiHJacobMACaiM, et al.Perivascular spaces, diffusivity along perivascular spaces, and free water in cerebral small vessel disease. Neurology2024; 102: e209306.
8.
XuJSuYFuJ, et al.Glymphatic pathway in sporadic cerebral small vessel diseases: from bench to bedside. Ageing Res Rev2023; 86: 101885.
9.
ZhangWZhouYWangJ, et al.Glymphatic clearance function in patients with cerebral small vessel disease. Neuroimage2021; 238: 118257.
10.
KamagataKAndicaCTakabayashiK, et al.Association of MRI indices of glymphatic system with amyloid deposition and cognition in mild cognitive impairment and Alzheimer disease. Neurology2022; 99: e2648–e2660.
11.
TianYCaiXZhouY, et al.Impaired glymphatic system as evidenced by low diffusivity along perivascular spaces is associated with cerebral small vessel disease: a population-based study. Stroke Vasc Neurol2023; 8: 413–423.
12.
LiYZhouYZhongW, et al.Choroid plexus enlargement exacerbates white matter hyperintensity growth through glymphatic impairment. Ann Neurol2023; 94: 182–195.
13.
ZhangKZhouYZhangW, et al.MRI-visible perivascular spaces in basal ganglia but not centrum semiovale or hippocampus were related to deep medullary veins changes. J Cereb Blood Flow Metab2022; 42: 136–144.
14.
ZhangXPeiXShiY, et al.Unveiling connections between venous disruption and cerebral small vessel disease using diffusion tensor image analysis along perivascular space (DTI-ALPS): a 7-T MRI study. Int J Stroke2025; 20: 497–506.
15.
WardlawJMSmithEEBiesselsGJ, et al.Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol2013; 12: 822–838.
16.
PutaalaJHaapaniemiEKasteM, et al.How does number of risk factors affect prognosis in young patients with ischemic stroke?Stroke2012; 43: 356–361.
17.
LuJLiDLiF, et al.Montreal Cognitive assessment in detecting cognitive impairment in Chinese elderly individuals: a population-based study. J Geriatr Psychiatry Neurol2011; 24: 184–190.
18.
SargurupremrajMSuzukiHJianX, et al.Cerebral small vessel disease genomics and its implications across the lifespan. Nat Commun2020; 11: 6285.
19.
WiltgenTMcGinnisJSchlaegerS, et al.LST-AI: a deep learning ensemble for accurate MS lesion segmentation. Neuroimage Clin2024; 42: 103611.
20.
JiangJLiuTZhuW, et al.UBO detector - a cluster-based, fully automated pipeline for extracting white matter hyperintensities. Neuroimage2018; 174: 539–549.
21.
FazekasFChawlukJBAlaviA, et al.MR Signal abnormalities at 1.5T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol1987; 149: 351–356.
22.
TournierJDSmithRRaffeltD, et al.MRtrix3: a fast, flexible and open software framework for medical image processing and visualisation. Neuroimage2019; 202: 116137.
23.
SmithSMJenkinsonMWoolrichMW, et al.Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage2004; 23: S208–S219.
24.
TustisonNJAvantsBBCookPA, et al.N4ITK: improved N3 bias correction. IEEE Trans Med Imaging2010; 29: 1310–1320.
25.
SchillingKGBlaberJHuoY, et al.Synthesized b0 for diffusion distortion correction (Synb0-DisCo). Magn Reson Imaging2019; 64: 62–70.
26.
MoriSOishiKJiangH, et al.Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template. Neuroimage2008; 40: 570–582.
27.
PasternakOSochenNGurY, et al.Free water elimination and mapping from diffusion MRI. Magn Reson Med2009; 62: 717–730.
28.
DueringMFinsterwalderSBaykaraE, et al.Free water determines diffusion alterations and clinical status in cerebral small vessel disease. Alzheimers Dement2018; 14: 764–774.
29.
SederevičiusDVidal-PiñeiroDSørensenØ, et al.Reliability and sensitivity of two whole-brain segmentation approaches included in FreeSurfer - ASEG and SAMSEG. Neuroimage2021; 237: 118113.
30.
BoutinaudPTsuchidaALaurentA, et al.3D Segmentation of perivascular spaces on T1-weighted 3 tesla MR images with a convolutional autoencoder and a U-shaped neural network. Front Neuroinform2021; 15: 641600.
31.
PuontiOIglesiasJEVan LeemputK. Fast and sequence-adaptive whole-brain segmentation using parametric Bayesian modeling. Neuroimage2016; 143: 235–249.
32.
PreacherKJHayesAF. Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav Res Methods2008; 40: 879–891.
33.
KimJH. Multicollinearity and misleading statistical results. Korean J Anesthesiol2019; 72: 558–569.
34.
CookRD. Detection of influential observation in linear regression. Technometrics1977; 19: 15–18.
35.
LahnaDSchwartzDLWoltjerR, et al.Venous collagenosis as pathogenesis of white matter hyperintensity. Ann Neurol2022; 92: 992–1000.
36.
KeithJGaoFQNoorR, et al.Collagenosis of the deep medullary veins: an underrecognized pathologic correlate of white matter hyperintensities and periventricular infarction?J Neuropathol Exp Neurol2017; 76: 299–312.
37.
WardlawJMBenvenisteHNedergaardM, et al.Perivascular spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol2020; 16: 137–153.
38.
Szubert-FranczakAENaduk-OstrowskaMPasiczK, et al.Intravoxel incoherent motion magnetic resonance imaging: basic principles and clinical applications. Pol J Radiol2020; 85: e624–e635.
39.
JiangDLiuLKongY, et al.Regional glymphatic abnormality in behavioral variant frontotemporal dementia. Ann Neurol2023; 94: 442–456.
40.
TuYLiZXiongF, et al.Decreased DTI-ALPS and choroid plexus enlargement in fibromyalgia: a preliminary multimodal MRI study. Neuroradiology2023; 65: 1749–1755.
41.
LiCZhangHWangJ, et al.Choroid plexus volume in rural Chinese older adults: distribution and association with cardiovascular risk factors and cerebral small vessel disease. J Am Heart Assoc2024; 13: e035941.
42.
CourtneyYHochstetlerALehtinenMK. Choroid plexus pathophysiology. Annu Rev Pathol2025; 20: 193–220.
43.
ZhouYXueRLiY, et al.Impaired meningeal lymphatics and glymphatic pathway in patients with white matter hyperintensity. Adv Sci (Weinh)2024; 11: e2402059.
44.
WangXLyuJDuanQ, et al.Deep medullary vein damage correlates with small vessel disease in small vessel occlusion acute ischemic stroke. Eur Radiol2024; 34: 6026–6035.
45.
SabayanBWestendorpRGJ. Neurovascular-glymphatic dysfunction and white matter lesions. Geroscience2021; 43: 1635–1642.
46.
HumphreysCASmithCWardlawJM. Correlations in post-mortem imaging-histopathology studies of sporadic human cerebral small vessel disease: systematic review. Neuropathol Appl Neurobiol2021; 47: 910–930.
47.
GouwAASeewannAvan der FlierWM, et al.Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. J Neurol Neurosurg Psychiatry2011; 82: 126–135.
48.
CaiJSunJChenH, et al.Different mechanisms in periventricular and deep white matter hyperintensities in old subjects. Front Aging Neurosci2022; 14: 940538.
49.
BlackSGaoFBilbaoJ. Understanding white matter disease: imaging-pathological correlations in vascular cognitive impairment. Stroke2009; 40: S48–S52.
50.
GriffantiLJenkinsonMSuriS, et al.Classification and characterization of periventricular and deep white matter hyperintensities on MRI: a study in older adults. Neuroimage2018; 170: 174–181.
51.
DebetteSMarkusHS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. Br Med J2010; 341: c3666.
52.
CharidimouAMeegahageRFoxZ, et al.Enlarged perivascular spaces as a marker of underlying arteriopathy in intracerebral haemorrhage: a multicentre MRI cohort study. J Neurol Neurosurg Psychiatry2013; 84: 624–629.
53.
BanerjeeGKimHJFoxZ, et al.MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden. Brain2017; 140: 1107–1116.
54.
ChenXLuoYZhangS, et al.Deep medullary veins: a promising neuroimaging marker for mild cognitive impairment in outpatients. BMC Neurol2023; 23: 3.
55.
XuZLiFXingD, et al.A novel imaging biomarker for cerebral small vessel disease associated with cognitive impairment: the deep-medullary-veins score. Front Aging Neurosci2021; 13: 720481.
56.
HurfordRCharidimouAFoxZ, et al.MRI-visible perivascular spaces: relationship to cognition and small vessel disease MRI markers in ischaemic stroke and TIA. J Neurol Neurosurg Psychiatry2014; 85: 522–525.
57.
DingJSigurðssonSJónssonPV, et al.Large perivascular spaces visible on magnetic resonance imaging, cerebral small vessel disease progression, and risk of dementia: the age, gene/environment susceptibility-Reykjavik study. JAMA Neurol2017; 74: 1105–1112.
58.
WardlawJMSmithCDichgansM. Small vessel disease: mechanisms and clinical implications. Lancet Neurol2019; 18: 684–696.
59.
LeeDHLeeECParkSW, et al.Pathogenesis of cerebral small vessel disease: role of the glymphatic system dysfunction. Int J Mol Sci2024; 25: 8752.
60.
AoDHZhangDDZhaiFF, et al.Brain deep medullary veins on 3-T MRI in a population-based cohort. J Cereb Blood Flow Metab2021; 41: 561–568.
61.
TianYLiSYangY, et al.Associations of deep medullary veins with vascular risk factors, laboratory indicators, and cerebral small vessel disease: a population-based study. Brain Behav2023; 13: e2974.
62.
TaokaTMasutaniYKawaiH, 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. Jpn J Radiol2017; 35: 172–178.
63.
LizanoPLutzOLingG, et al.Association of choroid plexus enlargement with cognitive, inflammatory, and structural phenotypes across the psychosis spectrum. Am J Psychiatry2019; 176: 564–572.
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