{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T04:20:25Z","timestamp":1789532425637,"version":"build-2803163510"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Umea University"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Fluids Barriers CNS"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>White matter lesions (WML) and dilated perivascular spaces (PVS) are features of small vessel disease (SVD), commonly observed in aging and dementia, with unknown pathophysiology. Human studies have documented contrast accumulation within and in proximity of SVD-lesions. However, whether such observations mainly reflect excessive blood-brain barrier (BBB) leakage, or altered microvascular density in the investigated regions, remains unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>To evaluate the roles of BBB leakage and vascular density in aging and SVD, dynamic contrast enhanced (DCE) MRI was used to estimate the permeability-surface area product (PS) and fractional plasma volume (<jats:inline-formula>\n                <jats:tex-math>$$\\:{v}_{p}$$<\/jats:tex-math>\n              <\/jats:inline-formula>) in normal-appearing brain tissue and in proximity of and within WML and PVS in a population-based cohort (<jats:italic>N<\/jats:italic>\u2009=\u200956; 34\/22 m\/f; age 64 to 84 years). Analysis of variance (ANOVA) was used to assess regional differences in PS and <jats:inline-formula>\n                <jats:tex-math>$$\\:{v}_{p}$$<\/jats:tex-math>\n              <\/jats:inline-formula> and analysis of covariance (ANCOVA) was used to assess regional differences in PS with <jats:inline-formula>\n                <jats:tex-math>$$\\:{v}_{p}$$<\/jats:tex-math>\n              <\/jats:inline-formula> and vascular risk as covariates.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Pronounced increases in PS and <jats:inline-formula>\n                <jats:tex-math>$$\\:{v}_{p}$$<\/jats:tex-math>\n              <\/jats:inline-formula> were observed from normal-appearing white matter (NAWM) to WML peripheries to WMLs. Similar PS and <jats:inline-formula>\n                <jats:tex-math>$$\\:{v}_{p}\\:$$<\/jats:tex-math>\n              <\/jats:inline-formula>increases were observed from basal ganglia (BG) to BG-PVS. Further, PS in NAWM and white matter (WM) PVS were found to increase with cortex-to-ventricular depth. However, ANCOVA models with <jats:inline-formula>\n                <jats:tex-math>$$\\:{v}_{p}$$<\/jats:tex-math>\n              <\/jats:inline-formula> as a covariate showed that variance in PS was mainly explained by v<jats:sub>p<\/jats:sub> (\u03b7<jats:sup>2<\/jats:sup>=0.17 to \u03b7<jats:sup>2<\/jats:sup>=0.35; all <jats:italic>p<\/jats:italic>\u2009&lt;\u200910<jats:sup>\u2212\u20093<\/jats:sup>), whereas the effect of region was only borderline-significant when comparing NAWM, WML peripheries and WML (<jats:italic>p<\/jats:italic>\u2009=\u20090.03) and non-significant for the other comparisons (<jats:italic>p<\/jats:italic>\u2009&gt;\u20090.29).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our findings support the notion that contrast leakage across the BBB accumulates within and in proximity of SVD-related lesions. However, high contrast accumulation may mainly reflect high vascularization, and to a lesser degree than previously recognized BBB dysfunction.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12987-025-00675-4","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T06:58:20Z","timestamp":1752649100000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["MRI contrast accumulation in features of cerebral small vessel disease: blood-brain barrier dysfunction or elevated vascular density?"],"prefix":"10.1186","volume":"22","author":[{"given":"Tomas","family":"Vikner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Garpebring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Bj\u00f6rnfot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Malm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Eklund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"W\u00e5hlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"key":"675_CR1","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1001\/jamaneurol.2018.3122","volume":"76","author":"S Debette","year":"2019","unstructured":"Debette S, Schilling S, Duperron MG, et al. Clinical significance of magnetic resonance imaging markers of vascular brain injury: A systematic review and Meta-analysis. JAMA Neurol. 2019;76:81\u201394.","journal-title":"JAMA Neurol"},{"key":"675_CR2","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/S1474-4422(19)30079-1","volume":"18","author":"JM Wardlaw","year":"2019","unstructured":"Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 2019;18:684\u201396.","journal-title":"Lancet Neurol"},{"key":"675_CR3","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/S1474-4422(23)00131-X","volume":"22","author":"M Duering","year":"2023","unstructured":"Duering M, Biessels GJ, Brodtmann A, et al. Neuroimaging standards for research into small vessel disease-advances since 2013. Lancet Neurol. 2023;22:602\u201318.","journal-title":"Lancet Neurol"},{"key":"675_CR4","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1001\/jama.2019.10551","volume":"322","author":"IM Nasrallah","year":"2019","unstructured":"Nasrallah IM, Pajewski NM, Auchus AP, et al. Association of intensive vs standard blood pressure control with cerebral white matter lesions. JAMA - J Am Med Assoc. 2019;322:524\u201334.","journal-title":"JAMA - J Am Med Assoc"},{"key":"675_CR5","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/s41582-020-0312-z","volume":"16","author":"JM Wardlaw","year":"2020","unstructured":"Wardlaw JM, Benveniste H, Nedergaard M, et al. Perivascular spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol. 2020;16:137\u201353.","journal-title":"Nat Rev Neurol"},{"key":"675_CR6","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1002\/ana.26475","volume":"92","author":"T Vikner","year":"2022","unstructured":"Vikner T, Karalija N, Eklund A, et al. 5-Year associations among cerebral arterial pulsatility, perivascular space dilation, and white matter lesions. Ann Neurol. 2022;92:871\u201381.","journal-title":"Ann Neurol"},{"key":"675_CR7","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1136\/svn-2016-000035","volume":"1","author":"Y Shi","year":"2016","unstructured":"Shi Y, Wardlaw JM. Update on cerebral small vessel disease: A dynamic whole-brain disease. Stroke Vasc Neurol. 2016;1:83\u201392.","journal-title":"Stroke Vasc Neurol"},{"key":"675_CR8","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.jns.2010.08.042","volume":"299","author":"JM Wardlaw","year":"2010","unstructured":"Wardlaw JM. Blood-brain barrier and cerebral small vessel disease. J Neurol Sci. 2010;299:66\u201371.","journal-title":"J Neurol Sci"},{"key":"675_CR9","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nrneurol.2017.188","volume":"14","author":"MD Sweeney","year":"2018","unstructured":"Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133\u201350.","journal-title":"Nat Rev Neurol"},{"key":"675_CR10","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/nm.4482","volume":"24","author":"A Montagne","year":"2018","unstructured":"Montagne A, Nikolakopoulou AM, Zhao Z, et al. Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med. 2018;24:326\u201337.","journal-title":"Nat Med"},{"key":"675_CR11","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.jalz.2016.09.006","volume":"13","author":"JM Wardlaw","year":"2017","unstructured":"Wardlaw JM, Makin SJ, Vald\u00e9s Hern\u00e1ndez MC, et al. Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study. Alzheimer\u2019s Dement. 2017;13:634\u201343.","journal-title":"Alzheimer\u2019s Dement"},{"key":"675_CR12","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.neurad.2017.10.001","volume":"45","author":"CH Sudre","year":"2018","unstructured":"Sudre CH, Gomez Anson B, Davagnanam I, et al. Bullseye\u2019s representation of cerebral white matter hyperintensities. J Neuroradiol = J Neuroradiol. 2018;45:114\u201322.","journal-title":"J Neuroradiol = J Neuroradiol"},{"key":"675_CR13","doi-asserted-by":"publisher","first-page":"1955","DOI":"10.1038\/s41598-022-06019-8","volume":"12","author":"J Jim\u00e9nez-Balado","year":"2022","unstructured":"Jim\u00e9nez-Balado J, Corlier F, Habeck C, et al. Effects of white matter hyperintensities distribution and clustering on late-life cognitive impairment. Sci Rep. 2022;12:1955.","journal-title":"Sci Rep"},{"key":"675_CR14","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13195-018-0460-1","volume":"11","author":"G Salvad\u00f3","year":"2019","unstructured":"Salvad\u00f3 G, Brugulat-Serrat A, Sudre CH, et al. Spatial patterns of white matter hyperintensities associated with alzheimer\u2019s disease risk factors in a cognitively healthy middle-aged cohort. Alzheimers Res Ther. 2019;11:12.","journal-title":"Alzheimers Res Ther"},{"key":"675_CR15","doi-asserted-by":"publisher","first-page":"221","DOI":"10.3389\/fneur.2018.00221","volume":"9","author":"Y Li","year":"2018","unstructured":"Li Y, Li M, Zuo L, et al. Compromised Blood-Brain barrier integrity is associated with total magnetic resonance imaging burden of cerebral small vessel disease. Front Neurol. 2018;9:221.","journal-title":"Front Neurol"},{"key":"675_CR16","doi-asserted-by":"publisher","first-page":"871","DOI":"10.2147\/CIA.S204269","volume":"14","author":"Y Li","year":"2019","unstructured":"Li Y, Li M, Yang L, et al. The relationship between blood-brain barrier permeability and enlarged perivascular spaces: a cross-sectional study. Clin Interv Aging. 2019;14:871\u20138.","journal-title":"Clin Interv Aging"},{"key":"675_CR17","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.neuroimage.2015.10.018","volume":"125","author":"AK Heye","year":"2016","unstructured":"Heye AK, Thrippleton MJ, Armitage PA, et al. Tracer kinetic modelling for DCE-MRI quantification of subtle blood-brain barrier permeability. NeuroImage. 2016;125:446\u201355.","journal-title":"NeuroImage"},{"key":"675_CR18","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/j.jalz.2019.01.013","volume":"15","author":"MJ Thrippleton","year":"2019","unstructured":"Thrippleton MJ, Backes WH, Sourbron S, et al. Quantifying blood-brain barrier leakage in small vessel disease: review and consensus recommendations. Alzheimer\u2019s Dement. 2019;15:840\u201358.","journal-title":"Alzheimer\u2019s Dement"},{"key":"675_CR19","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.neuroscience.2021.08.003","volume":"474","author":"A Chagnot","year":"2021","unstructured":"Chagnot A, Barnes SR, Montagne A. Magnetic resonance imaging of Blood\u2013Brain barrier permeability in dementia. Neuroscience. 2021;474:14\u201329.","journal-title":"Neuroscience"},{"key":"675_CR20","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1002\/mrm.22357","volume":"63","author":"LI Sacolick","year":"2010","unstructured":"Sacolick LI, Wiesinger F, Hancu I, et al. B1 mapping by Bloch-Siegert shift. Magn Reson Med. 2010;63:1315\u201322.","journal-title":"Magn Reson Med"},{"key":"675_CR21","doi-asserted-by":"publisher","first-page":"2107","DOI":"10.1109\/TMI.2016.2550102","volume":"35","author":"T Jerman","year":"2016","unstructured":"Jerman T, Pernus F, Likar B, et al. Enhancement of vascular structures in 3D and 2D angiographic images. IEEE Trans Med Imaging. 2016;35:2107\u201318.","journal-title":"IEEE Trans Med Imaging"},{"key":"675_CR22","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1159\/000375153","volume":"39","author":"GM Potter","year":"2015","unstructured":"Potter GM, Chappell FM, Morris Z, et al. Cerebral perivascular spaces visible on magnetic resonance imaging: development of a qualitative rating scale and its observer reliability. Cerebrovasc Dis. 2015;39:224\u201331.","journal-title":"Cerebrovasc Dis"},{"key":"675_CR23","doi-asserted-by":"publisher","first-page":"2733","DOI":"10.1002\/mrm.28830","volume":"86","author":"H-H Lee","year":"2021","unstructured":"Lee H-H, Novikov DS, Fieremans E. Removal of partial Fourier-induced Gibbs (RPG) ringing artifacts in MRI. Magn Reson Med. 2021;86:2733\u201350.","journal-title":"Magn Reson Med"},{"key":"675_CR24","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.neuroimage.2009.06.060","volume":"48","author":"DN Greve","year":"2009","unstructured":"Greve DN, Fischl B. Accurate and robust brain image alignment using boundary-based registration. NeuroImage. 2009;48:63\u201372.","journal-title":"NeuroImage"},{"key":"675_CR25","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1002\/mrm.21669","volume":"60","author":"LC Chang","year":"2008","unstructured":"Chang LC, Cheng GK, Basser PJ, et al. Linear least-squares method for unbiased Estimation of T1 from SPGR signals. Magn Reson Med. 2008;60:496\u2013501.","journal-title":"Magn Reson Med"},{"key":"675_CR26","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1088\/0031-9155\/53\/9\/010","volume":"53","author":"MC Schabel","year":"2008","unstructured":"Schabel MC, Parker DL. Uncertainty and bias in contrast concentration measurements using spoiled gradient echo pulse sequences. Phys Med Biol. 2008;53:2345\u201373.","journal-title":"Phys Med Biol"},{"key":"675_CR27","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1097\/01.rli.0000184756.66360.d3","volume":"40","author":"M Rohrer","year":"2005","unstructured":"Rohrer M, Bauer H, Mintorovitch J, et al. Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths. Invest Radiol. 2005;40:715\u201324.","journal-title":"Invest Radiol"},{"key":"675_CR28","doi-asserted-by":"publisher","first-page":"15338","DOI":"10.1038\/s41598-024-65944-y","volume":"14","author":"T Vikner","year":"2024","unstructured":"Vikner T, Garpebring A, Bj\u00f6rnfot C, et al. Blood\u2013brain barrier integrity is linked to cognitive function, but not to cerebral arterial pulsatility, among elderly. Sci Rep. 2024;14:15338.","journal-title":"Sci Rep"},{"key":"675_CR29","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1002\/ana.21549","volume":"65","author":"JM Wardlaw","year":"2009","unstructured":"Wardlaw JM, Doubal F, Armitage P, et al. Lacunar stroke is associated with diffuse blood-brain barrier dysfunction. Ann Neurol. 2009;65:194\u2013202.","journal-title":"Ann Neurol"},{"key":"675_CR30","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1136\/jnnp.2009.172072","volume":"81","author":"R Topakian","year":"2010","unstructured":"Topakian R, Barrick TR, Howe FA, et al. Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis. J Neurol Neurosurg Psychiatry. 2010;81:192\u20137.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"675_CR31","doi-asserted-by":"crossref","unstructured":"Rudilosso S, Stringer MS, Thrippleton M et al. Blood-brain barrier leakage hotspots collocating with brain lesions due to sporadic and Monogenic small vessel disease. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 2023; 271678X231173444.","DOI":"10.1177\/0271678X231173444"},{"key":"675_CR32","doi-asserted-by":"publisher","first-page":"e5159","DOI":"10.1002\/nbm.5159","volume":"37","author":"MJP van Osch","year":"2024","unstructured":"van Osch MJP, W\u00e5hlin A, Scheyhing P, et al. Human brain clearance imaging: pathways taken by magnetic resonance imaging contrast agents after administration in cerebrospinal fluid and blood. NMR Biomed. 2024;37:e5159.","journal-title":"NMR Biomed"},{"key":"675_CR33","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.mvr.2011.11.004","volume":"83","author":"J Luo","year":"2012","unstructured":"Luo J, Martinez J, Yin X, et al. Hypoxia induces angiogenic factors in brain microvascular endothelial cells. Microvasc Res. 2012;83:138\u201345.","journal-title":"Microvasc Res"},{"key":"675_CR34","doi-asserted-by":"publisher","first-page":"2238","DOI":"10.1152\/jappl.1992.72.6.2238","volume":"72","author":"JC LaManna","year":"1992","unstructured":"LaManna JC, Vendel LM, Farrell RM. Brain adaptation to chronic hypobaric hypoxia in rats. J Appl Physiol. 1992;72:2238\u201343.","journal-title":"J Appl Physiol"},{"key":"675_CR35","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1152\/japplphysiol.00318.2002","volume":"93","author":"P Pichiule","year":"2002","unstructured":"Pichiule P, LaManna JC. Angiopoietin-2 and rat brain capillary remodeling during adaptation and deadaptation to prolonged mild hypoxia. J Appl Physiol. 2002;93:1131\u20139.","journal-title":"J Appl Physiol"},{"key":"675_CR36","doi-asserted-by":"publisher","first-page":"3163","DOI":"10.1242\/jeb.00976","volume":"207","author":"JC LaManna","year":"2004","unstructured":"LaManna JC, Chavez JC, Pichiule P. Structural and functional adaptation to hypoxia in the rat brain. J Exp Biol. 2004;207:3163\u20139.","journal-title":"J Exp Biol"},{"key":"675_CR37","doi-asserted-by":"crossref","unstructured":"Liu Na L, Nan C, Xiangyuan et al. More severe vascular remodeling in deep brain regions caused by hemodynamic differences is a potential mechanism of hypertensive cerebral small vessel disease. J Cereb Blood Flow Metab 2025; 0271678X251327919.","DOI":"10.1177\/0271678X251327919"},{"key":"675_CR38","doi-asserted-by":"publisher","first-page":"2227","DOI":"10.1161\/STROKEAHA.118.022613","volume":"49","author":"MR Raman","year":"2018","unstructured":"Raman MR, Himali JJ, Conner SC, et al. Circulating vascular growth factors and magnetic resonance imaging markers of small vessel disease and atrophy in Middle-Aged adults. Stroke. 2018;49:2227\u20139.","journal-title":"Stroke"},{"key":"675_CR39","doi-asserted-by":"publisher","first-page":"711784","DOI":"10.3389\/fnagi.2021.711784","volume":"13","author":"A Kapoor","year":"2021","unstructured":"Kapoor A, Gaubert A, Marshall A, et al. Increased levels of Circulating angiogenic cells and signaling proteins in older adults with cerebral small vessel disease. Front Aging Neurosci. 2021;13:711784.","journal-title":"Front Aging Neurosci"},{"key":"675_CR40","doi-asserted-by":"publisher","first-page":"e028569","DOI":"10.1161\/JAHA.122.028569","volume":"12","author":"L Ding","year":"2023","unstructured":"Ding L, Hou B, Zang J, et al. Imaging of angiogenesis in white matter hyperintensities. J Am Heart Assoc. 2023;12:e028569.","journal-title":"J Am Heart Assoc"},{"key":"675_CR41","first-page":"370","volume":"14","author":"Y Guan","year":"2023","unstructured":"Guan Y, Liu J, Gu Y, et al. Effects of hypoxia on cerebral microvascular angiogenesis: benefits or damages?? Aging Dis. 2023;14:370\u201385.","journal-title":"Aging Dis"},{"key":"675_CR42","doi-asserted-by":"publisher","first-page":"191","DOI":"10.4103\/NRR.NRR-D-23-01843","volume":"20","author":"N Manukjan","year":"2025","unstructured":"Manukjan N, Fulton D, Ahmed Z, et al. Vascular endothelial growth factor: a double-edged sword in the development of white matter lesions. Neural Regen Res. 2025;20:191\u20132.","journal-title":"Neural Regen Res"},{"key":"675_CR43","doi-asserted-by":"publisher","first-page":"1824","DOI":"10.3174\/ajnr.A4828","volume":"37","author":"JW van Dalen","year":"2016","unstructured":"van Dalen JW, Mutsaerts HJMM, Nederveen AJ, et al. White matter hyperintensity volume and cerebral perfusion in older individuals with hypertension using arterial Spin-Labeling. AJNR Am J Neuroradiol. 2016;37:1824\u201330.","journal-title":"AJNR Am J Neuroradiol"},{"key":"675_CR44","doi-asserted-by":"publisher","unstructured":"Voorter PHM, Stringer MS, van Dinther M et al. Heterogeneity and Penumbra of White Matter Hyperintensities in Small Vessel Diseases Determined by Quantitative MRI. Stroke; 0. Epub ahead of print 13 December 2024. https:\/\/doi.org\/10.1161\/STROKEAHA.124.047910","DOI":"10.1161\/STROKEAHA.124.047910"},{"key":"675_CR45","doi-asserted-by":"publisher","first-page":"102525","DOI":"10.1016\/j.nicl.2020.102525","volume":"29","author":"S Buch","year":"2021","unstructured":"Buch S, Subramanian K, Jella PK, et al. Revealing vascular abnormalities and measuring small vessel density in multiple sclerosis lesions using USPIO. NeuroImage Clin. 2021;29:102525.","journal-title":"NeuroImage Clin"},{"key":"675_CR46","doi-asserted-by":"publisher","first-page":"2927","DOI":"10.1093\/brain\/awx228","volume":"140","author":"G Datta","year":"2017","unstructured":"Datta G, Colasanti A, Rabiner EA, et al. Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis. Brain. 2017;140:2927\u201338.","journal-title":"Brain"},{"key":"675_CR47","doi-asserted-by":"publisher","first-page":"100916","DOI":"10.1016\/j.arr.2019.100916","volume":"53","author":"A Low","year":"2019","unstructured":"Low A, Mak E, Rowe JB, et al. Inflammation and cerebral small vessel disease: A systematic review. Ageing Res Rev. 2019;53:100916.","journal-title":"Ageing Res Rev"},{"key":"675_CR48","doi-asserted-by":"publisher","first-page":"e1812","DOI":"10.1212\/WNL.0000000000207113","volume":"100","author":"EC Gertje","year":"2023","unstructured":"Gertje EC, Janelidze S, van Westen D, et al. Associations between CSF markers of inflammation, white matter lesions, and cognitive decline in individuals without dementia. Neurology. 2023;100:e1812\u201324.","journal-title":"Neurology"},{"key":"675_CR49","doi-asserted-by":"publisher","first-page":"121","DOI":"10.5853\/jos.2018.03608","volume":"21","author":"AS Das","year":"2019","unstructured":"Das AS, Regenhardt RW, Vernooij MW, et al. Asymptomatic cerebral small vessel disease: insights from population-based studies. J Stroke. 2019;21:121\u201338.","journal-title":"J Stroke"},{"key":"675_CR50","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.1002\/jmri.27815","volume":"54","author":"B Zhang","year":"2021","unstructured":"Zhang B, Wang Y, Wang B, et al. MRI-Based investigation of association between cerebrovascular structural alteration and white matter hyperintensity induced by high blood pressure. J Magn Reson Imaging. 2021;54:1516\u201326.","journal-title":"J Magn Reson Imaging"},{"key":"675_CR51","doi-asserted-by":"publisher","first-page":"120009","DOI":"10.1016\/j.neuroimage.2023.120009","volume":"271","author":"KM Lynch","year":"2023","unstructured":"Lynch KM, Sepehrband F, Toga AW, et al. Brain perivascular space imaging across the human lifespan. NeuroImage. 2023;271:120009.","journal-title":"NeuroImage"},{"key":"675_CR52","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1177\/1747493019830321","volume":"14","author":"F Francis","year":"2019","unstructured":"Francis F, Ballerini L, Wardlaw JM. Perivascular spaces and their associations with risk factors, clinical disorders and neuroimaging features: A systematic review and meta-analysis. Int J Stroke. 2019;14:359\u201371.","journal-title":"Int J Stroke"},{"key":"675_CR53","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1007\/s00415-017-8550-8","volume":"264","author":"Y Li","year":"2017","unstructured":"Li Y, Li M, Zhang X, et al. Higher blood-brain barrier permeability is associated with higher white matter hyperintensities burden. J Neurol. 2017;264:1474\u201381.","journal-title":"J Neurol"},{"key":"675_CR54","first-page":"61","volume":"16","author":"S Naganawa","year":"2017","unstructured":"Naganawa S, Nakane T, Kawai H, et al. Gd-based contrast enhancement of the perivascular spaces in the basal ganglia. Magn Reson Med Sci MRMS Off J Japan Soc Magn Reson Med. 2017;16:61\u20135.","journal-title":"Magn Reson Med Sci MRMS Off J Japan Soc Magn Reson Med"},{"key":"675_CR55","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1148\/radiol.2017170205","volume":"286","author":"EL Boespflug","year":"2018","unstructured":"Boespflug EL, Schwartz DL, Lahna D, et al. MR imaging-based multimodal autoidentification of perivascular spaces (mMAPS): automated morphologic segmentation of enlarged perivascular spaces at clinical field strength. Radiology. 2018;286:632\u201342.","journal-title":"Radiology"},{"key":"675_CR56","doi-asserted-by":"publisher","first-page":"1563","DOI":"10.1177\/0271678X20972856","volume":"41","author":"G Barisano","year":"2021","unstructured":"Barisano G, Sheikh-Bahaei N, Law M, et al. Body mass index, time of day and genetics affect perivascular spaces in the white matter. J Cereb Blood Flow Metab. 2021;41:1563\u201378.","journal-title":"J Cereb Blood Flow Metab"},{"key":"675_CR57","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.jneumeth.2015.09.001","volume":"256","author":"K Cai","year":"2015","unstructured":"Cai K, Tain R, Das S, et al. The feasibility of quantitative MRI of perivascular spaces at 7T. J Neurosci Methods. 2015;256:151\u20136.","journal-title":"J Neurosci Methods"},{"key":"675_CR58","doi-asserted-by":"publisher","first-page":"120685","DOI":"10.1016\/j.neuroimage.2024.120685","volume":"297","author":"JMJ Waymont","year":"2024","unstructured":"Waymont JMJ, Vald\u00e9s Hern\u00e1ndez M, del Bernal C. Systematic review and meta-analysis of automated methods for quantifying enlarged perivascular spaces in the brain. NeuroImage. 2024;297:120685.","journal-title":"NeuroImage"},{"key":"675_CR59","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1097\/RLI.0000000000000027","volume":"49","author":"WH Bouvy","year":"2014","unstructured":"Bouvy WH, Biessels GJ, Kuijf HJ, et al. Visualization of perivascular spaces and perforating arteries with 7 T magnetic resonance imaging. Invest Radiol. 2014;49:307\u201313.","journal-title":"Invest Radiol"},{"key":"675_CR60","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.3174\/ajnr.A7144","volume":"42","author":"IC George","year":"2021","unstructured":"George IC, Arrighi-Allisan A, Delman BN, et al. A novel method to measure venular perivascular spaces in patients with MS on 7T MRI. AJNR Am J Neuroradiol. 2021;42:1069\u201372.","journal-title":"AJNR Am J Neuroradiol"},{"key":"675_CR61","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1159\/000016043","volume":"10","author":"O Hoffmann","year":"2000","unstructured":"Hoffmann O, Weih M, Schreiber S, et al. Measurement of cerebral circulation time by contrast-enhanced doppler sonography. Cerebrovasc Dis. 2000;10:142\u20136.","journal-title":"Cerebrovasc Dis"},{"key":"675_CR62","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/S0301-5629(02)00477-5","volume":"28","author":"SJ Schreiber","year":"2002","unstructured":"Schreiber SJ, Franke U, Doepp F, et al. Dopplersonographic measurement of global cerebral circulation time using echo contrast-enhanced ultrasound in normal individuals and patients with arteriovenous malformations. Ultrasound Med Biol. 2002;28:453\u20138.","journal-title":"Ultrasound Med Biol"},{"key":"675_CR63","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1002\/mrm.10559","volume":"50","author":"J Wang","year":"2003","unstructured":"Wang J, Alsop DC, Song HK, et al. Arterial transit time imaging with flow encoding arterial spin tagging (FEAST). Magn Reson Med. 2003;50:599\u2013607.","journal-title":"Magn Reson Med"},{"key":"675_CR64","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1002\/mrm.22218","volume":"63","author":"M Qiu","year":"2010","unstructured":"Qiu M, Paul Maguire R, Arora J, et al. Arterial transit time effects in pulsed arterial spin labeling CBF mapping: insight from a PET and MR study in normal human subjects. Magn Reson Med. 2010;63:374\u201384.","journal-title":"Magn Reson Med"},{"key":"675_CR65","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1002\/hbm.25739","volume":"43","author":"I Hotz","year":"2022","unstructured":"Hotz I, Deschwanden PF, Liem F, et al. Performance of three freely available methods for extracting white matter hyperintensities: freesurfer, UBO detector, and BIANCA. Hum Brain Mapp. 2022;43:1481\u2013500.","journal-title":"Hum Brain Mapp"},{"key":"675_CR66","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.mri.2022.07.016","volume":"93","author":"J Bernal","year":"2022","unstructured":"Bernal J, Vald\u00e9s-Hern\u00e1ndez MDC, Escudero J, et al. Assessment of perivascular space filtering methods using a three-dimensional computational model. Magn Reson Imaging. 2022;93:33\u201351.","journal-title":"Magn Reson Imaging"},{"key":"675_CR67","doi-asserted-by":"publisher","first-page":"117786","DOI":"10.1016\/j.neuroimage.2021.117786","volume":"230","author":"J Bernal","year":"2021","unstructured":"Bernal J, Vald\u00e9s-Hern\u00e1ndez MdC, Escudero J, et al. A four-dimensional computational model of dynamic contrast-enhanced magnetic resonance imaging measurement of subtle blood-brain barrier leakage. NeuroImage. 2021;230:117786.","journal-title":"NeuroImage"}],"container-title":["Fluids and Barriers of the CNS"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12987-025-00675-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12987-025-00675-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12987-025-00675-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T12:36:01Z","timestamp":1757248561000},"score":1,"resource":{"primary":{"URL":"https:\/\/fluidsbarrierscns.biomedcentral.com\/articles\/10.1186\/s12987-025-00675-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,16]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["675"],"URL":"https:\/\/doi.org\/10.1186\/s12987-025-00675-4","relation":{},"ISSN":["2045-8118"],"issn-type":[{"value":"2045-8118","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,16]]},"assertion":[{"value":"14 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted in accordance with the Declaration of Helsinki and approved by the national ethical review authority (dnr: 2020\u201303710). Written informed consent was provided from all participants prior to the experiments.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"74"}}