Acknowledgement
This study was supported by grants from the SNUH Research Fund (No. 0420210750), the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (No. 9991006735, KMDF_PR_20200901_0062), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2021R1C1C1006407). The funding source had no role in the study design, data collection, data analysis, data interpretation, writing of the manuscript, or decision to submit it for publication.
References
- Wiley J. 2021 Alzheimer's disease facts and figures. Alzheimers Dement 2021;17:327-406 https://doi.org/10.1002/alz.12328
- Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer's disease drug development pipeline: 2019. Alzheimers Dement (N Y) 2019;5:272-293 https://doi.org/10.1016/j.trci.2019.05.008
- Cortes-Canteli M, Iadecola C. Alzheimer's disease and vascular aging: JACC focus seminar. J Am Coll Cardiol 2020;75:942-951 https://doi.org/10.1016/j.jacc.2019.10.062
- Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol 2019;18:684-696 https://doi.org/10.1016/S1474-4422(19)30079-1
- Liu Y, Braidy N, Poljak A, Chan DKY, Sachdev P. Cerebral small vessel disease and the risk of Alzheimer's disease: a systematic review. Ageing Res Rev 2018;47:41-48 https://doi.org/10.1016/j.arr.2018.06.002
- Knopman DS, Amieva H, Petersen RC, Chetelat G, Holtzman DM, Hyman BT, et al. Alzheimer disease. Nat Rev Dis Primers 2021;7:33
- Li X, Sundquist J, Zoller B, Sundquist K. Dementia and Alzheimer's disease risks in patients with autoimmune disorders. Geriatr Gerontol Int 2018;18:1350-1355 https://doi.org/10.1111/ggi.13488
- Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:257-262 https://doi.org/10.1016/j.jalz.2011.03.004
- McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:263-269 https://doi.org/10.1016/j.jalz.2011.03.005
- Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:270-279 https://doi.org/10.1016/j.jalz.2011.03.008
- Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:280-292 https://doi.org/10.1016/j.jalz.2011.03.003
- Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement 2018;14:535-562 https://doi.org/10.1016/j.jalz.2018.02.018
- Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA. Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol 2016;15:934-943 https://doi.org/10.1016/S1474-4422(16)30029-1
- Deschaintre Y, Richard F, Leys D, Pasquier F. Treatment of vascular risk factors is associated with slower decline in Alzheimer disease. Neurology 2009;73:674-680 https://doi.org/10.1212/WNL.0b013e3181b59bf3
- Iadecola C, Gottesman RF. Cerebrovascular alterations in Alzheimer disease. Circ Res 2018;123:406-408 https://doi.org/10.1161/CIRCRESAHA.118.313400
- Lee DY, Fletcher E, Martinez O, Zozulya N, Kim J, Tran J, et al. Vascular and degenerative processes differentially affect regional interhemispheric connections in normal aging, mild cognitive impairment, and Alzheimer disease. Stroke 2010;41:1791-1797 https://doi.org/10.1161/STROKEAHA.110.582163
- Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre. Brain 2013;136(Pt 9):2697-2706 https://doi.org/10.1093/brain/awt188
- Azarpazhooh MR, Avan A, Cipriano LE, Munoz DG, Sposato LA, Hachinski V. Concomitant vascular and neurodegenerative pathologies double the risk of dementia. Alzheimers Dement 2018;14:148-156 https://doi.org/10.1016/j.jalz.2017.07.755
- Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, et al. Vascular dysfunction-The disregarded partner of Alzheimer's disease. Alzheimers Dement 2019;15:158-167 https://doi.org/10.1016/j.jalz.2018.07.222
- Sachdev PS. Developing robust biomarkers for vascular cognitive disorders: adding 'V' to the AT(N) research framework. Curr Opin Psychiatry 2020;33:148-155 https://doi.org/10.1097/YCO.0000000000000577
- Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013;12:483-497 https://doi.org/10.1016/S1474-4422(13)70060-7
- Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 2017;96:17-42 https://doi.org/10.1016/j.neuron.2017.07.030
- Wong SM, Jansen JFA, Zhang CE, Hoff EI, Staals J, van Oostenbrugge RJ, et al. Blood-brain barrier impairment and hypoperfusion are linked in cerebral small vessel disease. Neurology 2019;92:e1669-e1677 https://doi.org/10.1212/WNL.0000000000007263
- Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol 2018;17:1016-1024 https://doi.org/10.1016/S1474-4422(18)30318-1
- Yoon SS, Jo SA. Mechanisms of amyloid-β peptide clearance: potential therapeutic targets for Alzheimer's disease. Biomol Ther (Seoul) 2012;20:245-255 https://doi.org/10.4062/biomolther.2012.20.3.245
- Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 2011;12:723-738 https://doi.org/10.1038/nrn3114
- Pluta R, Amek MU. Brain ischemia and ischemic blood-brain barrier as etiological factors in sporadic Alzheimer's disease. Neuropsychiatr Dis Treat 2008;4:855-864 https://doi.org/10.2147/NDT.S3739
- Kim HW, Hong J, Jeon JC. Cerebral small vessel disease and Alzheimer's disease: a review. Front Neurol 2020;11:927
- Noguchi-Shinohara M, Komatsu J, Samuraki M, Matsunari I, Ikeda T, Sakai K, et al. Cerebral amyloid angiopathy-related microbleeds and cerebrospinal fluid biomarkers in Alzheimer's disease. J Alzheimers Dis 2017;55:905-913 https://doi.org/10.3233/JAD-160651
- Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822-838 https://doi.org/10.1016/S1474-4422(13)70124-8
- Potter GM, Marlborough FJ, Wardlaw JM. Wide variation in definition, detection, and description of lacunar lesions on imaging. Stroke 2011;42:359-366 https://doi.org/10.1161/STROKEAHA.110.594754
- Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJNR Am J Neuroradiol 1987;8:421-426 https://doi.org/10.2214/ajr.149.2.351
- Kim KW, MacFall JR, Payne ME. Classification of white matter lesions on magnetic resonance imaging in elderly persons. Biol Psychiatry 2008;64:273-280 https://doi.org/10.1016/j.biopsych.2008.03.024
- de Leeuw FE, de Groot JC, Bots ML, Witteman JC, Oudkerk M, Hofman A, et al. Carotid atherosclerosis and cerebral white matter lesions in a population based magnetic resonance imaging study. J Neurol 2000;247:291-296 https://doi.org/10.1007/s004150050586
- Wen W, Sachdev P. The topography of white matter hyperintensities on brain MRI in healthy 60- to 64-year-old individuals. Neuroimage 2004;22:144-154 https://doi.org/10.1016/j.neuroimage.2003.12.027
- Sachdev P, Wen W. Should we distinguish between periventricular and deep white matter hyperintensities? Stroke 2005;36:2342-2343; author reply 2343-2344 https://doi.org/10.1161/01.STR.0000185694.52347.6e
- Kuller LH, Lopez OL, Newman A, Beauchamp NJ, Burke G, Dulberg C, et al. Risk factors for dementia in the cardiovascular health cognition study. Neuroepidemiology 2003;22:13-22 https://doi.org/10.1159/000067109
- Ye S, Dong S, Tan J, Chen L, Yang H, Chen Y, et al. White-matter hyperintensities and lacunar infarcts are associated with an increased risk of Alzheimer's disease in the elderly in China. J Clin Neurol 2019;15:46-53 https://doi.org/10.3988/jcn.2019.15.1.46
- Miwa K, Okazaki S, Sakaguchi M, Mochizuki H, Kitagawa K. Interleukin-6, interleukin-6 receptor gene variant, small-vessel disease and incident dementia. Eur J Neurol 2016;23:656-663 https://doi.org/10.1111/ene.12921
- Rosano C, Aizenstein HJ, Wu M, Newman AB, Becker JT, Lopez OL, et al. Focal atrophy and cerebrovascular disease increase dementia risk among cognitively normal older adults. J Neuroimaging 2007;17:148-155 https://doi.org/10.1111/j.1552-6569.2007.00093.x
- Meguro K, Ishii H, Kasuya M, Akanuma K, Meguro M, Kasai M, et al. Incidence of dementia and associated risk factors in Japan: the Osaki-Tajiri Project. J Neurol Sci 2007;260:175-182 https://doi.org/10.1016/j.jns.2007.04.051
- Hu HY, Ou YN, Shen XN, Qu Y, Ma YH, Wang ZT, et al. White matter hyperintensities and risks of cognitive impairment and dementia: a systematic review and meta-analysis of 36 prospective studies. Neurosci Biobehav Rev 2021;120:16-27 https://doi.org/10.1016/j.neubiorev.2020.11.007
- Tosto G, Zimmerman ME, Hamilton JL, Carmichael OT, Brickman AM. The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment. Alzheimers Dement 2015;11:1510-1519 https://doi.org/10.1016/j.jalz.2015.05.014
- Kim S, Choi SH, Lee YM, Kim MJ, Kim YD, Kim JY, et al. Periventricular white matter hyperintensities and the risk of dementia: a CREDOS study. Int Psychogeriatr 2015;27:2069-2077 https://doi.org/10.1017/S1041610215001076
- Lindemer ER, Salat DH, Smith EE, Nguyen K, Fischl B, Greve DN. White matter signal abnormality quality differentiates mild cognitive impairment that converts to Alzheimer's disease from nonconverters. Neurobiol Aging 2015;36:2447-2457 https://doi.org/10.1016/j.neurobiolaging.2015.05.011
- Nolze-Charron G, Mouiha A, Duchesne S, Bocti C. White matter hyperintensities in mild cognitive impairment and lower risk of cognitive decline. J Alzheimers Dis 2015;46:855-862 https://doi.org/10.3233/JAD-140618
- Eckerstrom C, Olsson E, Klasson N, Berge J, Nordlund A, Bjerke M, et al. Multimodal prediction of dementia with up to 10 years follow up: the Gothenburg MCI study. J Alzheimers Dis 2015;44:205-214 https://doi.org/10.3233/JAD-141053
- Hertze J, Palmqvist S, Minthon L, Hansson O. Tau pathology and parietal white matter lesions have independent but synergistic effects on early development of Alzheimer's disease. Dement Geriatr Cogn Dis Extra 2013;3:113-122 https://doi.org/10.1159/000348353
- Tapiola T, Pennanen C, Tapiola M, Tervo S, Kivipelto M, Hanninen T, et al. MRI of hippocampus and entorhinal cortex in mild cognitive impairment: a follow-up study. Neurobiol Aging 2008;29:31-38 https://doi.org/10.1016/j.neurobiolaging.2006.09.007
- Staekenborg SS, Koedam EL, Henneman WJ, Stokman P, Barkhof F, Scheltens P, et al. Progression of mild cognitive impairment to dementia: contribution of cerebrovascular disease compared with medial temporal lobe atrophy. Stroke 2009;40:1269-1274 https://doi.org/10.1161/STROKEAHA.108.531343
- Collins-Praino LE, Francis YI, Griffith EY, Wiegman AF, Urbach J, Lawton A, et al. Soluble amyloid beta levels are elevated in the white matter of Alzheimer's patients, independent of cortical plaque severity. Acta Neuropathol Commun 2014;2:83
- Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017;541:481-487 https://doi.org/10.1038/nature21029
- Yamazaki Y, Kanekiyo T. Blood-brain barrier dysfunction and the pathogenesis of Alzheimer's disease. Int J Mol Sci 2017;18:1965
- Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A. Impaired neurovascular coupling in aging and Alzheimer's disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol 2017;94:52-58 https://doi.org/10.1016/j.exger.2016.11.004
- Kandel BM, Avants BB, Gee JC, McMillan CT, Erus G, Doshi J, et al. White matter hyperintensities are more highly associated with preclinical Alzheimer's disease than imaging and cognitive markers of neurodegeneration. Alzheimers Dement (Amst) 2016;4:18-27 https://doi.org/10.1016/j.dadm.2016.03.001
- Zhou Y, Yu F, Duong TQ; Alzheimer's Disease Neuroimaging Initiative. White matter lesion load is associated with resting state functional MRI activity and amyloid PET but not FDG in mild cognitive impairment and early Alzheimer's disease patients. J Magn Reson Imaging 2015;41:102-109 https://doi.org/10.1002/jmri.24550
- Yi HA, Won KS, Chang HW, Kim HW. Association between white matter lesions and cerebral Aβ burden. PLoS One 2018;13:e0204313
- Caballero MAA, Song Z, Rubinski A, Duering M, Dichgans M, Park DC, et al. Age-dependent amyloid deposition is associated with white matter alterations in cognitively normal adults during the adult life span. Alzheimers Dement 2020;16:651-661 https://doi.org/10.1002/alz.12062
- Graff-Radford J, Arenaza-Urquijo EM, Knopman DS, Schwarz CG, Brown RD, Rabinstein AA, et al. White matter hyperintensities: relationship to amyloid and tau burden. Brain 2019;142:2483-2491 https://doi.org/10.1093/brain/awz162
- Glodzik L, Kuceyeski A, Rusinek H, Tsui W, Mosconi L, Li Y, et al. Reduced glucose uptake and Aβ in brain regions with hyperintensities in connected white matter. Neuroimage 2014;100:684-691 https://doi.org/10.1016/j.neuroimage.2014.06.060
- Weaver NA, Doeven T, Barkhof F, Biesbroek JM, Groeneveld ON, Kuijf HJ, et al. Cerebral amyloid burden is associated with white matter hyperintensity location in specific posterior white matter regions. Neurobiol Aging 2019;84:225-234 https://doi.org/10.1016/j.neurobiolaging.2019.08.001
- Al-Janabi OM, Brown CA, Bahrani AA, Abner EL, Barber JM, Gold BT, et al. Distinct white matter changes associated with cerebrospinal fluid amyloid-β1-42 and hypertension. J Alzheimers Dis 2018;66:1095-1104 https://doi.org/10.3233/JAD-180663
- Shams S, Granberg T, Martola J, Li X, Shams M, Fereshtehnejad SM, et al. Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment. J Cereb Blood Flow Metab 2016;36:621-628 https://doi.org/10.1177/0271678X15606141
- Wei K, Tran T, Chu K, Borzage MT, Braskie MN, Harrington MG, et al. White matter hypointensities and hyperintensities have equivalent correlations with age and CSF β-amyloid in the nondemented elderly. Brain Behav 2019;9:e01457
- van Westen D, Lindqvist D, Blennow K, Minthon L, Nagga K, Stomrud E, et al. Cerebral white matter lesions - associations with Aβ isoforms and amyloid PET. Sci Rep 2016;6:20709
- Kester MI, Goos JD, Teunissen CE, Benedictus MR, Bouwman FH, Wattjes MP, et al. Associations between cerebral small-vessel disease and Alzheimer disease pathology as measured by cerebrospinal fluid biomarkers. JAMA Neurol 2014;71:855-862 https://doi.org/10.1001/jamaneurol.2014.754
- Lo RY, Jagust WJ. Vascular burden and Alzheimer disease pathologic progression. Neurology 2012;79:1349-1355 https://doi.org/10.1212/WNL.0b013e31826c1b9d
- Soldan A, Pettigrew C, Zhu Y, Wang MC, Moghekar A, Gottesman RF, et al. White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease. Neurology 2020;94:e950-e960 https://doi.org/10.1212/WNL.0000000000008864
- Grimmer T, Faust M, Auer F, Alexopoulos P, Forstl H, Henriksen G, et al. White matter hyperintensities predict amyloid increase in Alzheimer's disease. Neurobiol Aging 2012;33:2766-2773 https://doi.org/10.1016/j.neurobiolaging.2012.01.016
- Moscoso A, Rey-Bretal D, Silva-Rodriguez J, Aldrey JM, Cortes J, Pias-Peleteiro J, et al. White matter hyperintensities are associated with subthreshold amyloid accumulation. Neuroimage 2020;218:116944
- Hedden T, Mormino EC, Amariglio RE, Younger AP, Schultz AP, Becker JA, et al. Cognitive profile of amyloid burden and white matter hyperintensities in cognitively normal older adults. J Neurosci 2012;32:16233-16242 https://doi.org/10.1523/JNEUROSCI.2462-12.2012
- Stefani A, Bernardini S, Panella M, Pierantozzi M, Nuccetelli M, Koch G, et al. AD with subcortical white matter lesions and vascular dementia: CSF markers for differential diagnosis. J Neurol Sci 2005;237:83-88 https://doi.org/10.1016/j.jns.2005.05.016
- Jonsson M, Zetterberg H, van Straaten E, Lind K, Syversen S, Edman A, et al. Cerebrospinal fluid biomarkers of white matter lesions - cross-sectional results from the LADIS study. Eur J Neurol 2010;17:377-382 https://doi.org/10.1111/j.1468-1331.2009.02808.x
- Walsh P, Sudre CH, Fiford CM, Ryan NS, Lashley T, Frost C, et al. CSF amyloid is a consistent predictor of white matter hyperintensities across the disease course from aging to Alzheimer's disease. Neurobiol Aging 2020;91:5-14 https://doi.org/10.1016/j.neurobiolaging.2020.03.008
- Goos JD, Kester MI, Barkhof F, Klein M, Blankenstein MA, Scheltens P, et al. Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke 2009;40:3455-3460 https://doi.org/10.1161/STROKEAHA.109.558197
- McAleese KE, Firbank M, Dey M, Colloby SJ, Walker L, Johnson M, et al. Cortical tau load is associated with white matter hyperintensities. Acta Neuropathol Commun 2015;3:60
- Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8:165-174 https://doi.org/10.1016/S1474-4422(09)70013-4
- Cordonnier C, Al-Shahi Salman R, Wardlaw J. Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 2007;130(Pt 8):1988-2003 https://doi.org/10.1093/brain/awl387
- Werring DJ. Cerebral microbleeds: pathophysiology to clinical practice. Cambridge: Cambridge University Press 2011
- Akoudad S, Wolters FJ, Viswanathan A, de Bruijn RF, van der Lugt A, Hofman A, et al. Association of cerebral microbleeds with cognitive decline and dementia. JAMA Neurol 2016;73:934-943 https://doi.org/10.1001/jamaneurol.2016.1017
- Miwa K, Tanaka M, Okazaki S, Yagita Y, Sakaguchi M, Mochizuki H, et al. Multiple or mixed cerebral microbleeds and dementia in patients with vascular risk factors. Neurology 2014;83:646-653 https://doi.org/10.1212/WNL.0000000000000692
- Goos JD, Teunissen CE, Veerhuis R, Verwey NA, Barkhof F, Blankenstein MA, et al. Microbleeds relate to altered amyloid-β metabolism in Alzheimer's disease. Neurobiol Aging 2012;33:1011.e1-e9 https://doi.org/10.1016/j.neurobiolaging.2011.12.012
- Chiang GC, Cruz Hernandez JC, Kantarci K, Jack CR Jr, Weiner MW; Alzheimer's Disease Neuroimaging Initiative. Cerebral microbleeds, CSF p-tau, and cognitive decline: significance of anatomic distribution. AJNR Am J Neuroradiol 2015;36:1635-1641 https://doi.org/10.3174/ajnr.A4351
- Kantarci K, Gunter JL, Tosakulwong N, Weigand SD, Senjem MS, Petersen RC, et al. Focal hemosiderin deposits and β-amyloid load in the ADNI cohort. Alzheimers Dement 2013;9(5 Suppl):S116-S123 https://doi.org/10.1016/j.jalz.2012.10.011
- Lim EY, Ryu SY, Shim YS, Yang DW, Cho AH. Coexistence of cerebral microbleeds and amyloid pathology in patients with cognitive complaints. J Clin Neurol 2020;16:83-89 https://doi.org/10.3988/jcn.2020.16.1.83
- Rauchmann BS, Ghaseminejad F, Mekala S, Perneczky R. Cerebral microhemorrhage at MRI in mild cognitive impairment and early alzheimer disease: association with tau and amyloid β at PET imaging. Radiology 2020;296:134-142 https://doi.org/10.1148/radiol.2020191904
- Dierksen GA, Skehan ME, Khan MA, Jeng J, Nandigam RN, Becker JA, et al. Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy. Ann Neurol 2010;68:545-548 https://doi.org/10.1002/ana.22099
- van der Vlies AE, Goos JD, Barkhof F, Scheltens P, van der Flier WM. Microbleeds do not affect rate of cognitive decline in Alzheimer disease. Neurology 2012;79:763-769 https://doi.org/10.1212/WNL.0b013e3182661f91
- Shams S, Granberg T, Martola J, Charidimou A, Li X, Shams M, et al. Cerebral microbleeds topography and cerebrospinal fluid biomarkers in cognitive impairment. J Cereb Blood Flow Metab 2017;37:1006-1013 https://doi.org/10.1177/0271678X16649401
- Benjamin P, Trippier S, Lawrence AJ, Lambert C, Zeestraten E, Williams OA, et al. Lacunar infarcts, but not perivascular spaces, are predictors of cognitive decline in cerebral small-vessel disease. Stroke 2018;49:586-593 https://doi.org/10.1161/STROKEAHA.117.017526
- Regenhardt RW, Das AS, Ohtomo R, Lo EH, Ayata C, Gurol ME. Pathophysiology of lacunar stroke: history's mysteries and modern interpretations. J Stroke Cerebrovasc Dis 2019;28:2079-2097 https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.05.006
- Fisher CM. Lacunes: small, deep cerebral infarcts. 1965. Neurology 1998;50:841
- Gouw AA, Seewann A, van der Flier WM, Barkhof F, Rozemuller AM, Scheltens P, et al. Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. J Neurol Neurosurg Psychiatry 2011;82:126-135 https://doi.org/10.1136/jnnp.2009.204685
- Wardlaw JM, Benveniste H, Nedergaard M, Zlokovic BV, Mestre H, Lee H, et al. Perivascular spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol 2020;16:137-153 https://doi.org/10.1038/s41582-020-0312-z
- van Swieten JC, van den Hout JH, van Ketel BA, Hijdra A, Wokke JH, van Gijn J. Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain 1991;114(Pt 2):761-774 https://doi.org/10.1093/brain/114.2.761
- Wardlaw JM, Doubal F, Armitage P, Chappell F, Carpenter T, Munoz Maniega S, et al. Lacunar stroke is associated with diffuse blood-brain barrier dysfunction. Ann Neurol 2009;65:194-202 https://doi.org/10.1002/ana.21549
- Maggi P, Macri SM, Gaitan MI, Leibovitch E, Wholer JE, Knight HL, et al. The formation of inflammatory demyelinated lesions in cerebral white matter. Ann Neurol 2014;76:594-608 https://doi.org/10.1002/ana.24242
- Mortensen KN, Sanggaard S, Mestre H, Lee H, Kostrikov S, Xavier ALR, et al. Impaired glymphatic transport in spontaneously hypertensive rats. J Neurosci 2019;39:6365-6377 https://doi.org/10.1523/JNEUROSCI.1974-18.2019
- Troili F, Cipollini V, Moci M, Morena E, Palotai M, Rinaldi V, et al. Perivascular unit: this must be the place. the anatomical crossroad between the immune, vascular and nervous system. Front Neuroanat 2020;14:17
- Martinez-Ramirez S, Pontes-Neto OM, Dumas AP, Auriel E, Halpin A, Quimby M, et al. Topography of dilated perivascular spaces in subjects from a memory clinic cohort. Neurology 2013;80:1551-1556 https://doi.org/10.1212/WNL.0b013e31828f1876
- Charidimou A, Meegahage R, Fox Z, Peeters A, Vandermeeren Y, Laloux P, et al. Enlarged perivascular spaces as a marker of underlying arteriopathy in intracerebral haemorrhage: a multicentre MRI cohort study. J Neurol Neurosurg Psychiatry 2013;84:624-629 https://doi.org/10.1136/jnnp-2012-304434
- Ramirez J, Berezuk C, McNeely AA, Scott CJ, Gao F, Black SE. Visible Virchow-Robin spaces on magnetic resonance imaging of Alzheimer's disease patients and normal elderly from the Sunnybrook Dementia Study. J Alzheimers Dis 2015;43:415-424 https://doi.org/10.3233/JAD-132528
- Banerjee G, Kim HJ, Fox Z, Jager HR, Wilson D, Charidimou A, et al. MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden. Brain 2017;140:1107-1116 https://doi.org/10.1093/brain/awx003
- Roher AE, Kuo YM, Esh C, Knebel C, Weiss N, Kalback W, et al. Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease. Mol Med 2003;9:112-122 https://doi.org/10.1007/BF03402043
- Chen W, Song X, Zhang Y. Assessment of the Virchow-Robin spaces in Alzheimer disease, mild cognitive impairment, and normal aging, using high-field MR imaging. AJNR Am J Neuroradiol 2011;32:1490-1495 https://doi.org/10.3174/ajnr.A2541
- Cai K, Tain R, Das S, Damen FC, Sui Y, Valyi-Nagy T, et al. The feasibility of quantitative MRI of perivascular spaces at 7T. J Neurosci Methods 2015;256:151-156 https://doi.org/10.1016/j.jneumeth.2015.09.001
- Patankar TF, Mitra D, Varma A, Snowden J, Neary D, Jackson A. Dilatation of the Virchow-Robin space is a sensitive indicator of cerebral microvascular disease: study in elderly patients with dementia. AJNR Am J Neuroradiol 2005;26:1512-1520
- Hansen TP, Cain J, Thomas O, Jackson A. Dilated perivascular spaces in the basal ganglia are a biomarker of small-vessel disease in a very elderly population with dementia. AJNR Am J Neuroradiol 2015;36:893-898 https://doi.org/10.3174/ajnr.A4237
- Shams S, Martola J, Charidimou A, Larvie M, Granberg T, Shams M, et al. Topography and determinants of magnetic resonance imaging (MRI)-visible perivascular spaces in a large memory clinic cohort. J Am Heart Assoc 2017;6:e006279
- Charidimou A, Hong YT, Jager HR, Fox Z, Aigbirhio FI, Fryer TD, et al. White matter perivascular spaces on magnetic resonance imaging: marker of cerebrovascular amyloid burden? Stroke 2015;46:1707-1709 https://doi.org/10.1161/STROKEAHA.115.009090
- Wang ML, Yu MM, Wei XE, Li WB, Li YH. Association of enlarged perivascular spaces with Aβ and tau deposition in cognitively normal older population. Neurobiol Aging 2021;100:32-38 https://doi.org/10.1016/j.neurobiolaging.2020.12.014
- Gertje EC, van Westen D, Panizo C, Mattsson-Carlgren N, Hansson O. Association of enlarged perivascular spaces and measures of small vessel and alzheimer disease. Neurology 2021;96:e193-e202 https://doi.org/10.1212/WNL.0000000000011046
- Brickman AM, Zahodne LB, Guzman VA, Narkhede A, Meier IB, Griffith EY, et al. Reconsidering harbingers of dementia: progression of parietal lobe white matter hyperintensities predicts Alzheimer's disease incidence. Neurobiol Aging 2015;36:27-32 https://doi.org/10.1016/j.neurobiolaging.2014.07.019
- Hoy AR, Ly M, Carlsson CM, Okonkwo OC, Zetterberg H, Blennow K, et al. Microstructural white matter alterations in preclinical Alzheimer's disease detected using free water elimination diffusion tensor imaging. PLoS One 2017;12:e0173982
- Mendes A, Bertrand A, Lamari F, Colliot O, Routier A, Godefroy O, et al. Cerebral microbleeds and CSF Alzheimer biomarkers in primary progressive aphasias. Neurology 2018;90:e1057-e1065
- Shams S, Wahlund LO. Cerebral microbleeds as a biomarker in Alzheimer's disease? A review in the field. Biomark Med 2016;10:9-18 https://doi.org/10.2217/bmm.15.101