Background and Aim: Dilated perivascular spaces (dPVS) have previously been associated with aging and hypertension-related cerebral microangiopathy. However, their risk factors, radiological features and clinical relevance have been poorly evaluated in CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a unique model to investigate the pathophysiology of ischemic small-vessel disease. The purpose of this study was to investigate these different aspects in a large cohort of patients with this disorder. Methods: Demographic and MRI data of 344 patients from a prospective cohort study were analyzed. The severity of dPVS was evaluated separately in the anterior temporal lobes, subinsular areas, basal ganglia and white matter, using validated semiquantitative scales. Logistic and multiple linear regression models were used to determine the risk factors associated with the severity of dPVS in these different regions and their relationships with cognition, disability and the MRI markers of the disease (white matter hyperintensities (WMH) lacunar infarcts, microbleeds and brain parenchymal fraction (BPF)). Results: The severity of dPVS was found to increase with age regardless of cerebral area (p < 0.001). In contrast with dPVS in other locations, the severity of dPVS in the temporal lobes or subinsular areas was also found strongly and specifically related to the extent of WMH (p < 0.001). Conversely, no significant association was detected with lacunar volume, number of microbleeds or BPF. A high degree of dPVS in the white matter was associated with lower cognitive performances independently of age and other MRI markers of the disease including BPF (p ≤ 0.04). Conclusions: In CADASIL, the progression of the hereditary microangiopathy with aging may promote the dilation of perivascular spaces throughout the whole brain but with variable extent according to cerebral location. In temporal lobes and subinsular areas, dPVS are common MRI features and may share a similar pathogenesis with the extension of WMH during the course of the disease. dPVS may also participate in the development of cognitive decline in this model of small-vessel disease, and their large number in white matter may alert clinicians to a higher risk of cognitive decline in CADASIL.

Keywords:
Dilated perivascular space, Small vessel disease, CADASIL, Magnetic resonance imaging, Risk factors, Cognition
1.
Zhu YC, Tzourio C, Soumaré A, Mazoyer B, Dufouil C, Chabriat H: Severity of dilated Virchow-Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease: a population-based study. Stroke 2010;41:2483-2490.
2.
Maclullich AM, Wardlaw JM, Ferguson KJ, Starr JM, Seckl JR, Deary IJ: Enlarged perivascular spaces are associated with cognitive function in healthy elderly men. J Neurol Neurosurg Psychiatry 2004;75:1519-1523.
3.
Zhu YC, Dufouil C, Soumaré A, Mazoyer B, Chabriat H, Tzourio C: High degree of dilated Virchow-Robin spaces on MRI is associated with increased risk of dementia. J Alzheimers Dis 2010;22:663-672.
4.
Doubal FN, MacLullich AM, Ferguson KJ, Dennis MS, Wardlaw JM: Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke 2010;41:450-454.
5.
Rouhl RP, van Oostenbrugge RJ, Knottnerus IL, Staals JE, Lodder J: Virchow-Robin spaces relate to cerebral small vessel disease severity. J Neurol 2008;255:692-696.
6.
Klarenbeek P, van Oostenbrugge RJ, Lodder J, Rouhl RP, Knottnerus IL, Staals J: Higher ambulatory blood pressure relates to enlarged Virchow-Robin spaces in first-ever lacunar stroke patients. J Neurol 2013;260:115-121.
7.
Martinez-Ramirez S, Pontes-Neto OM, Dumas AP, Auriel E, Halpin A, Quimby M, Gurol ME, Greenberg SM, Viswanathan A: Topography of dilated perivascular spaces in subjects from a memory clinic cohort. Neurology 2013;80:1551-1556.
8.
Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG: CADASIL. Lancet Neurol 2009;8:643-653.
9.
The LADIS Study Group: 2001-2011: a decade of the LADIS (Leukoaraiosis and Disability) Study: what have we learned about white matter changes and small-vessel disease? Cerebrovasc Dis 2011;32:577-588.
10.
Cumurciuc R, Guichard JP, Reizine D, Gray F, Bousser MG, Chabriat H: Dilation of Virchow-Robin spaces in CADASIL. Eur J Neurol 2006;13:187-190.
11.
Viswanathan A, Guichard JP, Gschwendtner A, Buffon F, Cumurcuic R, Boutron C, Vicaut E, Holtmannspötter M, Pachai C, Bousser MG, Dichgans M, Chabriat H: Blood pressure and haemoglobin A1c are associated with microhaemorrhage in CADASIL: a two-centre cohort study. Brain 2006;129:2375-2383.
12.
Jouvent E, Viswanathan A, Mangin JF, O'Sullivan M, Guichard JP, Gschwendtner A, Cumurciuc R, Buffon F, Peters N, Pachaï C, Bousser MG, Dichgans M, Chabriat H: Brain atrophy is related to lacunar lesions and tissue microstructural changes in CADASIL. Stroke 2007;38:1786-1790.
13.
Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O'Brien JT, Barkhof F, Benavente OR, Black SE, Brayne C, Breteler M, Chabriat H, Decarli C, de Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V, Oostenbrugge RV, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, van Buchem M, Norrving B, Gorelick PB, Dichgans M, Standards for Reporting Vascular Changes on Neuroimaging (STRIVE v1): Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822-838.
14.
Singhal S, Rich P, Markus HS: The spatial distribution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features. Am J Neuroradiol 2005;26:2481-2487.
15.
Yamamoto Y, Ihara M, Tham C, Low RW, Slade JY, Moss T, Oakley AE, Polvikoski T, Kalaria RN: Neuropathological correlates of temporal pole white-matter hyperintensities in CADASIL. Stroke 2009;40:2004-2011.
16.
Yao M, Jouvent E, During M, Godin O, Hervé D, Guichard JP, Zhu YC, Gschwendtner A, Opherk C, Dichgans M, Chabriat H: Extensive white matter hyperintensities may increase brain volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2012;43:3252-3257.
17.
Roher AE, Kuo YM, Esh C, Knebel C, Weiss N, Kalback W, Luehrs DC, Childress JL, Beach TG, Weller RO, Kokjohn TA: Cortical and leptomeningeal cerebrovascular amyloid and white-matter pathology in Alzheimer's disease. Mol Med 2003;9:112-122.
18.
Weller RO, Subash M, Preston SD, Mazanti I, Carare RO: Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol 2008;18:253-266.
19.
Miao Q, Paloneva T, Tuominen S, Pöyhönen M, Tuisku S, Viitanen M, Kalimo H: Fibrosis and stenosis of the long penetrating cerebral arteries: the cause of the white matter pathology in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Brain Pathol 2004;14:358-364.
20.
Ruchoux MM, Domenga V, Brulin P, Maciazek J, Limol S, Tournier-Lasserve E, Joutel A: Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Am J Pathol 2003;162:329-342.
21.
Kalimo H, Ruchoux M-M, Vitanen M, Kalaria RN: CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol 2002;12:371-384.
22.
Paquet C, Jouvent E, Mine M, Vital A, Hugon J, Chabriat H, Gray F: A cortical form of CADASIL with cerebral Aβ amyloidosis. Acta Neuropathol 2010;120:813-820.
23.
Groeschel S, Chong WK, Surtees R, Hanefeld F: Virchow-Robin spaces on magnetic resonance images: normative data, their dilatation, and a review of the literature. Neuroradiology 2006;48:745-754.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.