Incident lacunes preferentially localize to the edge of white matter hyperintensities: insights into the pathophysiology of cerebral small vessel disease
Abstract
White matter hyperintensities and lacunes are among the most frequent abnormalities on brain magnetic resonance imaging. They are commonly related to cerebral small vessel disease and associated with both stroke and dementia. We examined the spatial relationships between incident lacunes and white matter hyperintensities and related these findings to information on vascular anatomy to study possible mechanistic links between the two lesion types. Two hundred and seventy-six patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetically defined small vessel disease with mutations in the NOTCH3 gene were followed with magnetic resonance imaging over a total of 633 patient years. Using difference images and Jacobian maps from registered images we identified 104 incident lacunes. The majority (n = 95; 91.3%) of lacunes developed at the edge of a white matter hyperintensity whereas few lacunes were found to develop fully within (n = 6; 5.8%) or outside (n = 3; 2.9%) white matter hyperintensities. Adding information on vascular anatomy revealed that the majority of incident lacunes developed proximal to a white matter hyperintensity along the course of perforating vessels supplying the respective brain region. We further studied the spatial relationship between prevalent lacunes and white matter hyperintensities both in 365 patients with CADASIL and in 588 elderly subjects from the Austrian Stroke Prevention Study. The results were consistent with the results for incident lacunes. Lesion prevalence maps in different disease stages showed a spread of lesions towards subcortical regions in both cohorts. Our findings suggest that the mechanisms of lacunes and white matter hyperintensities are intimately connected and identify the edge of white matter hyperintensities as a predilection site for lacunes. Our observations further support and refine the concept of the white matter hyperintensity penumbra.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
WMHs manifest as regions of increased diffusivity in DTI and likely reflect the tip of the iceberg of underlying microstructural white matter changes: subtle white matter degeneration, detectable at first only with DTI, may gradually increase before becoming visible as macroscopic WMHs, which in turn give rise to lacunes.
“WMHs manifest as regions of increased diffusivity in DTI and likely reflect the tip of the iceberg of underlying microstructural white matter changes: subtle white matter degeneration, detectable at first only with DTI, may gradually increase before becoming visible as macroscopic WMHs (Pelletier et al., 2015), which in turn give rise to lacunes (Duering et al., 2013).”
From White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease (2018) · cites this paper as Duering et al., 2013
Cites
Advances in functional and structural MR image analysis and implementation as FSL
Smith, S. M., Jenkinson, M., Woolrich, M. W., Beckmann, C. F., Behrens, T. E. J., Johansen-Berg, H., Bannister, P. R., De Luca, M., Drobnjak, I., Flitney, D. E., et al. (2004) · NeuroImage · doi:10.1016/j.neuroimage.2004.07.051 · Cited by 13,630 · see citing works
Pantoni, L. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70104-6 · Cited by 3,405 · see citing works
Bayesian analysis of neuroimaging data in FSL
Woolrich, M., Jbabdi, S., Patenaude, B., Chappell, M., Makni, S., Behrens, T. E. J., Beckmann, C., Jenkinson, M., & Smith, S. M. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2008.10.055 · Cited by 2,774 · see citing works
Silent Brain Infarcts and the Risk of Dementia and Cognitive Decline
Vermeer, S. E., Prins, N. D., den Heijer, T., Hofman, A., Koudstaal, P. J., & Breteler, M. M. B. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa022066 · Cited by 2,313 · see citing works
Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia
Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cécillion, M., Maréchal, E., et al. (1996) · Nature · doi:10.1038/383707a0 · Cited by 2,068 · see citing works
Self-citationMechanisms of sporadic cerebral small vessel disease: insights from neuroimaging
Wardlaw, J. M., Smith, C., & Dichgans, M. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70060-7 · Cited by 1,657 · see citing works
Self-citationPathologic correlates of incidental MRI white matter signal hyperintensities
Fazekas, F., Kleinert, R., Offenbacher, H., Schmidt, R., Kleinert, G., Payer, F., Radner, H., & Lechner, H. (1993) · Neurology · doi:10.1212/wnl.43.9.1683 · Cited by 1,619 · see citing works
Self-citationPlasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis
Cai, Z., Jitkaew, S., Zhao, J., Chiang, H.-C., Choksi, S., Liu, J., Ward, Y., Wu, L.-G., & Liu, Z.-G. (2014) · Nature Cell Biology · doi:10.1038/ncb2883 · Cited by 1,322 · see citing works
Pathogenesis of Leukoaraiosis: A Review
Pantoni, L., & Garcia, J. H. (1997) · Stroke · doi:10.1161/01.str.28.3.652 · Cited by 1,225 · see citing works
O'Brien, J. T., Erkinjuntti, T., Reisberg, ., Román, G. C., Pantoni, L., Bowler, J., Ballard, C., DeCarli, C., Gorelick, P., Rockwood, K., et al. (2014) · International Journal of Stroke · doi:10.1111/ijs.12374_18 · Cited by 1,165 · see citing works
O'Brien, J. T., Erkinjuntti, T., Reisberg, B., Roman, G., Sawada, T., Pantoni, L., Bowler, J. V., Ballard, C., DeCarli, C., Gorelick, P. B., et al. (2003) · The Lancet Neurology · doi:10.1016/s1474-4422(03)00305-3 · Cited by 1,139 · see citing works
Chabriat, H., Joutel, A., Dichgans, M., Tournier-Lasserve, E., & Bousser, M.-G. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70127-9 · Cited by 1,088 · see citing works
Self-citationSpatial Normalization of Brain Images with Focal Lesions Using Cost Function Masking
Brett, M., Leff, A. P., Rorden, C., & Ashburner, J. (2001) · NeuroImage · doi:10.1006/nimg.2001.0845 · Cited by 931 · see citing works
Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease
Doubal, F. N., MacLullich, A. M. J., Ferguson, K. J., Dennis, M. S., & Wardlaw, J. M. (2010) · Stroke · doi:10.1161/strokeaha.109.564914 · Cited by 904 · see citing works
Is Breakdown of the Blood-Brain Barrier Responsible for Lacunar Stroke, Leukoaraiosis, and Dementia?
Wardlaw, J. M., Sandercock, P. A. G., Dennis, M. S., & Starr, J. (2003) · Stroke · doi:10.1161/01.str.0000058480.77236.b3 · Cited by 628 · see citing works
Dirnagl, U., Becker, K. J., & Meisel, A. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70054-7 · Cited by 588 · see citing works
Schmidt, R., Ropele, S., Enzinger, C., Petrovic, K., Smith, S., Schmidt, H., Matthews, P. M., & Fazekas, F. (2005) · Annals of Neurology · doi:10.1002/ana.20630 · Cited by 408 · see citing works
Self-citationPatterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis
O’Sullivan, M., Lythgoe, D. J., Pereira, A. C., Summers, P. E., Jarosz, J. M., Williams, S. C. R., & Markus, H. S. (2002) · Neurology · doi:10.1212/wnl.59.3.321 · Cited by 360 · see citing works
Nonrigid multimodality image registration
Mattes, D., Haynor, D. R., Vesselle, H. J., Lewellyn, T. K., & Eubank, W. B. (2001) · Proceedings of SPIE, the International Society for Optical Engineering/Proceedings of SPIE · doi:10.1117/12.431046 · Cited by 358 · see citing works
The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit
Shih, A. Y., Blinder, P., Tsai, P. S., Friedman, B., Stanley, G., Lyden, P. D., & Kleinfeld, D. (2013) · Nature Neuroscience · doi:10.1038/nn.3278 · Cited by 351 · see citing works
MRI white matter hyperintensities: Three-year follow-up of the Austrian Stroke Prevention Study
Schmidt, R., Fazekas, F., Kapeller, P., Schmidt, H., & Hartung, H.-P. (1999) · Neurology · doi:10.1212/wnl.53.1.132 · Cited by 342 · see citing works
Self-citationProgression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study
Schmidt, R., Enzinger, C., Ropele, S., Schmidt, H., & Fazekas, F. (2003) · The Lancet · doi:10.1016/s0140-6736(03)13616-1 · Cited by 306 · see citing works
Self-citationWhite Matter Hyperintensity Penumbra
Maillard, P., Fletcher, E. M., Harvey, D. J., Carmichael, O. T., Reed, B., Mungas, D., & DeCarli, C. S. (2011) · Stroke · doi:10.1161/strokeaha.110.609768 · Cited by 219 · see citing works
Incident subcortical infarcts induce focal thinning in connected cortical regions
Duering, M., Righart, R., Csanadi, E., Jouvent, E., Hervé, D., Chabriat, H., & Dichgans, M. (2012) · Neurology · doi:10.1212/wnl.0b013e3182749f39 · Cited by 218 · see citing works
Self-citationEvolution and testing of the lacunar hypothesis.
Bamford, J., & Warlow, C. P. (1988) · Stroke · doi:10.1161/01.str.19.9.1074 · Cited by 207 · see citing works
Viswanathan, A. (2006) · Brain · doi:10.1093/brain/awl177 · Cited by 205 · see citing works
Image registration via level-set motion: Applications to atlas-based segmentation
Vemuri, B. C., Ye, J., Chen, Y., & Leonard, C. M. (2002) · Medical Image Analysis · doi:10.1016/s1361-8415(02)00063-4 · Cited by 203 · see citing works
Duering, M., Zieren, N., Hervé, D., Jouvent, E., Reyes, S., Peters, N., Pachai, C., Opherk, C., Chabriat, H., & Dichgans, M. (2011) · Brain · doi:10.1093/brain/awr169 · Cited by 200 · see citing works
Self-citationZhu, Y.-C., Dufouil, C., Mazoyer, B., Soumaré, A., Ricolfi, F., Tzourio, C., & Chabriat, H. (2011) · American Journal of Neuroradiology · doi:10.3174/ajnr.a2366 · Cited by 181 · see citing works
Self-citationPathology of Lacunar Ischemic Stroke in Humans—A Systematic Review
Bailey, E. L., Smith, C., Sudlow, C. L. M., & Wardlaw, J. M. (2012) · Brain Pathology · doi:10.1111/j.1750-3639.2012.00575.x · Cited by 178 · cited 1× · see citing works
“Traditionally, lacunes are considered to result from occlusion of a single perforating artery (Bamford and Warlow, 1988; Bailey et al., 2012) whereas white matter hyperintensities are frequently attributed to chronic hypoperfusion (Fazekas et al.”
BackgroundThe cognitive profiles of CADASIL and sporadic small vessel disease
Charlton, R. A., Morris, R. G., Nitkunan, A., & Markus, H. S. (2006) · Neurology · doi:10.1212/01.wnl.0000216270.02610.7e · Cited by 173 · see citing works
Coevolution of white matter hyperintensities and cognition in the elderly
Maillard, P., Carmichael, O., Fletcher, E., Reed, B., Mungas, D., & DeCarli, C. (2012) · Neurology · doi:10.1212/wnl.0b013e3182617136 · Cited by 172 · see citing works
Progression of Leukoaraiosis and Cognition
Schmidt, R., Petrovic, K. E., Ropele, S., Enzinger, C., & Fazekas, F. (2007) · Stroke · doi:10.1161/strokeaha.107.489112 · Cited by 169 · see citing works
Self-citationSpectrum of Mutations in Biopsy-Proven CADASIL
Peters, N., Opherk, C., Bergmann, T., Castro, M., Herzog, J., & Dichgans, M. (2005) · Archives of Neurology · doi:10.1001/archneur.62.7.1091 · Cited by 161 · see citing works
Self-citationImpact of MRI markers in subcortical vascular dementia: A multi-modal analysis in CADASIL
Viswanathan, A., Godin, O., Jouvent, E., O’Sullivan, M., Gschwendtner, A., Peters, N., Duering, M., Guichard, J.-P., Holtmannspötter, M., Dufouil, C., et al. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.09.001 · Cited by 139 · see citing works
Self-citationCorrection of differential intensity inhomogeneity in longitudinal MR images
Lewis, E. B., & Fox, N. C. (2004) · NeuroImage · doi:10.1016/j.neuroimage.2004.04.030 · Cited by 125 · see citing works
Counting cavitating lacunes underestimates the burden of lacunar infarction
Potter, G. M., Doubal, F. N., Jackson, C. A., Chappell, F. M., Sudlow, C. L., Dennis, M. S., & Wardlaw, J. M. (2010) · Stroke · doi:10.1161/strokeaha.109.566307 · Cited by 113 · see citing works
Tertiary microvascular territories define lacunar infarcts in the basal ganglia
Feekes, J. A., Hsu, S., Chaloupka, J. C., & Cassell, M. D. (2005) · Annals of Neurology · doi:10.1002/ana.20505 · Cited by 96 · see citing works
Duering, M., Gonik, M., Malik, R., Zieren, N., Reyes, S., Jouvent, E., Hervé, D., Gschwendtner, A., Opherk, C., Chabriat, H., et al. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2012.10.084 · Cited by 89 · see citing works
Self-citationOn the Etiology of Incident Brain Lacunes
Gouw, A. A., van der Flier, W. M., Pantoni, L., Inzitari, D., Erkinjuntti, T., Wahlund, L., Waldemar, G., Schmidt, R., Fazekas, F., Scheltens, P., et al. (2008) · Stroke · doi:10.1161/strokeaha.108.521807 · Cited by 83 · see citing works
Self-citationCortical changes in cerebral small vessel diseases: a 3D MRI study of cortical morphology in CADASIL
Jouvent, E., Mangin, J.-F., Porcher, R., Viswanathan, A., O'Sullivan, M., Guichard, J.-P., Dichgans, M., Bousser, M.-G., & Chabriat, H. (2008) · Brain · doi:10.1093/brain/awn129 · Cited by 81 · see citing works
Self-citationKim, J. S., & Yoon, Y. (2012) · International Journal of Stroke · doi:10.1111/j.1747-4949.2012.00816.x · Cited by 78 · see citing works
Shape and Volume of Lacunar Infarcts
Hervé, D., Mangin, J., Molko, N., Bousser, M., & Chabriat, H. (2005) · Stroke · doi:10.1161/01.str.0000185678.26296.38 · Cited by 68 · see citing works
Self-citationZieren, N., Duering, M., Peters, N., Reyes, S., Jouvent, E., Hervé, D., Gschwendtner, A., Mewald, Y., Opherk, C., Chabriat, H., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.04.019 · Cited by 65 · see citing works
Self-citationWardlaw, J. M. (2008) · Stroke · doi:10.1161/strokeaha.108.523795 · Cited by 56 · see citing works
Small Centrum ovale Infarcts – A Pathological Study
Lammie, G. A., & Wardlaw, J. M. (1999) · Cerebrovascular Diseases · doi:10.1159/000015903 · Cited by 52 · see citing works
Automatic quantification of changes in the volume of brain structures
Calmon, G., Roberts, N., Eldridge, P. R., et al. (1998) · Lecture notes in computer science · doi:10.1007/bfb0056263 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Small vessel disease: mechanisms and clinical implications
Wardlaw, J. M., Smith, C., & Dichgans, M. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(19)30079-1 · Cited by 1,777 · see citing works
Self-citationNeuroimaging standards for research into small vessel disease—advances since 2013
Duering, M., Biessels, G. J., Brodtmann, A., Chen, C., Cordonnier, C., de Leeuw, F.-E., Debette, S., Frayne, R., Jouvent, E., Rost, N. S., et al. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00131-x · Cited by 1,144 · see citing works
Self-citationThe overlap between vascular disease and Alzheimer’s disease - lessons from pathology
Attems, J., & Jellinger, K. A. (2014) · BMC Medicine · doi:10.1186/s12916-014-0206-2 · Cited by 739 · see citing works
“SVD is a frequent cause of white matter lesions (WMLs; leukoaraiosis) that are increasingly detected by neuroimaging [118-121].”
BackgroundBaykara, E., Gesierich, B., Adam, R., Tuladhar, A. M., Biesbroek, J. M., Koek, H. L., Ropele, S., Jouvent, E., Initiative, A. D. N., Chabriat, H., et al. (2016) · Annals of Neurology · doi:10.1002/ana.24758 · Cited by 386 · see citing works
Self-citationWhite matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease
Araque Caballero, M. Á., Suárez-Calvet, M., Duering, M., Franzmeier, N., Benzinger, T., Fagan, A. M., Bateman, R. J., Jack, C. R., Levin, J., Dichgans, M., et al. (2018) · Brain · doi:10.1093/brain/awy229 · Cited by 179 · see citing works
“, 2015), which in turn give rise to lacunes (Duering et al., 2013).”
BackgroundSelf-citationStrategic white matter tracts for processing speed deficits in age-related small vessel disease
Duering, M., Gesierich, B., Seiler, S., Pirpamer, L., Gonik, M., Hofer, E., Jouvent, E., Duchesnay, E., Chabriat, H., Ropele, S., et al. (2014) · Neurology · doi:10.1212/wnl.0000000000000475 · Cited by 143 · see citing works
Self-citationSerum neurofilament light chain levels are related to small vessel disease burden
Duering, M., Konieczny, M. J., Tiedt, S., Baykara, E., Tuladhar, A. M., Leijsen, E. V., Lyrer, P., Engelter, S. T., Gesierich, B., Achmüller, M., et al. (2018) · Journal of Stroke · doi:10.5853/jos.2017.02565 · Cited by 132 · see citing works
Self-citation
- Authors
- Duering, M., Csanadi, E., Gesierich, B., Jouvent, E., Herve, D., Seiler, S., Belaroussi, B., Ropele, S., Schmidt, R., Chabriat, H., & Dichgans, M.
- Affiliations
- LMU Klinikum (DE)
- Medical University of Graz (AT)
- Assistance Publique – Hôpitaux de Paris (FR)
- German Center for Neurodegenerative Diseases (DE)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-07-17
- Volume
- 136
- Issue
- 9
- Pages
- 2717-2726
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2106430568
- Cited by
- 183
- References
- 47
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 13 · 2023: 13 · 2022: 21 · 2021: 10 · 2020: 15 · 2019: 12 · 2018: 20 · 2017: 17 · 2016: 18 · 2015: 13 · 2014: 9 · 2013: 1
- FWCI
- 8.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Austrian Science Fund (P20103)
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Assistance publique-Hôpitaux de Paris
- Stiftung zur Erforschung der Vaskulären Demenz
- Topics
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- lacunes, white matter hyperintensities, cerebral small vessel disease, CADASIL, Notch3, perforating vessels, lesion localization, lesion spread, stroke, dementia, vascular anatomy
- MeSH terms
- Receptor, Notch3, Adult, Aged, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Nerve Fibers, Myelinated, Cohort Studies, Disease Progression, CADASIL, Receptors, Notch, Young Adult, Leukoencephalopathies, Stroke, Lacunar
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
