Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL
Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic paradigm of small vessel disease (SVD) caused by NOTCH3 mutations that stereotypically lead to the vascular accumulation of NOTCH3 around smooth muscle cells and pericytes. Whit...
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| Format: | Article |
| Language: | English |
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BMC
2019-11-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-019-0844-x |
| _version_ | 1818531975380598784 |
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| author | Rikesh M. Rajani Julien Ratelade Valérie Domenga-Denier Yoshiki Hase Hannu Kalimo Raj N. Kalaria Anne Joutel |
| author_facet | Rikesh M. Rajani Julien Ratelade Valérie Domenga-Denier Yoshiki Hase Hannu Kalimo Raj N. Kalaria Anne Joutel |
| author_sort | Rikesh M. Rajani |
| collection | DOAJ |
| description | Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic paradigm of small vessel disease (SVD) caused by NOTCH3 mutations that stereotypically lead to the vascular accumulation of NOTCH3 around smooth muscle cells and pericytes. White matter (WM) lesions (WMLs) are the earliest and most frequent abnormalities, and can be associated with lacunar infarcts and enlarged perivascular spaces (ePVS). The prevailing view is that blood brain barrier (BBB) leakage, possibly mediated by pericyte deficiency, plays a pivotal role in the formation of WMLs. Herein, we investigated the involvement of BBB leakage and pericyte loss in CADASIL WMLs. Using post-mortem brain tissue from 12 CADASIL patients and 10 age-matched controls, we found that WMLs are heterogeneous, and that BBB leakage reflects the heterogeneity. Specifically, while fibrinogen extravasation was significantly increased in WMLs surrounding ePVS and lacunes, levels of fibrinogen leakage were comparable in WMLs without other pathology (“pure” WMLs) to those seen in the normal appearing WM of patients and controls. In a mouse model of CADASIL, which develops WMLs but no lacunes or ePVS, we detected no extravasation of endogenous fibrinogen, nor of injected small or large tracers in WMLs. Moreover, there was no evidence of pericyte coverage modification in any type of WML in either CADASIL patients or mice. These data together indicate that WMLs in CADASIL encompass distinct classes of WM changes and argue against the prevailing hypothesis that pericyte coverage loss and BBB leakage are the primary drivers of WMLs. Our results also have important implications for the interpretation of studies on the BBB in living patients, which may misinterpret evidence of BBB leakage within WM hyperintensities as suggesting a BBB related mechanism for all WMLs, when in fact this may only apply to a subset of these lesions. |
| first_indexed | 2024-12-11T17:39:29Z |
| format | Article |
| id | doaj.art-6ffdfc0c91ff45dfad7b2368eaf0bb03 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-11T17:39:29Z |
| publishDate | 2019-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-6ffdfc0c91ff45dfad7b2368eaf0bb032022-12-22T00:56:35ZengBMCActa Neuropathologica Communications2051-59602019-11-017111410.1186/s40478-019-0844-xBlood brain barrier leakage is not a consistent feature of white matter lesions in CADASILRikesh M. Rajani0Julien Ratelade1Valérie Domenga-Denier2Yoshiki Hase3Hannu Kalimo4Raj N. Kalaria5Anne Joutel6Institute of Psychiatry and Neuroscience of Paris – INSERM UMR1266, Paris Descartes UniversityInstitute of Psychiatry and Neuroscience of Paris – INSERM UMR1266, Paris Descartes UniversityInstitute of Psychiatry and Neuroscience of Paris – INSERM UMR1266, Paris Descartes UniversityNeurovascular Research Group, Institute of Neuroscience, Newcastle UniversityDepartment of Pathology, Haartman Institute, University of HelsinkiNeurovascular Research Group, Institute of Neuroscience, Newcastle UniversityInstitute of Psychiatry and Neuroscience of Paris – INSERM UMR1266, Paris Descartes UniversityAbstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic paradigm of small vessel disease (SVD) caused by NOTCH3 mutations that stereotypically lead to the vascular accumulation of NOTCH3 around smooth muscle cells and pericytes. White matter (WM) lesions (WMLs) are the earliest and most frequent abnormalities, and can be associated with lacunar infarcts and enlarged perivascular spaces (ePVS). The prevailing view is that blood brain barrier (BBB) leakage, possibly mediated by pericyte deficiency, plays a pivotal role in the formation of WMLs. Herein, we investigated the involvement of BBB leakage and pericyte loss in CADASIL WMLs. Using post-mortem brain tissue from 12 CADASIL patients and 10 age-matched controls, we found that WMLs are heterogeneous, and that BBB leakage reflects the heterogeneity. Specifically, while fibrinogen extravasation was significantly increased in WMLs surrounding ePVS and lacunes, levels of fibrinogen leakage were comparable in WMLs without other pathology (“pure” WMLs) to those seen in the normal appearing WM of patients and controls. In a mouse model of CADASIL, which develops WMLs but no lacunes or ePVS, we detected no extravasation of endogenous fibrinogen, nor of injected small or large tracers in WMLs. Moreover, there was no evidence of pericyte coverage modification in any type of WML in either CADASIL patients or mice. These data together indicate that WMLs in CADASIL encompass distinct classes of WM changes and argue against the prevailing hypothesis that pericyte coverage loss and BBB leakage are the primary drivers of WMLs. Our results also have important implications for the interpretation of studies on the BBB in living patients, which may misinterpret evidence of BBB leakage within WM hyperintensities as suggesting a BBB related mechanism for all WMLs, when in fact this may only apply to a subset of these lesions.http://link.springer.com/article/10.1186/s40478-019-0844-xCADASILSmall vessel diseaseBlood brain barrierWhite matter lesionsPericytes |
| spellingShingle | Rikesh M. Rajani Julien Ratelade Valérie Domenga-Denier Yoshiki Hase Hannu Kalimo Raj N. Kalaria Anne Joutel Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL Acta Neuropathologica Communications CADASIL Small vessel disease Blood brain barrier White matter lesions Pericytes |
| title | Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL |
| title_full | Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL |
| title_fullStr | Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL |
| title_full_unstemmed | Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL |
| title_short | Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL |
| title_sort | blood brain barrier leakage is not a consistent feature of white matter lesions in cadasil |
| topic | CADASIL Small vessel disease Blood brain barrier White matter lesions Pericytes |
| url | http://link.springer.com/article/10.1186/s40478-019-0844-x |
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