Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects

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Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common and best known monogenic small vessel disease. Here, we review the clinical, neuroimaging, neuropathological, genetic, and therapeutic aspects based on the most relevant articles published between 1994 and 2016 and on the personal experience of the authors, all directly involved in CADASIL research and care. We conclude with some suggestions that may help in the clinical practice and management of these patients.

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Most cited references 169

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Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.

S Alamowitch, F. Bach, M M Ruchoux … (1996)

Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.

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Subcortical ischaemic vascular dementia.

Gustavo C. Román, Timo Erkinjuntti, Anders Wallin … (2002)

Vascular dementia is the second most common type of dementia. The subcortical ischaemic form (SIVD) frequently causes cognitive impairment and dementia in elderly people. SIVD results from small-vessel disease, which produces either arteriolar occlusion and lacunes or widespread incomplete infarction of white matter due to critical stenosis of medullary arterioles and hypoperfusion (Binswanger's disease). Symptoms include motor and cognitive dysexecutive slowing, forgetfulness, dysarthria, mood changes, urinary symptoms, and short-stepped gait. These manifestations probably result from ischaemic interruption of parallel circuits from the prefrontal cortex to the basal ganglia and corresponding thalamocortical connections. Brain imaging (computed tomography and magnetic resonance imaging) is essential for correct diagnosis. The main risk factors are advanced age, hypertension, diabetes, smoking, hyperhomocysteinaemia, hyperfibrinogenaemia, and other conditions that can cause brain hypoperfusion such as obstructive sleep apnoea, congestive heart failure, cardiac arrhythmias, and orthostatic hypotension. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)and some forms of cerebral amyloid angiopathy have a genetic basis. Treatment is symptomatic and prevention requires control of treatable risk factors.

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Cadasil.

Hugues Chabriat, Anne Joutel, Martin Dichgans … (2009)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. Clinical and neuroimaging features resemble those of sporadic small-artery disease, although patients with CADASIL have an earlier age at onset of stroke events, an increased frequency of migraine with aura, and a slightly variable pattern of ischaemic white-matter lesions on brain MRI. NOTCH3 (Notch homolog 3), the gene involved in CADASIL, encodes a transmembrane receptor primarily expressed in systemic arterial smooth-muscle cells. Pathogenetic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. Functional and imaging studies in cultured cells, genetically engineered mice, and patients with CADASIL have all provided insights into the molecular and vascular mechanisms underlying this disease. A recent multicentre trial in patients with cognitive impairment emphasises the feasibility of randomised trials in patients with CADASIL. In this Review, we summarise the current understanding of CADASIL, a devastating disorder that also serves as a model for the more common forms of subcortical ischaemic strokes and pure vascular dementia.

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Author and article information

Contributors

Ilaria Di Donato: didonatoila@gmail.com

Silvia Bianchi: silviabianchi.si@gmail.com

Nicola De Stefano: destefano@unisi.it

Martin Dichgans: martin.dichgans@med.uni-muenchen.de

Maria Teresa Dotti: dotti@unisi.it

Marco Duering: marco.duering@med.uni-muenchen.de

Eric Jouvent: eric.jouvent@aphp.fr

Amos D. Korczyn: amoskor@tau.ac.il

Saskia A. J. Lesnik-Oberstein: lesnik@lumc.nl

Alessandro Malandrini: malandrini@unisi.it

Hugh S. Markus: hsm32@medschl.cam.ac.uk

Leonardo Pantoni: leonardo.pantoni@unifi.it

Silvana Penco: silvana.penco@ospedaleniguarda.it

Alessandra Rufa: rufa@unisi.it

Osman Sinanović: osman.sinanovic@ukctuzla.ba

Dragan Stojanov: drstojanov@gmail.com

Antonio Federico: +39.0577.585763 , federico@unisi.it

Journal

Journal ID (nlm-ta): BMC Med

Journal ID (iso-abbrev): BMC Med

Title: BMC Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1741-7015

Publication date (Electronic): 24 February 2017

Publication date PMC-release: 24 February 2017

Publication date Collection: 2017

Volume: 15

Electronic Location Identifier: 41

Affiliations

[1 ]ISNI 0000 0004 1757 4641, GRID grid.9024.f, Department of Medicine, Surgery and Neurosciences, Medical School, , University of Siena, ; Viale Bracci 2, 53100 Siena, Italy

[2 ]ISNI 0000 0004 0477 2585, GRID grid.411095.8, Institute for Stroke and Dementia Research, , Klinikum der Universität München, Ludwig-Maximilians-University LMU, ; Munich, Germany

[3 ]GRID grid.452617.3, , Munich Cluster for Systems Neurology (SyNergy), ; Munich, Germany

[4 ]ISNI 0000 0001 2217 0017, GRID grid.7452.4, , Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1161 INSERM, ; F-75205 Paris, France

[5 ]ISNI 0000 0000 9725 279X, GRID grid.411296.9, Department of Neurology, , AP-HP, Lariboisière Hospital, ; F-75475 Paris, France

[6 ]ISNI 0000 0004 1788 6194, GRID grid.469994.f, , DHU NeuroVasc Sorbonne Paris Cité, ; Paris, France

[7 ]ISNI 0000 0004 1937 0546, GRID grid.12136.37, Department of Neurology, , Tel Aviv University, ; Ramat Aviv, 69978 Israel

[8 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Clinical Genetics, , K5-R Leiden University Medical Center, ; PO Box 9600, 2300 RC Leiden, The Netherlands

[9 ]ISNI 0000000121885934, GRID grid.5335.0, Stroke Research Group, Department of Clinical Neurosciences, , University of Cambridge, ; Cambridge, UK

[10 ]NEUROFARBA Department, Neuroscience section, Largo Brambilla 3, 50134 Florence, Italy

[11 ]GRID grid.416200.1, Medical Genetic Unit, Department of Laboratory Medicine, , Niguarda Hospital, ; Milan, Italy

[12 ]ISNI 0000 0001 0682 9061, GRID grid.412410.2, Department of Neurology, , University Clinical Center Tuzla, School of Medicine University of Tuzla, ; 75000 Tuzla, Bosnia and Herzegovina

[13 ]ISNI 0000 0001 0942 1176, GRID grid.11374.30, Faculty of Medicine, , University of Nis, ; Bul. Dr. Zorana Djindjica 81, Nis, 18000 Serbia

Article

Publisher ID: 778

DOI: 10.1186/s12916-017-0778-8

PMC ID: 5324276

PubMed ID: 28231783

SO-VID: 52bafa8e-b7b6-44cc-9de0-d6dd5c5fe4e7

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 31 August 2016

Date accepted : 3 January 2017

Funding

Funded by: NIHR Senior Investigator award and his work is supported by the Cambridge University Hospital Comprehensive NIHR Biomedical Research Unit.

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ScienceOpen disciplines: Medicine

Keywords: cadasil,small vessel disease,notch 3,vascular dementia,genetics

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ScienceOpen disciplines: Medicine

Keywords: cadasil, small vessel disease, notch 3, vascular dementia, genetics

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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects

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Probing cerebral hemodynamics with BOLD fMRI

Most cited references 169

Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.

Subcortical ischaemic vascular dementia.

Cadasil.

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