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Journal of Neurology

, Volume 265, Issue 12, pp 2934–2943 | Cite as

The role of clinical and neuroimaging features in the diagnosis of CADASIL

  • Anna Bersano
  • Gloria Bedini
  • Hugh Stephen Markus
  • Paolo Vitali
  • Enrico Colli-Tibaldi
  • Franco Taroni
  • Cinzia Gellera
  • Silvia Baratta
  • Lorena Mosca
  • Paola Carrera
  • Maurizio Ferrari
  • Cristina Cereda
  • Gaetano Grieco
  • Silvia Lanfranconi
  • Franca Mazucchelli
  • Davide Zarcone
  • Maria Luisa De Lodovici
  • Giorgio Bono
  • Giorgio Battista Boncoraglio
  • Eugenio Agostino Parati
  • Maria Vittoria Calloni
  • Patrizia Perrone
  • Bianca Maria Bordo
  • Cristina Motto
  • Elio Agostoni
  • Alessandro Pezzini
  • Alessandro Padovani
  • Giuseppe Micieli
  • Anna Cavallini
  • Graziella Molini
  • Francesco Sasanelli
  • Maria Sessa
  • Giancarlo Comi
  • Nicoletta Checcarelli
  • Massimo Carmerlingo
  • Manuel Corato
  • Simona Marcheselli
  • Laura Fusi
  • Giampiero Grampa
  • Davide Uccellini
  • Simone Beretta
  • Carlo Ferrarese
  • Barbara Incorvaia
  • Carlo Sebastiano Tadeo
  • Laura Adobbati
  • Vincenzo Silani
  • Giuseppe Faragò
  • Nadia Trobia
  • Caspar Grond-Ginsbach
  • Livia Candelise
  • on behalf of Lombardia GENS-group
Original Communication
  • 304 Downloads

Abstract

Background

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL.

Methods

Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities.

Results

128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity.

Conclusions

A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.

Keywords

CADASIL NOTCH3 gene Stroke genetics Diagnosis Neuroimaging Monogenic disorders 

Notes

Acknowledgements

We thank Silvana Penco, MD, PhD, who prematurely died last year, for her precious support to the study conception and the achievement of study results. We thank also all the staff and participants of the Lombardia GENS study for their important contributions. Lombardia GENS investigators: Davide Zarcone, MD, (Ospedale S. Antonio Abate, Gallarate (VA), Director of Participating Center), Franca Mazzucchelli, MD, (Ospedale S. Antonio Abate, Gallarate (VA), PI of Participating Center); Giampiero Grampa, MD, (Ospedale di Circolo, Saronno (VA), Director of Participating Center); Laura Fusi; (Ospedale di Circolo, Saronno (VA), PI of Participating Center); Davide Uccellini, MD, (Ospedale Galmarini, Tradate (VA), PI of Participating Center); Mario Guidotti, MD, (Ospedale Valduce, Como, Director of Participating Center), Nicoletta Checcarelli, MD, (Ospedale Valduce, Como, PI of Participating Center), Maurizio Riva, MD, (Ospedale Maggiore, Lodi, Director of Participating Center); Simona Iurlaro; MD, (Ospedale Maggiore, Lodi, PI of Participating Center); Bianca Bordo Maria, MD, (Ospedale di Circolo, Desio (MI), PI of Participating Center); Francesco Sasanelli, MD, (Ospedale Predabissi, Vizzolo Predabissi (MI); Director of Participating Center); Graziella Molini, MD, (Ospedale Predabissi, Vizzolo Predabissi (MI); PI of Participating Center); Massimiliano Braga, MD (Ospedale Civile, Vimercate (MI), PI of Participating Center); Carlo Sebastiano Tadeo, MD, (Istituto Clinico Città Studi, Milano, Director of Participating Center); Barbara Incorvaia, MD, (Istituto Clinico Città Studi, Milano, Collaborator of Participating Center); Giovanni Meola, MD, Prof, (Istituto Policlinico San Donato, San Donato Milanese (MI), Director of Participating Center); Marinella Carpo, MD, PhD, (Ospedaliera Treviglio, Treviglio (BG), PI of Participating Center); Massimo Camerlingo (Casa di Cura Policlinico San Marco, Zingonia - Osio Sotto (BG), Director and PI of Participating Center), Giuseppina Borutti, MD (Ospedale Civile, Voghera (PV) PI of Participating Center); Patrizia Perrone, MD, (Ospedale di Legnano e di Cuggiono, Legnano (MI), Director of Participating Center); Maria Vittoria Calloni, MD, (Ospedale di Legnano e di Cuggiono, Legnano (MI), PI of Participating Center); Giorgio Bono, MD, Prof, (Ospedale di Circolo, Varese, Director of Participating Center); Marialuisa Delodovici, MD, (Ospedale di Circolo, Varese, PI of Participating Center), Elena Pinuccia Verrengia, MD, (Ospedale di Circolo, Varese, Collaborator of Participating Center), Lucia Tancredi, MD, (Ospedale Sant’Anna, Como, PI of Participating Center); Elio Agostoni, MD, (Ospedale Niguarda, PI of Participating Center); Cristina Motto(Ospedale Niguarda, Collaborator of Participating Center); Alessandro Terruzzi, MD,(Ospedale A. Manzoni, Lecco, Collaborator of Participating Center); Alessandro Padovani, MD, Prof (Spedali Civili, Brescia, Director of Participating Center); Alessandro Pezzini, Prof, (Spedali Civili, Brescia, PI of Participating Center); Mauro Magoni, MD, (Spedali Civili, Brescia, Director of Stroke Unit); Elisabetta Del Zotto , MD, (Spedali Civili, Brescia, Collaborator of Participating Center); Carlo Ferrarese, MD, Prof (Ospedale San Gerardo, Monza (MI), Director of Participating Center); Simone Beretta, MD, (Ospedale San Gerardo, Monza (MI), PI of Participating Center); Pietro Bassi, MD, (Ospedale San Giuseppe Milano, Milano, Director of Participating Center); Patrizia Lattuada, MD, (Ospedale San Carlo, Milano, PI of Participating Center); Elena Ballabio, MD, (Ospedale San Carlo, Milano, Collaborator of Participating Center); Paola Gambaro,MD, ( Ospedale L. Sacco, Milano, PI of Participating Center); Eugenio Agostino Parati, MD, (Istituto Neurologico C. Besta, Milano, Director of Participating Center); Giorgio Battista Boncoraglio, MD, (Istituto Neurologico C. Besta, Milano, PI of Participating Center); Livia Candelise, MD, Prof, (Fondazione Ospedale Maggiore Policlinico, Milano, Study Coordinator); Anna Bersano, MD, PhD (Istituto Neurologico C. Besta, Milano, Study Coordinator and PI of Participating Center); Sivia Lanfranconi, MD, (Fondazione Ospedale Maggiore Policlinico, Milano, Collaborator of Participating Center); Giancarlo Comi, MD, Prof, (Ospedale San Raffaele, Milano, Director of Participating Center); Maria Sessa, MD, (Ospedale di Cremona, Director and PI of Participating Center); Vincenzo Silani, MD, Prof, (Istituto Auxologico Italiano, Milano, Director of Participating Center); Laura Adobbati, MD, (Istituto Auxologico Italiano, Milano, Director of Stroke Unit and PI of Participating Center); Barbara Corrà. MD, (Istituto Auxologico Italiano, Milano, Collaborator of Participating Center); Giuseppe Micieli, MD, (Istituto Neurologico C. Mondino, Pavia, Director and PI of Participating Center); Anna Cavallini, MD, (Istituto Neurologico C. Mondino, Pavia, Director of Stroke Unit and Co-PI of Participating Center); Isabella Canavero, MD, (Istituto Neurologico C. Mondino, Pavia, Collaborator of Participating Center); Simona Marcheselli, MD, (Istituto Clinico Humanitas, Rozzano (MI), Director and PI of Participating Center); Manuel Corato, MD, (Istituto Clinico Humanitas, Rozzano (MI), Collaborator of Participating Center); Franco Taroni, MD, (Director and Study PI of Laboratorio di Biochimica e Genetica, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano), Cinzia Gellera, MD, (Collaborator and Study co-PI of Laboratorio di Biochimica e Genetica, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano), Silvia Baratta, PhD, (Collaborator of Laboratorio di Biochimica e Genetica, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano); Lorena Mosca, PhD (Collaborator of SS Genetica Medica , Azienda Ospedaliera Niguarda Ca’ Granda, Milano); Maurizio Ferrari, MD, Prof, (Director of Laboratorio di Biologia Molecolare Clinica, IRCCS Ospedale San Raffaele, Università Vita Salute San Raffaele,Milano); Paola Carrera, MD, (Collaborator and Study PI of Laboratorio di Biologia Molecolare Clinica, IRCCS Ospedale San Raffaele,Milano); Eloisa Arbustini, MD, Prof (Director and Study PI of Laboratorio di genetica, Fondazione IRCCS Istituto neurologico C.Mondino, Pavia, Centro Malattie Genetiche Cardiovascolari, Laboratorio di Genetica Molecolare, Fondazione IRCCS Policlinico San Matteo, Pavia); Maurizia Grasso, MD, (Study PI of Laboratorio di genetica, Fondazione IRCCS Istituto neurologico C.Mondino, Pavia, Centro Malattie Genetiche Cardiovascolari, Laboratorio di Genetica Molecolare, Fondazione IRCCS Policlinico San Matteo, Pavia); Giacomo Pietro Comi, MD, Prof (Director and Study PI of Laboratorio di Biochimica e Genetica, Centro Dino Ferrari, Dipartimento di Scienza Neurologiche, IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano), Stefania Corti, Prof, (Study Co-PI of Laboratorio di Biochimica e Genetica, Centro Dino Ferrari, Dipartimento di Scienza Neurologiche, IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano), Dario Ronchi, PhD, (Collaborator of Laboratorio di Biochimica e Genetica, Centro Dino Ferrari, Dipartimento di Scienza Neurologiche, IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano);Giampaolo Merlini, MD, Prof, (Director of Laboratorio di Biotecnologie e Tecnologie Biomediche Centro per lo Studio delle Amiloidosi Sistemiche, Fondazione IRCCS Policlinico San Matteo, Pavia); Laura Obici, MD, (Study PI of Laboratorio di Biotecnologie e Tecnologie Biomediche Centro per lo Studio delle Amiloidosi Sistemiche, Fondazione IRCCS Policlinico San Matteo, Pavia); Maria Teresa Bassi, PhD (Director and Study PI of Laboratorio di genetica; Istituto Eugenio Medea, Bosisio Parini (LC)); Cristina Cereda, PhD, (Director and Study PI of Laboratorio of genetica; Fondazione IRCCS Istituto C.Mondino, Pavia); Fabrizio Tagliavini, MD, (Director of UO di Neuropatologia, Fondazione IRCCS Istituto Nazionale Neurologico C. Besta); Hugh Stephen Markus, MD, Prof (GENS Advisory Board members; Department of Clinical Neurosciences, Cambridge, UK); Caspar Grond Ginsbach, PhD, (GENS Advisory Board member, Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany).

Funding

The Lombardia GENS project has received funding from the Regione Lombardia Government as a Research Independent Project (DGR n°VIII/006128-12/12/2007). Lombardia GENS is an investigator-driven, academic, non-profit consortium and is publicly funded. Hugh Markus is supported by an NIHR Senior Investigator award and his work is supported by the Cambridge University Hospitals NIHR Biomedical Research Centre.

Compliance with ethical standards

Conflicts of interest

The authors report no disclosures relevant to the manuscript.

Ethical standards

The author hereby declares that the research documented in the submitted manuscript has been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

Supplementary material

415_2018_9072_MOESM1_ESM.docx (28 kb)
Supplementary material 1 (DOCX 24 KB)
415_2018_9072_MOESM2_ESM.docx (17 kb)
Supplementary material 2 (DOCX 16 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Anna Bersano
    • 1
  • Gloria Bedini
    • 2
  • Hugh Stephen Markus
    • 3
  • Paolo Vitali
    • 4
  • Enrico Colli-Tibaldi
    • 4
  • Franco Taroni
    • 5
  • Cinzia Gellera
    • 5
  • Silvia Baratta
    • 5
  • Lorena Mosca
    • 6
  • Paola Carrera
    • 7
  • Maurizio Ferrari
    • 7
  • Cristina Cereda
    • 8
  • Gaetano Grieco
    • 8
  • Silvia Lanfranconi
    • 9
  • Franca Mazucchelli
    • 10
  • Davide Zarcone
    • 10
  • Maria Luisa De Lodovici
    • 11
  • Giorgio Bono
    • 11
  • Giorgio Battista Boncoraglio
    • 1
  • Eugenio Agostino Parati
    • 1
  • Maria Vittoria Calloni
    • 12
  • Patrizia Perrone
    • 12
  • Bianca Maria Bordo
    • 13
  • Cristina Motto
    • 14
  • Elio Agostoni
    • 14
  • Alessandro Pezzini
    • 15
  • Alessandro Padovani
    • 15
  • Giuseppe Micieli
    • 16
  • Anna Cavallini
    • 16
  • Graziella Molini
    • 17
  • Francesco Sasanelli
    • 17
  • Maria Sessa
    • 18
  • Giancarlo Comi
    • 18
  • Nicoletta Checcarelli
    • 19
  • Massimo Carmerlingo
    • 20
  • Manuel Corato
    • 21
  • Simona Marcheselli
    • 21
  • Laura Fusi
    • 22
  • Giampiero Grampa
    • 22
  • Davide Uccellini
    • 23
  • Simone Beretta
    • 24
  • Carlo Ferrarese
    • 24
  • Barbara Incorvaia
    • 25
  • Carlo Sebastiano Tadeo
    • 25
  • Laura Adobbati
    • 26
  • Vincenzo Silani
    • 26
  • Giuseppe Faragò
    • 27
  • Nadia Trobia
    • 1
  • Caspar Grond-Ginsbach
    • 28
  • Livia Candelise
    • 9
  • on behalf of Lombardia GENS-group
  1. 1.Cerebrovascular UnitNeurological Institute “C. Besta” IRCCS FoundationMilanItaly
  2. 2.Laboratory of Cellular NeurobiologyNeurological Institute “C. Besta” IRCCS FoundationMilanItaly
  3. 3.Stroke Research Group, Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK
  4. 4.NeuroradiologyIRCCS Foundation C, Mondino Neurological InstitutePaviaItaly
  5. 5.Clinical Pathology and Medical Genetic LaboratoryNeurological Institute “C. Besta” IRCCS FoundationMilanItaly
  6. 6.Laboratorio di GeneticaAzienda Ospedaliera Niguarda Ca’ GrandaMilanItaly
  7. 7.Unit of Genomics for Human Disease Diagnosis and Laboratory of Clinical Molecular BiologyIRCCS Ospedale San RaffaeleMilanItaly
  8. 8.Genomic and Post-Genomic CenterIRCCS C. Mondino National Neurological InstitutePaviaItaly
  9. 9.Neurology Unit, Department of Neuroscience and Sensory OrgansMaggiore Policlinico Hospital Foundation IRCCS Ca’ GrandaMilanItaly
  10. 10.Stroke UnitS. Antonio Abate HospitalGallarateItaly
  11. 11.Stroke UnitCircolo Hospital and Macchi Foundation, Varese HospitalVareseItaly
  12. 12.Stroke UnitLegnano and Cuggiono HospitalLegnanoItaly
  13. 13.Neurological Unit and Stroke UnitOspedale di DesioDesioItaly
  14. 14.Stroke UnitAzienda Ospedaliera Niguarda Ca GrandaMilanItaly
  15. 15.Department of Clinical and Experimental Sciences, Neurology ClinicUniversity of BresciaBresciaItaly
  16. 16.Neurology and Stroke Unit, Department of UrgencyIRCCS Foundation C. Mondino Neurological InstitutePaviaItaly
  17. 17.AO Melegnano-Ospedale di Vizzolo PredabissiMelegnanoItaly
  18. 18.Stroke UnitSan Raffaele HospitalMilanItaly
  19. 19.Stroke UnitValduce HospitalComoItaly
  20. 20.UO Neurologia Policlinico San MarcoZingoniaItaly
  21. 21.Istituto Clinico HumanitasRozzanoItaly
  22. 22.Stroke UnitOspedale di CircoloSaronnoItaly
  23. 23.Tradate HospitalTradateItaly
  24. 24.Stroke UnitAzienda Ospedaliera San Gerardo, Milan Bicocca UniversityMonzaItaly
  25. 25.Stroke UnitIstituto Clinico Città StudiMilanItaly
  26. 26.Stroke UnitIstituto AuxologicoMilanItaly
  27. 27.Neuroradiological UnitNeurological Institute “C. Besta” IRCCS FoundationMilanItaly
  28. 28.Department of NeurologyHeidelberg University HospitalHeidelbergGermany

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