CoChat
Sign Up
Cited by 44Cerebrovascular and genetic disordersIntracerebral and Subarachnoid Hemorrhage ResearchGenetic Neurodegenerative Diseases

Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association

Open access
Meschia, James F., Worrall, Bradford B., Elahi, Fanny M., Ross, Owen A., Wang, Michael M., Goldstein, Eric D., Rost, Natalia S., Majersik, Jennifer J. +2 more·2023·Stroke
DOI 10.1161/str.0000000000000444
Open this paper in CoChat — free accountOpen PDF

Abstract

Lacunar infarcts and vascular dementia are important phenotypic characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, the most common inherited cerebral small vessel disease. Individuals with the disease show variability in the nature and onset of symptoms and rates of progression, which are only partially explained by differences in pathogenic mutations in the NOTCH3 gene. Recognizing the disease early in its course and securing a molecular diagnosis are important clinical goals, despite the lack of proven disease-modifying treatments. The purposes of this scientific statement are to review the clinical, genetic, and imaging aspects of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, contrasting it with other inherited small vessel diseases, and to provide key prevention, management, and therapeutic considerations with the intent of reducing practice variability and encouraging production of high-quality evidence to support future treatment recommendations.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1161/str.0000000000000444

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • CADASIL is caused by pathogenic variants in the NOTCH3 gene on chromosome 19.

    “Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), the most common inherited small vessel disease, is caused by pathogenic variants in the NOTCH3 gene on chromosome 19.”

    From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [1]

    The Molecular Genetics of CADASIL and Other CSVDs section identifies disease-associated NOTCH3 mutations, supporting the genetic-cause portion of the claim. The passages do not state that NOTCH3 is on chromosome 19 (searched: “chromosome 19” and “19p13”), so that location is not verified by our copy; page numbers were unavailable. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Prominent microbleeds favor a small vessel disease diagnosis rather than MS.

    “Furthermore, a high CMB burden (>10) and region-specific CMB distribution were observed only in correctly diagnosed patients, suggesting that prominent microbleeds favor a small vessel disease diagnosis rather than MS.1,4,10”

    From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [1]

    The Brain Imaging for Detecting and Characterizing Disease section identifies cerebral microbleeds as an imaging feature of cerebral small vessel disease, and its table (p. e455) describes lobar-predominant microhemorrhages in hereditary cerebral amyloid angiopathy. It does not compare microbleeds in small vessel disease with those in multiple sclerosis or establish that a prominent burden favors one diagnosis over the other. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • CADASIL is characterized by migraine, recurrent ischemic strokes, and progressive cognitive decline.

    “It is characterized by migraine, recurrent ischemic strokes, and progressive cognitive decline.1”

    From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [1]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 93 · Cited by 44

Research works printed but not linked: 90

  1. Tan RYY, Traylor M, Megy K, Duarte D, Deevi SVV, Shamardina O, Mapeta RP, Ouwehand WH, Graf S; Downes K, et al; NIHR BioResource: Rare Diseases Consortium. How common are single gene mutations as a cause for lacunar stroke? A targeted gene panel study. Neurology. 2019;93:e2007-e2020. doi: 10.1212/WNL.0000000000008544 · DOI
  2. Muino E, Gallego-Fabrega C, Cullell N, Carrera C, Torres N, Krupinski J, Roquer J, Montaner J, Fernandez-Cadenas I. Systematic review of cysteine- sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL. Int J Mol Sci. 2017;18:1964. doi: 10.3390/ijms18091964 · DOI
  3. Guey S, Mawet J, Herve D, Duering M, Godin O, Jouvent E, Opherk C, Alili N, Dichgans M, Chabriat H. Prevalence and characteristics of migraine in CADA- SIL. Cephalalgia. 2016;36:1038-1047. doi: 10.1177/0333102415620909 · DOI
  4. Sangle N, Baringer JR, Majersik J, DeWitt LD. CADASIL with multiorgan involvement: a complete autopsy examination report. Can J Neurol Sci. 2016;43:202-205. doi: 10.1017/cjn.2015.240 · DOI
  5. Germain DP, Altarescu G, Barriales-Villa R, Mignani R, Pawlaczyk K, Pieruzzi F, Terryn W, Vujkovac B, Ortiz A. An expert consensus on practical clinical rec- ommendations and guidance for patients with classic Fabry disease. Mol Genet Metab. 2022;137:49-61. doi: 10.1016/j.ymgme.2022.07.010 · DOI
  6. Badachi S, John SK, Sekhar M, Mathew T. CARASIL: the backache, bald- ness, brain attack syndrome: the Indian scenario. Ann Indian Acad Neurol. 2020;23:559-561. doi: 10.4103/aian.AIAN_31_20 · DOI
  7. He Z, Wang L, Zhang Y, Yin C, Niu Y. Clinical features and pathogenicity assessment in patients with HTRA1-autosomal dominant disease. Neurol Sci. 2023;44:639-647. doi: 10.1007/s10072-022-06454-5 · DOI
  8. Uemura M, Nozaki H, Kato T, Koyama A, Sakai N, Ando S, Kanazawa M, Hishikawa N, Nishimoto Y, Polavarapu K, et al. HTRA1-related cerebral small vessel disease: a review of the literature. Front Neurol. 2020;11:545. doi: 10.3389/fneur.2020.00545 · DOI
  9. Budhdeo S, de Paiva ARB, Wade C, Lopes LCG, Della-Ripa B, Davagnanam I, Lucato L, Mummery CJ, Kok F, Houlden H, et al. A rare cause of mono- genic cerebral small vessel disease and stroke: cathepsin a-related arte- riopathy with strokes and leukoencephalopathy (CARASAL). J Neurol. 2022;269:6673-6677. doi: 10.1007/s00415-022-11302-9 · DOI
  10. Stam AH, Kothari PH, Shaikh A, Gschwendter A, Jen JC, Hodgkinson S, Hardy TA, Hayes M, Kempster PA, Kotschet KE, et al. Retinal vasculopa- thy with cerebral leukoencephalopathy and systemic manifestations. Brain. 2016;139:2909-2922. doi: 10.1093/brain/aww217 · DOI
  11. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Ronco P. Cerebrovascular disease related to COL4A1 muta- tions in HANAC syndrome. Neurology. 2009;73:1873-1882. doi: 10.1212/WNL.0b013e3181c3fd12 · DOI
  12. Verdura E, Herve D, Bergametti F, Jacquet C, Morvan T, Prieto-Morin C, Mackowiak A, Manchon E, Hosseini H, Cordonnier C, et al. Disruption of a mir-29 binding site leading to COL4A1 upregulation causes pontine auto- somal dominant microangiopathy with leukoencephalopathy. Ann Neurol. 2016;80:741-753. doi: 10.1002/ana.24782 · DOI
  13. Psychogios K, Xiromerisiou G, Kargiotis O, Safouris A, Fiolaki A, Bonakis A, Paraskevas GP, Giannopoulos S, Tsivgoulis G. Hereditary cerebral amyloid angiopathy mimicking CADASIL syndrome. Eur J Neurol. 2021;28:3866- 3869. doi: 10.1111/ene.14981 · DOI
  14. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and demen- tia. Nature. 1996;383:707-710. doi: 10.1038/383707a0 · DOI · Paper page
  15. Cho BPH, Jolly AA, Nannoni S, Tozer D, Bell S, Markus HS. Association of NOTCH3 variant position with stroke onset and other clinical features among patients with CADASIL. Neurology. 2022;99:e430-e439. doi: 10.1212/WNL.0000000000200744 · DOI
  16. Dupe C, Guey S, Biard L, Dieng S, Lebenberg J, Grosset L, Alili N, Herve D, Tournier-Lasserve E, Jouvent E, et al. Phenotypic variability in 446 CADA- SIL patients: impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors. J Cereb Blood Flow Metab. 2023;43:153-166. doi: 10.1177/0271678X221126280 · DOI
  17. Rutten JW, Hack RJ, Duering M, Gravesteijn G, Dauwerse JG, Overzier M, van den Akker EB, Slagboom E, Holstege H, Nho K, et al. Broad phe- notype of cysteine-altering NOTCH3 variants in UK Biobank: CADA- SIL to nonpenetrance. Neurology. 2020;95:e1835-e1843. doi: 10.1212/WNL.0000000000010525 · DOI
  18. Gravesteijn G, Dauwerse JG, Overzier M, Brouwer G, Hegeman I, Mulder AA, Baas F, Kruit MC, Terwindt GM, van Duinen SG, et al. Naturally occurring NOTCH3 exon skipping attenuates NOTCH3 protein aggregation and dis- ease severity in CADASIL patients. Hum Mol Genet. 2020;29:1853-1863. doi: 10.1093/hmg/ddz285 · DOI
  19. Rutten JW, Dauwerse HG, Peters DJ, Goldfarb A, Venselaar H, Haffner C, van Ommen GJ, Aartsma-Rus AM, Lesnik Oberstein SA. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of con- cept. Brain. 2016;139:1123-1135. doi: 10.1093/brain/aww011 · DOI
  20. Schoemaker D, Arboleda-Velasquez JF. Notch3 signaling and aggrega- tion as targets for the treatment of CADASIL and other NOTCH3-asso- ciated small-vessel diseases. Am J Pathol. 2021;191:1856-1870. doi: 10.1016/j.ajpath.2021.03.015 · DOI
  21. Costamagna G, Govoni A, Wise A, Corti S. Bridging the gap: gene therapy in a patient with spinal muscular atrophy type 1. Neurology. 2022;99:952- 956. doi: 10.1212/WNL.0000000000201294 · DOI
  22. Zellner A, Muller SA, Lindner B, Beaufort N, Rozemuller AJM, Arzberger T, Gassen NC, Lichtenthaler SF, Kuster B, Haffner C, et al. Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlight- ing accumulation of htra1 and its substrates. Acta Neuropathol Commun. 2022;10:6. doi: 10.1186/s40478-021-01303-6 · DOI
  23. Cho BPH, Harshfield EL, Al-Thani M, Tozer DJ, Bell S, Markus HS. Asso- ciation of vascular risk factors and genetic factors with penetrance of vari- ants causing monogenic stroke. JAMA Neurol. 2022;79:1303-1311. doi: 10.1001/jamaneurol.2022.3832 · DOI
  24. Wollenweber FA, Hanecker P, Bayer-Karpinska A, Malik R, Bazner H, Moreton F, Muir KW, Muller S, Giese A, Opherk C, et al. Cysteine-sparing CADASIL mutations in NOTCH3 show proaggregatory properties in vitro. Stroke. 2015;46:786-792. doi: 10.1161/STROKEAHA.114.007472 Stroke. 2023;54:e452-e464. DOI: 10.1161/STR.0000000000000444 October 2023 e463 · DOI
  25. Manini A, Pantoni L. CADASIL from bench to bedside: disease models and novel therapeutic approaches. Mol Neurobiol. 2021;58:2558-2573. doi: 10.1007/s12035-021-02282-4 · DOI
  26. Mishra A, Malik R, Hachiya T, Jurgenson T, Namba S, Posner DC, Kamanu FK, Koido M, Le Grand Q, Shi M, et al; COMPASS Consortium; INVENT Con- sortium; Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group; Estonian Biobank; PRECISE4Q Consortium; FinnGen Consortium; NINDS Stroke Genetics Network (SiGN); MEGASTROKE Consortium; SIREN Consortium; China Kadoorie Biobank Collaborative Group; VA Mil- lion Veteran Program; International Stroke Genetics Consortium (ISGC); Biobank Japan; CHARGE Consortium; GIGASTROKE Consortium. Stroke genetics informs drug discovery and risk prediction across ancestries. Nature. 2022;611:115-123. doi: 10.1038/s41586-022-05165-3 · DOI
  27. Rannikmae K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, Traylor M, Anderson CD, Battey TW, Radmanesh F, et al; METASTROKE Consortium. Common variation in col4a1/col4a2 is associated with spo- radic cerebral small vessel disease. Neurology. 2015;84:918-926. doi: 10.1212/WNL.0000000000001309 · DOI
  28. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O'Brien JT, Barkhof F, Benavente OR, et al; STandards for Report- Ing 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. doi: 10.1016/S1474-4422(13)70124-8 · DOI · Paper page
  29. Pasi M, Cordonnier C. Clinical relevance of cerebral small vessel diseases. Stroke. 2020;51:47-53. doi: 10.1161/STROKEAHA.119.024148 · DOI
  30. Rost NS, Brodtmann A, Pase MP, van Veluw SJ, Biffi A, Duering M, Hinman JD, Dichgans M. Post-stroke cognitive impairment and dementia. Circ Res. 2022;130:1252-1271. doi: 10.1161/CIRCRESAHA.122.319951 · DOI
  31. van Den Boom R, Lesnik Oberstein SA, van Duinen SG, Bornebroek M, Ferrari MD, Haan J, van Buchem MA. Subcortical lacunar lesions: an MR imag- ing finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Radiology. 2002;224:791- 796. doi: 10.1148/radiol.2243011123 · DOI · Paper page
  32. Jouvent E, Duering M, Chabriat H. Cerebral autosomal dominant arteriopa- thy with subcortical infarcts and leukoencephalopathy: lessons from neuro- imaging. Stroke. 2020;51:21-28. doi: 10.1161/STROKEAHA.119.024152 · DOI
  33. Opherk C, Gonik M, Duering M, Malik R, Jouvent E, Herve D, Adib-Samii P, Bevan S, Pianese L, Silvestri S, et al. Genome-wide geno- typing demonstrates a polygenic risk score associated with white mat- ter hyperintensity volume in CADASIL. Stroke. 2014;45:968-972. doi: 10.1161/STROKEAHA.113.004461 · DOI
  34. Sheng S, Wu L, Nalleballe K, Sharma R, Brown A, Ranabothu S, Kapoor N, Onteddu S. Fabry's disease and stroke: effectiveness of enzyme replace- ment therapy (ERT) in stroke prevention: a review with meta-analysis. J Clin Neurosci. 2019;65:83-86. doi: 10.1016/j.jocn.2019.03.064 · DOI
  35. Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, Powell JF. Diagnostic strategies in CADASIL. Neurology. 2002;59:1134-1138. doi: 10.1212/wnl.59.8.1134 · DOI · Paper page
  36. Pescini F, Nannucci S, Bertaccini B, Salvadori E, Bianchi S, Ragno M, Sarti C, Valenti R, Zicari E, Moretti M, et al. The cerebral autosomal-dominant arte- riopathy with subcortical infarcts and leukoencephalopathy (CADASIL) scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke. 2012;43:2871-2876. doi: 10.1161/STROKEAHA.112.665927 · DOI
  37. Koizumi T, Mizuta I, Watanabe-Hosomi A, Mukai M, Hamano A, Matsuura J, Ohara T, Mizuno T. The CADASIL Scale-J, a modified scale to prioritize access to genetic testing for JAPANESE CADASIL-sus- pected patients. J Stroke Cerebrovasc Dis. 2019;28:1431-1439. doi: 10.1016/j.jstrokecerebrovasdis.2019.03.026 · DOI
  38. Morley TJ, Han L, Castro VM, Morra J, Perlis RH, Cox NJ, Bastarache L, Ruderfer DM. Phenotypic signatures in clinical data enable systematic iden- tification of patients for genetic testing. Nat Med. 2021;27:1097-1104. doi: 10.1038/s41591-021-01356-z · DOI
  39. Goldman JS. Genetic testing and counseling in the diagnosis and manage- ment of young-onset dementias. Psychiatr Clin North Am. 2015;38:295- 308. doi: 10.1016/j.psc.2015.01.008 · DOI
  40. Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, Domenga V, Cecillon M, Vahedi K, Ducros A, et al. Skin biopsy immunostain- ing with a NOTCH3 monoclonal antibody for CADASIL diagnosis. Lancet. 2001;358:2049-2051. doi: 10.1016/S0140-6736(01)07142-2 · DOI · Paper page
  41. Lee SJ, Meng H, Elmadhoun O, Blaivas M, Wang MM. Cerebral autoso- mal dominant arteriopathy with subcortical infarcts and leukoencepha- lopathy affecting an African American man: identification of a novel 15-base pair NOTCH3 duplication. Arch Neurol. 2011;68:1584-1586. doi: 10.1001/archneurol.2011.781 · DOI
  42. Akinyemi RO, Owolabi MO, Ihara M, Damasceno A, Ogunniyi A, Dotchin C, Paddick SM, Ogeng'o J, Walker R, Kalaria RN. Stroke, cerebro- vascular diseases and vascular cognitive impairment in Africa. Brain Res Bull. 2019;145:97-108. doi: 10.1016/j.brainresbull.2018.05.018 · DOI
  43. Shindo A, Tabei KI, Taniguchi A, Nozaki H, Onodera O, Ueda A, Ando Y, Urabe T, Kimura K, Kitagawa K, et al. A nationwide survey and multicenter registry-based database of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japan. Front Aging Neuro- sci. 2020;12:216. doi: 10.3389/fnagi.2020.00216 · DOI
  44. Palazzo P, Le Guyader G, Neau JP. Intracerebral hemorrhage in CADASIL. Rev Neurol (Paris). 2021;177:422-430. doi: 10.1016/j.neurol.2020.10.009 · DOI
  45. Mancuso M, Arnold M, Bersano A, Burlina A, Chabriat H, Debette S, Enzinger C, Federico A, Filla A, Finsterer J, et al. Monogenic cerebral small- vessel diseases: diagnosis and therapy: consensus recommendations of the European Academy of Neurology. Eur J Neurol. 2020;27:909-927. doi: 10.1111/ene.14183 · DOI
  46. Li Q, Wang C, Li W, Zhang Z, Wang S, Wupuer A, Hu X, Wumaier K, Zhu Y, Li H, et al. A novel mutation in COL4A1 gene in a Chinese family with pon- tine autosomal dominant microangiopathy and leukoencephalopathy. Transl Stroke Res. 2022;13:238-244. doi: 10.1007/s12975-021-00926-0 · DOI
  47. Liao YC, Hu YC, Chung CP, Wang YF, Guo YC, Tsai YS, Lee YC. Intra- cerebral hemorrhage in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: prevalence, clinical and neuroimaging features and risk factors. Stroke. 2021;52:985-993. doi: 10.1161/STROKEAHA.120.030664 · DOI
  48. Khan MT, Murray A, Smith M. Successful use of intravenous tissue plas- minogen activator as treatment for a patient with cerebral autosomal domi- nant arteriopathy with subcortical infarcts and leukoencephalopathy: a case report and review of literature. J Stroke Cerebrovasc Dis. 2016;25:e53-e57. doi: 10.1016/j.jstrokecerebrovasdis.2015.12.006 · DOI
  49. Goldstein ED, Badi MK, Klaas JP, Glover P, Rozen TD, Huang JF, Lin MP, Meschia JF. A cross-sectional analysis of migraine-related disabil- ity in CADASIL: a Mayo Clinic cohort. Neurologist. 2019;24:161-164. doi: 10.1097/NRL.0000000000000253 · DOI
  50. Schon F, Martin RJ, Prevett M, Clough C, Enevoldson TP, Markus HS. "CADASIL coma": an underdiagnosed acute encephalopathy. J Neurol Neu- rosurg Psychiatry. 2003;74:249-252. doi: 10.1136/jnnp.74.2.249 · DOI
  51. Eikermann-Haerter K, Yuzawa I, Dilekoz E, Joutel A, Moskowitz MA, Ayata C. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leu- koencephalopathy syndrome mutations increase susceptibility to spreading depression. Ann Neurol. 2011;69:413-418. doi: 10.1002/ana.22281 · DOI
  52. Nannucci S, Rinnoci V, Pracucci G, MacKinnon AD, Pescini F, Adib-Samii P, Bianchi S, Dotti MT, Federico A, Inzitari D, et al. Location, number and factors associated with cerebral microbleeds in an Italian- British cohort of CADASIL patients. PLoS One. 2018;13:e0190878. doi: 10.1371/journal.pone.0190878 · DOI
  53. Glover PA, Goldstein ED, Badi MK, Brigham TJ, Lesser ER, Brott TG, Meschia JF. Treatment of migraine in patients with CADASIL: a system- atic review and meta-analysis. Neurol Clin Pract. 2020;10:488-496. doi: 10.1212/CPJ.0000000000000769 · DOI
  54. Pelzer N, Hoogeveen ES, Haan J, Bunnik R, Poot CC, van Zwet EW, Inderson A, Fogteloo AJ, Reinders MEJ, Middelkoop HAM, et al. Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: a monogenic small vessel disease. J Intern Med. 2019;285:317-332. doi: 10.1111/joim.12848 · DOI
  55. Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Mohr JP. The natural history of CADASIL: a pooled analysis of previously published cases. Stroke. 1999;30:1230-1233. doi: 10.1161/01.str.30.6.1230 · DOI · Paper page
  56. Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44:731-739. doi: 10.1002/ana.410440506 · DOI
  57. Reyes S, Viswanathan A, Godin O, Dufouil C, Benisty S, Hernandez K, Kurtz A, Jouvent E, O'Sullivan M, Czernecki V, et al. Apa- thy: a major symptom in CADASIL. Neurology. 2009;72:905-910. doi: 10.1212/01.wnl.0000344166.03470.f8 · DOI
  58. Brookes RL, Willis TA, Patel B, Morris RG, Markus HS. Depressive symptoms as a predictor of quality of life in cerebral small vessel dis- ease, acting independently of disability; a study in both sporadic small Stroke. 2023;54:e452-e464. DOI: 10.1161/STR.0000000000000444 vessel disease and CADASIL. Int J Stroke. 2013;8:510-517. doi: 10.1111/j.1747-4949.2011.00763.x · DOI
  59. Buffon F, Porcher R, Hernandez K, Kurtz A, Pointeau S, Vahedi K, Bousser MG, Chabriat H. Cognitive profile in CADASIL. J Neurol Neurosurg Psychiatry. 2006;77:175-180. doi: 10.1136/jnnp.2005.068726 · DOI
  60. Yuan P, Salvadore G, Li X, Zhang L, Du J, Chen G, Manji HK. Valproate activates the Notch3/c-Flip signaling cascade: a strategy to attenuate white matter hyperintensities in bipolar disorder in late life? Bipolar Disord. 2009;11:256-269. doi: 10.1111/j.1399-5618.2009.00675.x · DOI
  61. Wang J, Li J, Kong F, Lv H, Guo Z. Bipolar II disorder as the initial presen- tation of CADASIL: an underdiagnosed manifestation. Neuropsychiatr Dis Treat. 2017;13:2175-2179. doi: 10.2147/NDT.S142321 · DOI
  62. Dichgans M, Markus HS, Salloway S, Verkkoniemi A, Moline M, Wang Q, Posner H, Chabriat HS. Donepezil in patients with subcortical vascular cog- nitive impairment: a randomised double-blind trial in CADASIL. Lancet Neu- rol. 2008;7:310-318. doi: 10.1016/S1474-4422(08)70046-2 · DOI · Paper page
  63. Mobius HJ, Stoffler A. Memantine in vascular dementia. Int Psychogeriatr. 2003;15:207-213. doi: 10.1017/S1041610203009219 · DOI
  64. Clare L, Kudlicka A, Oyebode JR, Jones RW, Bayer A, Leroi I, Kopelman M, James IA, Culverwell A, Pool J, et al. Individual goal-oriented cognitive reha- bilitation to improve everyday functioning for people with early-stage demen- tia: a multicentre randomised controlled trial (the GREAT trial). Int J Geriatr Psychiatry. 2019;34:709-721. doi: 10.1002/gps.5076 · DOI
  65. Singhal S, Bevan S, Barrick T, Rich P, Markus HS. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004;127:2031-2038. doi: 10.1093/brain/awh223 · DOI
  66. Viswanathan A, Guichard JP, Gschwendtner A, Buffon F, Cumurcuic R, Boutron C, Vicaut E, Holtmannspotter M, Pachai C, Bousser MG, et al. Blood pressure and haemoglobin A1c are associated with microhaemorrhage in CADASIL: a two-centre cohort study. Brain. 2006;129:2375-2383. doi: 10.1093/brain/awl177 · DOI · Paper page
  67. Peters N, Freilinger T, Opherk C, Pfefferkorn T, Dichgans M. Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL. J Neu- rol Sci. 2007;260:100-105. doi: 10.1016/j.jns.2007.04.015 · DOI
  68. Adib-Samii P, Brice G, Martin RJ, Markus HS. Clinical spectrum of CADA- SIL and the effect of cardiovascular risk factors on phenotype: study in 200 consecutively recruited individuals. Stroke. 2010;41:630-634. doi: 10.1161/STROKEAHA.109.568402 · DOI · Paper page
  69. Ciolli L, Pescini F, Salvadori E, Del Bene A, Pracucci G, Poggesi A, Nannucci S, Valenti R, Basile AM, Squarzanti F, et al. Influence of vascu- lar risk factors and neuropsychological profile on functional performances in CADASIL: results from the Microvascular Leukoencephalopathy Study (MILES). Eur J Neurol. 2014;21:65-71. doi: 10.1111/ene.12241 · DOI
  70. Chabriat H, Herve D, Duering M, Godin O, Jouvent E, Opherk C, Alili N, Reyes S, Jabouley A, Zieren N, et al. Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leu- koencephalopathy: prospective cohort study. Stroke. 2016;47:4-11. doi: 10.1161/STROKEAHA.115.010696 · DOI
  71. Lee JS, Ko K, Oh JH, Park JH, Lee HK, Floriolli D, Paganini-Hill A, Fisher M. Cerebral microbleeds, hypertension, and intracerebral hem- orrhage in cerebral autosomal-dominant arteriopathy with subcorti- cal infarcts and leukoencephalopathy. Front Neurol. 2017;8:203. doi: 10.3389/fneur.2017.00203 · DOI
  72. Hack RJ, Cerfontaine MN, Gravesteijn G, Tap S, Hafkemeijer A, van der Grond J, Witjes-Ane MN, Baas F, Rutten JW, Lesnik Oberstein SAJ. Effect of NOTCH3 EGFr group, sex, and cardiovascular risk factors on CADASIL clinical and neuroimaging outcomes. Stroke. 2022;53:3133- 3144. doi: 10.1161/STROKEAHA.122.039325 · DOI
  73. Brice S, Reyes S, Jabouley A, Machado C, Rogan C, Gastellier N, Alili N, Guey S, Jouvent E, Herve D, et al. Trajectory pattern of cognitive decline in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Neurology. 2022;99:e1019-e1031. doi: 10.1212/WNL.0000000000200805 · DOI
  74. Donnini I, Rinnoci V, Nannucci S, Valenti R, Pescini F, Mariani G, Bianchi S, Dotti MT, Federico A, Inzitari D, et al. Pregnancy in CADASIL. Acta Neurol Scand. 2017;136:668-671. doi: 10.1111/ane.12784 · DOI
  75. Roine S, Poyhonen M, Timonen S, Tuisku S, Marttila R, Sulkava R, Kalimo H, Viitanen M. Neurologic symptoms are common during gesta- tion and puerperium in CADASIL. Neurology. 2005;64:1441-1443. doi: 10.1212/01.WNL.0000158655.71323.8A · DOI
  76. Lamberg JJ, Cherian VT. Neuraxial anesthesia in CADASIL syndrome. J Neu- rosurg Anesthesiol. 2013;25:216. doi: 10.1097/ANA.0b013e3182836086 · DOI
  77. Dieu JH, Veyckemans F. Perioperative management of a CADA- SIL type arteriopathy patient. Br J Anaesth. 2003;91:442-444. doi: 10.1093/bja/aeg182 · DOI
  78. Pfefferkorn T, von Stuckrad-Barre S, Herzog J, Gasser T, Hamann GF, Dichgans M. Reduced cerebrovascular co(2) reactivity in CADA- SIL: a transcranial Doppler sonography study. Stroke. 2001;32:17-21. doi: 10.1161/01.str.32.1.17 · DOI
  79. Tuominen S, Miao Q, Kurki T, Tuisku S, Poyhonen M, Kalimo H, Viitanen M, Sipila HT, Bergman J, Rinne JO. Positron emission tomog- raphy examination of cerebral blood flow and glucose metabo- lism in young CADASIL patients. Stroke. 2004;35:1063-1067. doi: 10.1161/01.STR.0000124124.69842.2d · DOI
  80. Bousser MG, Tournier-Lasserve E. Summary of the proceedings of the first international workshop on CADASIL. Paris, May 19-21, 1993. Stroke. 1994;25:704-707. doi: 10.1161/01.str.25.3.704 · DOI
  81. Dichgans M, Petersen D. Angiographic complications in CADASIL. Lancet. 1997;349:776-777. doi: 10.1016/S0140-6736(05)60202-4 · DOI
  82. Dong H, Blaivas M, Wang MM. Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcorti- cal infarcts and leukoencephalopathy. Brain Res. 2012;1456:64-71. doi: 10.1016/j.brainres.2012.03.037 · DOI
  83. Zhang X, Lee SJ, Young MF, Wang MM. The small leucine-rich proteoglycan BGN accumulates in CADASIL and binds to NOTCH3. Transl Stroke Res. 2015;6:148-155. doi: 10.1007/s12975-014-0379-1 · DOI
  84. Monet-Lepretre M, Haddad I, Baron-Menguy C, Fouillot-Panchal M, Riani M, Domenga-Denier V, Dussaule C, Cognat E, Vinh J, Joutel A. Abnormal recruitment of extracellular matrix proteins by excess NOTCH3 ECD: a new pathomechanism in CADASIL. Brain. 2013;136:1830-1845. doi: 10.1093/brain/awt092 · DOI
  85. Dabertrand F, Harraz OF, Koide M, Longden TA, Rosehart AC, Hill-Eubanks DC, Joutel A, Nelson MT. Pip2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary kir2.1 activity. Proc Natl Acad Sci U S A. 2021;118:e2025998118. doi: 10.1073/pnas.2025998118 · DOI
  86. Hanemaaijer ES, Panahi M, Swaddiwudhipong N, Tikka S, Winblad B, Viitanen M, Piras A, Behbahani H. Autophagy-lysosomal defect in human CADASIL vascular smooth muscle cells. Eur J Cell Biol. 2018;97:557-567. doi: 10.1016/j.ejcb.2018.10.001 · DOI
  87. Young KZ, Xu G, Keep SG, Borjigin J, Wang MM. Overlapping protein accu- mulation profiles of CADASIL and CAA: is there a common mechanism driving cerebral small-vessel disease? Am J Pathol. 2021;191:1871-1887. doi: 10.1016/j.ajpath.2020.11.015 · DOI
  88. Zellner A, Scharrer E, Arzberger T, Oka C, Domenga-Denier V, Joutel A, Lichtenthaler SF, Muller SA, Dichgans M, Haffner C. CADASIL brain vessels show a HTRA1 loss-of-function profile. Acta Neuropathol. 2018;136:111- 125. doi: 10.1007/s00401-018-1853-8 · DOI
  89. Neves KB, Morris HE, Alves-Lopes R, Muir KW, Moreton F, Delles C, Montezano AC, Touyz RM. Peripheral arteriopathy caused by NOTCH3 gain- of-function mutation involves ER and oxidative stress and blunting of NO/SGC/CGMP pathway. Clin Sci (Lond). 2021;135:753-773. doi: 10.1042/CS20201412 · DOI
  90. Donahue CP, Kosik KS. Distribution pattern of NOTCH3 mutations sug- gests a gain-of-function mechanism for CADASIL. Genomics. 2004;83:59- 65. doi: 10.1016/s0888-7543(03)00206-4 · DOI

Authors
Meschia, J. F., Worrall, B. B., Elahi, F. M., Ross, O. A., Wang, M. M., Goldstein, E. D., Rost, N. S., Majersik, J. J., Gutierrez, J., & on behalf of the American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Hypertension
ORCID
Venue
Stroke
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2023-10
Volume
54
Issue
10
Pages
e452-e464
ISSN
  • 0039-2499 (ISSN-L)
  • 1524-4628
DOI
10.1161/str.0000000000000444
OpenAlex
W4386019745
Cited by
44
References
93
Citations by year
2026: 17 · 2025: 13 · 2024: 14
FWCI
7.47
Type
journal article
Language
en
Open access
Locations
  • Stroke (publishedVersion)
  • PubMed (publishedVersion)
Funders
U.S. Department of Veterans Affairs (I01 BX003824)
Topics
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
CADASIL, NOTCH3 mutations, lacunar infarction, vascular dementia, molecular diagnosis, early recognition, disease progression, disease-modifying therapy, prevention, clinical management, neuroimaging
MeSH terms
Receptor, Notch3, American Heart Association, Cerebral Infarction, Humans, Magnetic Resonance Imaging, Mutation, Dementia, Vascular, CADASIL, Receptors, Notch

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