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Cited by 25Cerebrovascular and genetic disordersGenetic Neurodegenerative DiseasesIntracerebral and Subarachnoid Hemorrhage Research

Disease Severity Staging System for NOTCH3 -Associated Small Vessel Disease, Including CADASIL

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Gravesteijn, Gido, Rutten, Julie W., Cerfontaine, Minne N., Hack, Remco J., Liao, Yi-Chu, Jolly, Amy A., Guey, Stéphanie, Hsu, Shao-Lun +42 more·2025·JAMA Neurology
DOI 10.1001/jamaneurol.2024.4487PMC PMC13340440
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Abstract

Importance: Typical cysteine-altering NOTCH3 ( NOTCH3 cys ) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3 -SVD severity spectrum is needed and currently lacking. Objective: To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3 -SVD severity spectrum. Design, Setting, and Participants: A cohort study was performed in which the NOTCH3 -SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3 cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3 cys -positive cases from families with CADASIL; the validation set included 1713 NOTCH3 cys -positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3 cys -positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024. Main Outcomes and Measures: Percentage of cases following the sequence of events of the NOTCH3 -SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level. Results: The NOTCH3 -SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3 -SVD staging system. The NOTCH3 -SVD stages were associated with neuroimaging outcomes in the NOTCH3 cys -positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3 -SVD staging system captured disease progression and was associated with 18-year survival. Conclusions and Relevance: The NOTCH3 -SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3 cys variant to patients with end-stage disease. The NOTCH3 -SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.

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  • Population-based genetic studies demonstrate higher frequencies of pathogenic NOTCH3 variants in East and South Asians compared with the general population.

    “Population-based genetic studies demonstrate higher frequencies of pathogenic NOTCH3 variants in East and South Asians compared with the general population.8,15”

    From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [8]

    The Discussion (page unavailable) reports NOTCH3 cysteine-altering variants in about 1 in 300 people worldwide and 1 in 100 Asian individuals, supporting a higher frequency in Asians. It does not report separate frequencies for East and South Asians, so the claim’s specificity is not supported. (LLM, conf=0.87)

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References 43 · Cited by 25

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  1. [1]Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 2019; 18(7): 684- 696. doi: 10.1016/S1474-4422(19)30079-1 31097385 · DOI · Paper page
  2. [2]Narayan SK, Gorman G, Kalaria RN, Ford GA, Chinnery PF. The minimum prevalence of CADASIL in northeast England. Neurology. 2012; 78(13): 1025- 1027. doi: 10.1212/WNL.0b013e31824d586c 22422895 PMC3310314 · DOI
  3. [3]Rutten JW, Dauwerse HG, Gravesteijn G,. Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Ann Clin Transl Neurol. 2016; 3(11): 844- 853. doi: 10.1002/acn3.344 27844030 PMC5099530 · DOI
  4. [4]Kang CH, Kim YM, Kim YJ,. Pathogenic NOTCH3 variants are frequent among the Korean general population. Neurol Genet. 2021; 7(6): e639. doi: 10.1212/NXG.0000000000000639 34881353 PMC8650050 · DOI
  5. [5]Lee YC, Chung CP, Chang MH, Wang SJ, Liao YC. NOTCH3 cysteine-altering variant is an important risk factor for stroke in the Taiwanese population. Neurology. 2020; 94(1): e87- e96. doi: 10.1212/WNL.0000000000008700 31792094 · DOI
  6. [6]Cho BPH, Harshfield EL, Al-Thani M, Tozer DJ, Bell S, Markus HS. Association of vascular risk factors and genetic factors with penetrance of variants causing monogenic stroke. JAMA Neurol. 2022; 79(12): 1303- 1311. doi: 10.1001/jamaneurol.2022.3832 36300346 PMC9614680 · DOI
  7. [7]Hack RJ, Rutten JW, Person TN,; Regeneron Genetics Center. Cysteine-altering NOTCH3 variants are a risk factor for stroke in the elderly population. Stroke. 2020; 51(12): 3562- 3569. doi: 10.1161/STROKEAHA.120.030343 33161844 PMC7678653 · DOI
  8. [8]Cho BPH, Nannoni S, Harshfield EL,. NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants. J Neurol Neurosurg Psychiatry. 2021; 92(7): 694- 701. doi: 10.1136/jnnp-2020-325838 33712516 PMC8223663 · DOI
  9. [9]Rutten JW, Hack RJ, Duering M,. Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance. Neurology. 2020; 95(13): e1835- e1843. doi: 10.1212/WNL.0000000000010525 32732295 PMC7682826 · DOI
  10. [10]Hack RJ, Gravesteijn G, Cerfontaine MN,. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy family members with a pathogenic NOTCH3 variant can have a normal brain magnetic resonance imaging and skin biopsy beyond age 50 years. Stroke. 2022; 53(6): 1964- 1974. doi: 10.1161/STROKEAHA.121.036307 35300531 PMC9126263 · DOI
  11. [11]Pescini F, Bianchi S, Salvadori E,. A pathogenic mutation on exon 21 of the NOTCH3 gene causing CADASIL in an octogenarian paucisymptomatic patient. J Neurol Sci. 2008; 267(1-2): 170- 173. doi: 10.1016/j.jns.2007.10.017 18022198 · DOI
  12. [12]Zhang R, Ouin E, Grosset L,. Elderly CADASIL patients with intact neurological status. J Stroke. 2022; 24(3): 352- 362. doi: 10.5853/jos.2022.01578 36221938 PMC9561215 · DOI
  13. [13]Ling Y, De Guio F, Duering M,. Predictors and clinical impact of incident lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke. 2017; 48(2): 283- 289. doi: 10.1161/STROKEAHA.116.015750 28034964 · DOI
  14. [14]Lin HJ, Chen CH, Su MW,. Modifiable vascular risk factors contribute to stroke in 1080 NOTCH3 R544C carriers in Taiwan Biobank. Int J Stroke. 2024; 19(1): 105- 113. doi: 10.1177/17474930231191991 37485895 · DOI
  15. [15]Hack RJ, Cerfontaine MN, Gravesteijn G,; Effect of NOTCH3 EGFr Group. Effect of NOTCH3 EGFr group, sex, and cardiovascular risk factors on CADASIL clinical and neuroimaging outcomes. Stroke. 2022; 53(10): 3133- 3144. doi: 10.1161/STROKEAHA.122.039325 35862191 PMC9508953 · DOI
  16. [16]Cerfontaine MN, Hack RJ, Gesierich B,. Association of NOTCH3 variant risk category with 2-year clinical and radiologic small vessel disease progression in patients with CADASIL. Neurology. 2024; 102(10): e209310. doi: 10.1212/WNL.0000000000209310 38713890 PMC11177591 · DOI
  17. [17]Hack RJ, Gravesteijn G, Cerfontaine MN,. Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction. Brain. 2023; 146(7): 2913- 2927. doi: 10.1093/brain/awac486 36535904 PMC10316769 · DOI · Paper page
  18. [18]van den Boom R, Lesnik Oberstein S, Ferrari M, Haan J, van Buchem M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages—3rd-6th decades. Radiology. 2003; 229(3): 683- 690. doi: 10.1148/radiol.2293021354 14593195 · DOI · Paper page
  19. [20]Peters N, Opherk C, Danek A, Ballard C, Herzog J, Dichgans M. The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia. Am J Psychiatry. 2005; 162(11): 2078- 2085. doi: 10.1176/appi.ajp.162.11.2078 16263847 · DOI · Paper page
  20. [21]Jouvent E, Duchesnay E, Hadj-Selem F,. Prediction of 3-year clinical course in CADASIL. Neurology. 2016; 87(17): 1787- 1795. doi: 10.1212/WNL.0000000000003252 27694265 PMC5089530 · DOI · Paper page
  21. [23]Joutel A, Favrole P, Labauge P,. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. 2001; 358(9298): 2049- 2051. doi: 10.1016/S0140-6736(01)07142-2 11755616 · DOI · Paper page
  22. [24]Malandrini A, Gaudiano C, Gambelli S,. Diagnostic value of ultrastructural skin biopsy studies in CADASIL. Neurology. 2007; 68(17): 1430- 1432. doi: 10.1212/01.wnl.0000264018.46335.c8 17452591 · DOI · Paper page
  23. [25]Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol. 1987; 149(2): 351- 356. doi: 10.2214/ajr.149.2.351 3496763 · DOI
  24. [26]Duering M, Biessels GJ, Brodtmann A,. Neuroimaging standards for research into small vessel disease-advances since 2013. Lancet Neurol. 2023; 22(7): 602- 618. doi: 10.1016/S1474-4422(23)00131-X 37236211 · DOI · Paper page
  25. [27]Rutten JW, Haan J, Terwindt GM, van Duinen SG, Boon EMJ, Lesnik Oberstein SAJ. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014; 14(5): 593- 603. doi: 10.1586/14737159.2014.922880 24844136 · DOI
  26. [28]Muiño E, Gallego-Fabrega C, Cullell N,. Systematic review of cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL. Int J Mol Sci. 2017; 18(9): 1964. doi: 10.3390/ijms18091964 28902129 PMC5618613 · DOI
  27. [29]Brookes RL, Hollocks MJ, Tan RYY, Morris RG, Markus HS. Brief screening of vascular cognitive impairment in patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy without dementia. Stroke. 2016; 47(10): 2482- 2487. doi: 10.1161/STROKEAHA.116.013761 27625375 PMC5049939 · DOI
  28. [30]Chabriat H, Hervé D, Duering M,. Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: prospective cohort study. Stroke. 2016; 47(1): 4- 11. doi: 10.1161/STROKEAHA.115.010696 26578659 · DOI
  29. [32]Gravesteijn G, Rutten JW, Verberk IMW,. Serum neurofilament light correlates with CADASIL disease severity and survival. Ann Clin Transl Neurol. 2018; 6(1): 46- 56. doi: 10.1002/acn3.678 30656183 PMC6331956 · DOI
  30. [33]Duering M, Konieczny MJ, Tiedt S,. Serum neurofilament light chain levels are related to small vessel disease burden. J Stroke. 2018; 20(2): 228- 238. doi: 10.5853/jos.2017.02565 29886723 PMC6007291 · DOI · Paper page
  31. [34]Anisetti B, Greco E, Stojadinovic E,. Novel grading system for CADASIL severity: a multicenter cross-sectional study. Cereb Circ Cogn Behav. 2023; 5: 100170. doi: 10.1016/j.cccb.2023.100170 37441712 PMC10333271 · DOI
  32. [35]Liao YCC, Hu YCC, Chung CPP,. Intracerebral hemorrhage in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: prevalence, clinical and neuroimaging features and risk factors. Stroke. 2021; 52(3): 985- 993. doi: 10.1161/STROKEAHA.120.030664 33535780 · DOI
  33. [36]Liu JY, Yao M, Dai Y,. Rare NOTCH3 variants in a Chinese population-based cohort and its relationship with cerebral small vessel disease. Stroke. 2021; 52(12): 3918- 3925. doi: 10.1161/STROKEAHA.120.032265 34404235 · DOI
  34. [37]Reyes S, Viswanathan A, Godin O,. Apathy: a major symptom in CADASIL. Neurology. 2009; 72(10): 905- 910. doi: 10.1212/01.wnl.0000344166.03470.f8 19273824 · DOI
  35. [39]Ishiyama H, Kim H, Saito S,. Pro-hemorrhagic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy associated with NOTCH3 p.R75P mutation with low vascular NOTCH3 aggregation property. Ann Neurol. 2024; 95(6): 1040- 1054. doi: 10.1002/ana.26916 38520151 · DOI
  36. [40]Whittaker E, Thrippleton S, Chong LYW,. Systematic review of cerebral phenotypes associated with monogenic cerebral small-vessel disease. J Am Heart Assoc. 2022; 11(12): e025629. doi: 10.1161/JAHA.121.025629 35699195 PMC9238640 · DOI
  37. [41]Dupré N, Drieu A, Joutel A. Pathophysiology of cerebral small vessel disease: a journey through recent discoveries. J Clin Invest. 2024; 134(10): e172841. doi: 10.1172/JCI172841 38747292 PMC11093606 · DOI
  38. [42]Wilson JTL, Hareendran A, Hendry A, Potter J, Bone I, Muir KW. Reliability of the modified Rankin Scale across multiple raters: benefits of a structured interview. Stroke. 2005; 36(4): 777- 781. doi: 10.1161/01.STR.0000157596.13234.95 15718510 · DOI
  39. [43]Sachdev P, Cathcart S, Shnier R, Wen W, Brodaty H. Reliability and validity of ratings of signal hyperintensities on MRI by visual inspection and computerised measurement. Psychiatry Res. 1999; 92(2-3): 103- 115. doi: 10.1016/S0925-4927(99)00036-0 10674364 · DOI
  40. [44]Kapeller P, Barber R, Vermeulen RJ,; European Task Force of Age Related White Matter Changes. Visual rating of age-related white matter changes on magnetic resonance imaging: scale comparison, interrater agreement, and correlations with quantitative measurements. Stroke. 2003; 34(2): 441- 445. doi: 10.1161/01.STR.0000049766.26453.E9 12574557 · DOI

Authors
Gravesteijn, G., Rutten, J. W., Cerfontaine, M. N., Hack, R. J., Liao, Y.-C., Jolly, A. A., Guey, S., Hsu, S.-L., Park, J.-Y., Yuan, Y., Kopczak, A., Rifino, N., Neilson, S. J., Poggesi, A., Shourav, M. M. I., Saito, S., Ishiyama, H., Domínguez Mayoral, A., Nogueira, R., Muiño, E., Andersen, P., De Stefano, N., Santo, G., Sukhonpanich, N., Mele, F., Park, A., Lee, J. S., Rodríguez-Girondo, M., Vonk, S. J. J., Brodtmann, A., Börjesson-Hanson, A., Pantoni, L., Fernández-Cadenas, I., Silva, A. R., Montanaro, V. V. A., Kalaria, R. N., Lopergolo, D., Ihara, M., Meschia, J. F., Muir, K. W., Bersano, A., Pescini, F., Duering, M., Choi, J. C., Ling, C., Kim, H., Markus, H. S., Chabriat, H., Lee, Y.-C., & Lesnik Oberstein, S. A. J.
Affiliations
  • Leiden University Medical Center (NL)
  • National Yang Ming Chiao Tung University (TW)
  • University of Cambridge (GB)
  • Inserm (FR)
  • Asan Medical Center (KR)
  • Peking University First Hospital (CN)
  • Institut für Schlaganfall- und Demenzforschung (DE)
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • University of Glasgow (GB)
  • Azienda Ospedaliero-Universitaria Careggi (IT)
  • Mayo Clinic (US)
  • Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
  • National Cerebral and Cardiovascular Center (JP)
  • Unidad de Enfermedades Neurovasculares Infrecuentes, Hospital Virgen Macarena, Sevilla, Spain
  • Department of Neurology, Hospital SARAH Kubitschek, Rio de Janeiro, Brazil
  • Hospital de Sant Pau (ES)
  • Karolinska University Hospital (SE)
  • Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
  • Unidade Local de Saúde de Coimbra (PT)
  • Siriraj Hospital (TH)
  • Luigi Sacco Hospital (IT)
  • The Royal Melbourne Hospital (AU)
  • Jeju National University (KR)
  • Software developer in personal capacity, Weesp, the Netherlands
  • Monash University (AU)
  • Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden
  • University of Milan (IT)
  • Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  • University of Coimbra (PT)
  • Department of Neurology, Hospital SARAH Kubitschek, Brasília, Brazil
  • Translational and Clinical Research Institute, Newcastle University, Newcastle, United Kingdom
  • University of Siena (IT)
  • University of Basel (CH)
  • Department of Neurology, Peking University First Hospital, Beijing, China
  • Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
Corresponding author
Gravesteijn, Gido
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2025-01-01
Volume
82
Issue
1
Pages
49
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2024.4487
PMC
PMC13340440
OpenAlex
W4404864177
Cited by
25
References
43
Citations by year
2026: 16 · 2025: 9
FWCI
6.69
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Neurology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • Florence Research (University of Florence) (submittedVersion, cc-by)
Funders
  • Universität Basel
  • Università degli Studi di Milano
  • Università degli Studi di Siena
  • British Heart Foundation (RG/F/22/110052)
  • Newcastle University
  • European Commission (666881)
  • University of Glasgow
  • Universiteit Leiden
  • Monash University
  • ZonMw (91717325)
  • Jeju National University
  • Karolinska Institutet
  • Mahidol University
  • Leids Universitair Medisch Centrum
  • Universidade de Coimbra
  • Stiftung zur Erforschung der Vaskulären Demenz
  • Japan Society for the Promotion of Science (24KK0156)
  • Faculty of Medicine Siriraj Hospital, Mahidol University
Topics
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
Keywords
Notch3, cerebral small vessel disease, CADASIL, disease severity staging, ischemic stroke, intracerebral hemorrhage, cognitive decline, neurofilament light chain, brain volume, disease progression, modified Rankin Scale, UK Biobank, stroke risk prediction, dementia risk
MeSH terms
Receptor, Notch3, Adult, Aged, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Severity of Illness Index, Cohort Studies, CADASIL, Cerebral Small Vessel Diseases

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