CADASIL and genetics of cerebral ischaemia

  • R. N. Kalaria
  • W. C. Low
  • A. E. Oakley
  • J. Y. Slade
  • P. G. Ince
  • C. M. Morris
  • T. Mizuno
Conference paper


Recent advances suggest the existence of several autosomal dominantly inherited forms of cerebrovascular disorders. Mutations in diverse genes may induce direct pathological changes in intracranial vessels to cause cerebral ischaemic or haemorrhagic strokes leading to cognitive impairment and dementia. Similar pathology may also be caused by systemic vascular disease resulting from mutations and polymorphisms in genes that regulate cardiovascular physiology, blood coagulation and metabolic functions. The most common form of familial stroke appears to be CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is an arterial disease that has been linked to nucleotide substitutions and deletions in the Notch 3 gene. The pathogenesis of the disorder or how the mutations lead to cerebral infarcts and dementia is not known. However, elucidation of the microvascular pathology associated with such genetic disorders not associated with physiological risk factors for cardiovascular disease or stroke can bear much light on primary vascular mechanisms that lead to ischaemic blood flow and neuronal vulnerability.


Cerebral Ischaemia Moyamoya Disease Familial Hemiplegic Migraine Cerebrovascular Disorder Magnetic Resonance Imaging Lesion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Adair JC, Hart BL, Kornfeld M, Graham GD, Swanda RM, Ptacek LJ, Davis LE (1998) Autosomal dominant cerebral arteriopathy: neuropsychiatric syndrome in a family. Neuropsychiatr Neuropsychol Behav Neurol 11: 31–39Google Scholar
  2. Annaert W, De Strooper B (1999) Presenilins: molecular switches between proteolysis and signal transduction. TINS 22: 439–443PubMedGoogle Scholar
  3. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284: 770–776PubMedCrossRefGoogle Scholar
  4. Beatus P, Lundkvist J, Oberg C, Lendahl U (1999) The notch intracellular domain represses Notch 1-mediated activation through hairy/Enhancer of split (HES) promoters. Development 126: 3925–3935PubMedGoogle Scholar
  5. Bergmann M, Ebke M, Yuan Y, et al (1996) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a morphological study of a German family. Acta Neuropathol 92: 341–350PubMedCrossRefGoogle Scholar
  6. Caronti B, Calandriello L, Francia A, et al (1998) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Neuropathological and in vitro studies of abnormal elastogenesis. Acta Neurol Scand 98:259–267PubMedCrossRefGoogle Scholar
  7. Ceroni M, Poloni TE, Tonietti S, Fabozzi D, Uggetti C, Frediani F, Simonetti F, Malaspina A, Alimonti D, Celano M, Ferrari M, Carrera P (2000) Migraine with aura and white matter abnormalities: Notch 3 mutation. Neurology 54: 1869–1871PubMedCrossRefGoogle Scholar
  8. Chabriat H, Vahedi K, Iba-Zizen MT, Joutel A, Nibbio A, Nagy TG, Krebs MO, Julien J, Dubois B, Ducrocq X, et al (1995) Clinical spectrum of CADASIL: a study of 7 families. Lancet 346: 934–939PubMedCrossRefGoogle Scholar
  9. Chabriat H, Levy C, Taillia H, et al (1998) Patterns of MRI lesions in CADASIL. Neurology 51: 452–457PubMedCrossRefGoogle Scholar
  10. Chuah TL, Tan SM, Flanagan S, Hyland V, Sullivan AA, Henderson R, MacMillan J, Lander C (2001) CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy): an Australian perspective. J Clin Neurosci 8: 404–406PubMedCrossRefGoogle Scholar
  11. Coulthard A, Blank SC, Bushby KMD, et al (1999) Distribution of cranial MRI abnormalities in patients with symptomatic and subclinical CADASIL. Br J Radiol 73:256–265Google Scholar
  12. Dale T (1998) Signal transduction by the Wnt family of ligands. Biochem J 329: 209–223PubMedGoogle Scholar
  13. De Lange RPJ et al, Bolt J, Schanen C, et al (1999) Screening British CADASIL families for mutations in NOTCH3 gene. J Med Genet 37: 224–225CrossRefGoogle Scholar
  14. Desmond DW, Moroney JT, Lynch T, et al (1998) CADASIL in a North American family: clinical, pathologic, and radiologic findings. Neurology 51: 844–899PubMedCrossRefGoogle Scholar
  15. Desmond DW, Moroney JT, Lynch T, et al (1999) The natural history of CADASIL. A pooled analysis of previously published cases. Stroke 30: 1230–1233PubMedCrossRefGoogle Scholar
  16. Dichgans M, Mayer M, Uttner I, et al (1998) The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 44: 731–739PubMedCrossRefGoogle Scholar
  17. Dichgans M, Wick M, Gasser T (1999a) Cerebrospinal fluid findings in CADASIL. Neurology 39: 110–112Google Scholar
  18. Dichgans M, Filippi M, Bruning R, et al (1999b) Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology 52: 1361–1367PubMedCrossRefGoogle Scholar
  19. Dichgans M, Ludwig H, Muller-Hocker J, Messerschmidt A, Gasser T (2000) Small inframe deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch 3 EGF-like repeat domains. Eur J Hum Genet 4: 280–285CrossRefGoogle Scholar
  20. Escary JL, Cecillon M, Maciazek J, Lathrop M, Tournier-Lasserve E, Joutel A (2000) Evaluation of DHPLC analysis in mutational scanning of Notch 3, a gene with a high G-C content. Hum Mutat 16: 518–526PubMedCrossRefGoogle Scholar
  21. Filley CM, Thompson LL, Sze CI, et al (1999) White matter dementia in CADASIL. J Neurol Sci 163: 163–167PubMedCrossRefGoogle Scholar
  22. Grand MG, Kaine J, Fulling K, Atkinson J, Dowton SB, Farber M, Craver J, Rice K (1988) Cerebroretinal vasculopathy. A new hereditary syndrome. Opthalmology 95: 649–658Google Scholar
  23. Gutmann DH, Fischbeck KH, Sergott RC (1989) Hereditary retinal vasculopathy with cerebral white matter lesions. Am J Med Genet 34: 217–220PubMedCrossRefGoogle Scholar
  24. Hassan A, Markus H (2000) Genetics and ischaemic stroke. Brain 9: 1784–1812CrossRefGoogle Scholar
  25. Hedera P, Friedland RP (1997) CADASIL: study of two American families with predominant dementia. J Neurol Sci 146: 27–33PubMedCrossRefGoogle Scholar
  26. Ikeda H, Sasaki T, Yoshimoto T, Fukui M, Arinami T (1999) Mapping of a familial moyamoya disease gene to chromosome 3p24.2–p26. Am J Hum Genet 64: 533–537PubMedCrossRefGoogle Scholar
  27. Inoue TK, Ikezaki K, Sasazuki T, Matsushima T, Fukui M (2000) Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 15: 179–182PubMedCrossRefGoogle Scholar
  28. Jen J, Cohen AH, Yue Q, Stout JT, Vinters HV, Nelson S, Baloh RW (1997) Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Neurology 49: 1322–1330PubMedCrossRefGoogle Scholar
  29. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E (1996) Notch 3 mutations in CAD ASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383: 707–710PubMedCrossRefGoogle Scholar
  30. Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E (1997) Strong clustering and stereotyped nature of notch 3 mutations in CAD ASIL patients. Lancet 350:1511–1515PubMedCrossRefGoogle Scholar
  31. Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C, Tournier-Lasserve E (2000a) The ectodomain of the Notch 3 receptor accumulates within the cerebrovasculature of CAD ASIL patients. J Clin Invest 105: 597–605PubMedCrossRefGoogle Scholar
  32. Joutel A, Chabriat H, Vahedi K, Domenga V, Vayssiere C, Ruchoux MM, Lucas C, Leys D, Bousser MG, Tournier-Lasserve E (2000b) Splice site mutation causing a seven amino acid Notch 3 in-frame deletion in CAD ASIL. Neurology 9: 1874–1875CrossRefGoogle Scholar
  33. Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG (2000c) De novo mutation in the Notch 3 gene causing CAD ASIL. Ann Neurol 3: 388–391CrossRefGoogle Scholar
  34. Kalaria RN (1996) Cerebral vessels in ageing and Alzheimer’s disease. Pharm Ther 72: 193–214CrossRefGoogle Scholar
  35. Kalaria RN (2001) Advances in molecular genetics and pathology of cerebrovascular disorders. Trends Neurosci 24: 392–400PubMedCrossRefGoogle Scholar
  36. Kalaria RN, Cookson NJ, Mizuno T, Oakley A, Singleton AB, Morris CM, De Lange RPJ, Burn DJ, StClair D (2000) Microvascular pathology in familial multiinfarct dementia or CAD ASIL: implications for cerebral blood flow. Ischemic blood flow in the brain. Springer, TokyoGoogle Scholar
  37. Kalimo H, Haltia M (1997) Vascular diseases. In: Graham DI, Lantos PL (eds) Greenfield’s neuropathology, 6th edn. Arnold, London, pp 315–396Google Scholar
  38. Kalimo H, Viitanen M, Amberla K, Juvonen V, Marttila R, Poyhonen M, Rinne JO, Savontaus M, Tuisku S, Winblad B (1999) CAD ASIL: hereditary disease of the arteries causing brain infarcts and dementia. Neuropathol Appl Neurobiol 25: 257–265PubMedCrossRefGoogle Scholar
  39. Kamimura K, Takahashi K, Uyama E, Tokunaga M, Kotorii S, Uchino M, Tabira T (1999) Identification of a Notch 3 mutation in a Japanese CAD ASIL family. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Alzheimer Dis Assoc Disord 13: 222–225PubMedCrossRefGoogle Scholar
  40. Kimble J, Simpson P (1997) The lin-12/notch signaling pathway and its regulation. Ann Rev Cell Dev Biol 13: 333–361CrossRefGoogle Scholar
  41. Kotorii S, Takahashi K, Kamimura K, Arima K, Yamada H, Uyama E, Uchino M, Suenaga A, Matsumoto M, Kuchel G, Rouleau GA, Tabira T (2001) Mutations of the Nootch 3 gene in non-caucasian patients with suspected CAD ASIL syndrome. Dement Geriatr Cogn Disord 12: 185–193PubMedCrossRefGoogle Scholar
  42. Lammie GA, Rakshi J, Rossor MN, et al (1995) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)-confirmation by cerebral biopsy in 2 cases. Clin Neuropathol 14: 201–206PubMedGoogle Scholar
  43. Leys D, Erkinjuntti T, Desmond DW, Schmidt R, Englund E, Asquier F, Parnetti L, Ghika J, Kalaria RN, Chabriat H, Scheltens P, Bogousslavsky J (1999) Vascular dementia: the role of cerebral infarcts. Alzheimer Dis Assoc Disord 13: S38–48PubMedGoogle Scholar
  44. Malandrini A, Carrera P, Ciacci G, et al (1997) Unusual clinical features and early brain MRI lesions in a family with cerebral autosomal dominant arteriopathy. Neurology 48: 1200–1203PubMedCrossRefGoogle Scholar
  45. Mellies JK, Baumer T, Muller JA, et al (1998) SPECT study of a German CADASIL family: a phenotype with migraine and progressive dementia only. Neurology 50:1715–1721PubMedCrossRefGoogle Scholar
  46. Oberstein SA, Ferrari MD, Bakker E, et al (1999) Diagnostic Notch 3 sequence analysis in CADASIL: three new mutations in Dutch patients. Neurology 52: 1913–1915PubMedCrossRefGoogle Scholar
  47. Oliveri RL, Muglia M, De Stefano N, Mazzei R, Labate A, Conforti FL, Patitucci A, Gabriele AL, Tagarelli G, Magariello A, Zappia M, Gambardella A, Federico A, Quattrone A (2001) A novel mutation in the Notch 3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: genetic and magnetic resonance spectroscopic findings. Arch Neurol 58: 1418–1422PubMedCrossRefGoogle Scholar
  48. Ray WJ, Yao M, Nowotny P, et al (1999) Evidence for a physical interaction between presenilin and Notch. Proc Natl Acad Sci USA 96: 3263–3268PubMedCrossRefGoogle Scholar
  49. Ruchoux MM, Maurage E (1997) Review on CADASIL. J Neuropathol Exp Neurol 56: 947–964PubMedCrossRefGoogle Scholar
  50. Salloway S, Hong J, et al (1998) CADASIL syndrome: a genetic form of vascular dementia. J Geriatr Psychiatry Neurol 11: 71–77PubMedGoogle Scholar
  51. Shimizu K, Chiba S, Kumano K, Hosoya N, Takahashi T, Kanda Y, Hamada Y, Yazaki Y, Hirai H (1999) Mouse Jagged 1 physically interacts with Notch 2 and other Notch receptors. J Biol Chem 274: 32961–32969PubMedCrossRefGoogle Scholar
  52. Sourander P, Walinder J (1977) Hereditary multi-infarct dementia. Acta Neuropathol 39: 247–254PubMedCrossRefGoogle Scholar
  53. Stevens DL, Hewlett RH, Brownell B (1977) Chronic familial vascular encephalopathy. Lancet i: 1364–1365CrossRefGoogle Scholar
  54. Thomas NJ, Morris CM, Scaravilli F, Johanssen J, Rossor M, De Lange RPJ, StClair D, Nicoll J, Blank SC, Coulthard A, Bushby KMD, Ince PG, Burn DJ, Kalaria RN (2000) Hereditary vascular dementia linked to Notch 3 mutations. Ann NY Acad Sci 903: 293–298PubMedCrossRefGoogle Scholar
  55. Tournier-Lasserve E (1999) CACNA1A mutations: hemiplegic migraine, episodic ataxia type 2, and the others. Neurology 53: 3–4PubMedCrossRefGoogle Scholar
  56. Trojano L, Ragno M, Manca A, et al (1998) A kindred affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A 2-year neuropsychological follow-up. J Neurol 245: 217–222PubMedCrossRefGoogle Scholar
  57. Tuominen S, Juvonen V, Amberla K, Jolma T, Rinne JO, Tuisku S, Kurki T, Marttila R, Poyhonen M, Savontaus ML, Viitanen M, Kalimo H (2001) Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch 3 mutation. Stroke 32: 1767–1774PubMedCrossRefGoogle Scholar
  58. Utatsu Y, Utatsu Y, Takashima H, Michizono K, Kanda N, Endou K, Mitsuyama Y, Fujimoto T, Nagai M, Umehara F, Higuchi I, Arimura K, Nakagawa M, Osame M (1997) Autosomal dominant early onset dementia and leukoencephalopathy in a Japanese family: clinical neuroimaging and genetic studies. J Neurol Sci 147: 55–62PubMedCrossRefGoogle Scholar
  59. Wang T, Sharma SD, Fox N, Rossor M, Brown MJ, Sharma P (2000) Description of a simple test for CADASIL disease and determination of mutation frequencies in sporadic ischaemic stroke and dementia patients. J Neurol Neurosurg Psychiatry 69: 652–654PubMedCrossRefGoogle Scholar
  60. Weil S, Reifenberger G, Dudel C, Yousry TA, Schriever S, Noachtar S (1999) Cerebroretinal vasculopathy mimicking a brain tumor: a case of a rare hereditary syndrome. Neurology 53: 629–631PubMedCrossRefGoogle Scholar
  61. Weinmaster G (1997) The ins and outs of Notch signaling. Mol Cell Neurosci 9: 91–108PubMedCrossRefGoogle Scholar
  62. Yamauchi T, Tada M, Houkin K, Tanaka T, Nakamura Y, Kuroda S, Abe H, Inoue T, Ikezaki K, Matsushima T, Fukui M (2000) Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 31: 930–935PubMedCrossRefGoogle Scholar
  63. Yousry TA, Seelos K, Mayer M, et al (1999) Characteristic MR lesion pattern and correlation of Tl and T2 lesion volume with neurolgic and neuropsychological findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). AJNR Am J Neuroradiol 20: 91–100PubMedGoogle Scholar
  64. Zhang H, Sourander P, Olsson Y (1994) The microvascular changes in cases of hereditary multi-infarct disease of the brain. Acta Neuropathol 87: 317–324PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2002

Authors and Affiliations

  • R. N. Kalaria
    • 1
    • 2
  • W. C. Low
    • 1
  • A. E. Oakley
    • 1
  • J. Y. Slade
    • 1
  • P. G. Ince
    • 1
  • C. M. Morris
    • 1
  • T. Mizuno
    • 1
  1. 1.Institute for Ageing and Health, and Department of PsychiatryUniversity of Newcastle upon TyneUK
  2. 2.Wolfson Research Centre, Institute for Ageing and HealthNewcastle General HospitalNewcastle upon TyneUK

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