Journal of Neurology

, Volume 255, Issue 8, pp 1203–1208 | Cite as

Enhanced L-arginine-induced vasoreactivity suggests endothelial dysfunction in CADASIL

  • N. PetersEmail author
  • T. Freilinger
  • C. Opherk
  • T. Pfefferkorn
  • M. Dichgans



Mutations in the Notch3 gene are the cause of CADASIL, a hereditary small vessel disease leading to stroke and vascular dementia. The disease is characterized by ultrastructural granular deposits within small arterial vessels and degeneration of vascular smooth muscle cells. Yet, little is known about endothelial function in CADASIL. Vasoreactivity induced by L-arginine, which is the substrate for endothelial nitric oxide synthase, is a parameter of endothelial function and has been shown to be altered in patients with cerebrovascular disease.


To assess endothelial function in CADASIL, L-arginine-induced vasoreactivity was studied in 25 CADASIL subjects and 24 non-CADASIL control subjects without previous history of cerebrovascular disease by transcranial Doppler sonography of the middle cerebral artery.


Resting mean flow velocity was significantly reduced in patients (43.7 ± 14.5 cm/s) compared to controls (57.0 ± 10.4 cm/s) [p < 0.001]. Patients exhibited a significantly higher pulsatility index (PI = 0.94 ± 0.19) than control subjects (PI = 0.79 ± 0.11) [p < 0.01]. L-arginine-induced vasoreactivity was significantly increased in patients (36.1 ± 15.5 % ) versus controls (27.9 ± 8.5 %) [p < 0.05]. In patients, there was a significant reduction of the PI following L-arginine application (PI = 0.86 ± 0.13) compared to resting PI [p < 0.01].


Our results may indicate a pathogenic role of impaired cerebral hemodynamics and endothelial dysfunction in CADASIL. Our finding of enhanced L-arginine vasoreactivity might have therapeutic implications for CADASIL and sporadic small vessel disease.

Key words

CADASIL small vessel disease L-arginine vasoreactivity endothelial dysfunction 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, et al. (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710PubMedCrossRefGoogle Scholar
  2. 2.
    Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, et al. (1998) The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 44:731–739PubMedCrossRefGoogle Scholar
  3. 3.
    Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M (2004) Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain 127:2533–2539PubMedCrossRefGoogle Scholar
  4. 4.
    Ruchoux MM, Maurage CA (1997) CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol 56:947–964PubMedCrossRefGoogle Scholar
  5. 5.
    Mayer M, Straube A, Bruening R, Uttner I, Pongratz D, Gasser T, et al. (1999) Muscle and skin biopsies are a sensitive diagnostic tool in the diagnosis of CADASIL. J Neurol 246:526–532PubMedCrossRefGoogle Scholar
  6. 6.
    Miao Q, Paloneva T, Tuominen S, Poyhonen M, Tuisku S, Viitanen M, et al. (2004) Fibrosis and stenosis of the long penetrating cerebral arteries: the cause of the white matter pathology in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Brain Pathol 14:358–364PubMedGoogle Scholar
  7. 7.
    O’Sullivan M, Jarosz JM, Martin RJ, Deasy N, Powell JF, Markus HS (2001) MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology 56:628–634PubMedGoogle Scholar
  8. 8.
    Auer DP, Putz B, Gossl C, Elbel G, Gasser T, Dichgans M (2001) Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology 218:443–451PubMedGoogle Scholar
  9. 9.
    Chabriat H, Levy C, Taillia H, Iba-Zizen MT, Vahedi K, Joutel A, et al. (1998) Patterns of MRI lesions in CADASIL. Neurology 51:452–457PubMedGoogle Scholar
  10. 10.
    Mellies JK, Baumer T, Muller JA, Tournier-Lasserve E, Chabriat H, Knobloch O, et al. (1998) SPECT study of a German CADASIL family: a phenotype with migraine and progressive dementia only. Neurology 50:1715–1721PubMedGoogle Scholar
  11. 11.
    Chabriat H, Bousser MG, Pappata S (1995) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a positron emission tomography study in two affected family members. Stroke 26:1729–1730PubMedGoogle Scholar
  12. 12.
    van den Boom R, Lesnik Oberstein SA, Spilt A, Behloul F, Ferrari MD, Haan J, et al. (2003) Cerebral hemodynamics and white matter hyperintensities in CADASIL. J Cereb Blood Flow Metab 23:599–604PubMedCrossRefGoogle Scholar
  13. 13.
    Chabriat H, Pappata S, Ostergaard L, Clark CA, Pachot-Clouard M, Vahedi K, et al. (2000) Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking. Stroke 31:1904–1912PubMedGoogle Scholar
  14. 14.
    Pfefferkorn T, von Stuckrad-Barre S, Herzog J, Gasser T, Hamann GF, Dichgans M (2001) Reduced cerebrovascular CO(2) reactivity in CADASIL: A transcranial Doppler sonography study. Stroke 32:17–21PubMedGoogle Scholar
  15. 15.
    Singhal S, Markus HS (2005) Cerebrovascular reactivity and dynamic autoregulation in nondemented patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). J Neurol 252:163–167PubMedCrossRefGoogle Scholar
  16. 16.
    Hussain MB, Singhal S, Markus HS, Singer DR (2004) Abnormal vasoconstrictor responses to angiotensin II and noradrenaline in isolated small arteries from patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Stroke 35:853–858PubMedCrossRefGoogle Scholar
  17. 17.
    Gobron C, Vahedi K, Vicaut E, Stucker O, Laemmel E, Baudry N, Bousser MG, Chabriat H (2007) Characteristic features of in vivo skin microvascular reactivity in CADASIL. J Cereb Blood Flow Metab 27:250–257PubMedCrossRefGoogle Scholar
  18. 18.
    Dubroca C, Lacombe P, Domenga V, Maciazek J, Levy B, Tournier-Lasserve E, Joutel A, Henrion D (2005) Impaired vascular mechanotransduction in a transgenic mouse model of CADASIL arteriopathy. Stroke 36:113–117PubMedCrossRefGoogle Scholar
  19. 19.
    Lacombe P, Oligo C, Domenga V, Tournier-Lasserve E, Joutel A (2005) Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke 36:1053–1058PubMedCrossRefGoogle Scholar
  20. 20.
    Ruchoux MM, Maurage CA (1998) Endothelial changes in muscle and skin biopsies in patients with CADASIL. Neuropathol Appl Neurobiol 24:60–65PubMedCrossRefGoogle Scholar
  21. 21.
    Zimmermann C, Wimmer M, Haberl RL (2004) L-arginine-mediated vasoreactivity in patients with a risk of stroke. Cerebrovasc Dis 17:128–133PubMedCrossRefGoogle Scholar
  22. 22.
    Pretnar-Oblak J, Zaletel M, Zvan B, Sabovic M, Pogacnik T (2006) Cerebrovascular reactivity to L-Arginine in patients with lacunar infarctions. Cerebrovasc Dis 21:180–186PubMedCrossRefGoogle Scholar
  23. 23.
    Micieli G, Bosone D, Zappoli F, Marcheselli S, Argenteri A, Nappi G (1999) Vasomotor response to CO2 and L-Arginine in patients with severe internal carotid artery stenosis; pre- and post-surgical evaluation with transcranial Doppler. J Neurol Sci 163:153–158PubMedCrossRefGoogle Scholar
  24. 24.
    Reutens DC, McHugh MD, Toussaint PJ, Evans AC, Gjedde A, Meyer E, Stewart DJ (1997) L-arginine infusion increases basal but not activated cerebral blood flow in humans. J Cereb Blood Flow Metab 17:309–315PubMedCrossRefGoogle Scholar
  25. 25.
    Dalkara T, Morikawa E, Panahian N, Moskowitz MA (1994) Blood flow-dependent functional recovery in a rat model of focal cerebral ischemia. Am J Physiol 267:H678–H683PubMedGoogle Scholar
  26. 26.
    Ruchoux MM, Chabriat H, Bousser MG, Baudrimont M, Tournier-Lasserve E (1994) Presence of ultrastructural arterial lesions in muscle and skin vessels of patients with CADASIL. Stroke 25:2291–2292PubMedGoogle Scholar
  27. 27.
    Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M (2005) Spectrum of mutations in biopsyproven CADASIL: implications for diagnostic strategies. Arch Neurol 62:1091–1094PubMedCrossRefGoogle Scholar
  28. 28.
    Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, et al. (1997) Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 350:1511–1515PubMedCrossRefGoogle Scholar
  29. 29.
    Holtmannspotter M, Peters N, Opherk C, Martin D, Herzog J, Bruckmann H, Samann P, Gschwendtner A, Dichgans M (2005) Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: a two-year follow-up study. Stroke 36:2559–2565PubMedCrossRefGoogle Scholar
  30. 30.
    Smulders RA, Aarsen M, Teerlink T, De Vries PM, Van Kamp GJ, Donker AJ, et al. (1997) Haemodynamic and biochemical responses to L-arginine and L-lysine infusions in normal subjects: L-arginine-induced vasodilatation cannot be explained by non-specific effects of cationic amino acids. Clin Sci (Lond) 92:367–374PubMedGoogle Scholar
  31. 31.
    Vallance P, Collier J, Moncada S (1989) Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo. Cardiovasc Res 23:1053–1057PubMedCrossRefGoogle Scholar
  32. 32.
    Furuta A, Ishii N, Nishihara Y, Horie A (1991) Medullary arteries in aging and dementia. Stroke 22:442–446PubMedGoogle Scholar
  33. 33.
    Koga Y, Akita Y, Nishioka J, Yatsuga S, Povalko N, Tanabe Y, et al. (2005) Larginine improves the symptoms of strokelike episodes in MELAS. Neurology 64:710–712PubMedCrossRefGoogle Scholar
  34. 34.
    Madajka M, Korda M, White J, Malinski T (2003) Effect of aspirin on constitutive nitric oxide synthase and the biovailability of NO. Thromb Res 110:317–321PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • N. Peters
    • 1
    Email author
  • T. Freilinger
    • 1
  • C. Opherk
    • 1
  • T. Pfefferkorn
    • 1
  • M. Dichgans
    • 1
  1. 1.Dept. of Neurology, Klinikum GrosshadernLudwig-Maximilians-UniversityMunichGermany

Personalised recommendations