Journal of Neurology

, Volume 256, Issue 5, pp 750–757 | Cite as

Effects of statins on the progression of cerebral white matter lesion

Post hoc analysis of the ROCAS (Regression of Cerebral Artery Stenosis) study
  • Vincent C. T. MokEmail author
  • Wynnie W. M. Lam
  • Yu Hua Fan
  • Adrian Wong
  • Ping Wing Ng
  • Tak Hon Tsoi
  • Vincent Yeung
  • Ka Sing Wong
Original Communication


Arteriosclerotic related cerebral white matter lesion (WML) is associated with increased risk of death, stroke, dementia, depression, gait disturbance, and urinary incontinence. We investigated the effects of statins on WML progression by performing a post hoc analysis on the ROCAS (Regression of Cerebral Artery Stenosis) study, which is a randomized, double-blind, placebo-controlled study evaluating the effects of statins upon asymptomatic middle cerebral artery stenosis progression among stroke-free individuals. Two hundreds and eight randomized subjects were assigned to either placebo (n = 102) or simvastatin 20 mg daily (n = 106) for 2 years. Baseline severity of WML was graded visually into none, mild, and severe. Volume (cm3) of WML was determined quantitatively at baseline and at end of study using a semi-automated method based on MRI. Primary outcome was the change in WML volume over 2 years. After 2 years of follow-up, there was no significant change in WML volume between the active and the placebo group as a whole. However, stratified analysis showed that for those with severe WML at baseline, the median volume increase in the active group (1.9 cm3) was less compared with that in the placebo group (3.0 cm3; P = 0.047). Linear multivariate regression analysis identified that baseline WML volume (β = 0.63, P < 0.001) and simvastatin treatment (β = −0.214, P = 0.043) independently predicted change in WML volume. Our findings suggest that statins may delay the progression of cerebral WML only among those who already have severe WML at baseline.


Statins White matter lesion progression 



This work was supported by research grants from Merck Sharp and Dohme Ltd, Direct Grant from the Chinese University of Hong Kong, and the Research Fund of the Department of Medicine and Therapeutics, The Chinese University of Hong Kong.


  1. 1.
    Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC (2002) Subcortical ischaemic vascular dementia. Lancet Neurol 1(7):426–436PubMedCrossRefGoogle Scholar
  2. 2.
    Longstreth WT Jr, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA et al (1996) Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke 27(8):1274–1282PubMedGoogle Scholar
  3. 3.
    Henon H, Vroylandt P, Durieu I, Pasquier F, Leys D (2003) Leukoaraiosis more than dementia is a predictor of stroke recurrence. Stroke 34(12):2935–2940PubMedCrossRefGoogle Scholar
  4. 4.
    Briley DP, Haroon S, Sergent SM, Thomas S (2000) Does leukoaraiosis predict morbidity and mortality? Neurology 54(1):90–94PubMedGoogle Scholar
  5. 5.
    Inzitari D, Simoni M, Pracucci G, Poggesi A, Basile AM, Chabriat H et al (2007) Risk of rapid global functional decline in elderly patients with severe cerebral age-related white matter changes: the LADIS study. Arch Intern Med 167(1):81–88PubMedCrossRefGoogle Scholar
  6. 6.
    Longstreth WT Jr, Arnold AM, Beauchamp NJ Jr, Manolio TA, Lefkowitz D, Jungreis C et al (2005) Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 36(1):56–61PubMedCrossRefGoogle Scholar
  7. 7.
    Schmidt R, Enzinger C, Ropele S, Schmidt H, Fazekas F (2003) Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. Lancet 361(9374):2046–2048PubMedCrossRefGoogle Scholar
  8. 8.
    Sachdev P, Wen W, Chen X, Brodaty H (2007) Progression of white matter hyperintensities in elderly individuals over 3 years. Neurology 68(3):214–222PubMedCrossRefGoogle Scholar
  9. 9.
    Garde E, Lykke Mortensen E, Rostrup E, Paulson OB (2005) Decline in intelligence is associated with progression in white matter hyperintensity volume. J Neurol Neurosurg Psychiatry 76(9):1289–1291PubMedCrossRefGoogle Scholar
  10. 10.
    van den Heuvel DM, ten Dam VH, de Craen AJ, Admiraal-Behloul F, Olofsen H, Bollen EL et al (2006) Increase in periventricular white matter hyperintensities parallels decline in mental processing speed in a non-demented elderly population. J Neurol Neurosurg Psychiatry 77(2):149–153PubMedCrossRefGoogle Scholar
  11. 11.
    Schmidt R, Petrovic K, Ropele S, Enzinger C, Fazekas F (2007) Progression of leukoaraiosis and cognition. Stroke 38(9):2619–2625PubMedCrossRefGoogle Scholar
  12. 12.
    Bowler JV, Gorelick PB (2007) Advances in vascular cognitive impairment 2006. Stroke 38(2):241–244PubMedCrossRefGoogle Scholar
  13. 13.
    Schmidt R, Scheltens P, Erkinjuntti T, Pantoni L, Markus HS, Wallin A et al (2004) White matter lesion progression: a surrogate endpoint for trials in cerebral small-vessel disease. Neurology 63(1):139–144PubMedGoogle Scholar
  14. 14.
    Dufouil C, Chalmers J, Coskun O, Besancon V, Bousser MG, Guillon P et al (2005) Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. Circulation 112(11):1644–1650PubMedCrossRefGoogle Scholar
  15. 15.
    (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344(8934):1383–9Google Scholar
  16. 16.
    (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360(9326):7–22Google Scholar
  17. 17.
    Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C et al (1990) Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 323(19):1289–1298PubMedCrossRefGoogle Scholar
  18. 18.
    Amarenco P, Labreuche J, Lavallee P, Touboul PJ (2004) Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 35(12):2902–2909PubMedCrossRefGoogle Scholar
  19. 19.
    Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE et al (2006) High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 355(6):549–559PubMedCrossRefGoogle Scholar
  20. 20.
    Ii M, Losordo DW (2007) Statins and the endothelium. Vascul Pharmacol 46(1):1–9PubMedCrossRefGoogle Scholar
  21. 21.
    Mok V, Lam W, Chen X, Wong A, Ng P, Tsoi T, et al. Statin for asymptomatic middle cerebral artery stenosis: the ROCAS (Regression of Cerebral Artery Stenosis) study. Cerebrovasc Dis (in press)Google Scholar
  22. 22.
    Fan YH, Lam WW, Mok VC, Huang RX, Wong KS (2003) Variability and validity of a simple visual rating scale in grading white matter changes on magnetic resonance imaging. J Neuroimaging 13(3):255–258PubMedCrossRefGoogle Scholar
  23. 23.
    Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M et al (2001) A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 32(6):1318–1322PubMedGoogle Scholar
  24. 24.
    Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F et al (1993) Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 43(9):1683–1689PubMedGoogle Scholar
  25. 25.
    ten Dam VH, van den Heuvel DM, van Buchem MA, Westendorp RG, Bollen EL, Ford I et al (2005) Effect of pravastatin on cerebral infarcts and white matter lesions. Neurology 64(10):1807–1809PubMedCrossRefGoogle Scholar
  26. 26.
    Bernick C, Katz R, Smith NL, Rapp S, Bhadelia R, Carlson M et al (2005) Statins and cognitive function in the elderly: the Cardiovascular Health Study. Neurology 65(9):1388–1394PubMedCrossRefGoogle Scholar
  27. 27.
    van Straaten EC, Fazekas F, Rostrup E, Scheltens P, Schmidt R, Pantoni L et al (2006) Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study. Stroke 37(3):836–840PubMedCrossRefGoogle Scholar
  28. 28.
    Sterzer P, Meintzschel F, Rosler A, Lanfermann H, Steinmetz H, Sitzer M (2001) Pravastatin improves cerebral vasomotor reactivity in patients with subcortical small-vessel disease. Stroke 32(12):2817–2820PubMedCrossRefGoogle Scholar
  29. 29.
    O’Driscoll G, Green D, Taylor RR (1997) Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 95(5):1126–1131PubMedGoogle Scholar
  30. 30.
    Essig M, Nguyen G, Prie D, Escoubet B, Sraer JD, Friedlander G (1998) 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins. Circ Res 83(7):683–690PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Vincent C. T. Mok
    • 1
    Email author
  • Wynnie W. M. Lam
    • 2
  • Yu Hua Fan
    • 3
  • Adrian Wong
    • 1
  • Ping Wing Ng
    • 4
  • Tak Hon Tsoi
    • 5
  • Vincent Yeung
    • 6
  • Ka Sing Wong
    • 1
  1. 1.Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SARChina
  2. 2.Department of Radiology and Organ ImagingThe Chinese University of Hong KongHong Kong SARChina
  3. 3.Department of NeurologyThe First Affiliated Hospital, Sun Yat-Sen UniversityGuangzhouChina
  4. 4.Department of Medicine and GeriatricsUnited Christian HospitalHong Kong SARChina
  5. 5.Department of MedicinePamela Youde Nethersole Eastern HospitalHong Kong SARChina
  6. 6.Department of MedicineOur Lady of Maryknoll HospitalHong Kong SARChina

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