Skip to main content

Advertisement

SpringerLink
Log in

Periventricular white matter hyperintensities increase the likelihood of progression from amnestic mild cognitive impairment to dementia

  • ORIGINAL COMMUNICATION
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Background

White matter hyperintensities (WMH) have an effect on cognition and are increased in severity among individuals with amnestic mild cognitive impairment (aMCI). The influence of WMH on progression of aMCI to Alzheimer’s disease (AD) is less clear.

Methods

Data were drawn from a three-year prospective, double blind, placebo controlled clinical trial that examined the effect of donepezil or vitamin E on progression from aMCI to AD. WMH from multiple brain regions were scored on MR images obtained at entry into the trial from a subset of 152 study participants using a standardized visual rating scale. Cox proportional hazards models adjusting for age, education and treatment arm were used to investigate the role of WMH on time to progression.

Results

55 of the 152 (36.2 %) aMCI subjects progressed to AD. Only periventricular hyperintensities (PVH) were related to an increased risk of AD within three years (HR = 1.59, 95 % CI = 1.24 – 2.05, p-value < 0.001). Correcting for medial temporal lobe atrophy or the presence of lacunes did not change statistical significance.

Conclusion

PVH are associated with an increased risk of progression from aMCI to AD. This suggests that PVH, an MRI finding thought to represent cerebrovascular damage, contributes to AD onset in vulnerable individuals independent of Alzheimer pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Morris JC, Price AL (2001) Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. J Mol Neurosci 17:101–118

    Article  PubMed  CAS  Google Scholar 

  2. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56:303–308

    Article  PubMed  CAS  Google Scholar 

  3. Price JL, Morris JC (1999) Tangles and plaques in nondemented aging and «preclinical» Alzheimer’s disease. Ann Neurol 45:358–368

    Article  PubMed  CAS  Google Scholar 

  4. Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 256:183–194

    Article  PubMed  CAS  Google Scholar 

  5. Bennett DA, Wilson RS, Schneider JA, et al. (2002) Natural history of mild cognitive impairment in older persons. Neurology 59:198–205

    PubMed  CAS  Google Scholar 

  6. Ganguli M, Dodge HH, Shen C, DeKosky ST (2004) Mild cognitive impairment, amnestic type: an epidemiologic study. Neurology 63:115–121

    PubMed  Google Scholar 

  7. Morris JC, Storandt M, Miller JP, et al. (2001) Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 58:397–405

    Article  PubMed  CAS  Google Scholar 

  8. Petersen RC (2000) Mild cognitive impairment: transition between aging and Alzheimer’s disease. Neurologia 15:93–101

    Article  PubMed  CAS  Google Scholar 

  9. DeCarli C, Miller BL, Swan GE, Reed T, Wolf PA, Carmelli D (2001) Cerebrovascular and brain morphologic correlates of mild cognitive impairment in the National Heart, Lung, and Blood Institute Twin Study. Arch Neurol 58:643–647

    Article  PubMed  CAS  Google Scholar 

  10. Lopez OL, Jagust WJ, Dulberg C, et al. (2003) Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol 60:1394–1399

    Article  PubMed  Google Scholar 

  11. Riley KP, Snowdon DA, Markesbery WR (2002) Alzheimer’s neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol 51:567–577

    Article  PubMed  Google Scholar 

  12. Englund E (2002) Neuropathology of white matter lesions in vascular cognitive impairment. Cerebrovasc Dis 13(Suppl 2):11–15

    Article  PubMed  Google Scholar 

  13. Nordahl CW, Ranganath C, Yonelinas AP, DeCarli C, Reed BR, Jagust WJ (2005) Different mechanisms of episodic memory failure in mild cognitive impairment. Neuropsychologia 43:1688–1697

    Article  PubMed  Google Scholar 

  14. DeCarli C, Murphy DG, Tranh M, et al. (1995) The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults. Neurology 45:2077–2084

    PubMed  CAS  Google Scholar 

  15. Tullberg M, Fletcher E, DeCarli C, et al. (2004) White matter lesions impair frontal lobe function regardless of their location. Neurology 63:246–253

    PubMed  CAS  Google Scholar 

  16. DeCarli C (2003) The role of cerebrovascular disease in dementia. Neurologist 9:123–136

    Article  PubMed  Google Scholar 

  17. DeCarli C, Mungas D, Harvey D, et al. (2004) Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia. Neurology 63:220–227

    PubMed  CAS  Google Scholar 

  18. Wolf H, Ecke GM, Bettin S, Dietrich J, Gertz HJ (2000) Do white matter changes contribute to the subsequent development of dementia in patients with mild cognitive impairment? A longitudinal study. Int J Geriatr Psychiatry 15:803–812

    Article  PubMed  CAS  Google Scholar 

  19. Petersen RC, Thomas RG, Grundman M, et al. (2005) Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 352:2379–2388

    Article  PubMed  CAS  Google Scholar 

  20. DeCarli C, Frisoni GB, Clark CM, et al. (2007) Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia. Arch Neurol 64:108–115

    Article  PubMed  Google Scholar 

  21. Grundman M, Petersen RC, Ferris SH, et al. (2004) Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol 61:59–66

    Article  PubMed  Google Scholar 

  22. Wechsler D (1987) WMS-R Wechsler Memory Scale – Revised Manual. New York, Harcourt Brace Jovanovich Inc

  23. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140:566–572

    Article  PubMed  CAS  Google Scholar 

  24. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944

    PubMed  CAS  Google Scholar 

  25. Grundman M, Sencakova D, Jack CR Jr, et al. (2002) Brain MRI hippocampal volume and prediction of clinical status in a mild cognitive impairment trial. J Mol Neurosci 19:23–27

    Article  PubMed  CAS  Google Scholar 

  26. Grundman M, Jack CR Jr, Petersen RC, et al. (2003) Hippocampal volume is associated with memory but not monmemory cognitive performance in patients with mild cognitive impairment. J Mol Neurosci 20:241–248

    Article  PubMed  CAS  Google Scholar 

  27. Scheltens P, Barkhof F, Leys D, et al. (1993) A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 114:7–12

    Article  PubMed  CAS  Google Scholar 

  28. Scheltens P, Leys D, Barkhof F, et al. (1992) Atrophy of medial temporal lobes on MRI in «probable» Alzheimer’s disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 55:967–972

    PubMed  CAS  Google Scholar 

  29. Burns JM, Church JA, Johnson DK, et al. (2005) White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease. Arch Neurol 62:1870–1876

    Article  PubMed  Google Scholar 

  30. de Groot JC, de Leeuw FE, Oudkerk M, et al. (2002) Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol 52:335–341

    Article  PubMed  Google Scholar 

  31. Prins ND, van Dijk EJ, den Heijer T, et al. (2004) Cerebral white matter lesions and the risk of dementia. Arch Neurol 61:1531–1534

    Article  PubMed  Google Scholar 

  32. de la Torre JC (2002) Vascular basis of Alzheimer’s pathogenesis. Ann N Y Acad Sci 977:196–215

    Article  PubMed  CAS  Google Scholar 

  33. Launer LJ (2002) Demonstrating the case that AD is a vascular disease: epidemiologic evidence. Ageing Res Rev 1:61–77

    Article  PubMed  Google Scholar 

  34. Pansari K, Gupta A, Thomas P (2002) Alzheimer’s disease and vascular factors: facts and theories. Int J Clin Pract 56:197–203

    PubMed  CAS  Google Scholar 

  35. van der Flier WM, Middelkoop HA, Weverling-Rijnsburger AW, et al. (2004) Interaction of medial temporal lobe atrophy and white matter hyperintensities in AD. Neurology 62:1862–1864

    PubMed  CAS  Google Scholar 

  36. Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 62:1148–1155

    PubMed  CAS  Google Scholar 

  37. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR (1997) Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277:813–817

    Article  PubMed  CAS  Google Scholar 

  38. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM (2003) Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 348:1215–1222

    Article  PubMed  Google Scholar 

  39. Cummings JL, Benson DF (1988) Psychological dysfunction accompanying subcortical dementias. Annu Rev Med 39:53–61

    Article  PubMed  CAS  Google Scholar 

  40. American Psychiatry Association (1994) Diagnostic and statistical manual of mental disorders, 4th ed. Washington, American Psychiatry Association

  41. Barkhof F, Scheltens P (2006) Is the whole brain periventricular? J Neurol Neurosurg Psychiatry 77:143–144

    Article  PubMed  CAS  Google Scholar 

  42. DeCarli C, Fletcher E, Ramey V, Harvey D, Jagust WJ (2005) Anatomical mapping of white matter hyperintensities (WMH): exploring the relationships between periventricular WMH, deep WMH, and total WMH burden. Stroke 36:50–55

    Article  PubMed  Google Scholar 

  43. Desmond DW (2004) The neuropsychology of vascular cognitive impairment: is there a specific cognitive deficit? J Neurol Sci 226:3–7

    Article  PubMed  Google Scholar 

  44. Selden NR, Gitelman DR, Salamon- Murayama N, Parrish TB, Mesulam MM (1998) Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain 121(Pt 12):2249–2257

    Article  PubMed  Google Scholar 

  45. Fazekas F, Kleinert R, Offenbacher H, et al. (1993) Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 43:1683–1689

    PubMed  CAS  Google Scholar 

  46. Olichney JM, Hansen LA, Lee JH, Hofstetter CR, Katzman R, Thal LJ (2000) Relationship between severe amyloid angiopathy, apolipoprotein E genotype, and vascular lesions in Alzheimer’s disease. Ann N Y Acad Sci 903:138–143

    Article  PubMed  CAS  Google Scholar 

  47. DeCarli C, Reed T, Miller BL, Wolf PA, Swan GE, Carmelli D (1999) Impact of apolipoprotein E epsilon4 and vascular disease on brain morphology in men from the NHLBI twin study. Stroke 30:1548–1553

    PubMed  CAS  Google Scholar 

  48. van Straaten EC, Fazekas F, Rostrup E, et al. (2006) Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study. Stroke 37:836–840

    Article  PubMed  Google Scholar 

  49. Visser PJ, Verhey FR, Hofman PA, Scheltens P, Jolles J (2002) Medial temporal lobe atrophy predicts Alzheimer’s disease in patients with minor cognitive impairment. J Neurol Neurosurg Psychiatry 72:491–497

    PubMed  CAS  Google Scholar 

  50. Salloway S, Ferris S, Kluger A, et al. (2004) Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology 63:651–657

    PubMed  CAS  Google Scholar 

  51. Thal LJ, Ferris SH, Kirby L, et al. (2005) A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 30:1204–1215

    Article  PubMed  CAS  Google Scholar 

  52. Ancelin ML, Christen Y, Ritchie K (2007) Is antioxidant therapy a viable alternative for mild cognitive impairment? Examination of the evidence. Dement Geriatr Cogn Disord 24:1–19

    Article  PubMed  CAS  Google Scholar 

  53. Hull M, Berger M, Heneka M (2006) Disease-modifying therapies in Alzheimer’s disease: how far have we come? Drugs 66:2075–2093

    Article  PubMed  Google Scholar 

  54. Burns A, O’Brien J, Auriacombe S, et al. (2006) Clinical practice with antidementia drugs: a consensus statement from British Association for Psychopharmacology. J Psychopharmacol 20:732–755

    Article  PubMed  CAS  Google Scholar 

  55. Dufouil C, Chalmers J, Coskun O, 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 112:1644–1650

    Article  PubMed  Google Scholar 

  56. Hanon O, Forette F (2004) Prevention of dementia: lessons from SYST-EUR and PROGRESS. J Neurol Sci 226:71–74

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dept. of Neurology and Alzheimer Center, VU Medical Center, De Boelelaan 1117, 7057, 1007 MB, Amsterdam, The Netherlands

    E. C. W. van Straaten, P. Scheltens & L. J. Thal

  2. Division of Biostatistics, Dept. of Public Health Sciences, University of California at Davis, California, USA

    D. Harvey

  3. Dept. of Radiology, VU University Medical Center, Amsterdam, The Netherlands

    F. Barkhof

  4. Dept. of Neurology, Mayo Clinic, Rochester, USA

    R. C. Petersen

  5. Dept. of Radiology, Mayo Clinic, Rochester, USA

    C. R. Jack Jr.

  6. Dept. of Neurology and Imaging of Dementia and Aging (IDeA) Laboratory, Center for Neuroscience, University of California at Davis, California, USA

    C. DeCarli

Authors
  1. E. C. W. van Straaten
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Harvey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Scheltens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. Barkhof
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. C. Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. J. Thal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. R. Jack Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. DeCarli
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the members of the Alzheimer’s Disease Cooperative Study Group*

Corresponding author

Correspondence to E. C. W. van Straaten.

Additional information

*Members of the Alzheimer’s Disease Cooperative Study who participated in this MRI study are presented in the appendix at the end of the paper.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Straaten, E.C.W., Harvey, D., Scheltens, P. et al. Periventricular white matter hyperintensities increase the likelihood of progression from amnestic mild cognitive impairment to dementia. J Neurol 255, 1302–1308 (2008). https://doi.org/10.1007/s00415-008-0874-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-008-0874-y

Key words

Search

Navigation