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The effect of white matter lesions on cognition in the elderly—small but detectable

Nature Clinical Practice Neurology volume 3, pages 620–627 (2007)Cite this article

Abstract

The extent to which white matter changes affect brain function in elderly individuals is a matter for debate. Although there is a consensus that large confluent white matter lesions (WMLs) can be attributed to small-vessel disease and might denote anatomical damage to axons, the clinical effect of WMLs with regard to cognitive impairment is less certain. In this Review, we argue that WMLs are associated with greater detectable progressive cognitive deterioration than is normal aging, but other causes of progressive cognitive deterioration, such as Alzheimer's disease, are associated with greater cognitive decline than are WMLs. This view has important implications for the development of drugs for the treatment and prevention of cognitive impairment and dementia.

Key Points

  • Focal white matter lesions (WMLs) can be attributed to small-vessel disease and are associated with variable degrees of demyelination, axonal loss and gliosis

  • The effect of WMLs on global cognitive performance in cross-sectional studies is relatively small, even for severe lesions, and amounts at most to 0.7 points out of a maximum of 30 on the Mini-Mental State Examination scale

  • In longitudinal studies, the rate of cognitive deterioration attributable to WMLs is, on average, 12 times lower than that attributable to Alzheimer's disease

  • Only individuals with the more-severe degrees of WMLs have clinically relevant cognitive decline, and these patients might be candidates for drug therapy targeted to small-vessel cerebrovascular disease

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Figure 1: Quantifying the severity of white matter lesions.
Figure 2: Cognitive correlates of white matter lesions.
Figure 3: Natural history of cognitive impairment associated with white matter lesions.

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References

  1. Hachinski VC et al. (1987) Leuko-araiosis. Arch Neurol 44: 21–23

    Article  CAS  Google Scholar 

  2. Gootjes L et al. (2004) Regional distribution of white matter hyperintensities in vascular dementia, Alzheimer's disease and healthy aging. Dement Geriatr Cogn Disord 18: 180–188

    Article  CAS  Google Scholar 

  3. Fazekas F et al. (1993) Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 43: 1683–1689

    Article  CAS  Google Scholar 

  4. Pantoni L and Garcia JH (1997) Pathogenesis of leukoaraiosis: a review. Stroke 28: 652–659

    Article  CAS  Google Scholar 

  5. Fazekas F et al. (1998) Pathophysiologic mechanisms in the development of age-related white matter changes of the brain. Dement Geriatr Cogn Disord 9 (Suppl 1): S2–S5

    Article  Google Scholar 

  6. Burns JM 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  Google Scholar 

  7. van der Flier W et al. (2005) Small vessel disease and general cognitive function in nondisabled elderly: the LADIS study. Stroke 36: 2116–2120

    Article  Google Scholar 

  8. Prins ND et al. (2004) Cerebral white matter lesions and the risk of dementia. Arch Neurol 61: 1531–1534

    Article  Google Scholar 

  9. Prins ND et al. (2005) Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain 128: 2034–2041

    Article  Google Scholar 

  10. Jones DK et al. (1999) Characterization of white matter damage in ischemic leukoaraiosis with diffusion tensor MRI. Stroke 30: 393–407

    Article  CAS  Google Scholar 

  11. Nave RD et al. (2007) Whole-brain histogram and voxel-based analyses of diffusion tensor imaging in patients with leukoaraiosis: correlation with motor and cognitive impairment. AJNR Am J Neuroradiol 28: 1313–1319

    Article  Google Scholar 

  12. Charlton RA et al. (2006) White matter damage on diffusion tensor imaging correlates with age-related cognitive decline. Neurology 24: 217–222

    Article  Google Scholar 

  13. Nitkunan A et al. (2006) Correlations between MRS and DTI in cerebral small vessel disease. NMR Biomed 19: 610–616

    Article  CAS  Google Scholar 

  14. Medina D et al. (2006) White matter changes in mild cognitive impairment and AD: a diffusion tensor imaging study. Neurobiol Aging 27: 663–672

    Article  Google Scholar 

  15. Bartzokis G et al. (2003) White matter structural integrity in healthy aging adults and patients with Alzheimer disease: a magnetic resonance imaging study. Arch Neurol 60: 393–398

    Article  Google Scholar 

  16. Brooks WM et al. (1997) 1H-MRS differentiates white matter hyperintensities in subcortical arteriosclerotic encephalopathy from those in normal elderly. Stroke 28: 1940–1943

    Article  CAS  Google Scholar 

  17. O'Sullivan M et al. (2004) Diffusion tensor MRI correlates with executive dysfunction in patients with ischaemic leukoaraiosis. J Neurol Neurosurg Psychiatry 75: 441–447

    Article  CAS  Google Scholar 

  18. O'Sullivan M et al. (2001) Normal-appearing white matter in ischemic leukoaraiosis: a diffusion tensor MRI study. Neurology 57: 2307–2310

    Article  CAS  Google Scholar 

  19. Fazekas F et al. (2005) MTI of white matter hyperintensities. Brain 128: 2926–2932

    Article  Google Scholar 

  20. Deary IJ et al. (2006) White matter integrity and cognition in childhood and old age. Neurology 66: 505–512

    Article  CAS  Google Scholar 

  21. Dufouil C et al. (2003) Influence of education on the relationship between white matter lesions and cognition. Neurology 60: 831–836

    Article  CAS  Google Scholar 

  22. Longstreth WT Jr et al. (1996) Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: the Cardiovascular Health Study. Stroke 27: 1274–1282

    Article  Google Scholar 

  23. de Groot JC et al. (2000) Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. Ann Neurol 47: 145–151

    Article  CAS  Google Scholar 

  24. Gouw AA et al. (2006) Simple versus complex assessment of white matter hyperintensities in relation to physical performance and cognition: the LADIS study. J Neurol 253: 1189–1196

    Article  CAS  Google Scholar 

  25. Au R et al. (2006) Association of white matter hyperintensity volume with decreased cognitive functioning: the Framingham Heart Study. Arch Neurol 63: 246–250

    Article  Google Scholar 

  26. Soderlund H et al. (2006) Cerebral changes on MRI and cognitive function: the CASCADE study. Neurobiol Aging 27: 16–23

    Article  Google Scholar 

  27. Gunning-Dixon FM and Raz N (2000) The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. Neuropsychology 14: 224–232

    Article  CAS  Google Scholar 

  28. Agüero-Torres H et al. (2002) The impact of somatic and cognitive disorders on the functional status of the elderly. J Clin Epidemiol 55: 1007–1012

    Article  Google Scholar 

  29. Comijs HC et al. (2005) The impact of change in cognitive functioning and cognitive decline on disability, well-being, and the use of healthcare services in older persons: results of Longitudinal Aging Study Amsterdam. Dement Geriatr Cogn Disord 19: 316–323

    Article  Google Scholar 

  30. Cahn-Weiner DA et al. (2002) Tests of executive function predict instrumental activities of daily living in community-dwelling older individuals. Appl Neuropsychol 9: 187–191

    Article  Google Scholar 

  31. Rapp MA et al. (2005) Relationship of neuropsychological performance to functional status in nursing home residents and community-dwelling older adults. Am J Geriatr Psychiatry 13: 450–459

    Article  Google Scholar 

  32. Burback D et al. (1999) Key methodological features of randomized controlled trials of Alzheimer's disease therapy: minimal clinically important difference, sample size and trial duration. Dement Geriatr Cogn Disord 10: 534–540

    Article  Google Scholar 

  33. Hachinski V et al. (2006) National Institute of Neurological Disorders and Stroke–Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 37: 2220–2241

    Article  Google Scholar 

  34. O'Sullivan M et al. (2005) Brief cognitive assessment for patients with cerebral small vessel disease. J Neurol Neurosurg Psychiatry 76: 1140–1145

    Article  CAS  Google Scholar 

  35. Bennett DA et al. (2006) Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 66: 1837–1844

    Article  CAS  Google Scholar 

  36. Nolan KA et al. (1998) Absence of vascular dementia in an autopsy series from a dementia clinic. J Am Geriatr Soc 46: 597–604

    Article  CAS  Google Scholar 

  37. Winnock M et al. (2002) Longitudinal analysis of the effect of apolipoprotein E ε4 and education on cognitive performance in elderly subjects: the PAQUID study. J Neurol Neurosurg Psychiatry 72: 794–797

    Article  CAS  Google Scholar 

  38. Clark CM et al. (1999) Variability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer's Disease. Arch Neurol 56: 857–862

    Article  CAS  Google Scholar 

  39. Ross ED et al. (2005) Relationship of leukoaraiosis to cognitive decline and cognitive aging. Cogn Behav Neurol 18: 89–97

    Article  Google Scholar 

  40. Breteler MM et al. (1994) Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study. Neurology 44: 1246–1252

    Article  CAS  Google Scholar 

  41. De Groot JC et al. (2002) Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol 52: 335–341

    Article  Google Scholar 

  42. Bowler JV and Gorelick PB (2007) Advances in vascular cognitive impairment 2006. Stroke 38: 241–244

    Article  Google Scholar 

  43. Snowdon DA et al. (1997) Brain infarction and the clinical expression of Alzheimer disease: the Nun Study. JAMA 277: 813–817

    Article  CAS  Google Scholar 

  44. Smith CD et al. (2000) White matter volumes and periventricular white matter hyperintensities in aging and dementia. Neurology 54: 838–842

    Article  CAS  Google Scholar 

  45. Starr JM et al. (1997) Age-associated cognitive decline in healthy old people. Age Ageing 26: 295–300

    Article  CAS  Google Scholar 

  46. Lobo A et al. (2000) Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54 (Suppl 5): S4–S9

    CAS  PubMed  Google Scholar 

  47. Longstreth WT Jr 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: 56–61

    Article  Google Scholar 

  48. Jellinger KA (2002) Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109: 813–836

    Article  CAS  Google Scholar 

  49. Inzitari D 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: 81–88

    Article  Google Scholar 

  50. Schmidt R et al. (2007) Progression of leukoaraiosis and cognition. Stroke 38: 2619–2625

    Article  Google Scholar 

  51. Roberson ED and Mucke L (2006) 100 years and counting: prospects for defeating Alzheimer's disease. Science 314: 781–784

    Article  Google Scholar 

  52. Dufouil C 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  Google Scholar 

  53. Fazekas F et al. (1987) MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol 149: 351–356

    Article  CAS  Google Scholar 

  54. Jim version 3.0 (Xinapse Systems, Thorpe Waterville, UK)

  55. Pantoni L et al. (2002) Visual rating scales for age-related white matter changes (leukoaraiosis): can the heterogeneity be reduced? Stroke 33: 2827–2833

    Article  Google Scholar 

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Acknowledgements

Genoveffa Borsci, IRCCS Fatebenefratelli, Brescia, helped in the measurement of white matter lesion volumes shown in Figure 1. Livio Anglani, statistician at the IRCCS Fatebenefratelli in Brescia, helped with the drawing of Figure 3.

Author information

Authors and Affiliations

  1. GB Frisoni is Deputy Scientific Director and Head of the Psychogeriatric Ward and Laboratory of Epidemiology Neuroimaging and Telemedicine (LENITEM), and S Galluzi is a Geriatrician and Researcher at LENITEM, at IRCCS Fatebenefratelli Hospital, Brescia, Italy.,

    Giovanni B Frisoni & Samantha Galluzzi

  2. L Pantoni is a Neurologist in the Department of Neurological and Psychiatric Sciences and Professor at the School of Neurology and at the School of Child Neuropsychiatry, University of Florence, Florence, Italy.,

    Leonardo Pantoni

  3. M Filippi is Director of the Neuroimaging Research Unit, Ospedale San Raffaele, and of the Magnetic Resonance Unit, Fondazione Don Gnocchi, Milan, Italy.,

    Massimo Filippi

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  1. Giovanni B Frisoni
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Correspondence to Giovanni B Frisoni.

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Frisoni, G., Galluzzi, S., Pantoni, L. et al. The effect of white matter lesions on cognition in the elderly—small but detectable. Nat Rev Neurol 3, 620–627 (2007). https://doi.org/10.1038/ncpneuro0638

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