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White matter hyperintensities: a target for the prevention of cognitive decline?
  1. D Leys1,
  2. S Bombois2
  1. 1Department of Neurology, Stroke, EA2691, Lille University Hospital, Lille, France
  2. 2Department of Neurology, Memory Units, EA2691, Lille University Hospital, Lille, France
  1. Correspondence to:
 D Leys
 Department of Neurology (EA2691), Lille University Hospital, F-59037 Lille, France;

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Lowering blood pressure might decrease the rate of cognitive decline in ε4 carriers and in subjects with white matter hyperintensities, a risk factor for cognitive decline

White matter hyperintensities (WMH) are frequent in apparently normal elderly subjects, in patients with vascular risk factors such as high blood pressure levels, in stroke patients, and in patients with either vascular dementia or Alzheimer’s disease (AD). In this issue, the papers by Garde et al (see pages 1289-91),1 Jokinen et al (see pages 1229-33),2 and de Leeuw et al (see pages 1286-8)3 provide evidence that WMH also influence cognitive functions independently of the underlying pathology. These three studies provide new information leading to potential strategies to prevent cognitive decline.

The more severe the progression of WMH over time, the more severe the cognitive decline in both AD patients3 and normal elderly subjects.1 This finding suggests that WMH should be regarded as risk factors for cognitive decline per se. Therefore, any therapeutic option that may slow the progression of WMH might help decrease the rate of cognitive decline in AD patients3 and normal subjects.1 As the major risk factor for WMH is arterial hypertension, blood pressure lowering drugs should therefore be tested first to examine this hypothesis in patients who already have WMH. When the role of cerebral atrophy is taken into account, the influence of WMH on cognitive functions remains significant,2 suggesting that the results of previous studies1–3 are not the consequence of cerebral atrophy which is frequently associated with WMH. After a stroke, WMH are also independently associated with cognitive impairment.3 The hypothesis of de Leeuw et al,3 that blood pressure lowering in patients with WMH might decrease the rate of cognitive decline in AD patients, is therefore valid also for stroke patients. However, white matter changes on CT scan in stroke patients are associated with an increased risk of stroke recurrence.4 It is, therefore, difficult to evaluate the effect of blood pressure lowering drugs on WMH progression only: the reduction in stroke recurrences may account for some of the results, besides a possible reduction in the rate of progression of WMH.

The aim of the three studies1–3 was not to explain why only some patients have rapid progression of WMH over time. Genetic factors might explain differences in the susceptibility of cerebral white matter to high blood pressure: in the Rotterdam study5: (i) APOE ε4 carriers had significantly more subcortical WMH than APOE ε3ε3 carriers, irrespective of their baseline levels of blood pressure;5 and (ii) an ε4 allele and a high level of blood pressure were strongly associated with the presence of WMH, while hypertension alone or the presence of an ε4 allele alone were not.5

These radiological1–3 and genetic5 findings open a window for selective prevention of cognitive impairment in high risk subjects. The hypothesis that lowering blood pressure might be more beneficial in subjects with WMH and in ε4 carriers should now be tested in randomised trials.


The authors thank Professor Florence Pasquier for her critical reading of a preliminary version of this editorial commentary.

Lowering blood pressure might decrease the rate of cognitive decline in ε4 carriers and in subjects with white matter hyperintensities, a risk factor for cognitive decline


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