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In the paper from the Rotterdam Scan Study (this issue pp9-14),1 de Leeuw et al take another step towards understanding the conundrum of white matter disease (leukoarosis) and its associations with aging and gender. This will hopefully lead towards better understanding of cognitive decline with age, Alzheimer's disease, and vascular dementia.
The assessment of the role of white matter disease in these processes poses several problems. White matter disease is difficult to quantify. The existence of upwards of some 12 different scales for assessing white matter lesion load, few of which have been validated for interobserver or intraobserver variability, or tested in populations other than the one in which they were generated, testifies to the difficulty of trying to make some sense out of different degrees of “spotty brains”.2 This difficulty in quantification combined with small sample sizes in some previous studies, may have confounded the difficulty of trying to tease out any association between vascular risk factors (hypertension, diabetes, carotid atheroma), so called vascular dementia, Alzheimer's disease, and “normal” age related cognitive decline. Further difficulty is the clinical distinction of Alzheimer's from vascular dementia. Increasing recognition of the overlap in risk factors between Alzheimer's disease and vascular dementia,3 4 suggests that in fact attempts to make too rigid a distinction between the two may have been counterproductive rather than helpful in studies of possible disease mechanisms.
de Leeuw et al studied a large well characterised population of normal people aged between 60 and 90 years with MR scanning. They carefully measured and rated the white matter lesions in the periventricular and subcortical regions in different brain regions. A strength of the study is the use of two independent raters who were able to achieve excellent interrater agreement for white matter lesion load. Periventricular and subcortical white matter lesion load increased with age in men and women and in all regions of the brain. However, women at all ages tended to have a greater lesion load than men, particularly in the frontal lobes where this difference reached statistical significance for frontal capping. As the distribution of possible confounding variables such as hypertension, diabetes, and carotid atheroma was equal between the sexes, it is unlikely that this finding is the result of some other association.
The major problem in this study was the declining response rate with age, from 73% of all those invited to come for a scan in the 60–70 year age group to only 48% in the 80–90 year age group. Therefore, as the authors rightly point out, their study may have underestimated the true prevalence of white matter disease in the general population. The authors report elsewhere on the association with diabetes,5 carotid atheroma,6 atrial fibrillation,7and cognitive ability.8
The authors speculate on two points in need of future study. Firstly, that the increased white matter lesions in women may be the cause of the observed increase in dementia in women compared with men of the same age. Secondly, they suggest that this might be due to loss of a protective effect of oestrogen in postmenopausal women. However, they did not collect data in the present study to test this hypothesis, rather it was a suggestion based on work elsewhere.9Possible protective mechanisms for oestrogen suggested by the authors (reduced susceptibility to ischaemia, increased cerebral blood flow, protection against oxidative stress, enhanced synaptogenesis, and prevention of neuronal atrophy) simply serve to highlight the fact that although we are better informed about associations of white matter disease, cognitive decline, aging, vascular risk factors, and actual dementia, we still know relatively little about which is cause, which is effect, and the primary underlying mechanism of these processes. However, the demographic time bomb presented by increased survival into old age certainly justifies greater imaginative effort on the part of epidemiologists, imagers, neuroscientists, and geneticists to sort out the primary cause.
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