Heuvel, D.M.J. van den
Citation
Heuvel, D. M. J. van den. (2005, November 17). White matters : a longitudinal study on
causes and consequences of white matter hyperintensities in the elderly. Retrieved from
https://hdl.handle.net/1887/3729
Version:
Corrected Publisher’s Version
Chapter
10
General Discussion
The general objective of this thesis was to prospectively investigate possible caus-es and consequenccaus-es of WMHs in a group of non-demented elderly individuals with pre-existing vascular disease or at risk of developing this condition. The studies presented in this thesis are based on the MRI substudy of the PROspective Study of the Elderly at Risk (PROSPER). In the previous chapters these studies were described in detail, focussing on i) methods for quantifying WMHs, ii) caus-es of WMHs, iii) impact of WMHs on cognitive functioning and, finally, iv) preven-tion of progression of ischemic lesions (i.e.WMHs and infarcts) by a pharmalogi-cal intervention. In this chapter the main findings are summarized and relevant issues related to the topics mentioned above are discussed. The chapter closes with clinical implications of our findings and suggestions for future research.
Summary of Main Findings
Methods for measuring white matter hyperintensities
Volumetric measurements of WMHs have been proposed as an alternative for existing visual rating scales. Currently, several volumetric WMHs analysis meth-ods are available, however, they are time-consuming and elaborate1-6. In
chap-ter 3 we report on a new, inhouse developed, fully automatic segmentation tech-nique that combines FLAIR and dual MR sequences (PD/T2) for volumetric analy-sis of WMHs in the elderly. Our method uses an established artificial intelligence technique (fuzzy inference system). The reproducibility of the segmentation tech-nique was evaluated in a group of subjects who underwent scan-rescan on MR with repositioning. The accuracy of the segmentation technique was evaluated by comparing the automatic segmentation of WMHs with manual expert delineation of WMHs. Our results show that the automated segmentation technique is highly reproducible. In addition, our method demonstrates high volumetric and spatial agreement with manual expert delineation and does not require, on average, more than 2 minutes per subject. These results demonstrate that our new seg-mentation technique is fast, accurate, and reliable. However, there are limitations to our method; hence, quality control by visual inspection remains mandatory. For follow-up studies aimed at assessing changes in WMHs over time, the accu-racy of WMH measurements is critical. Visual rating scales are hampered by floor-and ceiling effects floor-and their reliability is usually modest to low. Hence, the detec-tion of change on repetitive WMH measurements is problematic using these scales7. Volumetric WMH measurements might overcome these problems. In
chapter 4 we investigated the potential of a widely used visual semiquantitative rating scale (i.e. Scheltens’ scale)8, 9and an inhouse developed quantitative
volu-metric measurement to study white matter (WM) changes over time in a longitu-dinal study10. We compared both methods in their reliability and sensitivity to
In order to examine the sensitivity of either method to detect longitudinal WM changes, associations of the 3-years change in WMH ratings and WMH volume measurements with an ‘external standard’ (i.e. age) were evaluated.
We observed that, compared to the visual rating scale, the volumetric measure-ment was more sensitive in its ability to detect changes in WMH with advancing age. Our data suggest that volumetric measurements of WMH offer a more reli-able, sensitive and objective alternative to visual rating scales in studying longi-tudinal WM changes.
Causes of white matter hyperintensities
Several risk factors may underlie the pathogenetic mechanisms in the develop-ment of WMHs. Cross-sectional studies have shown positive associations between age and various cerebrovascular risk factors on the one hand and severity of WMHs on the other hand11-17. However, longitudinal data are scarce18-22. We
per-formed a longitudinal study with repeated measurements of WMHs in a large group of elderly subjects. Periventricular and deep WMHs were assessed using a volumetric semi-automated method. In the chapters 5,6 and 7 we report on the various risk factors that were associated with the presence and three-year pro-gression of deep and periventricular WMHs.
association with baseline deep WMH remained. Moreover, the longitudinal associ-ation between smoking and progression of total and periventricular WMH persist-ed. Our data suggest that the development and progression of WMHs may take many years and that different pathological processes probably underlie the devel-opment of deep and periventricular WMHs.
Impact of white matter hyperintensities on cognitive functioning
Findings from longitudinal studies on the role of WMHs in the etiology of cogni-tive decline are conflicting. Longitudinal data are limited, but even more scarce are studies investigating changes in cognitive performance over time in combina-tion with serial MRI measurements22-25. In chapter 8 we studied the association
between the presence and progression of deep and periventricular WMHs and cognitive decline. Cognitive functioning was assessed using a battery of cognitive function tests with an emphasis on memory and executive functioning. We found that the volume of periventricular WMHs at baseline was longitudinally associat-ed with rassociat-educassociat-ed mental processing speassociat-ed. Moreover, we found that the progres-sion in periventricular WMH volume paralleled the decline in mental processing speed. This suggests that periventricular WMHs give rise to impairment in pro-cessing speed. In contrast, neither presence nor progression of deep WMHs were associated with change in performance on any of the cognitive tests. We conclude that periventricular WMH are not to be considered benign but probably cause impairment in processing speed.
Prevention of progression of WMHs and infarcts by pharmalogical intervention Subjects with severe WMHs and brain infarcts perform worse on cognitive tests and have an increased risk of dementia16,26-28. The contribution of WMHs and
infarcts to the development of cognitive decline raises the question how we can prevent the development of these lesions. In chapter 9 we studied the effect of a statin based cholesterol lowering drug (pravastatin) on the progression of cere-bral ischemic disease visible on conventional MR (i.e. WMHs and cerecere-bral infarcts). We found that the volumes of WMHs and infarcts progressed significant-ly during the period of observation but there was no statistical difference between the placebo and pravastin treatment groups. Our findings show that treatment with pravastatin does not influence the progression of ischemic brain lesions in elderly individuals over a three-year period.
Methodological issues
Study designThe studies presented in this thesis are based on longitudinal data. In general, there are two reasons to conduct longitudinal research: i) to describe patterns of change, and ii) to describe temporal relations between predictor and outcome variables29. Temporality is one of the most important criteria for causality (i.e.
cause precedes effect in time)30. Hence, longitudinal studies are believed to be a
variables. However, longitudinal data pose several disadvantages and challenges. Selective attrition of participants is one of these challenges31, 32. In our study loss
of participants to follow-up was evaluated. From the original 646 subjects at baseline, 92 (14%) dropped out of the study during follow-up. Compared with the follow-up participants, at baseline the dropouts performed significantly worse on some of the cognitive tests, had higher total WMH volumes and more often a his-tory of myocardial infarction (table 2, appendix). Thus, we most likely missed the ‘extremes’ of the variables under study. Hence, the reported associations between risk factors and progression of WMHs and the associations between WMHs and cognitive performance have probably been underestimated in our study. Another challenge in longitudinal research is the measurement of change29.
For example, in case of measurement of change in cognitive functioning, the change scores equal true score plus measurement error, plus the learning and practice effects. That is, with repeated cognitive testing one should always be aware of the fact that the performance improves by merely doing a test more than once. We used different test versions to circumvent direct learning effects. Other forms of learning, for example procedural learning, are more difficult to be ruled out. However, as we compared scores between groups, and since there is no indication that practice effects are different in those with and without WMHs, we think in our comparisons this is not at play. Furthermore, other sources of error must have been controlled for. Within the PROSPER study trained nurses have administered neuropsychological tests and evaluation of cognitive function-ing has been strictly protocolised. With regard to the measurements of WMHs we reduced error by employing a highly reproducible semiautomated volumetric method of quantifying WMHs.
Study population
All subjects in our study belonged to a selected sample from the population at large. They were included if they had either pre-existing vascular disease or raised risk of such disease because of smoking, hypertension, or diabetes. Moreover, the study was conducted within a non-demented sample with little con-trast on cognitive functioning at baseline. The selective vascular risk profile of our subjects probably has influenced the overall frequency of WMHs. Although the overall prevalence of any WMHs in our study (98%) is comparable with the preva-lence of WMHs in the Cardiovascular Health Study33 and the Rotterdam Scan
Study34, 35, the prevalence of severe WMHs in our study is probably higher. The use
of this enriched sample for WMHs provided greater statistical power, but could also limit the applicability of the current findings to the general unselected popu-lation. However, the selection on risk factors and cognitive performance might have weakened the results, and the observed associations may thus be underes-timations. They have no major consequence when statistical significant relations are found.
Follow-up period
be small. Hence, the associations between risk factors and WMH and between WMH and cognitive decline may have been underestimated.
Specificity of WMH measurements
MRI studies on age-related WMHs have often reported discrepancies between the extent of WMHs and the presence of clinical abnormalities (e.g. cognitive disabil-ity, high or low blood pressure). That is, the strength of the associations between the volume of WMHs and clinical conditions is often moderate or poor. Assuming there is in fact a close relationship, the observed discrepancy is referred to as the clinico-radiological paradox36. The use of sensitive measures of WMHs could be one way of resolving this paradox. In our study we used a volumetric WMH meas-urement method. Compared to the widely used visual WMH ratings, the volumet-ric measurements increase the sensitivity and precision of the WMH estimates. However, improving sensitivity may not suffice when the specificity of the WMH measurements remains low. Conventional MRI is not specific for characterizing WMHs since it is not able to distinguish between WMHs of different etiology (e.g. ischemia, inflammation) and of different histological composition (e.g. demyeli-nation, gliosis, oedema, axonal loss). Moreover, conventional MRI is not specific for characterizing the severity of tissue damage of WMHs. That is, different sever-ity of tissue damage may have the same appearance on MRI images and conven-tional MRI sequences are insensitive to the presence of diffuse, microscopic dis-ease in the normal appearing white matter (NAWM). Etiology, histological compo-sition and severity of tissue damage are, however, important properties of WMHs. For example, with Magnetization Transfer Imaging (MTI) it has been shown that within WMHs different severity of damage corresponds to different clinical expres-sion37, 38. Therefore, the non-differential inclusion of WMHs of different etiology,
histological composition and severity might have weakened or obscured the asso-ciation of WMHs and risk factors and cognitive functioning in our study.
Implications and future research
The majority of published longitudinal studies on WMHs had a longitudinal design with repeated measurements of the determinant (i.e. risk factors) or outcome measure (i.e. cognition) but with only single measurements of WMHs. Our study has expanded on earlier longitudinal studies since it is one of the few studies on the topic with serial WMH measurements. This enabled us to look at the tempo-ral relationship between risk factors and cognitive functioning in relation to pro-gression of WMHs.
rel-atively intact until the later stages39, 40. We therefore suggest that, at least,
periventricular WMHs in elderly subjects are not to be considered benign. Other studies support this hypothesis; the presence of WMHs has amongst others been associated with an increased risk of stroke41, 42, gait disturbances43, depressive
symptoms26, 44, dementia45, 46, and even death47.
The impact of WMHs on health status of elderly individuals warrants the need to identify the (modifiable) risk factors that underlie the development of WMHs. That is, with respect to pharmacological intervention, elderly at risk should be identi-fied. There seems to be a great complexity regarding underlying causes and, con-sequently, risk factors for the development of WMHs. In our study we found asso-ciations between volumes of WMHs and vascular risk factors. However, it is essen-tial to identify other markers of disease. Hence, the current focus in research should aim at unraveling etiology, histological composition and severity of tissue damage of WMHs. MRI applications like MR spectroscopy (MRS), MTI and diffu-sion weighted MRI (DWI) have the potential of revealing even very subtle pathol-ogy in the normal appearing white matter and may allow for the detection of dif-ferent underlying pathology in white matter changes. In addition, MRS, MTI and DTI provide quantitative measures that allow for the separation of different sever-ity of tissue damage. The associations between origin, histological composition and severity of WMHs and specific risk factors should be further explored with use of these imaging techniques. This may eventually allow for new insights and more effective pharmacological treatment strategies in the prevention of WMHs.
Major conclusions
i) Our new inhouse developed semi-automated volumetric method for WMH measurement is fast, accurate, and reliable and is suitable for longitudi-nal studies with repeated WMH measurements (chapters 3 & 4).
ii) Gender-related differences might affect the development of deep white matter hyperintensities (chapter 5).
iii) Lower cerebral blood flow is related to the occurrence of WMH (chapter 6).
iv) Hypertension is a risk factor for deep WMHs whereas smoking is a risk factor for periventricular WMH (chapter 7).
v) We found supporting evidence for the role of periventricular WMHs as a causal factor in the decline of cognitive speed (chapter 8).
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