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
6
Decline of cerebral blood flow is linked with increase of
periventricular but not deep white matter hyperintensities
VH ten Dam, MD1 HM Murray, MSc4
DMJ van den Heuvel, MSc2 MA van Buchem, MD PhD2
AJM de Craen, PhD1 RGJ Westendorp, MD PhD1
ELEM Bollen, MD PhD3 GJ Blauw, MD PhD1
on behalf of the PROSPER study group†
Institutional affiliations: From the departments of 1Gerontology and Geriatrics, 2Radiology, 3Neurology, Leiden University Medical Center, The Netherlands. 4Robertson
Centre for Biostatistics, North Glasgow University NHS Trust, Glasgow, Scotland, UK. †See appendix for members
Abstract
Introduction
Increasing age is associated with a decline of cerebral blood flow1, 2.
Cross-sec-tional studies have estimated the rate of this decline at about 4.8 mL/min per
year1. Total cerebral blood flow is partly determined by brain volume, but
ather-osclerotic disease, small-vessel disease, and decline of metabolic need of the
brain probably also play a role in the decline of cerebral blood flow with age2-6.
Moreover, whole brain and regional perfusion of the brain are reduced in individ-uals with white matter hyperintensities (WMH) compared to subjects without
WMH5, 7. Furthermore, within WMH there is a significant decrease of regional
cere-bral blood flow from outer ring to inner core8.
White matter hyperintensities are commonly observed on brain MRI of elderly subjects and have been associated with ischemia. According to their location they can be separated in periventricular and deep WMH. Periventricular WMH have been related to cognitive decline, while deep WMH have been associated with late
onset depression9, 10. Neuro-anatomical studies suggest that periventricular and
deep WMH have a different etiology. The development of periventricular WMH has been attributed to arteriosclerosis and lipohyalinosis of the penetrating medullary arteries, periventricular venous collagenosis, and breakdown of the blood-brain barrier, while deep WMH are thought to be caused by fibrohyalinosis and
perive-nous damage of the cerebral arteries11-14.
We performed a baseline brain MRI in a large group of non-demented elderly sub-jects with a repeated brain MRI after almost three years. At both occasions we measured total cerebral blood flow, and volume of total, periventricular, and deep WMH. Because decline of cerebral blood flow and periventricular WMH both have hypertension as a strong common risk factor, we hypothesized that decline of cerebral blood flow over time would be associated with an increase of
periventric-ular but not deep WMH15, 16.
Materials and Methods
All participants of this MRI study are participants of the PROSPER study. The PROSPER Study is a randomized, double-blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) reduces the risk of coro-nary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with sig-nificant risk of developing this condition. Inclusion and exclusion criteria of the
PROSPER study have been described in detail elsewhere17. A nested MRI substudy
was performed within the PROSPER study. The clinical characteristics of this sub-set of subjects, who were not significantly different from the main cohort, have
been published elsewhere18. In short, in total 535 subjects had valid
blood flow measurement, which is sensitive for movement artefacts, was per-formed during each MRI session. Due to absence of measurement (n=41), move-ment artefacts (n=82), wrong scanning plane (n=9), and technical problems (n=13) another 145 subjects were excluded for the present analysis (Figure 1). Hence, 390 pairs of MRI with both WMH and cerebral blood flow measurements were used, consisting of 225 men and 165 women aged 70-82 years (mean 74.5 , SD 3.2). The LUMC institutional ethic review board approved the protocol for the MRI study and all participants gave written informed consent.
We performed MRI of the brain on a system operating at 1.5 Tesla field strength (Philips Medical Systems, Best, The Netherlands). We obtained PD-T2/dual fast spin echo images (Time to echo (TE) 27/120 ms, Time to repeat (TR) 3000 ms, echo train length factor 10, 48 contiguous 3 mm slices, matrix 256x256, field of view (FOV) 220) of all subjects at baseline and follow up. Total cerebral blood flow was measured in both internal carotid arteries and both vertebral arteries, using
a gradient echo phase-contrast MRI19. We used a triggered gradient echo
phase-contrast technique with one number of signal average and retrospective gating with the use of a peripheral pulse unit. TR / TE was 14.7 / 9.1 ms; flip angle 7.5º; slice thickness 5 mm, matrix 256x154, FOV 250x188 mm. The scans were per-formed in a plane perpendicular to the carotid and vertebral arteries.
For quantification of the WMH, the Dual Echo MR images were transferred to an off-line workstation. White matter hyperintensities volumes were assessed using inhouse developed semi-automated lesion detection software (Division of Image
Processing, Department of Radiology, Leiden, The Netherlands)20. By combining
fuzzy clustering, connectivity rules, and mathematical morphology the program identifies potential lesions on the Dual Echo T2 weighted FSE sequence. Lesions connected to the lateral ventricles were labelled as periventricular WMH. Inferior and superior boundaries of periventricular WMH were within two slices caudal to the most caudal slice and cranial to the most cranial slice showing the lateral ven-tricles. Lesions not connected to the lateral ventricles were labelled as deep WMH. White matter hyperintensities were subsequently edited manually and reviewed by two trained raters to correct for misclassification (i.e. grey matter, Virchow-Robin spaces, cerebro spinal fluid).
The images of the cerebral blood flow were analysed using inhouse developed
software19, 21. With this automatic method the blood vessel is identified manually,
after which delineation of the vessel is drawn automatically. Then, flow volume is calculated by integrating the flow velocity values within this contour, multiplied with the area. Total cerebral blood flow is calculated by adding flow from the left and right internal carotid artery and the flow in both vertebral arteries and is expressed as ml/min. All cerebral blood flow measurements were corrected for
atrophy3, 22. Atrophy was expressed as intracranial volume minus whole brain
Figure. Flow chart of study participants
White matter hyperintensities
N=535
Cerebral blood flow
N=390
Second MRI
N=554
First MRI
N=638
No cerebral blood flow value
N=145
No white matter hyperintensities value
N=19
No second MRI
N=84
Table 1. Volume of total, periventricular, and deep WMH and cerebral blood flow at base-line and after 33 months of follow-up.
________________________________________________________________________ Baseline Follow-up p-value* (n=390) (n=390)
________________________________________________________________________
White matter hyperintensities (mL)
Total 1.6 (0.5-6.2) 2.8 (0.8-10.1) <0.001 Periventricular 1.0 (0.2-4.2) 1.8 (0.5-7.6) <0.001 Deep 0.5 (0.1-1.5) 0.7 (0.2-2.1) <0.001
Total cerebral blood flow (mL/min) 516 (463-578) 501 (442-567) <0.001 ________________________________________________________________________ Data are reported as median (interquartile range).
* Wilcoxon Signed Rank test used.
Table 2. Association between change in cerebral blood flow from baseline and increase in total, periventricular, and deep WMH from baseline.
________________________________________________________________________
Model Crude Adjusted†
Changes from baseline in cerebral load of total, periventricular, and deep matter hyperintensities, and cerebral blood flow at follow-up were compared using the Wilcoxon Signed Rank test. Medians (interquartile range) are reported for base-line and follow-up measurements. The association between prevalence of volume of WMH at baseline and cerebral blood flow at baseline was analysed using logis-tic regression because the white matter hyperintensity data were skewed to the right and could not be transformed. The volume of total, periventricular, and deep matter hyperintensities were dichotomized around the 90th percentile and cere-bral blood flow was entered per 50 ml/min. First, unadjusted odds ratios (OR) (95% Confidence Interval (CI)) were calculated, which were then adjusted for age, sex, and brain atrophy. The analysis of progression of the load of total, periventricular, and deep WMH and change from baseline of cerebral blood flow at follow-up, was also performed with logistic regression analysis. Increase of vol-umes of WMH were dichotomized around the 90th percentile and odds ratios (95% CI) were calculated representing a decrease in cerebral blood flow of 50 ml/min from baseline. Level of significance was set at p<0.05.
Results
At baseline, the median volume of total WMH was 1.6 mL and the median cere-bral blood flow was 516 mL/min (table 1). At the end of follow up, total volume of WMH had increased significantly to 2.8 mL (p<0.001). The increase in total WMH was attributable to increases in both periventricular (p<0.001) and deep WMH (p<0.001). Moreover, at the end of follow-up, total cerebral blood flow had decreased significantly (p<0.001).
Discussion
Using a longitudinal design, we here report on the association between cerebral blood flow and WMH in a large elderly population. We found that decline of cere-bral blood flow during follow-up was significantly associated with increase of periventricular but not deep WMH.
We performed the first, large, longitudinal study investigating the relation between cerebral blood flow and WMH. In this study we found no association between baseline cerebral blood flow and volume of total, periventricular, or deep WMH at baseline. One of the reasons for the absence of the cross-sectional
asso-ciation is that values of cerebral blood flow vary widely between subjects19. Hence,
a very large number of subjects has to be included in order to find a significant association. However, variation in change of cerebral blood flow in individual sub-jects are smaller and therefore longitudinal studies are more sensitive for detect-ing associations.
In our longitudinal study, we found that a reduction of total cerebral blood flow was not associated with an increase of deep WMH, whereas an association was observed between reduction of total cerebral blood flow and large increases of periventricular WMH. Periventricular WMH are typically located symmetrically in both cerebral hemispheres, which is suggestive for a diffuse perfusion distur-bance. On the contrary, deep WMH are often smaller and frequently have an asymmetrical distribution over both hemispheres, which is more indicative for local perfusion disturbances. The cerebral blood flow measurements we used in our study is able to detect cerebral blood flow changes based on widespread
small-vessel disease23. Local cerebral blood flow reductions, for example caused
by small thrombo-embolic events giving rise to occlusion of one single vessel, are less likely to be detected by this method, since they will not substantially affect total cerebral blood flow.
White matter hyperintensities are present in most brains of elderly people. Most
of these lesions do not show progression over time24. However, presence of a large
volume of baseline WMH predicts strong progression over time24. For example,
after three years of follow-up, the Austrian stroke prevention study found
sub-stantial progression of WMH in 17.9 % of their participants25. To investigate the
relation between cerebral blood flow and the progression of WMH over time, we selected subjects with a high progression of white matter lesion load. Therefore we used the upper 10 percentile of progression of the load of WMH over time and analysed these data using logistic regression.
per-flow may give rise to cerebral hypoperfusion16, 26. Most sensitive area to ischemia
due to hypoperfusion is the periventricular region. This area is supplied by lentic-ulostriate and long medullary arteries which converge towards the periventricular
region12. Due to this angio-architecture, the perfusion pressure of the
periventric-ular white matter is relatively low and particperiventric-ularly sensitive for fluctuations in total cerebral blood flow. Such fluctuations may result in ischemia, which may give rise to breakdown of the blood-brain barrier or perivenous collagenosis and may damage the periventricular white matter. This may visible on MRI as WMH. This MRI Study was originally designed to assess the effect of pravastatin on the progression of cerebral disease. However, there was no benefit of pravastatin on
the progression of white matter lesions or cerebral blood flow22, 27.We nevertheless
performed all longitudinal analyses adjusting for treatment allocation, which did not affect the results.
In conclusion, this prospective MRI study shows that decrease of total cerebral blood flow in elderly subjects is associated with increases in volume of periven-tricular but not deep WMH. Perivenperiven-tricular WMH may be a manifestation of small-vessel disease of the brain in elderly people, which has been associated with
cere-bral infarcts and dementia6. Further studies investigating the relation between
Reference List
1. Buijs PC, Krabbe-Hartkamp MJ, Bakker CJ et al. Effect of age on cerebral bloodflow: measurement with ungated two-dimensional phase-contrast MR angiography in 250 adults. Radiology 1998 December;209(3):667-74.
2. Leenders KL, Perani D, Lammertsma AA et al. Cerebral blood flow, blood volume and oxygen utilization. Normal values and effect of age. Brain 1990 February;113 ( Pt 1):27-47.
3. Van Laere KJ, Dierckx RA. Brain perfusion SPECT: age- and sex-related effects corre-lated with voxel-based morphometric findings in healthy adults. Radiology 2001 December;221(3):810-7.
4. Meltzer CC, Cantwell MN, Greer PJ et al. Does cerebral blood flow decline in healthy aging? A PET study with partial-volume correction. J Nucl Med 2000 November;41(11):1842-8.
5. Meguro K, Hatazawa J, Itoh M, Miyazawa H, Matsuzawa T, Yamadori A. Cerebral blood flow correlated with carotid blood flow in neurologically normal elderly with severe white matter lesions. Eur J Neurol 1998 March;5(2):143-9.
6. Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol 2002 November;1(7):426-36.
7. Marstrand JR, Garde E, Rostrup E et al. Cerebral perfusion and cerebrovascular reac-tivity are reduced in white matter hyperintensities. Stroke 2002 April;33(4):972-6.
8. Sachdev P, Wen W, Shnier R, Brodaty H. Cerebral blood volume in T2-weighted white matter hyperintensities using exogenous contrast based perfusion MRI. J Neuropsychiatry Clin Neurosci 2004;16(1):83-92.
9. De Groot JC, De Leeuw FE, Oudkerk M et al. Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol 2002 September;52(3):335-41.
10. O’Brien J, Desmond P, Ames D, Schweitzer I, Harrigan S, Tress B. A magnetic reso-nance imaging study of white matter lesions in depression and Alzheimer’s disease. Br J Psychiatry 1996 April;168(4):477-85.
11. Van Swieten JC, van den Hout JH, van Ketel BA, Hijdra A, Wokke JH, Van Gijn J. Periventricular lesions in the white matter on magnetic resonance imaging in the eld-erly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain 1991 April;114 ( Pt 2):761-74.
12. Moody DM, Brown WR, Challa VR, Ghazi-Birry HS, Reboussin DM. Cerebral microvas-cular alterations in aging, leukoaraiosis, and Alzheimer’s disease. Ann N Y Acad Sci 1997 September 26;826:103-16.
13. Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of the blood-brain bar-rier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke 2003 March;34(3):806-12.
15. Lipsitz LA, Gagnon M, Vyas M et al. Antihypertensive therapy increases cerebral blood flow and carotid distensibility in hypertensive elderly subjects. Hypertension 2005 February;45(2):216-21.
16. Matsushita K, Kuriyama Y, Nagatsuka K, Nakamura M, Sawada T, Omae T. Periventricular white matter lucency and cerebral blood flow autoregulation in hyper-tensive patients. Hypertension 1994 May;23(5):565-8.
17. Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly individuals at risk of vas-cular disease (PROSPER): a randomised controlled trial. Lancet 2002 November 23;360(9346):1623-30.
18. van den Heuvel DMJ, Admiraal-Behloul F, ten Dam VH et al. Different progression rates for deep white matter hyperintensities in elderly men and women. Neurology 2004 November 9;63(9):1699-701.
19. Spilt A, Box FM, van der Geest RJ et al. Reproducibility of total cerebral blood flow measurements using phase contrast magnetic resonance imaging. J Magn Reson Imaging 2002 July;16(1):1-5.
20. van den Heuvel DMJ, ten Dam VH, de Craen AJ et al. Measuring longitudinal white mat-ter changes: comparison of a visual rating scale with a volumetric measurement. Submitted 2005.
21. Box FM, Spilt A, van Buchem MA, van der Geest RJ, Reiber JH. Automatic model-based contour detection and blood flow quantification in small vessels with velocity encoded magnetic resonance imaging. Invest Radiol 2003 September;38(9):567-77.
22. ten Dam VH, Box FM, de Craen AJ et al. Effect of pravastatin on cerebral blood flow and parenchyma volume in elderly at risk for vascular disease. Submitted 2005.
23. van den Boom R, Lesnik Oberstein SA, Spilt A et al. Cerebral hemodynamics and white matter hyperintensities in CADASIL. J Cereb Blood Flow Metab 2003 May;23(5):599-604.
24. Schmidt R, Enzinger C, Ropele S, Schmidt H, Fazekas F. Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. Lancet 2003 June 14;361(9374):2046-8.
25. Schmidt R, Fazekas F, Kapeller P, Schmidt H, Hartung HP. MRI white matter hyperin-tensities: three-year follow-up of the Austrian Stroke Prevention Study. Neurology 1999 July 13;53(1):132-9.
26. Russell RW. How does blood-pressure cause stroke? Lancet 1975 December 27;2(7948):1283-5.
