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Decline in Total Cerebral Blood Flow Is Linked with Increase in Periventricular but Not Deep White Matter Hyperintensities¹

¹ From the Departments of Gerontology and Geriatrics (V.H.t.D., A.J.M.d.C., R.G.J.W., G.J.B.), Radiology (D.M.J.v.d.H., M.A.v.B.), and Neurology (E.L.E.M.B.), Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands; and Robertson Centre for Biostatistics, University of Glasgow, Glasgow, Scotland (H.M.M.). Members of the PROSPER study group are listed in the Acknowledgments. Received December 29, 2005; revision requested February 27, 2006; revision received April 4; accepted May 9; final version accepted August 23. Address correspondence to A.J.M.d.C. (e-mail: A.J.M.deCraen{at}lumc.nl).

	ABSTRACT

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Purpose: To retrospectively investigate the association between changes in total cerebral blood flow and progression of total, periventricular, and deep white matter hyperintensities over time.

Materials and Methods: The institutional ethics review board approved the protocol for the prospective magnetic resonance (MR) imaging study, and all participants gave written informed consent. Participants also agreed to future retrospective analysis of their MR data for research purposes. In this substudy of the Prospective Study of Pravastatin in the Elderly at Risk, investigators performed a repeated MR imaging examination after an average interval of 33 months (standard deviation, 1.4) in 390 elderly men and women (ages 70–82 years at baseline) without dementia who were at high vascular risk. White matter hyperintensities were quantified with a semiautomatic method, and total cerebral blood flow was measured with a gradient-echo phase-contrast MR imaging technique. The association between total cerebral blood flow and volume of white matter hyperintensities was analyzed with logistic regression.

Results: There was no association between baseline cerebral blood flow and prevalence of total, periventricular, or deep white matter hyperintensities at baseline MR imaging. Moreover, decline in cerebral blood flow was not associated with increase in total load of white matter hyperintensities. When the total volume of white matter hyperintensities was separated into periventricular and deep hyperintensities, for every 50 mL/min decrease in total cerebral blood flow there was a 1.32 (95% confidence interval: 1.06, 1.66; P = .015) increase in risk for developing periventricular white matter hyperintensities; there was no association, however, between decrease in total cerebral blood flow and risk of developing deep white matter hyperintensities (odds ratio, 1.00 [95% confidence interval: 0.79, 1.25]; P = .98).

Conclusion: Decline in total cerebral blood flow is associated with increase in volume of periventricular but not deep white matter hyperintensities.

© RSNA, 2007

Increasing age is associated with decline in cerebral blood flow (1,2). Cross-sectional studies have been performed to estimate the rate of this decline, about 4.8 mL/min per year (1). Total cerebral blood flow is partly determined by brain volume, but atherosclerosis, small-vessel disease, and decline in metabolic need of the brain probably also play roles in the decline of cerebral blood flow with age (2–6). Moreover, whole-brain perfusion and regional perfusion of the brain are reduced in individuals with white matter hyperintensities in comparison with perfusion in control subjects (5,7). Furthermore, white matter hyperintensities have lower regional cerebral blood volume compared with blood volume in contralateral normal-appearing white matter (8).

White matter hyperintensities are commonly observed on magnetic resonance (MR) images of the brain in elderly subjects and have been associated with ischemia. White matter hyperintensities can be separated into two regions according to their anatomic location: a periventricular region, which is the area adjacent to the ventricles, and a subcortical or deep region, which is the area beneath the cortex. Periventricular white matter hyperintensities have been related to cognitive decline, while deep white matter hyperintensities have been associated with late-onset depression (9,10). Results of neuroanatomic studies suggest that periventricular and deep white matter hyperintensities have different causes. The development of periventricular white matter hyperintensities has been attributed to arteriosclerosis and lipohyalinosis of the penetrating arteries, periventricular venous collagenosis, and breakdown of the blood-brain barrier, while deep white matter hyperintensities are thought to be caused by fibrohyalinosis and perivascular demyelination (11–14).

The aim of our study was to retrospectively investigate the association between changes in total cerebral blood flow and progression in volume of total, periventricular, and deep white matter hyperintensities over time.

	MATERIALS AND METHODS

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The study was sponsored by an investigator-initiated grant from Bristol Myers-Squibb (Princeton, NJ). The sponsor had no role in the design, data collection, data analyses, and data interpretation of the study or the writing of the report. The authors declare the following arrangements with the sponsoring company and/or other companies making competing products: research support and travel grants (G.J.B., M.A.v.B., E.L.E.M.B., and R.G.J.W).

Participants
All participants of this MR imaging study are participants of the Prospective Study of the Elderly at Risk (PROSPER) trial. The PROSPER study was a randomized, double-blind, placebo-controlled trial performed to test the hypothesis that treatment with pravastatin (40 mg/d) reduces the risk of coronary heart disease–related death, nonfatal myocardial infarction, and fatal or nonfatal stroke in elderly men and women who have preexisting vascular disease or are at high risk of developing this condition. Inclusion and exclusion criteria of the PROSPER study have been described in detail elsewhere (15). A nested MR imaging substudy was performed within the PROSPER study. The inclusion of the participants for this substudy has been described elsewhere (16). Participants were 70–82 years old at baseline and had a history of vascular disease or were at increased vascular risk. In 535 patients, there were valid measurements without artifacts of white matter hyperintensities at baseline and at follow-up. The mean interval between baseline and follow-up MR imaging was 33 months ± 1.4 (standard deviation). Cerebral blood flow measurement, which is sensitive for movement artifacts, was performed during each MR imaging session. Of 535 patients, 145 were excluded from the present analysis because of absence of measurement (n = 41), movement artifacts (n = 82), wrong imaging plane (n = 9), and technical problems (n = 13). Hence, 390 patients with pairs of MR images with both white matter hyperintensities and cerebral blood flow measurements were included. The mean age was 75 years ± 3.2, and 226 (57.9%) of 390 patients were men (Table 1).

Imaging and Evaluation
We performed MR imaging of the brain with a system that operated at a 1.5-T field strength (Philips Medical Systems, Best, the Netherlands). For the quantification of white matter hyperintensities and the parenchymal measurements, we performed intermediate-weighted and T2-weighted dual-echo fast spin-echo imaging (3000/27, 120 [repetition time msec/echo time msec]; echo train length, 10; 48 continuous 3-mm sections; matrix, 256 x 256; and field of view, 220 mm) in all subjects at baseline and follow-up. We also performed fluid-attenuated inversion recovery imaging (8000/100; 48 continuous sections; matrix, 256 x 256; and field of view, 220 mm) at baseline and follow-up. Total cerebral blood flow was measured in both internal carotid arteries and both vertebral arteries by using a gradient-echo phase-contrast MR imaging technique (17). We used a triggered gradient-echo phase-contrast technique, with one signal acquired and retrospective gating with the use of a peripheral pulse unit (14.7/9.1; flip angle, 7.5°; section thickness, 5 mm; matrix, 256 x 256; and field of view, 250 mm). The imaging was performed in a plane perpendicular to the carotid and vertebral arteries. All subjects refrained from smoking for at least 90 minutes before cerebral blood flow measurement.

For quantification of the white matter hyperintensities, the dual-echo MR images were transferred to an off-line workstation. White matter hyperintensities volumes were assessed by using in-house developed semiautomated lesion detection software (Division of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands) (18). By combining fuzzy clustering, connectivity rules, and mathematic morphology, the program helps identify potential lesions on the dual-echo T2-weighted fast spin-echo images. White matter hyperintensities were defined as hyperintense lesions on both intermediate-weighted and T2-weighted images. Lesions connected to the lateral ventricles were labeled as periventricular white matter hyperintensities. Inferior and superior boundaries for periventricular white matter hyperintensities were within two sections caudad to the most caudal section and craniad to the most cranial section that showed the lateral ventricles. Lesions not connected to the lateral ventricles were labeled as deep white matter hyperintensities (Figure). White matter hyperintensities were subsequently edited manually and reviewed by two trained raters (V.H.t.D., D.M.J.v.d.H.) who used fluid-attenuated inversion recovery hard-copy images as a reference to correct for misclassification (ie, gray matter, Virchow-Robin spaces, cerebrospinal fluid).

View larger version (100K): [in this window] [in a new window] [Download PPT slide]   Transverse T2-weighted MR image (3000/27, 120; 3-mm sections; matrix, 256 x 256; field of view, 220 mm) shows the results of our computerized semiautomatic detection system for quantification of volumes of deep and periventricular white matter hyperintensities. Red indicates deep hyperintensities, and blue indicates periventricular hyperintensities.

Parenchymal (whole-brain) volume was segmented with in-house developed semiautomatic software (D.M.J.v.d.H.; Division of Image Processing, Department of Radiology, Leiden University Medical Center) (20). The volume of parenchyma was expressed in cubic centimeters. In this study, atrophy was expressed as intracranial volume minus whole-brain parenchymal volume divided by intracranial volume and given as a percentage.

Statistical Analysis
Data analysis in this study was performed by multiple investigators (V.H.t.D., A.J.M.d.C., G.J.B., M.A.v.B., and R.G.J.W.) in consensus. Changes from baseline in cerebral load of total, periventricular, and deep white matter hyperintensities and cerebral blood flow at follow-up were compared by using the Wilcoxon signed rank test. Medians and interquartile ranges are reported for baseline and follow-up measurements.

The cross-sectional association between volume of white matter hyperintensities at baseline and cerebral blood flow at baseline was analyzed by using logistic regression, because the white matter hyperintensity data were skewed to the right and could not be transformed. The baseline volume of total, periventricular, and deep white matter hyperintensities was dichotomized around the 90th percentile, and cerebral blood flow was entered into the model per 50 mL/min. First, unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and then they were adjusted for age, sex, and brain atrophy.

To investigate the relationship between cerebral blood flow and the progression of white matter hyperintensities over time, we selected patients with a high progression in load of white matter hyperintensities (lesion load). Therefore, we used the upper 10th percentile of progression in the load of white matter hyperintensities over time. Analysis of the progression of the volume of total, periventricular, and deep white matter hyperintensities and change in cerebral blood flow from baseline to follow-up was performed with logistic regression analysis. Increase in volume of white matter hyperintensities was dichotomized around the 90th percentile, and ORs and 95% CIs were calculated, and they represented a decrease in cerebral blood flow of 50 mL/min from baseline. Unadjusted odds ratios were calculated and then adjusted for age, sex, treatment allocation, baseline cerebral blood flow, and brain atrophy. Level of significance was set at P < .05.

This MR imaging study was originally designed to assess the effect of pravastatin on the progression of cerebral disease. Although pravastatin showed no benefit for the progression of white matter hyperintensities or cerebral blood flow (21,22), we performed all longitudinal analyses by adjusting for treatment allocation, which did not affect the results. Data were analyzed by using statistical software (SPSS, version 12.0; SPSS, Chicago, Ill).

	RESULTS

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White Matter Hyperintensities and Cerebral Blood Flow
At baseline, the median volume of total white matter hyperintensities was 1.6 cm³ (interquartile range, 0.5–6.2 cm³), and the median cerebral blood flow was 516 mL/min (interquartile range, 463–578 mL/min) (Table 2). At the end of follow-up, total median volume of white matter hyperintensities had increased significantly to 2.8 cm³ (interquartile range, 0.8–10.1 cm³; P < .001). The increase in volume of total white matter hyperintensities was attributable to increases in volumes of both periventricular (P < .001) and deep white matter (P < .001) hyperintensities. Moreover, at the end of follow-up, total cerebral blood flow had decreased significantly to 501 mL/min (range, 442–567 mL/min; P < .001).

Follow-up
Decline in total cerebral blood flow was not significantly associated with an increased risk of developing white matter hyperintensities (OR, 1.17 [95% CI: 0.96, 1.42]; P = .13) (Table 3). However, when we separated total volume of white matter hyperintensities into periventricular and deep hyperintensities, for every 50 mL decrease in total cerebral blood flow there was a 1.23 (95% CI: 1.01, 1.50; P = .039) increase in the risk of progression of periventricular white matter hyperintensities; however, there was no association between decrease in total cerebral blood flow and risk of increased volume of deep white matter hyperintensities (OR, 1.02 [95% CI: 0.83, 1.24]; P = .86). When we adjusted for age, sex, brain atrophy, treatment allocation, and baseline cerebral blood flow, the observed associations remained: The OR was 1.32 (95% CI: 1.06, 1.66; P = .015) for periventricular white matter hyperintensities, and the OR was 1.00 (95% CI: 0.79, 1.25; P = .98) for deep white matter hyperintensities.

	DISCUSSION

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White matter hyperintensities are present in the brains of most elderly people. Most of these lesions do not show progression over time (24). However, presence of a large volume of baseline white matter hyperintensities helps predict strong progression over time (23). For example, after 3 years of follow-up, authors of the Austrian stroke prevention study (25) found substantial progression of white matter hyperintensities in 17.9% of their participants who had a large volume of white matter hyperintensities at baseline.

In our study, decrease in total cerebral blood flow was associated with an increase in volume of periventricular white matter hyperintensities. In general, autoregulatory mechanisms of the cerebral arterioles compensate for decreases in total cerebral blood flow to keep perfusion pressure constant. When this autoregulation is damaged—for example, by long-term hypertension that causes arteriosclerosis or lipohyalinosis—decrease in cerebral blood flow may lead to cerebral hypoperfusion (26,27). The most sensitive area for ischemia due to hypoperfusion is the periventricular region. This area is supplied by lenticulostriate and long medullary arteries, which converge toward the periventricular region (12). Because of this angioarchitecture, the perfusion pressure of the periventricular white matter is relatively low and particularly sensitive to fluctuations in total cerebral blood flow. Such fluctuations may result in ischemia, which may lead to breakdown of the blood-brain barrier or perivenous collagenosis and may damage the periventricular white matter. This damage may subsequently be seen on MR images as white matter hyperintensities.

In our study, we divided white matter hyperintensities into periventricular and deep hyperintensities. We labeled lesions connected to the lateral ventricles as periventricular white matter hyperintensities. Lesions that were not connected to the lateral ventricles were labeled as deep white matter hyperintensities. This method may be a limitation of our study; we probably overestimated the periventricular hyperintensities, since the confluent lesions connected to the ventricles were labeled as periventricular.

In conclusion, results of this MR imaging study show that a decrease in total cerebral blood flow in elderly subjects is associated with an increase in volume of periventricular but not deep white matter hyperintensities.

	ADVANCE IN KNOWLEDGE

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• After 33 months of follow-up, we found that a decline in cerebral blood flow was significantly (P = .015) associated with an increase in periventricular white matter hyperintensities but not with an increase in deep white matter hyperintensities.
  

	ACKNOWLEDGMENTS

 
The following are members of the PROSPER study group. Executive committee: (Glasgow) J. Shepherd (chairman and principal investigator), S. M. Cobbe, I. Ford, A. Gaw, P. W. Macfarlane, C. J. Packard, D. J. Stott; (Leiden) G. J. Blauw (principal investigator), E. L. E. M. Bollen, A. M. Kamper, R. G. J. Westendorp; (Cork) M. B. Murphy (principal investigator), I. J. Perry. Endpoint committee: S. M. Cobbe (chairman), W. J. Jukema, P. W. Macfarlane, A. E. Meinders, D. J. Stott, B. J. Sweeny, C. Twomey.

	FOOTNOTES

 

Abbreviations: CI = confidence interval • OR = odds ratio • PROSPER = Prospective Study of the Elderly at Risk

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantor of integrity of entire study, A.J.M.d.C.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, V.H.t.D., M.A.v.B.; clinical studies, V.H.t.D., D.M.J.v.d.H., M.A.v.B.; statistical analysis, V.H.t.D., A.J.M.d.C., H.M.M.; and manuscript editing, V.H.t.D., D.M.J.v.d.H., A.J.M.d.C., H.M.M., R.G.J.W., G.J.B., M.A.v.B.

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This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: 2431052111v1 243/1/198    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by ten Dam, V. H. Articles by van Buchem, M. A. Search for Related Content PubMed PubMed Citation Articles by ten Dam, V. H. Articles by van Buchem, M. A.