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Published online before print November 21, 2007, 10.1148/radiol.2453061932
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(Radiology 2008;246:198-204.)
© RSNA, 2007

Neuroradiology

Effect of Cerebrovascular Risk Factors on Regional Cerebral Blood Flow1

Peter Jan van Laar, MD, Yolanda van der Graaf, MD, PhD, Willem P. T. M. Mali, MD, PhD, Jeroen van der Grond, PhD, and Jeroen Hendrikse, MD, PhD For the SMART Study Group

1 From the Department of Radiology (P.J.v.L., W.P.T.M.M., J.v.d.G., J.H.) and Julius Center for Health Science and Primary Care (Y.v.d.G.), University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands. Received November 13, 2006; revision requested January 17, 2007; revision received January 30; accepted March 16; final version accepted May 9. Address correspondence to P.J.v.L. (e-mail: p.j.vanlaar{at}umcutrecht.nl).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
ADVANCE IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 
Purpose: To prospectively investigate which cerebrovascular risk factors are related to regional cerebral blood flow (rCBF), as measured noninvasively with arterial spin-labeling (ASL) magnetic resonance (MR) imaging, in a large group of patients with symptomatic atherosclerotic disease.

Materials and Methods: Ethics committee approval and informed consent were obtained. One hundred thirty consecutive patients (107 men, 23 women; mean age, 58 years ± 10 [standard deviation]) with symptomatic atherosclerotic disease were included in the study. Cerebrovascular risk factors (body mass index, carotid artery stenosis, diabetes mellitus, hyperhomocysteinemia, hyperlipidemia, hypertension, and smoking) were assessed by means of a questionnaire and physical, ultrasonographic, and laboratory examinations. The control group consisted of 10 subjects (eight men, two women; mean age, 58 years ± 15) without symptomatic atherosclerotic disease. rCBF measurements were performed with ASL MR imaging. The effects of the individual cerebrovascular risk factors on the rCBF were assessed by using linear regression analysis.

Results: Hypertension was significantly associated with higher rCBF (adjusted β = 6.5 mL/min/100 g; 95% confidence interval: 1.4 mL/min/100 g, 11.7 mL/min/100 g). Hyperhomocysteinemia was significantly related to lower rCBF (adjusted β = –7.4 mL/min/100 g; 95% confidence interval: –12.7 mL/min/100 g, –2.1 mL/min/100 g). No significant associations between rCBF and the other cerebrovascular risk factors were found.

Conclusion: In patients with symptomatic atherosclerotic disease, hypertension is related to higher rCBF and hyperhomocysteinemia is related to lower rCBF.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ADVANCE IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 
Aunique aspect of arterial spin-labeling (ASL) magnetic resonance (MR) imaging is that it enables one to study the regional cerebral blood flow (rCBF) noninvasively (1–5). This technique involves the use of magnetically labeled arterial blood as an endogenous tracer to rapidly obtain quantitative measurements of the perfusion in the brain (in milliliters per minute per 100 g of brain tissue). In this respect, ASL MR examinations have been performed in patients with acute stroke (6,7), obstructive carotid artery disease (7–9), brain tumors (10–13), epilepsy (14,15), human immunodeficiency virus (16), and dementia (17,18). ASL perfusion measurements have also been used to evaluate the effectiveness of vascular interventions such as carotid endarterectomy (19,20) and extracranial-intracranial bypass surgery (21).

To our knowledge, no ASL perfusion measurements had been performed in a large group of patients. Such a study would offer the possibility to correlate rCBF with cerebrovascular risk factors. Knowledge about the effects of cerebrovascular risk factors on rCBF could influence the choice of therapeutic intervention in patients with chronic low rCBF.

Thus far, methods to measure rCBF, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), have involved the use of radiation or the administration of intravenous contrast agents (22–25). Consequently, related studies typically involve small sample sizes and thus have limited value in revealing relationships between cerebrovascular risk factors and rCBF. To show these relationships, large patient groups are required. The purpose of our study was to prospectively investigate which cerebrovascular risk factors are related to rCBF, as measured noninvasively with ASL MR imaging, in a large group of patients with symptomatic atherosclerotic disease.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
ADVANCE IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 
Patients and Control Subjects
The ethics committee of our institution approved our study protocol; written informed consent was obtained from all participants. All patients were participants in the Second Manifestations of Arterial Disease (SMART) Study, an ongoing single-center (University Medical Center Utrecht) prospective cohort study that began in September 1996. The SMART Study was ethics committee approved, and written informed consent was obtained from all participants. All eligible patients aged 18–79 years who were newly referred to our institution with risk factors for atherosclerotic disease or symptomatic atherosclerosis were screened for additional risk factors and severity of atherosclerosis. Definitions of the diseases that qualified patients for enrollment in the SMART Study are reported elsewhere (26).

For the current study, the data of 130 consecutive patients (107 men, 23 women; mean age, 58 years ± 10 [standard deviation]) with symptomatic atherosclerosis who were included in the SMART Study between March and September 2003 were used. Patients with contraindications to MR imaging (ie, pacemaker and claustrophobia) were excluded. All patients were assigned to one of four disease categories: cerebrovascular disease, cardiovascular disease, peripheral arterial disease, and abdominal aortic aneurysm. Patients with stroke or transient ischemic attack at study inclusion and patients who reported having a stroke in the past were considered to have cerebrovascular disease. Patients with myocardial infarction and those who had undergone coronary surgery or angioplasty in the past or at study inclusion were considered to have cardiovascular disease. Peripheral arterial disease was defined as intermittent claudication or rest pain at study inclusion or history of vascular surgery or angioplasty. The presence of abdominal aortic aneurysm or a history of previous surgery for it was the criterion for abdominal aortic aneurysm (Table 1). The control group consisted of 10 healthy subjects (eight men, two women; mean age, 58 years ± 15) without symptomatic atherosclerosis or abnormalities at MR imaging and MR angiography of the brain who were matched for age and sex with the patients.


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  		Table 1. Patient Characteristics

 
Cerebrovascular Risk Factors
At study enrollment, the patients' risk factors were assessed by means of an extensive questionnaire and physical, ultrasonographic (US), and laboratory examinations. Smoking history was categorized as current, past, or never smoker. The subjects' height and weight were measured, and the body mass index (in kilograms per square meter) was calculated by dividing the weight by the height squared. Systolic and diastolic blood pressure (in millimeters of mercury) was measured twice, with the patient in the supine position, by using a sphygmomanometer. Hypertension was considered to be present when the mean systolic blood pressure was 160 mm Hg or higher and/or the mean diastolic blood pressure was 95 mm Hg or higher. A fasting venous blood sample was taken to determine glucose, lipid, and homocysteine levels. Diabetes mellitus was defined as a glucose level of 7.0 mmol/L or higher or the reported treatment for diabetes. Hyperlipidemia was defined as a total cholesterol level higher than 5.0 mmol/L, a low-density lipoprotein cholesterol level higher than 3.2 mmol/L, or the reported treatment for elevated cholesterol level. Hyperhomocysteinemia was defined as a total homocysteine level of 16.3 µmol/L or higher in women or 18.8 µmol/L or higher in men. Internal carotid artery stenosis was measured with color Doppler-assisted duplex US. Internal carotid artery stenosis of 70% or greater was defined as a peak systolic velocity of 210 cm/sec or higher. Seventeen patients had internal carotid artery stenosis of 70% or greater. Of these 17 patients, five had bilateral disease and 11 had internal carotid artery occlusion.

MR Image Acquisition and Evaluation
The MR imaging examinations were performed by using a 1.5-T whole-body system (Gyroscan ACS-NT; Philips Medical Systems, Best, the Netherlands). The technique used to perform perfusion ASL MR imaging has been described in detail in previous articles (27,28). Briefly, perfusion imaging was performed by using a turbo transfer insensitive labeling technique, which is based on a pulsed ASL sequence with labeling of the brain-feeding arteries. The perfusion imaging section (thickness, 10 mm) was aligned with the orbitomeatal angle and positioned above the ventricles through the centrum semiovale to include the cortical gray matter flow territory of the middle cerebral artery (Figure). This was done to prevent potential differences in transit delay within the region of interest that can occur when the posterior and anterior circulations simultaneously supply blood to the brain tissue (29). A single perfusion imaging section was used to acquire reproducible measurements and to prevent the potential transit time differences between sections that can occur with the multisection method. The labeling slab (section thickness, 140 mm) was set 10 mm below and parallel to the perfusion imaging section. For image acquisition, a series of 13 35° excitation pulses were applied with increasing delay times from 200 to 2600 msec in constant 200-msec intervals. The pulses were followed by a single-shot gradient echo-planar imaging readout. Other MR imaging parameters were 3000/5.6, 62% partial Fourier acquisition, 240 x 240-mm field of view, 64 x 64 matrix, 3336.7 Hz/pixel bandwidth, 50 signals acquired, and imaging time of 5 minutes. The coefficient of variation of the ASL MR imaging measurements at multiple inversion times was 11% (8).


Figure 1A
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  		Figure a: (a) Sagittal T1-weighted MR image (512/15, 90° flip angle) shows positioning of the ASL slab and the section used for perfusion imaging (3000/5.6 [repetition time msec/echo time msec], 35° flip angle). The large rectangle outlines the labeling section, and the thin rectangle outlines the imaging section. (b) Transverse rCBF map shows locations of the regions of interest (in red). Cerebral blood flow (CBF) scale, in milliliters per minute per 100 g of brain tissue, is on the right.

 

Figure 1B
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  		Figure b: (a) Sagittal T1-weighted MR image (512/15, 90° flip angle) shows positioning of the ASL slab and the section used for perfusion imaging (3000/5.6 [repetition time msec/echo time msec], 35° flip angle). The large rectangle outlines the labeling section, and the thin rectangle outlines the imaging section. (b) Transverse rCBF map shows locations of the regions of interest (in red). Cerebral blood flow (CBF) scale, in milliliters per minute per 100 g of brain tissue, is on the right.

 
The rCBF values were quantified as described previously (28). Regions of interest in the cortical gray matter of the left and right middle cerebral artery flow territories were selected (Figure). One author (P.J.v.L., 5 years experience) selected the middle cerebral artery flow territory in all subjects on the basis of established flow territory templates (30). The region-of-interest sizes in one hemisphere ranged from 7 to 9 cm2. Areas of cortical infarction were excluded from the region of interest on the basis of the ASL MR source image findings. For each subject, bilateral rCBF values were averaged to derive a final rCBF metric. rCBF quantification was performed on the basis of established kinetic perfusion models (31,32). The equilibrium magnetization of blood was estimated by fitting the unlabeled signal in the brain tissue to a saturation-recovery curve. The other parameters were fixed and were obtained from the literature: The longitudinal relaxation rate of tissue was 1.0 sec–1; the longitudinal relaxation rate of blood, 0.71 sec–1; and the brain-blood partition coefficient of water, 0.9 mL/g (33,34).

Statistical Analyses
To test for significant differences in rCBF between the patients assigned to one of the four disease categories and the control subjects, one-way analysis of variance (SPSS 12.0.0; SPSS, Chicago, Ill) was performed. P < .05 was considered to indicate significance. Since the one-way analysis of variance did not reveal significant differences between the groups, no further post hoc tests were performed.

We assessed the effects of the individual cerebrovascular risk factors and the disease categories on the rCBF by using linear regression analysis (SPSS 12.0.0) after evaluating whether the continuous variables were normally distributed. For each factor, we calculated the crude and adjusted (for age and sex) regression coefficients (β), which yielded the slope of the regression that was fit by the model and indicated the increase (positive value) or decrease (negative value) in rCBF, in milliliters per minute per 100 g of brain tissue per unit of the independent variable. For the test results, 95% confidence intervals (CIs), being more informative than P values, were given (35). A 95% CI that did not include the value of 0 had a P value of less than .05.


   RESULTS
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
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IMPLICATIONS FOR PATIENT CARE...
 References
 
No significant differences (P > .05) in rCBF between the different disease categories (Table 2) were found. All continuous variables were normally distributed (Table 3). Both increasing systolic blood pressure and hypertension were associated with higher rCBF. Hyperhomocysteinemia was related to lower rCBF. After adjustment for age and sex, hypertension (adjusted β = 6.5 mL/min/100 g; 95% CI: 1.4 mL/min/100 g, 11.7 mL/min/100 g) and hyperhomocysteinemia (adjusted β = –7.4 mL/min/100 g; 95% CI: –12.7 mL/min/100 g, –2.1 mL/min/100 g) remained significantly associated with rCBF. Additional adjustment for the presence of cerebrovascular disease did not materially alter the associations between rCBF and hypertension (adjusted β = 6.2 mL/min/100 g; 95% CI: 1.0 mL/min/100 g, 11.4 mL/min/100 g) and between rCBF and hyperhomocysteinemia (adjusted β = –7.0 mL/min/100 g; 95% CI: –12.2 mL/min/100 g, –1.6 mL/min/100 g). The use of antihypertensive medication did not affect the relationship between hypertension and rCBF. No significant associations between rCBF and the other cerebrovascular risk factors were found (Table 3).


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  		Table 2. rCBF Values for Patients and Control Subjects

 

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  		Table 3. Linear Regression Coefficients for Relationships between Individual Cerebrovascular Risk Factors and rCBF

 

   DISCUSSION
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
ADVANCE IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 
The most important findings of our study were that in patients with symptomatic atherosclerotic disease, hypertension was associated with higher rCBF and hyperhomocysteinemia was associated with lower rCBF. The relationship between hypertension and rCBF in our study is consistent with the results from a technetium 99m (99mTc) hexamethylpropyleneamine oxime SPECT study (36). In that study, evaluation of the relationship between vascular risk factors and rCBF revealed that the presence of hypertension was associated with higher rCBF. A significant positive association between systolic blood pressure and rCBF was also found in that previous study (36).

In other studies, however, either no significant association (37) or an inverse association (38) between blood pressure and rCBF has been reported. Furthermore, hypertension has been reported to be associated with a global decrease in cerebral blood flow (23). The discrepancies between these results and our study findings can probably be explained by differences in the study populations: In the previous studies (23,37,38), few patients with symptomatic atherosclerotic disease were included. In addition, all of these studies involved the use of xenon 133 inhalation SPECT, which has lower spatial resolution and reliability compared with 99mTc-hexamethylpropyleneamine oxime SPECT and ASL MR imaging (39).

The positive relationship between hypertension and rCBF in patients with atherosclerotic disease in our study suggests that such patients may be susceptible to changes in cerebral perfusion pressure. Our results are compatible with the concept that these patients may have diminished autoregulatory capacity of the cerebral circulation such that the cerebral blood flow is directly dependent on the perfusion pressure (40,41). Autoregulation is mainly a function of the small cerebral arteries and arterioles (40), and it has been suggested that atherosclerosis impairs the contractility of these vessels (42).

The inverse relationship between hyperhomocysteinemia and rCBF in our study is in agreement with the previously reported inverse relationships between hyperhomocysteinemia and both cerebral blood flow and cerebrovascular reactivity in animal experiments and in healthy humans (43,44). Our findings are also in accordance with the increased risk of structural brain changes, such as cerebral infarcts and white matter lesions, in subjects with hyperhomocysteinemia (45). The mechanisms through which hyperhomocysteinemia might cause decreased rCBF are unclear. Hyperhomocysteinemia can promote endothelial dysfunction and injury, which are followed by platelet activation and thrombus formation (46). Another mechanism that could explain the effect of homocysteine on rCBF is the direct neurotoxic effect of homocysteine caused by the activation of the N-methyl-D-aspartate glutamate receptors (47). Excessive stimulation of these receptors is known to mediate focal ischemia in the brain.

Furthermore, although we observed a trend toward lower rCBF values in patients with elevated low-density lipoprotein levels, this relationship was not significant. This finding is consistent with the nonsignificant relationship between reduced cerebral blood flow and elevated cholesterol level in healthy subjects (48). Another study revealed that even long-lasting hypercholesterolemia was not associated with alterations in cerebral blood flow (24).

The rCBF values measured in the control subjects in our study are in agreement with gray matter rCBF values of 66–81 mL/min/100 g, which were measured at multiple inversion times in previously performed ASL examinations (8,49,50). Although ASL rCBF measurements are highly comparable to the rCBF measurements obtained with other techniques (51), ASL is well known to yield slightly overestimated rCBF values in the gray matter owing to the presence of label in the vasculature (49).

Our study had limitations. A general drawback of ASL MR imaging is the intrinsic low signal-to-noise ratio, which is caused by the low amount of labeled arterial blood. Therefore, in our study, 50 pairs of subtracted control and labeled images were acquired to ensure a sufficient signal-to-noise ratio. Since a total imaging time of 5 minutes was needed to acquire these data, proper head fixation was necessary to prevent motion artifacts. ASL MR imaging will benefit substantially from the increased signal-to-noise ratios and longer longitudinal relaxation times achieved with 3.0-T MR imaging systems (52). In patients with severe atherosclerosis, the presence of collateral blood flow may increase the time for transit of the labeled blood to the brain tissue. ASL MR imaging performed at a single inversion time point results in an underestimated rCBF value. Acquiring images at multiple inversion times, as was done in our study, can correct for such rCBF underestimations. In addition to ASL at multiple inversion times, techniques for quantitative imaging of perfusion with use of a single subtraction, or QUIPSS (QUIPSS II and QUIPSS II with thin-section TI1 periodic saturation, or Q2-TIPS), have been developed. These techniques allow one to render ASL relatively insensitive to transit delays by applying saturation pulses to obtain a sharply defined and uniformly shaped bolus profile (53,54).

Continuous ASL is also sensitive to transit times, but because of the steady-state behavior of this sequence, the effect is smaller than that with pulsed ASL. Further improvements in continuous ASL can be achieved by using a predelay of typically 0.9–1.5 seconds between the continuous labeling and the readout, which renders continuous ASL methods almost insensitive to transit time differences (7). Previous PET and SPECT examinations of rCBF in patients with cerebrovascular risk factors have been invasive and time consuming. Unlike ASL MR imaging, most SPECT examinations yield only relative ratios rather than quantitative measurements of perfusion (39). During the past several years, the technical and theoretic foundations of ASL MR imaging have evolved from feasibility studies into practical-use examinations. Future technical improvements may lead to further reduced acquisition times for ASL MR imaging and increased spatial resolution. The ability to obtain rCBF maps by using a noninvasive, widely available modality such as MR imaging may greatly enhance the usefulness of rCBF measurements.

In conclusion, to our knowledge, our study is the first in which the clinical feasibility and usefulness of noninvasive ASL MR imaging perfusion measurements were assessed in a large patient population. Our study results show that in patients with symptomatic atherosclerotic disease, hypertension is related to higher rCBF, possibly because of altered cerebrovascular autoregulatory function. In addition, hyperhomocysteinemia is related to lower rCBF, possibly because of endothelial cell damage and direct neurotoxic effect.


   ADVANCE IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
ADVANCE IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 


   IMPLICATIONS FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
ADVANCE IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
References
 


   ACKNOWLEDGMENTS
 
We gratefully acknowledge the members of the SMART Study Group of University Medical Center Utrecht: From the Julius Center for Health Sciences and Primary Care: A. Algra, MD, PhD; Y. van der Graaf, MD, PhD; D. E. Grobbee, MD, PhD; and G. E. H. M. Rutten, MD, PhD. From the Department of Vascular Medicine: F. L. J. Visseren, MD, PhD. From the Department of Nephrology: P. J. Blankenstijn, MD, PhD. From the Department of Vascular Surgery: F. L. Moll, MD, PhD. From the Department of Neurology: L. J. Kappelle, MD, PhD. From the Department of Radiology: W. P. T. M. Mali, MD, PhD. From the Department of Cardiology: P. A. Doevendans, MD, PhD.


   FOOTNOTES
 

Abbreviations: ASL = arterial spin labeling • CI = confidence interval • rCBF = regional cerebral blood flow • SMART = second manifestations of arterial disease

Guarantors of integrity of entire study, P.J.v.L., J.H.; 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, P.J.v.L.; clinical studies, P.J.v.L., J.v.d.G., J.H.; statistical analysis, P.J.v.L., Y.v.d.G., J.H.; and manuscript editing, all authors

Authors stated no financial relationship to disclose.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
ADVANCE IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 

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