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(Stroke. 1996;27:2026-2032.)
© 1996 American Heart Association, Inc.

Articles

Flow-Related Anaerobic Metabolic Changes in Patients With Severe Stenosis of the Internal Carotid Artery

J. van der Grond, PhD; B.C. Eikelboom, MD, PhD W.P.Th.M. Mali, MD, PhD

the Departments of Radiology (J. van der G., W.P.Th.M.M.) and Vascular Surgery (B.C.E.), University Hospital Utrecht (Netherlands).

Correspondence to Dr J. van der Grond, Department of Radiology, University Hospital Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands. E-mail j.vandergrond@rrn.azu.nl.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose We sought to investigate whether the combination of blood flow measurements in the major cerebral arteries and measurements of cerebral metabolism can provide new insight into the hemodynamic effect of carotid lesions in patients with severe stenosis (>70% reduction in diameter) of the internal carotid artery (ICA).

Methods Fifty-six patients with unilateral severe stenosis of the ICA and 14 control subjects underwent MR imaging, ¹H MR spectroscopy, and MR angiography. Anaerobic metabolic changes were studied by assessing N-acetyl aspartate/choline and lactate/N-acetyl aspartate ratios in the symptomatic and asymptomatic hemispheres. Quantitative flow was measured in the common carotid arteries (CCAs), the ICAs, the basilar artery, and the middle cerebral arteries (MCAs).

Results Blood flow was significantly decreased in the CCA, ICA, and MCA on the ipsilateral side compared with the contralateral side. Flow in the basilar artery was increased, whereas flow in the contralateral MCA was decreased compared with control subjects. We found a significant correlation between anaerobic metabolic changes and the reduction in blood flow in the CCA, ICA, and MCA on the ipsilateral side.

Conclusions This study shows that cerebral metabolism is less impaired in patients with relatively high flow in the major cerebral arteries on the ipsilateral side than in patients with relatively low flow on that side. The combination of MR spectroscopy and MR angiography can be of additional value in the understanding of cerebral hemodynamics and metabolism in patients with vascular disorders.

Key Words: carotid arteries • cerebral blood flow • cerebral ischemia • magnetic resonance imaging

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients with severe stenosis (>70% reduction in diameter) or occlusion of the ICA who have suffered from transient or minor neurological deficit often have diminished cerebral perfusion.^{1 2 3 4 5 6 7 8 9 10 11} Despite increasingly sophisticated methods for assessing cerebral perfusion or collateral circulation, the importance of hemodynamic factors in the pathogenesis of changes in cerebral perfusion is still not clear. The CBF in patients with severe carotid lesions has been studied extensively with dynamic susceptibility contrast MRI,^{1 2 3 4} SPECT,^{5 6 7 8 10 12 13 14 15 16 17} PET,^{12 15 18 19} and ¹³³Xe radionuclide CT.^{9 14} Recently, Powers¹² reviewed the concept that CBF is determined by the ratio of regional CPP to regional CVR (rCPP/rCVR). A decrease in the CPP has little effect on the CBF since the CVR is lowered by vasodilation.¹² This phenomenon is known as autoregulation. However, when the capacity for compensatory vasodilation has been exceeded, autoregulation fails. When regional CPP continues to fall, the OEF increases to maintain CMRO₂. When the OEF has reached its maximum, CMRO₂ starts to decline.¹² In this concept, the primary determinant of CPP is the adequacy of collateral pathways and the vasodilatory capacity rather than the degree of carotid stenosis, which correlates poorly with the CBF.¹² In symptomatic patients with severe lesions in the ICA, a decreased CBF in the ipsilateral hemisphere is not uncommon.^{5 6 7 8 9 10 11} In these patients, the limits of autoregulation have probably been exceeded. However, it is not clear whether this reduction in CBF was caused by reduced arterial blood supply or by reduced metabolic demands. Nevertheless, the finding of anaerobic metabolic changes (increased lactate/NAA and decreased NAA/choline ratios)^{20 21} in the so-called border-zone regions in the brain^{22 23} suggests that the reduction in CBF may be caused by reduced arterial pressure rather than by reduced metabolic demands. Therefore, the collateral capacity is insufficient to keep the CBF at a level that is enough to maintain normal cellular metabolism in some patients. When blood flow through the ipsilateral ICA (if it is not completely occluded) further decreases in these patients, it is likely that this will have a direct effect on CBF and probably also on cerebral metabolism. The relationship between arterial blood flow and the CBF is poorly investigated and is not straightforward. A correlation between blood flow and CBF²⁴ and an improved CBF after revascularization^{9 18 25} were found. However, in another study this correlation was not found.²⁶ At present, little is known about the possible correlation between arterial ipsilateral flow and changes in cerebral metabolism.

The purpose of this study is to investigate whether the combination of blood flow measurements in the major cerebral arteries and measurements of cerebral metabolism can provide new insight into the hemodynamic effect of carotid lesions in patients with severe stenosis of the ICA.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Fifty-six patients with unilateral severe stenosis (>70% reduction in diameter) of the ICA (31 left side, 25 right side; 37 men, 19 women) were studied. The age range was 45 to 78 years (mean±SD, 64.0±10.6 years). All patients had suffered transient ischemic attacks or minor ischemic stroke and were investigated within 12 weeks (mean±SD, 5.7±4.5 weeks) after the onset of symptoms. All patients were selected by the departments of vascular surgery or neurology as being candidates for carotid endarterectomy because of transient ischemic attack or minor ischemic stroke and severe stenosis of the ICA. The distribution of lesions, age, and sex reflected a normal distribution for all patients who were candidates for carotid endarterectomy between February 1995 and February 1996 in our hospital. All patients underwent duplex sonography and intra-arterial digital subtraction angiography. However, quantification of the carotid artery stenosis was only based on intra-arterial digital subtraction angiography.

The control group consisted of 14 subjects (9 men, 5 women; age range, 49 to 81 years; mean±SD, 60.3±11.3 years). None of the control subjects had suffered a cerebral event, and MRI of the brain was normal in all of them (no white or gray matter signal abnormalities on T₁- and T₂-weighted MRI). On MRA all control subjects showed normal carotid bifurcations without any sign of atherosclerotic lesions in the CCAs, ICAs, and ECAs. Study protocols were approved by the Human Research Committee of our hospital.

MRI, MRS, and MRA
MRI, MRS, and MRA studies were performed on a Philips Gyroscan ACS-NT15 whole-body system operating at 1.5 T. For MRI we made 19 sagittal T₁-weighted scout slices (slice thickness, 4 mm; 0.6-mm slice gap; TR, 545 ms; TE, 15 ms) and 15 transaxial T₂-weighted slices (slice thickness, 7 mm; 1.5-mm slice gap; TR, 2000 ms; TE, 20 and 100 ms).

After MRI, the VOI for ¹H MRS was chosen from the transaxial images. MRS was performed with a single-volume technique. In each subject two single VOIs were selected in the centrum semiovale: one in the symptomatic hemisphere and one in the asymptomatic hemisphere. The anterior-posterior and left-right dimensions of the VOI were chosen such that regions containing subcutaneous lipid were excluded and were typically 70 mm and 35 mm in anterior-posterior and left-right directions. In all subjects the caudal-cranial dimension of the VOI was 15 mm. All volumes were positioned at least 2 cm away from gray/white matter hyperintensities. If this was not possible, the dimensions of the VOI were changed. If infarcts were present on MRI, care was taken to maintain the 2-cm distance between lesions and the selected VOIs. In each MR examination the dimensions of the selected VOIs were kept equal in the symptomatic and asymptomatic hemispheres. All VOIs contained primarily white matter. After selection of a VOI, the 90° pulse length was determined. To minimize eddy currents and to maximize the water-echo signal, localized spectroscopy was first performed without water suppression for adjustment of the gradients ("gradient tuning"). This was followed by localized automatic shimming of the VOI, resulting typically in a water-resonance line width of 6 Hz (full width at half height) or less. Water suppression was performed by selective excitation (60-Hz bandwidth), followed by a spoiler gradient. A double spin-echo point-resolved spectroscopy sequence was used for VOI localization.^{27 28} Each measurement was performed with a TR of 2000 ms, a TE of 136 ms, 2048 time domain data points, 4000-Hz spectral width, and 64 averages. After zero-filling to 4096 data points, gaussian multiplication of 5 Hz, exponential multiplication of -4 Hz (line broadening), Fourier transformation, and linear baseline correction, total choline, total creatine, NAA (referenced at 2.01 ppm), and lactate peaks were identified by their chemical shifts.²⁹ Since we were unable to calculate absolute metabolic concentrations, concentrations are expressed as the ratio between peak intensities (NAA/choline, NAA/creatine, and lactate/NAA ratios). To distinguish lactate resonances from lipid resonances at a TE of 136 ms, lactate was defined as an inverted resonance at 1.33 ppm with a signal-to-noise ratio larger than 2 and a clear identifiable 7-Hz J-coupling.

After MRI and MRS, quantitative flow measurements were performed in the CCAs, ICAs, basilar artery, and MCAs. All subjects underwent the same MRA protocol. First, two nontriggered two-dimensional phase-contrast MRA survey scans in coronal and sagittal orientations were performed to visualize the CCAs, carotid bifurcations, ICAs, ECAs, and the circle of Willis. In the sagittal orientation we used the following: 2 slices; slice thickness, 50 mm; -5 mm slice gap (overcontiguous slices); field of view, 250x250 mm; TR, 14 ms; TE, 7 ms; flip angle, 20°; velocity sensitivity, 30 cm/s; and 4 averages. In the coronal orientation we used a single slice (thickness, 60 mm) with the same parameters. Thereafter, two two-dimensional phase-contrast single slices for quantitative flow measurement were positioned. One slice was positioned perpendicular to both CCAs and the other slice perpendicular to the C3 segments of the ICAs and to the basilar artery (slice thickness, 5 mm; field of view, 250x250 mm; TR, 16 ms; TE, 9 ms; flip angle, 7.5°; velocity sensitivity, 100 cm/s; and 8 averages). Quantitative flow measurements were performed with previously optimized scan protocols featuring a radio-frequency spoiled gradient echo sequence with full echo sampling.³⁰ These measurements were followed by a three-dimensional time-of-flight MRA measurement of the circle of Willis (50 slices; slice thickness, 0.6 mm; field of view, 100x100 mm; TR, 32 ms; TE, 7 ms; flip angle, 20°; and 2 averages). On the basis of the reconstruction of the circle of Willis in three directions, two two-dimensional phase-contrast single slices were positioned perpendicular to the left and right MCA (slice thickness, 5 mm; field of view, 250x250 mm; TR, 17 ms; TE, 10 ms; flip angle, 8°; velocity sensitivity, 70 cm/s; and 24 averages). The diameters of the anterior cerebral arteries and the posterior cerebral arteries were too small to perform reliable flow measurements. All volume flow data were obtained by integrating across manually drawn regions-of-interest that enclosed the vessel lumen as closely as possible. All images were evaluated by the same reader. Total patient time, including patient handling, was 35 minutes, from which approximately 15 to 20 minutes were used for MRA.

Statistical Analysis
For statistical analysis, repeated measures ANOVA was used to compare metabolic ratios by groups (four groups: symptomatic and asymptomatic hemispheres in patients and left and right hemispheres in control subjects, for a total of six comparisons). ANOVA by groups was also used to compare differences in blood flow of the CCAs, basilar artery, ICAs, and MCAs. Tests for linear correlation between metabolic ratios and blood flow were performed with bivariate Pearson correlation tests. Paired analysis of differences in metabolic ratios and differences in blood flow was performed using the Bonferroni t method (Dunn's multiple-comparison procedure [six comparisons]). All data are expressed as mean±SD. A value of P<.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Fig 1 shows the T₂-weighted MRI of a 64-year-old patient with a severe stenosis of the right ICA. The rectangles represent the left-right and anterior-posterior dimensions of the VOIs in the symptomatic and asymptomatic hemispheres. Fig 2 shows the corresponding ¹H MR spectra. These spectra are representative for all subjects in terms of spectral resolution, baseline flattening, and signal-to-noise ratio. The results of ANOVA by groups for the NAA/choline, NAA/creatine, and lactate/NAA ratios are shown in Table 1. There were no significant differences in metabolic ratios between the left and right hemispheres in control subjects. Therefore, the metabolic ratios for the control subjects represent the mean value of the left and right hemispheres. Lactate was found asymmetrically in none of the control subjects. Table 1 shows that on the symptomatic side the NAA/choline ratio is decreased compared with the asymptomatic side and with healthy control subjects. Lactate was found more frequently on the symptomatic side. We did not find a correlation between neurological symptoms (transient ischemic attack or minor stroke) and metabolic changes or between metabolic changes and the time interval between onset of symptoms and the MR study. For the choline, creatine, and NAA resonances, we also compared the peak intensity (in arbitrary units) between the symptomatic and asymptomatic hemispheres in patients and between the left and right hemispheres in the control subjects. We found an increase of 24±19% for choline, an increase of 3±12% for creatine, and a decrease of 7±6% for NAA on the symptomatic side compared with the asymptomatic side. No metabolic left-right asymmetry was found for the control subjects. Because of differences in scan conditions, comparison of signal intensities between patients and control subjects is not useful.

View larger version (89K): [in this window] [in a new window]   Figure 1. Transversal T2-weighted MRI slice in the centrum semiovale of a 64-year-old man with severe stenosis of the right ICA. The white box within the brain parenchyma indicates the VOI selected for 1H MRS.

View larger version (16K): [in this window] [in a new window]   Figure 2. 1H MR spectra from the two VOI selected from the patient shown in Fig 1. The left spectrum is obtained from the symptomatic hemisphere, whereas the right spectrum is obtained from the homologous contralateral region. The chemical-shift axis in parts per million (PPM) is positioned below each spectrum. Cho indicates choline; Cr, creatine; and Lac, lactate.

View this table: [in this window] [in a new window]   Table 1. Metabolic Ratios for Patients (n=56) for Symptomatic and Asymptomatic Hemispheres and for Control Subjects (n=14)

Table 2 shows the results of the flow measurements in the CCAs, ICAs, basilar artery, and MCAs. ANOVA showed that no flow asymmetries were present in the control group. Therefore, flow measurements of the left and right corresponding arteries in control subjects are grouped. This table shows that on the stenosed side flow is significantly reduced in the CCA, ICA, and MCA compared with the contralateral side and also compared with the control subjects. On the contralateral side flow was increased in the CCA compared with control subjects, whereas flow was decreased in the MCA compared with control subjects. Furthermore, flow in the basilar artery was significantly higher in patients than in control subjects.

View this table: [in this window] [in a new window]   Table 2. Quantitative Flow Data for the CCA, Basilar Artery, ICA, and MCA for Patients (n=56) and Control Subjects (n=14)

Fig 3 shows the relationship between arterial flow in the ipsilateral CCA, ICA, and MCA with the ipsilateral NAA/choline and lactate/NAA ratios, respectively. Table 3 shows the corresponding correlation coefficient and significance. No significant correlation was found between flow in the basilar artery and the NAA/choline or lactate/NAA ratio. In addition, no significant correlation was found between flow and metabolic ratios on the asymptomatic side.

View larger version (27K): [in this window] [in a new window]   Figure 3. Plots of individual flow data in the ipsilateral CCA, ICA, and MCA against the corresponding individual ipsilateral NAA/choline (left) and lactate (Lac)/NAA (right) ratios. Horizontal lines indicate statistically significant correlations. Statistics are shown in Table 3.

View this table: [in this window] [in a new window]   Table 3. Correlation Coefficient (r) and Significance Between Ischemic Metabolic Changes and Flow in the CCA, ICA, and MCA on the Symptomatic Side and the Basilar Artery for Patients With Unilateral Severe Stenosis of the ICA (n=56)

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study demonstrates that patients with severe stenosis of the ICA who suffered transient or minor permanent ischemic attack have a high incidence of cerebral lactate and decreased NAA/choline ratios in the symptomatic hemisphere. Increased lactate is likely to be caused by anaerobic glycolysis,^{31 32 33 34 35} whereas decreased NAA/choline ratios are caused by increased choline (if changes in phospholipid metabolism are assumed) and by decreased NAA as a result of neuronal loss.^{36 37 38 39} Since it was shown in our previous studies that there were no local metabolic differences in the centrum semiovale within one hemisphere in this patient category,^{20 21} we have used a single-volume technique in the present study instead of two-dimensional spectroscopic imaging. This new protocol has a number of advantages compared with our previous protocol. Because of the larger volume studied, a higher signal-to-noise ratio can be obtained. Furthermore, a higher signal-to-noise ratio was also obtained by the use of a relatively short TE of 136 ms compared with 272 ms in our previous study. Both advantages result in a signal-to-noise ratio that is 6 to 10 times higher than in our previous studies. Therefore, relatively smaller metabolic asymmetries and lower concentrations of lactate can be detected. Moreover, the present protocol is much faster. The acquisition time in our present protocol is approximately 4 to 5 minutes, compared with 16 minutes in our previous protocol. Compared with our previous study, we found a higher incidence of lactate and lower NAA/choline and NAA/creatine ratios for patients as well as for control subjects. The finding of a higher frequency of lactate is likely to be caused by the increased signal-to-noise ratio in the present study. Differences in metabolic ratios of the patients and control subjects between this and our previous studies^{20 21} are probably caused by different effects of T₂ on various metabolites because of the shorter TE used. Nevertheless, patient variability and unnoticed changes in patient inclusion criteria may also have small effects on the changes in metabolic ratios.

MRA measurements showed that flow in the CCA, ICA, and MCA was decreased on the stenosed (symptomatic) side compared with the contralateral side. Similar MRA results for flow in the CCA and ICA have been described earlier.^{40 41 42 43} The mean values of flow in our study are comparable to these previous reports.^{40 41 42 43} However, since it is expected that cerebropetal flow is not only dependent on the actual grade of stenosis in the ICA but also on the presence of collateral pathways and the level of vasodilation,¹² it is not useful to compare our data with these studies in detail. Blood flow in our control group was lower than that described by the group of Enzmann et al.⁴⁴ This might be due to age effects, since it has been shown that cerebral blood flow is decreasing with age.⁴⁵ The age range in our study was 49 to 81 years compared with 22 to 38 years in the study of Enzmann et al. More interesting in our study was the finding of increased flow in the basilar artery and decreased flow in both MCAs. The relatively small difference in flow between stenosed and contralateral MCA is likely to be caused by collateral circulation in the circle of Willis, by shunting blood from the asymptomatic side into the symptomatic side via the anterior communicating artery. Additionally, increased flow in the basilar artery was found. It is therefore likely that the symptomatic MCA is also provided by collateral flow via the posterior communicating artery, which is an important collateral pathway.⁴⁶ However, the results from our study do not show whether increased flow in the basilar artery is a result of collateral flow via the posterior communicating artery or via leptomeningeal vessels. Flow in the ECA, which can be calculated from the difference in flow between the CCA and ICA, was lower on the stenosed side than on the contralateral side (133 mL/min versus 199 mL/min). The finding of decreased flow in the "symptomatic" ECA is surprising since it was expected that redistribution of blood flow (eg, via the ophthalmic artery) would cause an increased flow in the symptomatic ECA. We currently do not have a plausible explanation for this finding.

At present, in patients with severe lesions in the ICA, the effect of changes in ipsilateral arterial flow on the CBF is not clear.^{9 18 24 25 26} This study shows that when ipsilateral arterial blood flow is decreased, the NAA/choline ratio is decreased and the lactate/NAA ratio is increased in the ipsilateral hemisphere. Previous findings of decreased ipsilateral CBF in patients with severe stenosis of the ICA^{5 6 7 8 9 10 11} suggest that in some of these patients collateral flow is limited or has already reached a maximum capacity. According to the concept of compensatory response to reduced CPP, it is expected that a persisting decrease in CMRO₂ (as measured with PET) leads to cerebral infarctions.³⁶ Since we selected our VOI outside infarcted regions, the observed metabolite changes in this study probably occurred after CBF was decreased but before the CMRO₂ was decreased. Compared with metabolic changes occurring in infarcted regions,^{31 32 33 34 35} the decreases in NAA/choline and lactate/NAA are relatively small. It is possible that, although the OEF is probably increased to maintain the CMRO₂, small anaerobic changes already have taken place. The results of this study show that the CBF and cerebral metabolism are still coupled at this point. Further decrease in arterial flow will probably increase the OEF but also will increase anaerobic changes as measured with MRS. It should be noted that the metabolic parameters in this study are different from those used in PET studies. Therefore, anaerobic metabolic changes measured with MRS could be originating from other metabolic processes or from cell types other than those studied with PET. In this respect, it would be very interesting to match the results of MRS with the results of PET studies in the same patient population.

In conclusion, the results of this study show that in patients with severe stenosis of the ICA, the patients with relatively high flow in the major cerebral arteries on the ipsilateral side have less compromised cerebral metabolism than the patients with relatively low flow on that side. Therefore, the combination of MRS and MR flow measurements in the major cerebral arteries can be of additional value in the understanding of cerebral hemodynamics and metabolism in patients with vascular disorders. In particular, patients who have the combination of reduced ipsilateral arterial blood flow, low NAA/choline ratios, and increased lactate are probably at risk for infarction in the long term or if cerebral perfusion decreases further.^{36 47 48 49} Compared with SPECT, PET, and xenon techniques, MR measurements are faster, easier, and more available and hence more suitable for potential clinical applications.

	Selected Abbreviations and Acronyms

 

CBF = cerebral blood flow CCA = common carotid artery CMRO2 = cerebral oxygen metabolism CPP = cerebral perfusion pressure CVR = cerebrovascular resistance ECA = external carotid artery ICA = internal carotid artery MCA = middle cerebral artery MRA = magnetic resonance angiography MRS = magnetic resonance spectroscopy NAA = N-acetyl aspartate OEF = oxygen extraction fraction PET = positron emission tomography SPECT = single-photon emission computed tomography TE = echo time TR = repetition time VOI = volume(s) of interest

	Acknowledgments

 
This study was supported by the Heart Foundation of the Netherlands (grant D94-012).

Received March 25, 1996; revision received July 29, 1996; accepted July 30, 1996.

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