(Stroke. 1995;26:822-828.)
© 1995 American Heart Association, Inc.
Articles |
Cerebral Metabolism of Patients With Stenosis or Occlusion of the Internal Carotid Artery
A 1H-MR Spectroscopic Imaging Study
From the Departments of Radiology (J. van der G., W.P.T.M.M.), Vascular Surgery (R.B., B.C.E.), and Neurology (L.J.K.), University Hospital Utrecht, Netherlands.
Correspondence to Dr J. van der Grond, Department of Radiology, University Hospital Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.
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Abstract |
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Background and Purpose Occlusion or severe stenosis of extracranial vessels may lead to hypoperfusion without overt infarction of brain tissue. The aim of this study was to investigate whether occlusion of the internal carotid artery or stenosis with reduction in diameter of more than 70% leads to altered cerebral metabolism in regions in which no infarcts are visible with magnetic resonance imaging.
Methods We studied 10 control subjects and 55 patients with transient or nondisabling cerebral ischemia (25 patients with severe unilateral stenosis, 15 patients with unilateral occlusion, and 15 patients with bilateral severe stenosis or occlusion of the internal carotid artery). All subjects underwent magnetic resonance imaging and 1H magnetic resonance spectroscopic imaging. Cerebral metabolism was studied by assessing ratios of N-acetyl aspartate (NAA) to choline and to creatine as well as lactate from noninfarcted frontal, mesial, and parietal regions in the centrum semiovale in both hemispheres.
Results All patients with unilateral stenosis or occlusion of the internal carotid artery had decreased NAA/choline ratios in noninfarcted areas in the hemisphere on the side of the stenosis or occlusion and normal NAA/choline ratios in the contralateral hemisphere. Patients with bilateral stenosis or occlusion had decreased NAA/choline ratios in both hemispheres. In one third of all patients, cerebral lactate was found in regions without abnormalities on magnetic resonance imaging.
Conclusions A severe reduction in the diameter of the internal carotid artery affects cerebral metabolism in regions that are not infarcted. These changes are reflected in a decreased NAA/choline ratio and a high incidence of cerebral lactate. These regions are probably at risk for infarction in the long term or if cerebral perfusion decreases further.
Key Words: carotid arteries • cerebral blood flow • cerebral ischemia • magnetic resonance imaging
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Introduction |
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The border-zone regions in the brain, located in the most distal part of the perfusion territory of the main cerebral arteries, receive the lowest cerebral blood flow1 and are the first areas to suffer ischemic damage when blood flow decreases.2 In some patients, leptomeningeal vessels and flow adjustments in the circle of Willis may compensate for reduced blood flow, for instance, as a result of narrowing of the internal carotid artery (ICA). In other patients, however, cerebral perfusion may be so low that this causes the so-called border-zone infarcts. In general, these border-zone territories are located between the supply area of the anterior and the middle cerebral artery, between the middle and the posterior cerebral artery, and between the deep and the superficial supply area of the middle cerebral artery.
Previous 1H magnetic resonance (MR) spectroscopy studies have shown that cerebral infarcts are characterized by decreased N-acetyl aspartate (NAA) and choline concentrations and sometimes by increased lactate concentration.3 4 5 6 7 8 9 10 11 12 13 However, changes of cerebral metabolism in regions that are likely to be hypoperfused, but are not infarcted, have not yet been studied. Because these regions may become irreversibly damaged in the long term, early identification and quantification of metabolic changes in these regions may be important in identifying patients at risk. The goal of this study was to investigate whether occlusion of the ICA or stenosis with reduction in diameter of more than 70% leads to alteration of cerebral metabolism in noninfarcted border-zone regions located in the centrum semiovale.
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Subjects and Methods |
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Patients
Twenty-five patients with unilateral severe stenosis (>70% diameter reduction) of the ICA (16 left side, 9 right side; 21 men, 4 women), 15 patients with unilateral occlusion of the ICA (9 left side, 6 right side; 12 men, 3 women), and 15 patients with bilateral severe stenosis (>70% reduction) or occlusion of the ICA (11 men, 4 women) were studied. The age range was 45 to 78 years (64.0±10.6 years, mean±SD). All patients had suffered transient ischemic attacks or minor ischemic stroke and were examined within 12 weeks after the onset of symptoms. All patients were selected by the departments of vascular surgery or neurology as candidates for carotid endarterectomy or an extracranial-intracranial bypass operation because of transient ischemic attack or minor ischemic stroke and stenosis or occlusion of the ICA, respectively. The distribution of lesions, age, and sex reflected a normal distribution for all patients who were candidates for carotid endarterectomy or an extracranial-intracranial bypass operation between October 1993 and September 1994 in our hospital. Quantification of the carotid artery stenosis was based on arterial digital subtraction angiography.
The control group consisted of 10 subjects (8 men, 2 women). The age range was 29 to 69 years (49.7±13.9 years, mean±SD). 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). Study protocols were approved by the human research committee.
Magnetic Resonance Imaging and Magnetic Resonance Spectroscopic
Imaging
The MRI and MR spectroscopic imaging (MRSI) studies were
performed using a Philips Gyroscan S15 whole-body system operating at
1.5 T. First, proton MR images were obtained: 7 sagittal
T1-weighted scout slices (slice thickness, 5 mm; 1-mm slice
gap; repetition time [TR], 450 milliseconds; echo time [TE], 30
milliseconds) and 14 transaxial T2-weighted slices (slice
thickness, 7 mm; 1.6-mm slice gap; TR, 2000 milliseconds; TE, 50 and
100 milliseconds).
After MRI, the volume of interest (VOI) for 1H-MRSI was chosen from the transaxial images. For each subject, a 15-mm-thick transverse slice was selected through the centrum semiovale. The anterior-posterior and left-right dimensions of the VOI were chosen such that regions containing subcutaneous lipid were excluded and were typically 110 mm and 90 mm in anterior-posterior and left-right directions, respectively. This was followed by determination of the 90° pulse length. 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 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 with selective inversion of the water resonance with an adiabatic inversion pulse, followed by a double spin-echo point resolved spectroscopy sequence14 15 for VOI localization at the zero crossing of water.16 Gradient phase encoding was applied in two dimensions. Phase-encoding steps (16x16) were used over a field of view of 200x200 mm, resulting in an in-plane spatial resolution of 12.5 mm and a nominal voxel size of 2.34 mL. For each phase-encoding step, two averages with a TR of 2000 milliseconds, a TE of 272 milliseconds, 512 time-domain data points, and 1000-Hz spectral width were used. The total procedure including patient preparation, MRI, and MRSI lasted approximately 40 minutes.
After acquisition, MRSI data were transferred to a SUN IPX workstation for further processing. Free induction decays were zero-filled to 1024 data points. In the time domain, gaussian multiplication of 5 Hz was used, followed by exponential multiplication of -4 Hz (line broadening). After Fourier transformation in spectral and spatial dimensions, two-dimensional MR spectroscopic images were created. Individual metabolite images were generated by spectral integration over individual resonances. Individual peak intensities and spectroscopic images were calculated from modulus spectra without additional baseline correction. In the reconstruction of the spectroscopic images, the integration boundaries were selected interactively on the basis of visual inspection of the frequency domain spectra. Because of very good B0 homogeneity over the whole VOI, no additional correction method was needed to correct for possible B0 inhomogeneities. Metabolite maps were interpolated to a 128x128 matrix and were scaled individually. The display software (SUNSPEC1, Philips Medical Systems) provided simultaneous display of the MRI and spectroscopic images. 1H-MR spectra were selected by mouse control of a cursor on T2-weighted MR images from regions without gray and/or white matter hyperintensities on MRI and from areas away from the borders of the VOI to avoid lipid contamination and chemical shift artifacts. Metabolites were determined by their chemical shift17 : total choline at 3.22 ppm, total creatine at 3.05 ppm, NAA at 2.01 ppm, and lactate at 1.33 ppm. NAA, choline, and creatine were quantified by measurement of peak height (in all individual subjects, all peak shapes were approximately similar). Because we were unable to calculate absolute metabolic concentrations, relative metabolic concentrations are expressed as the ratios between peak intensities. To distinguish lactate resonances from lipid resonances, lactate was defined as a resonance at 1.33 ppm with a signal-to-noise ratio larger than 2, with a clearly identifiable 7-Hz J-coupling. Furthermore, no additional resonances at 0.9 ppm (-CH3 resonance from lipids) should be present. Lactate was quantified as present or absent. In each individual, six spectra were chosen in the centrum semiovale. In each hemisphere, one spectrum was selected in the frontal region, one in the mesial region, and one in the parietal region. All selected regions contained primarily white matter. All spectra were selected at least 2.5 cm from white matter hyperintensities and at least 2.5 cm from each other to avoid signal cross-contamination.
Statistical Analysis
For statistical analysis, repeated-measures ANOVA was used
to compare metabolite ratios by groups (hemispheres) and by location
within the groups. The groups (n=7) were defined as (1) normal control
subjects and the symptomatic and asymptomatic hemispheres of patients
with (2) unilateral stenosis of the ICA, (3) unilateral occlusion of
the ICA, and (4) bilateral stenosis/occlusion of the ICA. Locations in
the normal control group (n=6) were defined as frontal, mesial, and
parietal regions in both hemispheres in the centrum semiovale. In the
patient groups, locations (n=3) were defined as frontal, mesial, and
parietal regions in one (symptomatic or asymptomatic) hemisphere.
Analysis of differences in metabolite ratios was performed using the
Bonferroni t method (Dunn's multiple-comparison procedure).
All data are expressed as mean±SD; P<.05 was considered
statistically significant.
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Results |
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Fig 1
shows an MRSI data set of a patient with
occlusion of the right ICA. Fig 2 shows two
1H-MR spectra from voxels that were selected from the same
patient shown in Fig 1. Although no infarcts were seen on MRI in this
patient, a lactate spot was observed between the supply area of the
right middle cerebral artery and the right posterior cerebral
artery.
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ANOVA by location in the control subjects (a total of six locations, three in each hemisphere) showed that, in white matter regions in the centrum semiovale, there were no significant regional differences in the NAA/choline ratio or in the NAA/creatine ratio. ANOVA by location in the other six subgroups (three locations in one hemisphere) also showed no significant differences for the NAA/choline and NAA/creatine ratios within one hemisphere. For this reason, metabolite ratios are expressed as the mean of the frontal, mesial, and parietal regions in both hemispheres in the control subjects and as the mean of these regions in one hemisphere (symptomatic or asymptomatic) in the three patient groups. No correlation was found between spectral alterations and clinical symptoms (transient ischemic attack, reversible ischemic neurological deficit, or stroke) or previous occurrences of infarction in the same hemisphere. Although the mean age of the control subjects (49.7 years) was significantly lower (P<.05) than that of all patients (64.0 years), no correlation was found between spectral alterations and age in the control group or in the symptomatic and asymptomatic hemispheres of the patient groups.
Ratios of N-Acetyl Aspartate to Choline and
Creatine
There was a statistically significant difference between groups
for NAA/choline (F6,113=16.54, P<.001) but not
for NAA/creatine (F6,113=3.48, P>.05). Table 1 summarizes all metabolite ratios, showing significant
differences between the NAA/choline ratios in control subjects and the
symptomatic hemisphere of all three patient groups (P<.001)
and between the NAA/choline ratios in control subjects and the
asymptomatic hemisphere of patients with bilateral stenosis or
occlusion of the ICA (P<.005).
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In Fig 3 the individual NAA/choline ratios of all three
patient groups and control subjects are plotted, showing a significant
difference between the symptomatic and asymptomatic hemisphere for
patients with unilateral stenosis and for patients with unilateral
occlusion of the ICA (P<.01 and P<.005,
respectively). Because a decreased NAA/choline ratio may be caused by a
decreased NAA concentration or by an increased choline concentration,
we calculated the left/right ratio of the absolute intensities of NAA
and choline in control subjects and the symptomatic/asymptomatic ratio
of NAA and choline in patients with unilateral stenosis or occlusion of
the ICA. The left/right ratio of NAA in control subjects ranged from
1.23 to 0.85 (mean, 1.03), and the left/right ratio of choline ranged
from 1.25 to 0.93 (mean, 1.04), showing that the sensitivity of the
head coil for NAA and choline is homogeneous in the volume of interest.
This is important because in most of the patients the symptomatic
hemisphere was the left hemisphere. The left/right ratio of NAA and
choline in control subjects and the symptomatic/asymptomatic asymmetry
in NAA and choline of the patients are plotted in Fig 4.
This shows that the symptomatic/asymptomatic ratio for choline is
significantly (P<.05) increased compared with the
left/right ratio in the control group, indicating increased choline in
the symptomatic hemisphere. These differences were not found for
NAA.
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indicates patient ratios for the hemisphere on the side of the
stenosis or occlusion (symptomatic side); 
, ratios for the
contralateral hemisphere; OS, occlusion/stenosis. The shaded area
represents the NAA/choline ratio for the volunteers
(mean±2xSD). **P <.01, ***P<.005, symptomatic
hemisphere compared with asymptomatic hemisphere.
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Lactate and Cerebral Infarcts
Table 2 shows the number of patients with cerebral
infarcts located outside the measured areas and the number of patients
in whom lactate was found in noninfarcted regions. There was no obvious
relationship between the presence of infarction in the symptomatic
hemisphere and the presence of lactate in the noninfarcted posterior
border zone on that same side. Patients with bilateral arterial lesions
more often showed evidence of lactate than those with unilateral
stenosis or occlusion, but this difference was not statistically
significant. Four patients with lactate in the symptomatic hemisphere
also had lactate in the asymptomatic hemisphere: one with unilateral
stenosis and three with bilateral obstruction. Lactate was not
present in any of the control subjects. Patients with cerebral
lactate in the symptomatic hemisphere had a significantly
(P<.05) decreased NAA/choline ratio in that hemisphere
compared with the symptomatic hemisphere of patients
without cerebral lactate (2.05±0.53 and 2.46±0.53,
respectively).
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Discussion |
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The most important finding of this study is that patients with severe unilateral stenosis or with unilateral occlusion of the ICA, who have suffered transient or minor permanent ischemic attacks, have decreased NAA/choline ratios due to an increase of choline in noninfarcted brain tissue on the side of the stenosis or occlusion of the ICA. Patients with severe bilateral stenosis or occlusion of the ICA have decreased NAA/choline ratios in both hemispheres compared with control subjects. Cerebral lactate was present in normal-appearing white matter in the symptomatic hemisphere in 33% of all patients.
The presence of lactate and the decrease in the NAA/choline ratio are typical changes associated with cerebral infarction, but there are some important differences between the metabolic changes seen in cerebral infarction and the metabolic changes seen in our study. Brain infarction results in a marked decrease of cellular density: dead neurons and dead glial cells are removed by macrophages, while edema, astrocytes, and new glial cells partially fill the infarcted regions, resulting in a large decrease in NAA, a decrease in choline, and an increase in lactate.3 4 5 6 7 8 9 10 11 12 13 In the present study, a decreased NAA/choline ratio was also observed. However, this was caused mainly by an increase in choline, whereas the NAA concentration remained unchanged. Nevertheless, the high incidence of cerebral lactate in the symptomatic hemisphere of our patients combined with the presence of carotid lesions suggest that the changes in choline are probably caused by ischemic changes. The presence of cerebral lactate and the relatively low NAA/choline ratios in the symptomatic hemisphere are probably not directly related to each other, but the finding of a correlation may indicate what our patients have in common: ie, cerebral damage, probably caused by hypoperfusion.
The observed metabolic changes in the symptomatic hemisphere of patients with carotid lesions may have been caused by changes in T1 and T2 relaxation times rather than by metabolic changes. This is not likely, however, since no significant differences were found in T1 and T2 relaxation times for choline, creatine, and NAA between infarcted regions and control regions.18 19 Spectra obtained in brain infarcts and in normal tissue with the same acquisition parameters are directly comparable with respect to relative signal intensities, as well as intensities scaled with internal or external standards.18 Furthermore, in our study all spectra were obtained from regions containing normal-appearing white matter and not containing edema. Therefore, it is unlikely that an increase in choline in the symptomatic hemisphere is due to changes in relaxation parameters rather than to changes in concentration.
Although there were no significant differences in the NAA/choline ratio in the asymptomatic hemisphere of patients with unilateral carotid lesions compared with control subjects, the mean NAA/choline ratio in the asymptomatic hemisphere was slightly lower. In addition to pathological causes, a decrease in NAA/choline ratio in the asymptomatic hemisphere of patients with unilateral carotid lesions could also be caused by an effect of aging, since our control subjects were significantly younger than the patients. However these age-related changes are likely to be small, since studies have shown that the mean NAA/choline ratio in white matter regions is not significantly lower in elderly control subjects than in younger control subjects.20 21 Furthermore, no trend of decreasing NAA/choline with age was found in any of the groups in our study.
Increased choline concentrations in cerebral infarcts or in border-zone regions that are not infarcted have not been described previously, although a single case report describes an increase of choline in acute stroke.22 There are several explanations for increased choline in low-perfusion areas. In the brain, choline is involved in two important pathways: in the phospholipid biosynthesis in all brain cells23 24 and in the synthesis of acetylcholine in cholinergic neurons.24 However, increased choline may also be caused by phospholipid breakdown25 or acetylcholine breakdown. From our data it is not clear which process causes increased cerebral choline in patients with carotid lesions.
It has been shown that in the synthesis of acetylcholine the choline concentration is rate limiting24 26 ; therefore, increased choline is related to increased acetylcholine synthesis. However, because the acetylcholine output is reported to be decreased in focal ischemia,27 increased choline must have another origin. This latter study27 also showed that in focal ischemia, increased choline is not caused by the breakdown of acetylcholine. Acetylcholine itself is stored in membranous vesicles, where it is likely to be invisible to MRSI because of immobilization of the molecule.28 Hence, changes in choline are probably not related to changes in acetylcholine metabolism. Because the most prominent contributions in cerebral "choline" come from phosphorylated cholines,29 changes in phospholipid metabolism may be the cause of the observed changes in cerebral choline in hypoperfused areas. It has been shown that in extreme ischemia large amounts of free phosphatidylcholine are the result of membrane degradation and are the main source of free choline.30 Increased phospholipid breakdown and/or reduced phospholipid biosynthesis are probably the main causes of increased cerebral choline. However, from our data it is not clear to what extent the membranes are affected and whether there is any accumulation of cholines due to reduced cerebral blood flow.
In contrast to the changes in cerebral choline, no changes in NAA were observed. NAA (plus N-acetyl-aspartyl-glutamate) is the most prominent resonance in the water-suppressed proton spectrum of the normal human brain. NAA occurs only in the brain and is generally present in a low concentration at birth, rising to higher levels during development. It is synthesized from aspartate and acetyl-SCoA, but its primary function remains as yet uncertain. It may form part of the intracellular anion pool, a reservoir of acetyl groups, or a source of N-blocked end groups for synthesis into special proteins. In the brain its concentration is higher in gray than in white matter,31 32 and it is mainly located in axons.32 33 NAA is almost absent in glial tumors.34 NAA has been shown to be present only in cultured neurons and not in other cell cultures, except for oligodendrocyte precursor cells,35 and almost completely disappears after injection of neurotoxin.36 These observations suggest that NAA is present mainly in neurons. Our results show that in hypoperfused regions that are not infarcted the NAA concentration is not decreased, indicating that the neuron is probably still intact and functioning.
The creatine resonance in proton MRSI consists of free creatine plus phosphocreatine. Phosphocreatine serves as storage for high-energy phosphates and buffers the ATP concentration in the cytosol. This energy process is regulated by the creatine kinase reaction, in which the enzyme creatine kinase regulates the equilibrium between creatine and phosphorylated creatine. Because the observed creatine resonance in MRSI represents creatine plus phosphocreatine, an equilibrium shift of the creatine kinase reaction does not alter the amount of "total creatine" observed in 1H-MRSI. The regional concentration of total creatine in the cerebrum has been found to be higher in cortical gray matter than in white matter.31 37 38 In the centrum semiovale, no regional differences in NAA/creatine ratio were found.39 In cerebral infarcts, however, the concentration of creatine plus phosphocreatine is reduced.5 7 9 10 11 In our study, no reduction in the NAA/creatine ratio was found in the symptomatic hemisphere in any of the patient groups, indicating that the cerebral energy balance was probably undisturbed.
One third of our patients had elevated lactate in regions that were not infarcted; the metabolic role of lactate is not yet completely understood. Previous studies of human stroke with 1H-MRSI have shown that lactate is present in the acute stage of infarction and may decrease slowly over the following 6 months or longer.5 9 11 12 22 In patients with severe stenosis or occlusion of the ICA, infarcted tissue is still perfused at a low level.40 41 42 Although this regional perfusion is low, it is probably sufficient to accommodate the metabolic demands, since positron emission tomography studies have shown luxury perfusion in chronic infarcted regions.43 44 45 In these chronic infarcted regions, lactate is produced continuously from blood glucose.46 It has also been found that in the subacute and chronic stages of infarction, lactate is associated with the presence of large numbers of macrophages, which infiltrate 3 days after the onset of infarction,13 suggesting that brain macrophages are a major source of elevated brain lactate signals in chronic infarction. However, at present it remains unclear whether lactate in cerebral infarction is produced consistently by anaerobic glycolysis or by infiltrating inflammatory and phagocytic cells. Because we selected regions outside cerebral infarcts and infarcts were observed in only 9 of the 18 patients with lactate, it is very likely that lactate is produced by anaerobe glycolysis caused by hypoperfusion in these regions rather than by infiltrating inflammatory and phagocytic cells. The regions with lactate may be at particular risk for cerebral infarction if perfusion decreases further.47 48 49 On the other hand, the presence of lactate was not correlated with previous occurrences of infarction in the same hemisphere. The explanation for this paradox may be that thromboembolism also continues to be an important cause of infarction in poorly perfused hemispheres or that misery perfusion is unusually distributed within a single hemisphere.
Conclusion
In conclusion, the results of this study show that severe
reduction in diameter of the ICA affects cerebral metabolism in regions
that are not infarcted. These changes are reflected in a decreased
NAA/choline ratio and a high incidence of cerebral lactate. These
metabolic changes are probably caused by hypoperfusion. In addition,
the regions showing a decreased NAA/choline ratio and cerebral lactate
are probably at risk for infarction in the long term if cerebral
perfusion decreases further.
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Acknowledgments |
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This study was supported by the Dutch Heart Foundation grants Dg4012, 900-574-020, and 900-537-063.
Received November 22, 1994; revision received January 26, 1995; accepted February 17, 1995.
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