(Stroke. 1995;26:1007-1013.)
© 1995 American Heart Association, Inc.
Articles |
Continuing Ischemic Damage After Acute Middle Cerebral Artery Infarction in Humans Demonstrated by Short-Echo Proton Spectroscopy
Presented in part at the Second Meeting of the Society of Magnetic Resonance, San Francisco, Calif, August 6-12, 1994, and published in abstract form in Proc Soc Magn Reson. 1994;1:188.
From the Divisions of Clinical Neuroscience (D.E.S., M.M.B.) and Biochemistry (F.A.H., A. van den B., M.A.M., J.R.G.), St George's Hospital Medical School, London, UK.
Correspondence to Dr Dawn E. Saunders, Division of Clinical Neuroscience, St George's Medical School, Cranmer Terr, Tooting, London SW 17 ORE, UK.
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Abstract |
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Background and Purpose Proton MR spectroscopy is a noninvasive method of monitoring in vivo metabolite concentration changes over time. The aim of this work was to study the ischemic penumbra in humans by measuring the metabolic changes that occur after a middle cerebral artery territory infarction.
Methods Diagnostic MRI and short–echo time MR spectroscopy were performed on a 1.5-T system. Localized proton MR spectroscopy was performed within the area of cerebral infarction and in a homologous area of the contralateral hemisphere. The residual water resonance in the spectra was removed with the use of the Hankel Lanczos singular value decomposition method, after which peak area estimates were obtained by means of the variable projection time domain fitting analysis. The unsuppressed water signal was used as an internal concentration standard. Ten patients with acute middle cerebral artery infarction were studied within 28 hours of stroke onset and followed up for a period of up to 3 months.
Results Significant changes were seen in the initial spectra from the infarct compared with the contralateral spectra. Lactate, a marker of anaerobic metabolism, was present within the infarct but not detected in the contralateral hemisphere. N-Acetyl aspartate, a neuronal marker, and total creatine were significantly reduced. The initial choline signal, arising from choline-containing compounds within the cell and cell membrane, remained unchanged in the infarct core compared with the contralateral hemisphere. Further reductions in N-acetyl aspartate and total creatine concentrations occurred within the first week. A fall in the lactate concentration was seen within the infarct core during the first 7 to 10 days. Similar reductions in the choline concentration were observed during this period.
Conclusions The demonstration of the continuing loss of cerebral metabolites within an infarct region suggests that further cell loss occurs up to 10 days after infarction. The continuing loss of neurons may represent continued ischemic damage after middle cerebral artery infarction.
Key Words: spectroscopy, nuclear magnetic resonance • cerebral infarction • metabolism
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Stroke is an important cause of morbidity and mortality in the Western world. At present there are no proven drug treatments for acute stroke, although agents such as N-methyl-D-aspartate antagonists and thrombolytics are currently being assessed in clinical trials. The rationale for using such agents, given after the onset of stroke, assumes that at least some of the neurons within the area of ischemia are potentially viable but will die if not salvaged within a few hours of infarction. This potentially viable tissue has been referred to as the ischemic penumbra.
The original concept of the ischemic penumbra arose from studies in the baboon model of stroke, which demonstrated that moderate reductions in cerebral blood flow (CBF) abolished the electrical function in the brain without loss of membrane integrity.1 The recovery of evoked potentials in a region of suboptimal blood flow led to the hypothesis of the ischemic penumbra.2 There is very little evidence for the ischemic penumbra in humans. Positron emission tomography (PET) studies have demonstrated regions of mismatch between CBF and oxygen utilization in stroke patients, but reversibility of these changes has not been demonstrated.3 However, PET studies of blood flow and metabolism rely on delivery of 15O to cells and therefore have limited applicability to the study of anaerobic metabolism or changes that occur at very low blood flow. 133Xe measurements of CBF have demonstrated a region of reduced flow after cerebral infarction that is substantially larger than the defect seen by CT,4 although again reversible changes have not been identified. We have therefore used MR spectroscopy (MRS) to study the metabolic correlates of the ischemic penumbra in humans. MRS is a noninvasive technique that allows longitudinal studies of intracellular metabolites after cerebral ischemia.
Previous proton MRS studies in humans have shown that after acute cerebral infarction, lactate5 6 7 8 9 10 11 produced by anaerobically respiring cells appears, while N-acetyl aspartate (NAA), a neuronal marker, and total creatine/phosphocreatine (Cr/PCr) are reduced6 7 8 9 10 11 within the infarct region compared with the contralateral hemisphere. Most previous studies6 7 8 9 10 have used long–echo time (TE, 136 or 272 ms) spectra, which only contain signals from NAA, Cr/PCr, choline-containing compounds (Cho), and lactate. Quantitation of these spectra to determine metabolite concentrations requires either that T2 relaxation times of the individual metabolites be assumed or the acquisition of an additional spectrum from the contralateral hemisphere to provide an internal standard. Proton MRS at a short TE (30 ms) has the advantages of negligible T2-weighting of these metabolite peaks, an improved signal-to-noise ratio, and the detection of additional metabolites with short T2 relaxation times, such as mobile lipids, proteins, myoinositol, glucose, glutamate, and glutamine. A disadvantage has been the difficulty of analyzing spectra with many overlapping peaks that are superimposed on a broad background signal. Recent improvements in localization techniques and methods of spectral analysis have allowed short-TE spectroscopy data to be acquired and analyzed. Methods for reliably quantitating metabolites in normal subjects, with the use of water as an internal concentration standard,12 13 14 15 have now been developed. We have used these techniques to determine metabolite concentrations in patients with acute (5 to 28 hours from onset; mean, 19.5 hours) middle cerebral artery (MCA) territory infarction and to follow the metabolite changes during the next 12 weeks. This is the first longitudinal short-TE study in stroke patients and the first study to attempt to quantitate metabolite concentrations in cerebral infarcts with the use of contralateral water as an internal standard. Part of this study was presented to the Society of Magnetic Resonance and published as an abstract.16
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Subjects and Methods |
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Ten patients (mean age, 63 years; age range, 42 to 90 years; 2 women, 8 men) with acute cortical MCA territory infarction were studied within 28 hours (range, 5 to 28 hours; mean, 19.5 hours) of onset of neurological deficit during an 8-month period. The presumed cause of infarction was embolic in 7 patients: 3 patients were found to have carotid stenosis, and 4 patients had associated atrial fibrillation. The cause was not identified in 3 patients, but no patients had suffered a hypotensive episode before the event. No patient had a previous episode of cerebral infarction. Patients were followed up when possible at 3 days and 1, 2, 3, 6, and 12 weeks. Data collected between days 7 and 10 have been grouped together for analysis. Four patients died within 1 week, 1 patient died after 2 weeks, and 1 after 6 weeks. Contralateral data were acquired on at least one occasion from 7 of the 10 patients studied. To assess reproducibility of the technique in a single patient, five spectra were collected from 1 patient on five separate occasions during a 4-month period. The study was approved by the local district ethics committee.
Both MRI and MRS were carried out on a whole-body 1.5-T MRI system
(Signa, GE) with the use of a standard quadrature head coil. Proton
density (repetition time [TR], 3500 ms; TE, 19 ms),
T1-weighted (TR, 600 ms; TE, 16 ms), and
T2-weighted (TR, 3500 ms; TE, 95 ms) images were acquired
with the fast spin-echo technique for diagnostic purposes. A volume of
4 to 8 cm3 was selected for MRS within the center of the
infarct from the T2-weighted images. The same voxel was
selected at follow-up by matching anatomic landmarks. An anatomically
identical voxel of equal size to the infarct voxel was selected from
the normal contralateral hemisphere (Fig 1
).
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Before MRS data were acquired, the manufacturer's automated shim routine was used to optimize the field homogeneity over a volume that encompassed the intended voxel for spectroscopy. Patients with hemorrhage within the infarct, which prevented adequate shimming (line width >5 Hz), were excluded at this stage. MRS was then implemented with the proton brain examination (PROBE), the manufacturer's automated spectroscopy protocol. This protocol incorporates a stimulated echo-acquisition mode (STEAM)17 18 localization sequence with a TE of 30 ms, TR of 2020 ms, and mixing time of 13.7 ms and also performs automated optimization of water suppression and localized shimming over the voxel. PROBE acquires 32 transients of the water signal and then 256 water-suppressed transients for the metabolite spectrum.
Resonance peaks of the spectra were assigned as follows: (1) Cr/PCr methylene singlet at 3.94 ppm, (2) myoinositol at 3.56 ppm, (3) Cho at 3.22 ppm, (4) Cr/PCr methyl singlet at 3.03 ppm, (5) NAA methyl singlet at 2.01 ppm, (6) lactate doublet at 1.33 ppm, (7) glutamate and glutamine at 2.1 to 2.45 ppm, and (8) water at 4.7 ppm.19 20 Lipid/macromolecule peaks were assigned at 0.9 and 1.3 ppm.21 The time domain data (the raw free induction decays) were analyzed by means of the variable projection (VARPRO) method.22 Before the VARPRO parameter estimation, the residual water signal was removed with the use of the Hankel Lanczos singular value decomposition technique.23 24 The first eight data points of the free induction decays were excluded from the VARPRO fit to minimize the effects of baseline distortion. VARPRO was implemented assuming that the Cr/PCr, Cho, and NAA metabolite peaks had equivalent line widths, since the overall line width is predominantly determined by shimming. Lactate was fitted by a doublet resonance with identical amplitudes and line widths and 7-Hz line splitting. When necessary, additional broader resonances from lipids/macromolecules were assigned underneath the lactate doublet.
We calculated metabolite concentrations using the water signal as a reference and assuming a water concentration in normal brain of 41.7 mol/L,12 25 which is equivalent to a fractional concentration of 75%. We made corrections for changes in water concentration due to edema by using the water signal acquired from the contralateral hemisphere as the internal standard. No corrections for T1 or T2 relaxation were made (see "Discussion"). Statistical analysis was performed with the use of Student's t tests for comparison of means and paired t tests to observe longitudinal changes.
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Results |
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Reproducibility
The results of collecting five spectra from the contralateral MCA territory of 1 patient on five separate occasions (Table 1
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show excellent reproducibility of metabolite
concentration measurements in noninfarcted brain, with a maximum SD of
10%.
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Initial Metabolite Concentration Changes (Day 1)
Initial mean metabolite concentration differences were calculated
by comparison of the metabolite concentrations obtained from the
spectra acquired from the contralateral hemisphere with the spectra
obtained from the region of MCA infarction (Fig 2). The
concentrations of NAA and Cr/PCr were found to be significantly reduced
in the infarct compared with the contralateral hemisphere. Lactate was
detected at high concentrations in the infarct but not detected in the
contralateral hemisphere. Cho was not significantly different in the
infarct region compared with the contralateral hemisphere. The mean
values are summarized in Table 2.
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Quantitation of the myoinositol peak was found to be unreliable because of contributions from underlying metabolites. Identification of the glutamine and glutamate resonances was limited by their low signal-to-noise ratio in the spectra acquired from the infarct, and quantitation has not yet been attempted.
Metabolite Concentration Changes From Day 1 to Day 10
Longitudinal changes in the concentrations of NAA, Cr/PCr, Cho,
and lactate in the infarct region, from day 1 to 3 months after
infarction, from the 7 surviving patients are shown in Fig 3. The remaining 3 patients died before a second
examination could be performed. The concentration of NAA in the infarct
fell in 6 of the 7 patients between day 1 and days 7 to 10. In the
seventh patient, the concentration of NAA increased a small amount
during the same period. The mean infarct NAA concentration at days 7 to
10 fell significantly compared with day 1. The concentration of Cr/PCr
within the infarct fell in all patients during the same period. The
concentration of Cho increased in 5 patients and decreased in 2
patients between the initial examination and days 7 to 10. The mean
concentration of Cho at these two times was not altered significantly.
The concentrations of lactate fell in 6 of the 7 patients within the
first week, and in the remaining patient the concentration of lactate
increased by a small amount. The mean decrease in lactate concentration
during the first 7 to 10 days was not significant. The mean metabolite
concentrations at days 1 and 7-10 are shown in Table 3.
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Metabolite Concentration Changes From Day 7 to 3 Months
In the period from 7 days to 3 months, the most marked change was
the significant elevation of Cho in all 5 surviving patients studied.
The Cho concentration was elevated by 14 days and peaked at 3 weeks in
2 patients and 6 weeks in 3 patients. The peak concentrations were
above the concentration of Cho in the contralateral hemisphere (mean
contralateral Cho concentration, 2.1±0.3 mmol/L; mean peak infarct Cho
concentration, 3.1±0.6 mmol/L; P<.005) (Fig 3
). A partial
recovery in the concentration of Cr/PCr was seen in 4 patients at 6
weeks and 3 months. A partial recovery of the reduction of NAA was seen
in only 2 patients, and although the volume of infarction in these
patients was greater than the voxel size, the thickness of the infarct
was slightly less than that of the voxel. The increase in NAA is
probably due to the inclusion of normal brain within the voxel.
Lipid/Macromolecule Resonances
Small resonances at 0.9 and 1.3 ppm (Fig 2, peaks 7 and 8) were
identified in the contralateral hemisphere of 6 of the 7 patients
studied. Such resonances have previously been assigned to
lipid21 but more recently are thought to arise from
macromolecules such as proteins.26 27 28 We have also
identified these resonances in healthy volunteers. In 3 patients we
identified a resonance at 1.4 ppm (Fig 2, peak 6), which corresponds to
a macromolecule peak identified in animal work.26 28
Increases of the resonances at 0.9 and 1.3 ppm were visible in the
infarct region from as early as 16 hours from stroke onset (Fig 4). Larger increases were seen at 3 days, and further
increases were seen up to 3 weeks after infarct. From 3 weeks to 3
months these resonances decreased in amplitude.
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Discussion |
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This study has clearly demonstrated a reduction of the concentration of NAA (a neuronal marker) and Cr/PCr and the appearance of lactate (a marker of anaerobic metabolism) in the region of cerebral infarction within 28 hours after an acute stroke. The most striking new finding is that the concentrations of NAA and Cr/PCr continued to fall after the initial measurement (day 1) for the first 7 to 10 days after infarction. This study also showed an increase of the lipid/macromolecule resonances (Figs 2
and 4), which persisted for 3
weeks after MCA territory infarction and subsequently fell.
We were able to quantify lactate concentrations by using the VARPRO
method and short-TE spectra to distinguish lactate from the underlying
macromolecule peaks (Fig 2). Because these peaks occur under the
lactate peak and can interfere with the accurate quantitation of
lactate, the identification of these peaks and the ability to
distinguish them from lactate is important in quantitation. The
immediate presence of lactate in the center of the infarct after an
acute stroke, as well as the subsequent fall in concentration of
lactate, is in accordance with long-TE studies.5 6 7 8 9 10 11 In the
first 2 to 3 days lactate production is likely to reflect
anaerobic metabolism in surviving neurons or glia, but
subsequently lactate is thought to be produced by macrophages that
migrate to the site of ischemia,29 where they
engulf neuronal tissue.30 The extent of the contribution
of lactate production from macrophages is unknown, and our findings of
the gradual reduction of lactate production may represent a
fall in the number of surviving neurons or glia. Animal models of
cerebral ischemia confirm an immediate increase of cerebral
lactate before a significant infiltration of brain leukocytes can
occur.31 32 Spectroscopic imaging studies in humans after
stroke have detected lactate in a region larger than the final area of
infarction, suggesting that either lactate is produced in surrounding
tissue or it diffuses through the brain, potentially causing further
neuronal damage.33 Animal studies have indicated that high
levels of lactate in the acute stages of the ischemic process
correlate with a worse clinical outcome,34 35 but our data
were unable to demonstrate this. The detection of lactate, however,
does not necessarily suggest that infarction will occur, particularly
if blood flow can be restored. Animal studies of acute ischemia
have shown rapid and reversible increases in lactate levels on
induction of ischemia by means of arterial
occlusion.36 Further studies of stroke patients very early
after onset may provide valuable information about the pathophysiology
of ischemia and potential reversibility of ischemic
damage.
NAA is found almost exclusively in neurons in the human brain,37 38 where it has been shown to be produced in the mitochondria.39 It has also been found in the oligodendrocyte type II astrocyte progenitor cells in rats,40 but where these cells have been identified in humans they have been found to represent only 2% to 3% of the glial population.41 Although NAA is present at the highest level of any amino acid in the brain except glutamate, its function is unknown. The observed reduction of NAA in human stroke is consistent with work carried out in animals that demonstrates an initial rapid decrease of NAA followed by a subsequent further decline.36 Other longitudinal studies in humans demonstrated similar reductions in NAA.7 8 9 10 42 One study was unable to demonstrate a significant reduction of NAA within the first week of stroke onset because the initial study was undertaken within 60 hours of onset, often after a greater than 50% reduction in NAA had already occurred.11 The fall in NAA concentration cannot be explained simply by an increase in edema because we have corrected for changes in the concentration of water within the infarct. It has been suggested that NAA is actively degraded by enzymes within the injured neurons in the first few days or hours after infarction.6 This remains a possibility, but it would appear unlikely that enzymes would remain active for up to 7 to 10 days within an ischemic neuron.
Cr/PCr is found in both neurons and glial cells40 and acts as a phosphate transport system and energy buffer within the cell. The initial reduction in Cr/PCr and further reduction at 7 to 10 days are larger than the error introduced by possible changes in the T2 relaxation time. Neurons are known to be more sensitive to ischemia than glial cells,29 and this is supported by our observation that NAA concentration is more significantly reduced within 28 hours from onset compared with Cr/PCr. In normal brain the Cho peak consists predominantly of glycerolphosphocholine and phosphocholine; both compounds are involved in membrane synthesis and degradation.43 44 Cho is also a precursor and degradation product of acetylcholine, an important neurotransmitter. We have found a variable early change in Cho concentration but a subsequent rise from day 7 to 3 months. Animal studies have demonstrated an elevation in tissue Cho after a reduction in CBF but have not shown a change in tissue acetylcholine, suggesting that spectroscopic changes in Cho levels do not result from changes in acetylcholine concentrations.45 Enhanced Cho production after experimental ischemia has been found to be limited to brain tissue fractions containing macrophages46 and may reflect membrane degradation after cell lysis. The variability of the initial changes in Cho concentration in the acute stroke period in this study are in accordance with other human studies.8 10 Some studies have demonstrated only increases in Cho concentration,9 whereas others report a decrease.47
We observed a partial recovery of Cr/PCr concentration in 4 patients and NAA concentration in 2 patients. The percent increase in Cr/PCr was greater than the increase in NAA, indicating that despite partial volume effects, this represented a true increase in Cr/PCr, which has not previously been reported in stroke. The observed increase in Cho and Cr/PCr supports the hypothesis that this represents the migration of glial cells into the infarct during repair (gliosis), where they contribute to the Cho and Cr/PCr signals, but, as nonneuronal tissue, not to the NAA signal. These spectroscopic changes have also been reported in the hippocampus of epilepsy patients who were subsequently found to have pathological changes of gliosis.48 Other spectroscopy studies have reported a reversible reduction of NAA in both acute multiple sclerosis lesions49 50 51 and cerebral infarction.52 It has been suggested that the function of the mitochondria is reversibly impaired during inflammation in acute multiple sclerosis lesions, resulting in the reversible reduction of the production of NAA within the damaged neuron.50 Since it is known that neurons do not regenerate, the increase in the NAA peak in a small number of our patients is most likely due to a combination of effects: partial volume effects, contributions from underlying macromolecules,26 27 and inaccuracy in analysis of low signal-to-noise ratio data. The differentiation of the adult oligodendrocyte type II progenitor cell41 (known to contain NAA in rats40 ) into glial cells may explain very small increases in NAA concentration in chronic infarction. However, because they only constitute 1% to 2% of the brain cell population, their presence is unlikely to explain all of the increase we observed.
In accordance with work carried out at short TE in normal
volunteers,50 we observed peaks at 0.9 and 1.3 ppm in the
contralateral hemisphere, as well as at 1.45 ppm in 3 patients (Fig 2).
Increases in these peaks have been reported in stroke6 53
and demyelination.50 51 This is the first report of
changes in these resonance peaks during 3 months after stroke. The 0.9-
and 1.3-ppm resonances have previously been assigned to the methylene
and methyl groups of lipid, respectively,21 and have been
shown to appear in myeloma cells after the addition of lipid droplets
into the cytoplasm.54 More recent work in animal models
has shown that these resonances arise from mobile
proteins26 28 and correlate with peaks found in
humans.27 The significance of the appearances of these
peaks is as yet unknown and may only represent increased MRS
visibility of cell membrane lipids after cell breakdown. However, the
assignment of these signals will influence the interpretation of proton
spectra obtained from the cerebral cortex.
Quantitation methods in which water is used as an internal standard
have become accepted in measurements of metabolites in the normal
brain.12 13 14 15 Using water as an internal standard, we
obtained metabolite concentrations in the contralateral hemisphere of
our stroke patients consistent with results obtained from normal
volunteers.12 13 14 15 The direct comparison of metabolite
concentrations calculated from spectra acquired from two different
regions of the coil requires that the head coil sensitivity is constant
over these regions. We have shown, by performing experiments on a
phantom containing a solution of metabolites treated with 0.5 mmol/L of
gadolinium diethylenetriamine penta-acetic acid, that the maximum
difference in the calculated metabolite concentration attributable to
magnetic field variation was only 3.7%, thereby allowing direct
comparison of spectra from the infarct and contralateral sides (data
not shown). Repeated spectroscopy examinations in the contralateral
hemisphere demonstrate that measurements of the metabolite
concentrations are highly reproducible (Table 1). The results
demonstrate that for the three metabolites quantitated, the error
estimate calculated by the VARPRO analysis and the SD due to
experimental error are of the same magnitude. Three main factors will
introduce errors into the quantitation of metabolite changes within a
region of infarction. First, alterations in the chemical environment of
the lesion could alter the relaxation times of metabolites and water,
thereby affecting the signal intensity and quantitation. In normal
brain, with the TR and TE used in this study, the correction factors
for water and metabolites are nearly equal and therefore cancel out.
T1 relaxation times of metabolites have been reported to
remain unchanged in the infarct region,55 56 and
T2 relaxation times have been shown to remain within the
normal range55 and to both increase42 and
decrease by up to 50%.56 Even a 50% reduction in
metabolite T2 will only reduce the signal by an additional
5%. We calculated that the largest error introduced into the
quantitation will be due to changes in the T2 of water,
which we found to be lengthened in the chronic stages (264±122 ms,
n=3) compared with normal brain (90±3 ms, n=3). Second, edema within
the infarct will result in an increase in water signal. By using the
water signal from the contralateral signal, we eliminated the error
produced by both the increase in water concentration and lengthening of
the T2 relaxation time of water within the infarct. Third,
the edema will cause the reduction of either normal or infarcted brain
within the selected voxel, resulting in a small apparent reduction in
metabolite concentration; we have not corrected for this factor.
However, the maximum theoretical increase in water concentration is
30%, and the metabolite concentration changes that we observed are
much greater.
In conclusion, the demonstration by MRS of the continuing loss of cerebral metabolites within an infarct region suggests that further neuronal loss occurs up to 7 to 10 days after MCA infarction. These findings are consistent with the hypothesis of cell loss within the ischemic penumbra and lend further hope to the idea that appropriate therapeutic intervention after the onset of stroke could reverse these changes and improve outcome. The observed increase in Cr/PCr and Cho is consistent with the pathology of gliosis, which occurs as part of the repair process within the infarct. In the future, this method may determine whether drugs such as N-methyl-D-aspartate antagonists have an effect on both the spread of ischemic cell damage and the resulting inflammation and repair.
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Acknowledgments |
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This study was supported by the Stroke Association (England). Franklyn A. Howe, Aad van den Boogaart, and John R. Griffiths were supported by the Cancer Research Campaign (UK). We would like to thank C. Heron, M. Graves, S. Powell, E. Scurr, and S. Nyak for their assistance in this project.
Received November 29, 1994; revision received March 8, 1995; accepted March 8, 1995.
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