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Proton Magnetic Resonance Spectroscopy of the Motor Cortex in 70 Patients With Amyotrophic Lateral Sclerosis
Christoph Pohl, MD;
Wolfgang Block, PhD;
Jochen Karitzky, MD;
Frank Träber, PhD;
Stephan Schmidt, MD;
Christoph Grothe, MD;
Rolf Lamerichs, PhD;
Hans Schild, MD;
Thomas Klockgether, MD
Arch Neurol. 2001;58:729-735.
ABSTRACT
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Objective To evaluate proton magnetic resonance spectroscopy for detection and
monitoring of upper motoneuron degeneration in patients with amyotrophic lateral
sclerosis.
Methods Seventy patients with amyotrophic lateral sclerosis according to the
El Escorial criteria were compared with 48 healthy control subjects. Single-volume
proton magnetic resonance spectroscopy (echo time, 272 milliseconds; repetition
time, 2000 milliseconds) was performed in both motor cortices for detection
of N-acetylaspartate (NAA), phosphocreatine + creatine
([P]Cr), and choline-containing compounds (Cho) to calculate the metabolite
ratios NAA/Cho, NAA/(P)Cr, and Cho/(P)Cr. In addition, absolute metabolite
concentrations of NAA, (P)Cr, and Cho were obtained in 30 patients and 15
controls with the unsuppressed water signal used as an internal reference.
Results Absolute concentrations of NAA (P<.001)
and (P)Cr (P<.05) were reduced in motor cortices
of patients, whereas Cho concentrations remained unchanged. The NAA/Cho and
NAA/(P)Cr ratios were reduced in all El Escorial subgroups (P<.001). The Cho/(P)Cr ratio was elevated in patients with definite
amyotrophic lateral sclerosis (P<.05). Metabolite
ratio changes corresponded to the lateralization of clinical symptoms and
were weakly correlated with disease duration and disease severity. In follow-up
observations of 16 patients during a mean (±SD) of 12.1 ± 8.7
months, NAA/Cho dropped by 9.1% (P<.01), and Cho/(P)Cr
increased by 7.0% (P<.01). Changes of metabolite
ratios were significantly correlated with progression of disease severity.
Conclusions Measurement of NAA concentrations and NAA/Cho ratios appear to be most
suitable for detection of motor cortex degeneration by single-volume proton
magnetic resonance spectroscopy. Reduced NAA/Cho ratios correspond to aspects
of the clinical presentation and reflect disease progression in follow-up
measurements.
INTRODUCTION
AMYOTROPHIC lateral sclerosis (ALS) is a neurodegenerative disorder
characterized by progressive degeneration of motoneurons in the motor cortex,
brainstem, and spinal cord.1 Whereas lower
motoneuron involvement in ALS is easily detected by electromyography, electrophysiologic
examination of central motor pathways and conventional magnetic resonance
imaging provide only limited information with respect to upper motoneuron
(UMN) degeneration or bulbar involvement.2, 3, 4, 5
Proton magnetic resonance spectroscopy (1H-MRS) has been introduced
as a method to detect and to quantify subtle neurodegenerative changes not
apparent on conventional magnetic resonance imaging. It has been repeatedly
shown that 1H-MRS demonstrates metabolite changes in the motor
cortex and brainstem of patients with ALS.6, 7, 8, 9, 10, 11, 12, 13, 14, 15
Since these changes have been attributed to neuronal loss, 1H-MRS
may be used to detect cortical and bulbar neurodegeneration.
Even more important, 1H-MRS findings may serve as surrogate
markers for ALS disease progression in therapeutic trials.16
However, most 1H-MRS studies in ALS have been performed in a limited
number of patients, and the relationship between spectroscopic findings and
the heterogeneous clinical presentation of the disease is far from clear.
In addition, little is known about long-term changes in 1H-MRS
findings in the course of ALS. To resolve these questions, we conducted a
follow-up and extension of our previously published study15
analyzing single-volume 1H-MRS for the detection and monitoring
of neuronal degeneration in the motor cortex of patients with ALS. Seventy
patients were investigated for up to 2 years and compared with 48 healthy
controls. For better interpretation of 1H-MRS findings, metabolite
ratios and absolute metabolite concentrations were determined.
SUBJECTS AND METHODS
SUBJECTS
Seventy patients with ALS according to the El Escorial criteria17 were recruited from the Department of Neurology at
the University Hospital of Bonn, Bonn, Germany (mean [±SD] age, 55.4
± 12.7 years; 39 men and 31 women). No patient had a history of any
other neurologic disease. At the time of their first 1H-MRS examination,
15 patients were classified as having suspected ALS, 18 patients as possible
ALS, 10 patients as probable ALS, and 27 patients as definite ALS. In 16 patients,
follow-up investigations were performed within 4 to 24 months (3 with suspected
ALS, 3 with possible ALS, 4 with probable ALS, and 6 with definite ALS). Mean
duration of the observation period was 12.1 ± 8.7 months. All but 2
of these patients received riluzole treatment during the whole observation
period. Forty-eight healthy volunteers (aged 51.8 ± 17.6 years; 31
men and 17 women) without history of any neurologic disease served as control
subjects. All patients and control subjects gave informed consent.
Patients underwent physical examination at the time of each 1H-MRS
examination. The following information was obtained for further statistical
analysis: (1) hemisphere dominance for motor functions as determined by handedness;
(2) disease duration in months, defined as the latency between when the patient
first noted weakness subsequently attributed to ALS and the 1H-MRS
examination; (3) disease severity as assessed by the score of Jablecki et
al,18 which encompasses the evaluation of speech,
swallowing, respiration, ambulation, muscle strength, and extremity function
(a high score indicates greater impairment); (4) lateralization of clinical
symptoms with respect to the severity of extremity pareses (asymmetry of clinical
presentation was assumed if there was a minimum of 1 point difference in at
least 1 muscle of the muscle strength subscales of the Jablecki et al score);
and (5) location of disease onset differentiating bulbar- vs limb-onset ALS.
MAGNETIC RESONANCE EXAMINATION
Seventy patients with ALS and 48 controls were investigated by 1H-MRS for determination of relative metabolite concentrations of N-acetylaspartate (NAA), phosphocreatine + creatine ([P]Cr),
and choline-containing compounds (Cho) by means of the NAA/Cho, NAA/(P)Cr,
and Cho/(P)Cr ratios. In 30 patients and 15 controls, absolute metabolite
concentrations of NAA, (P)Cr, and Cho in millimoles per liter of brain tissue
were also determined with the unsuppressed water signal used as an internal
reference. Of the 16 patients undergoing follow-up 1H-MRS investigations,
8 were examined twice, 7 were examined 3 times, and 1 was examined 4 times
(total of 25 follow-ups) to determine relative metabolite concentrations.
The 1H-MRS examiners (W.B. and F.T.) were not aware of clinical
data.
Details of the 1H-MRS protocol for determination of relative
metabolite concentrations are given elsewhere.15
In brief, investigations were performed on 1.5-T whole-body magnetic resonance
systems (Gyroscan S15/ACS II and Gyroscan ACS-NT; Philips Medical Systems,
Best, the Netherlands). A spectroscopic volume of interest (40 x 30
x 25 mm) was placed anterior to the central sulcus in the motor cortex
and subjacent white matter including the primary motor cortex within Brodmann
areas 4 and 6 (Figure 1). The 1H-MR spectra were acquired with a repetition time of 2000 milliseconds,
echo time of 272 milliseconds, and 128 signal averages. Relative metabolite
concentrations for NAA, (P)Cr, and Cho were determined by lorentzian curve
fitting of the corresponding resonance in the frequency spectra. From these
data, the metabolite ratios NAA/Cho, NAA/(P)Cr, and (P)Cr/Cho were determined.
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Figure 1. Sagittal (A), coronal (B), and
transaxial (C) magnetic resonance images demonstrating the localization of
the volume of interest. Proton magnetic resonance spectra were acquired in
a cubic volume of interest of 40 x 30 x 25 mm placed anterior
to the central sulcus and subjacent to the white matter.
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Metabolite ratios were calculated in both hemispheres of all patients
with ALS and 12 healthy controls. Measurements in dominant and nondominant
hemispheres yielded consistent results in these 12 control subjects. We therefore
assumed that 1H-MRS findings were independent of hemisphere lateralization
of motor functions, and measurements in the remaining 36 controls were thus
performed only in the dominant hemisphere. Consequently, data for 140 patient
and 60 control motor cortices were available.
Absolute concentrations of NAA, (P)Cr, and Cho were determined from
spin-echo spectra in the volume of interest described above, with the brain
water signal used as an internal reference.9
For this purpose, an additional acquisition of 1H-MR spectra was
obtained without water suppression, with repetition time and echo time of
3000 and 272 milliseconds, respectively, and averaged over 16 or 32 free induction
decays, yielding NAA/water signal ratios. In the postprocessing of these unsuppressed
spectra, polynomial baseline subtraction removed the broad lorentzian slopes
of the water resonance curve underlying the much smaller metabolite peaks.
To determine NAA/water concentration ratios by extrapolation to repetition
time of  and echo time of 0 milliseconds, T2 relaxation times and relative
fractions of cerebrospinal fluid and tissue water within the volume of interest
water were obtained by a biexponential fit to a series of unsuppressed spin-echo
spectra with echo times of 30, 70, 136, 272, 400, 700, and 1000 milliseconds
and 4 signal averages each. Errors caused by variations in the assumed T1
values of mixed gray-white matter (800 milliseconds) and cerebrospinal fluid
(3000 milliseconds) were minimized by a long repetition time of 6000 milliseconds.
Metabolite T1 and T2 values were not measured on an individual basis, but
were taken from our comparative analysis in healthy volunteers and patients
with ALS published previously.15 Metabolite
concentrations were expressed as millimoles per liter of brain tissue by a
mixed gray-white matter water content of 72%, corresponding to 40 mol/L.
Metabolite concentration measurements were performed in both hemispheres
of 30 patients with ALS and 5 healthy controls. Measurements in dominant and
nondominant hemispheres yielded consistent results in these 5 controls. We
therefore assumed that 1H-MRS findings were independent of hemisphere
lateralization of motor functions, and measurements in the remaining 10 controls
were thus performed only in the dominant hemisphere. Consequently, data from
60 ALS and 20 control motor cortices were available.
STATISTICAL ANALYSIS
Clinical characteristics and metabolite concentrations of patients and
controls were compared by means of  2 tests or t test for unpaired samples. Clinical characteristics and metabolite
ratios in different El Escorial subgroups were compared by 1-way analysis
of variance (ANOVA) with subsequent post hoc Tukey tests including the covariates
age, sex, and hemisphere dominance for motor functions. Sensitivity and specificity
analyses were performed for a range of NAA/Cho and NAA/(P)Cr ratios and NAA
concentrations to generate receiver operating characteristic curves.19 The relationship between clinical variables and metabolite
ratios was tested by unpaired t test (lateralization
of clinical symptoms, bulbar vs limb onset of ALS) and Pearson correlation
(disease duration, severity). Changes of metabolite ratios between the first
and the last 1H-MRS investigation in patients undergoing follow-up
measurements were tested for significant differences by paired t test. The relationship between metabolite ratio changes and progress
of disease severity was evaluated by Pearson correlation for all follow-up
investigations. P values less than .05 were considered
statistically significant. Calculations were performed with the SPSS software
package (SPSS Inc, Chicago, Ill). Data are presented as mean ± SD,
unless otherwise indicated.
RESULTS
PATIENT CHARACTERISTICS
The ALS and control groups were well matched for age (P = .21) and sex (P = .65) (Table 1). Disease duration of patients with ALS at the initial 1H-MRS investigation was 22.4 ± 20.3 months; disease severity
was 10.9 ± 5.3 according to the Jablecki et al score.
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Table 1. Group Characteristics*
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When patients with ALS were analyzed according to El Escorial subgroups,
there were no significant differences between patients and controls with respect
to age (P = .35) and sex (P
= .41) (Table 1). There were no
significant differences of disease duration among different El Escorial subgroups.
In contrast, disease severity was significantly different, with most severe
clinical presentation in definite ALS and less severe presentation in possible
ALS (ANOVA: disease duration, P = .12; disease severity, P<.001).
GROUP COMPARISON OF 1H-MRS MEASUREMENTS
Group comparison of patients and control subjects showed a significant
reduction in NAA concentrations (P<.001) and (P)Cr
concentrations (P = .04), whereas Cho concentrations
remained unchanged (P = .85) (Table 2).
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Table 2. Metabolite Concentration at First Proton Magnetic Resonance
Spectroscopy*
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When ALS subgroups according to El Escorial criteria were compared with
healthy control subjects, NAA/Cho and NAA/(P)Cr ratios were significantly
reduced in all El Escorial groups (ANOVA: P<.001),
whereas the Cho/(P)Cr ratio was significantly elevated only in the subgroup
with definite ALS (ANOVA: P = .03) (Table 3). Group differences were not influenced by the covariates
age, sex, or hemisphere dominance of motor functions.
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Table 3. Metabolite Ratios at First Proton Magnetic Resonance Spectroscopy*
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Receiver operating characteristic curves illustrated that the NAA/(P)Cho
ratio and the NAA concentration had a greater accuracy in the detection of
UMN abnormality than the NAA/(P)Cr ratio (Figure 2).
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Figure 2. Receiver operating characteristic
curves to determine sensitivity and specificity of various proton magnetic
resonance spectroscopy surrogate markers for upper motoneuron degeneration.
Note that the ratio of N-acetylaspartate (NAA) to
choline-containing compounds (Cho) and the NAA concentration have a greater
accuracy in the detection of upper motoneuron abnormality than the ratio of
NAA to phosphocreatine + creatine ([P]Cr).
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CLINICAL FINDINGS AND 1H-MRS MEASUREMENTS
In patients with asymmetric clinical presentation (n = 48), NAA/Cho
ratios were significantly lower in the motor cortex contralateral to the clinically
predominantly affected side (P = .04). There were
no such side differences for the NAA/(P)Cr ratio (P
= .07) or the Cho/(P)Cr ratio (P = .29).
No significant differences were observed between patients with bulbar
onset (n = 24) vs limb onset (NAA/Cho, P = .96; NAA/(P)Cr, P = .91; Cho/(P)Cr, P = .82).
There was a weak, but significant, correlation between disease duration
and reduced NAA/Cho ratios (r = -0.16; P = .03; Figure 3) as well as elevated Cho/(P)Cr ratios (r = 0.18; P = .02). No significant correlation was detected between
disease duration and NAA/(P)Cr ratios (P = .73).
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Figure 3. Scatterplots of the ratio of N-acetylaspartate (NAA) to choline-containing compounds
(Cho) vs disease duration (A) and of the NAA/Cho ratio vs disease severity
(B). The continuous line represents the correlation graph. Note severely decreased
NAA/Cho ratios in early disease and in less affected patients, including those
with suspected or possible amyotrophic lateral sclerosis (ALS) according to
El Escorial criteria.
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There was a weak, but significant, correlation between disease severity
and reduced NAA/Cho ratios (r = -0.24; P = .001; Figure 3) as well as elevated Cho/(P)Cr ratios (r = 0.20; P = .04-08). No significant correlation was detected between
disease severity and NAA/(P)Cr ratios (P = .28).
FOLLOW-UP MEASUREMENTS
In patients with ALS undergoing follow-up 1H-MRS measurements
(n = 16), NAA/Cho ratio decreased by 9% (P = .003)
and NAA/(P)Cr ratio by 2% (P = .49), whereas Cho/(P)Cr
ratio increased by 7% (P = .006) between the first
and the most recent measurement (mean observation period, 12.1 ± 8.7
months)(Table 4). In individual
patients, different patterns of NAA/Cho ratio changes emerged with respect
to onset and slope of NAA/Cho deterioration (Figure 4). In late disease stages, no further decrease in NAA/Cho
ratios was observed at values of about 1.7. Of 3 patients without clinical
signs of UMN involvement at first 1H-MRS measurement, 2 exhibited
a marked decrease of NAA/Cho and presented clinical signs of UMN dysfunction
at follow-up investigations, whereas 1 had stable 1H-MRS measurements
and no clinical UMN involvement during a period of 6 months.
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Table 4. Change of Metabolite During Follow-up*
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Figure 4. Follow-up data of the ratios of N-acetylaspartate (NAA) to choline-containing compounds
(Cho) in 16 patients with amyotrophic lateral sclerosis (first vs last measurement).
A, Measurements in the dominant motor cortex. B, Measurements obtained in
the nondominant motor cortex. Note that, in individual patients, different
patterns of NAA/Cho ratio changes emerged with respect to onset and slope
of NAA/Cho deterioration. In late disease stages, no further decrease of NAA/Cho
ratios was observed at values of about 1.7.
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There was a significant correlation between the decline of the NAA/Cho
ratio and the progress of disease severity as indicated by an increase in
the Jablecki et al score (r = 0.55; P<.001; Figure 5). Moreover,
there was a significant correlation between the progress of disease severity
and an increase of the Cho/(P)Cr ratio (r = 0.52; P<.001), whereas the NAA/(P)Cr change over time did
not correlate with disease progress (P = .07).
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Figure 5. Scatterplot of the decrease of
the ratio of N-acetylaspartate (NAA) to choline-containing
compounds (Cho) (motor cortex measurements of both hemispheres) in a total
of 25 follow-up investigations of patients with amyotrophic lateral sclerosis
vs increase of disease severity. The continuous line represents the correlation
graph.
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COMMENT
This study is an expansion of our previous work15
on motor cortex 1H-MRS in ALS. We confirmed our previous results
of reduced NAA/Cho and NAA/(P)Cr ratios. In addition, we observed reduced
absolute NAA and (P)Cr concentrations by quantitative measurements and found
that NAA/(P)Cho ratios as well as NAA concentrations have a greater accuracy
in the detection of UMN abnormality than NAA/(P)Cr ratios.
Most 1H-MRS studies in ALS have demonstrated that either
NAA concentrations6, 9 or NAA/(P)Cr,7, 11, 12 NAA/Cho,10, 11
and NAA/([P]Cr + Cho)14 ratios are reduced
in the motor cortex of patients with ALS. Since NAA is present only in neurons,20 it has been concluded that these metabolite changes
indicate loss or dysfunction of UMN. The present observation that metabolite
changes are more severe on the hemisphere contralateral to the clinically
predominantly affected extremities further supports that 1H-MRS
truly reflects neurodegeneration in ALS. There is a substantial debate on
the interpretation of data obtained by different 1H-MRS protocols.
By theory, absolute quantification of NAA appears to be more attractive than
relative quantification of metabolite ratios, since data are robust against
changes of metabolites serving as denominators. However, because the clinical
application of quantitative 1H-MRS is time consuming and still
suffers from technical limitations, measurements of relative metabolite concentrations
are still in common use. In this context, the NAA/(P)Cr ratio was considered
the most valuable surrogate marker, since the (P)Cr peak was thought to remain
unaffected by the neurodegenerative disease process.7, 12
However, we and others observed a stronger decrease of the NAA/Cho than the
NAA/(P)Cr ratio, suggesting that either Cho levels are increased or (P)Cr
levels are reduced in the ALS motor cortex.11, 15
In the present study, we used 1H-MRS with absolute quantification
to interpret the changes in metabolite ratios. We found that (P)Cr concentrations
were indeed reduced, whereas Cho concentrations were unchanged in the ALS
motor cortex. We conclude that NAA/Cho appears to be more valuable than NAA/(P)Cr
to characterize motor cortex degeneration in ALS, since the latter metabolite
ratio is confounded by a parallel decrease of (P)Cr levels, leading to a decrease
in sensitivity and specificity for identification of UMN degeneration.
The mechanisms leading to a decrease in (P)Cr concentrations in cortical
areas of patients with ALS are unclear. Possibly as a result of the high variability
of quantitative (P)Cr measurements, reduction of (P)Cr concentrations has
not been observed in 2 smaller spectroscopic investigations of the ALS motor
cortex.6, 9 Alternatively, reduction
of (P)Cr might be due to the larger spectroscopic volume of interest used
in the present study, including subcortical apart from cortical regions. However,
a parallel decrease of NAA and (P)Cr concentrations without changes of Cho
concentrations has also been observed in the cortex of patients with Alzheimer
disease, suggesting that cortical (P)Cr reduction might indeed be found in
various neurodegenerative disorders.21 The
(P)Cr peak detected by 1H-MRS consists of signals derived from
creatine and phosphocreatine located in astrocytes, oligodendrocytes, and
neurons.22 Therefore, changes in (P)Cr concentrations
detected by 1H-MRS are not specific for neuronal damage and do
not show whether the equilibrium between creatine and phosphocreatine is altered
or whether the concentrations of both compounds are decreased to the same
degree. Therefore, decreased (P)Cr concentrations might be nonspecifically
linked to neuronal death. Alternatively, it might be speculated that decreased
(P)Cr indicates a disturbed cellular energy buffering and transport system
in degenerating UMNs. This would be consistent with actual hypotheses that
adenosine triphosphate depletion and oxidative damage might play a role in
the pathogenesis of ALS.23 In particular, a
recent experimental study reported that orally administered creatine extended
survival of transgenic ALS mice and had a neuroprotective effect because of
a reduction of oxidative damage in spinal and cortical motoneurons.24
To evaluate motor cortex 1H-MRS for diagnostic purposes,
we compared measurements in different ALS subgroups according to the El Escorial
criteria. We found the most prominent reduction of NAA/Cho in patients with
definite ALS, indicating that more widespread clinical involvement is associated
with pronounced motor cortex degeneration. However, there was also a substantial
decrease in NAA/Cho ratios in patients without an established diagnosis of
probable or definite ALS. Although the diagnostic value of 1H-MRS
is limited by the overlap of metabolite ratios in the motor cortex of healthy
control subjects and patients with ALS, these findings indicate that the method
may increase diagnostic certainty in some patients with missing clinical UMN
signs.7, 12 Because 1H-MRS
is a well-tolerated procedure that can be easily performed along with conventional
magnetic resonance imaging, it might add to the spectrum of procedures used
in the diagnosis of motoneuron disorders.
Unlike a previous study,25 this study
did not find an association of altered NAA ratios with bulbar vs limb onset
of the disease. Therefore, our data do not point to a more severe UMN involvement
or different pathologic process in the bulbar group. Because of considerable
variation of the metabolite ratios in early disease stages, we found only
weak correlations of 1H-MRS findings with duration and severity
of ALS symptoms. These findings reflect a marked interindividual variability
of UMN involvement in the course of ALS, as known from pathological examinations.26 Moreover, they suggest that the extent of motor cortex
degeneration is not of critical importance for the overall clinical impairment
in patients with ALS. Motor cortex 1H-MRS findings are correlated
with limb function, as previously shown by other investigators.14, 25
Apart from diagnostic issues, 1H-MRS might be used for monitoring
of UMN degeneration in patients with ALS.16
Herein we report 1H-MRS findings in 16 patients with ALS followed
up longitudinally for an average period of 1 year. We found a significant
decline in NAA/Cho ratios along with a significant increase in Cho/(P)Cr ratios.
By contrast, decrease in NAA/(P)Cr ratios failed to reach significance, indicating
that NAA/Cho ratios might be superior not only for diagnostic purposes but
for disease monitoring as well. Interestingly, the average 9.1% decline in
NAA/Cho observed in this study resembles the annual 9.3% decrease in NAA concentrations
found in cortical areas of patients with Alzheimer disease.21
However, as we did not perform serial 1H-MRS measurements within
predetermined observation intervals, our data on natural course of NAA deterioration
in the ALS motor cortex clearly need extension and reproduction. Nevertheless,
they might help to determine what observation periods are necessary to detect
neuroprotective effects on 1H-MRS findings in therapeutic trials.
As observed in our previous study, there was considerable interindividual
variability for onset and slope of NAA/Cho deterioration, ranging from patients
with marked early NAA/Cho reduction to patients without progressive changes
of the NAA/Cho ratio up to 2 years after disease onset.15
Investigations by 1H-MRS in patients with advanced cases of definite
ALS and severe but stable disease demonstrated a deteriorated plateau of NAA/Cho
ratios reaching values of about 1.7. In addition, we found a moderate correlation
between decline of metabolite alterations with the clinical progression of
the disease. These findings suggest that changes in NAA/Cho ratios might be
taken as surrogate markers to estimate the activity of the neurodegenerative
process in the motor cortex of individual patients with ALS. Therefore, 1H-MRS appears to be a promising tool for monitoring the active phase
of the ALS disease process.
AUTHOR INFORMATION
Accepted for publication September 29, 2000.
This study was supported by a research grant from BONFOR, Bonn (Dr Pohl)
and by research grant TR428/1-1 from the Deutsche Forschungsgemeinschaft,
Bonn (Drs Träber and Schild).
Drs Pohl and Block contributed equally to this work.
We thank all of the patients, their relatives, and the volunteers for
their cooperation in this study.
From the Departments of Neurology (Drs Pohl, Schmidt, Grothe, and Klockgether)
and Radiology (Drs Block, Träber, and Schild), University of Bonn, Bonn,
Germany; Department of Neurology, University of Ulm, Ulm, Germany (Dr Karitzky);
and Philips Medical Systems, Best, the Netherlands (Dr Lamerichs).
Corresponding author and reprints: Christoph Pohl, MD, Department
of Neurology, University of Bonn, Sigmund-Freud-Str 25, D-53105 Bonn, Germany
(e-mail: c.pohl{at}uni-bonn.de).
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