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Original Contribution |

Detection of Cerebral Degeneration in Amyotrophic Lateral Sclerosis Using High-Field Magnetic Resonance Spectroscopy FREE

Sanjay Kalra, MD; Christopher C. Hanstock, PhD; W. R. Wayne Martin, MD; Peter S. Allen, PhD; Wendy S. Johnston, MD
[+] Author Affiliations

Author Affiliations: Division of Neurology, Department of Medicine (Drs Kalra, Martin, and Johnston), and Department of Biomedical Engineering (Drs Hanstock and Allen), University of Alberta, Edmonton.


Arch Neurol. 2006;63(8):1144-1148. doi:10.1001/archneur.63.8.1144.
Text Size: A A A
Published online

Background  Clinical assessment is insensitive to the degree of cerebral involvement in amyotrophic lateral sclerosis (ALS). Regional brain concentrations N-acetylaspartylglutamate (NAA) plus myo-inositol (Ins), as measured by magnetic resonance spectroscopy, are respectively decreased and increased, suggesting that these compounds may provide a biomarker of the degree of cerebral involvement in ALS.

Objective  To test the hypothesis that the NAA/Ins ratio may provide an index of cerebral involvement in patients with ALS.

Design  High-field (3.0-T) magnetic resonance spectroscopy was performed to determine the NAA/creatine plus phosphocreatine (NAA/Cr), NAA/choline (NAA/Cho), Ins/Cr, and NAA/Ins ratios in the motor cortex.

Participants  Seventeen patients with ALS and 15 healthy control subjects were studied.

Results  In patients with ALS, the greatest abnormality was a 22% decrease in NAA/Ins (71% sensitivity and 93% specificity, P = .001); Ins/Cr was increased 18% (88% sensitivity and 53% specificity, P = .04), NAA/Cr was decreased 10% (88% sensitivity and 47% specificity, P = .04), and NAA/Cho was decreased 14% (53% sensitivity and 87% specificity, P = .047). Correlation of the ALS Functional Rating Scale with NAA/Ins approached statistical significance (R = 0.43, P = .07).

Conclusion  The NAA/Ins ratio may provide a meaningful biomarker in ALS given its optimal sensitivity and specificity profile.

Figures in this Article

Clinical assessment of upper motor neuron (UMN) signs in amyotrophic lateral sclerosis (ALS) is insensitive, resulting in delays in diagnosis and treatment. Indeed, pathologic evidence of corticospinal tract degeneration has been demonstrated in the absence of UMN signs in patients in whom lower motor neuron signs predominated.1

Proton magnetic resonance spectroscopy (MRS) can provide insight into the integrity of UMN pathways in ALS in vivo. The resonance arising from N-acetylaspartate plus N-acetylaspartylglutamate (NAA) is a marker of neuronal integrity. N-acetylaspartate and N-acetylaspartylglutamate levels are decreased in the brain in ALS in a spatially dependent manner that reflects its pathologic distribution.2Myo-inositol (Ins) is a cyclitol involved in intracellular signaling.3 It is a putative spectroscopic glial marker4 and is increased in the motor cortex in ALS.5,6

Our objective was to determine how well these spectroscopic markers could detect cerebral pathologic features in patients with ALS. Because simultaneous study of cerebral tissue is impossible and because correlation with necropsy material temporally distant to the MRS examination would be invalid because of disease progression, we studied patients with established ALS in whom UMN signs were evident and clearly indicative of the presence of cerebral disease. A favorable accuracy profile in this clinically homogeneous group would merit further trials to evaluate the ability of these spectroscopic markers to detect disease progression and to assist in early diagnosis.

To date, the findings of decreased NAA and increased Ins measured in isolation have suboptimal discriminatory power to distinguish patients with ALS from healthy subjects. Measuring NAA and Ins in the same patient could potentially improve on this. We hypothesized that the NAA/Ins ratio would be a more accurate marker of cerebral disease because the 2 measures are affected in opposite directions and may reflect distinct pathophysiological processes that are co-occurring in ALS. At a conventional magnetic field strength (1.5 T), the resonances of Ins are difficult to resolve because they originate from a strongly coupled and complex spin system and overlap significantly with resonances arising from glutamate, glutamine, glycine, and taurine. Therefore, subjects were studied using a high-field magnetic resonance system7 using a sequence tailored to optimize detection of Ins.8

SUBJECTS

Subjects were recruited from the ALS Clinic at the University of Alberta, Edmonton. Patients met El Escorial criteria9 for probable or definite ALS; therefore, all had examination findings indicating UMN dysfunction. Patients were administered the ALS Functional Rating Scale (ALSFRS) questionnaire (score range, 0-40). Upper motor neuron functioning was evaluated by measuring finger and foot tapping speed10 (taps per 10 seconds) and spasticity using the Modified Ashworth Scale. Healthy age-matched control subjects were free of neurological or psychiatric disease. Subjects were required to be able to lie flat for 75 minutes for the magnetic resonance examination. All subjects gave informed consent, and the study was approved by the Human Research Ethics Board of the University of Alberta.

IMAGING

Magnetic resonance spectroscopy was performed at 3.0 T using a quadrature birdcage resonator for transmission and reception. Orthogonal gradient-echo images were used to position the volume of interest in the motor cortex contralateral to the most severe UMN findings (Figure 1). In the case of symmetric signs on physical examination, the motor cortex of the dominant hemisphere, as inferred by handedness, was studied. The volume of interest measured 2 × 3 × 2 cm and was centered on and placed parallel to the precentral gyrus to maximize affected tissue content. A stimulated echo acquisition mode sequence was used for single-voxel spectroscopy (repetition time, 3000 milliseconds; 256 averages in 8 separate bins). Using a computational spectrum simulation method,11 we determined that the optimal sequence timings for measuring Ins distinct from the contaminating background were a mixing time of 40 milliseconds and an echo time of 160 milliseconds.8 These parameters minimized contributions from glutamate, glutamine, taurine, and macromolecules.

Place holder to copy figure label and caption
Figure 1.

Voxel placement and magnetic resonance spectrum. Axial (A) and sagittal (B) gradient-echo images demonstrating placement of the volume of interest in the left motor cortex of a healthy subject. C, A proton magnetic resonance spectrum acquired at 3.0 T from this region is shown on the right. Cho indicates choline; Cr, creatine plus phosophocreatine; Ins, myo-inositol; and NAA, N-acetylaspartate plus N-acetylaspartylglutamate.

Graphic Jump Location

Segmentation of the volume of interest into gray matter, white matter, and cerebrospinal fluid was performed using a double inversion recovery 1-dimensional projection method with a point-resolved spectroscopy localization scheme.12 This method uses simultaneous nulling of the water signal from 2 compartments, leaving only that from the third compartment.

Magnetic resonance spectroscopy data bins were summed off-line in MATLAB (The MathWorks, Inc, Natick, Mass) following automatic phase correction and frequency registration. Automated baseline fitting and metabolite peak quantification were performed using LCModel13 (available at: http://www.s-provencher.com/pages/lcmodel.shtml), in which simulated spectra were used as the basis spectra. Metabolite resonance peak areas were normalized to creatine plus phosophocreatine (Cr). The error estimate of the fit of a peak (percent standard deviation) was used as a measure of the precision of the quantification.

STATISTICAL ANALYSIS

Group differences in metabolite ratios were analyzed using the Mann-Whitney test. Spearman rank correlation coefficients (R) were computed to evaluate relationships between metabolite ratios and clinical variables. Statistical significance was set at 2-tailed P<.05. Receiver operating characteristic analysis was performed for metabolite ratios using MedCalc version 7.4 (MedCalc Software, Mariakerke, Belgium). The cutoff value with the highest accuracy (minimal false negatives and false positives) was determined using MedCalc, and the sensitivity and specificity for a ratio were determined at this cutoff.

Seventeen patients with ALS (3 definite and 14 probable) and 15 healthy control subjects were studied. There was no difference in age or sex distribution (Table 1). All spectra were of good quality (the LCModel fit percent SD for the metabolite peaks was <20%); none were rejected.

Table Graphic Jump LocationTable 1. Clinical Characteristics of Patients With Amyotrophic Lateral Sclerosis (ALS) and Healthy Control Subjects*

In the ALS group, NAA/Cr, NAA/choline (NAA/Cho), and NAA/Ins were decreased, and Ins/Cr was increased (Figure 2 and Table 2). The greatest difference was a 22% decrease in NAA/Ins. Receiver operating characteristic curves (eFigure) were similar for NAA/Cr, NAA/Cho, and Ins/Cr. The area under the receiver operating characteristic curve was greatest for NAA/Ins, reflecting its superior sensitivity and specificity profile. The NAA/Cr and Ins/Cr ratios offered the best sensitivity (88%), and the NAA/Ins ratio offered the best specificity (93%).

Place holder to copy figure label and caption
Figure 2.

Distribution of metabolite ratios. Ratios of N-acetylaspartate plus N-acetylaspartylglutamate (NAA) are reduced in amyotrophic lateral sclerosis (ALS). The myo-inositol (Ins)– creatine plus phosphocreatine (Cr) ratio is increased. The greatest abnormality is a decrease in NAA/Ins. The mean for each group is indicated by a horizontal bar. Cho indicates choline; open circles, control subjects; and solid circles, subjects with ALS.

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Table Graphic Jump LocationTable 2. Spectroscopy Results and Accuracy Profiles*
Place holder to copy figure label and caption
eFigure.

Receiver operating characteristic curves for the metabolite ratios. The N-acetylaspartate plus N-acetylaspartylglutamate (NAA)–myo-inositol (Ins) ratio has the greatest area under the curve, reflecting its superior sensitivity and specificity profile. Cho indicates choline; Cr, creatine plus phosphocreatine.

Graphic Jump Location

In 13 patients and 15 control subjects who underwent segmentation, there was no difference in total parenchymal volume (gray matter plus white matter content, mean ± SD, 10.7 ± 0.5 mL vs 10.3 ± 0.8 mL) or in individual fractions (percentages) of gray matter (37.1% ± 16.0% vs 31.6% ± 18.0%), white matter (52.0% ± 16.6% vs 54.6% ± 19.4%), or cerebrospinal fluid (10.8% ± 4.2% vs 13.8% ± 6.3%). Tissue segmentation was incomplete in 4 patients because of fatigue that curtailed the examination session or because of technical difficulties at the time of imaging.

Correlations of the ALSFRS approached statistical significance for NAA/Ins (R = 0.43, P = .07) and were absent for NAA/Cr, NAA/Cho, and Ins/Cr. Magnetic resonance spectroscopic indices did not correlate with symptom duration, contralateral finger or foot tapping rates, or the Modified Ashworth Scale score.

High-field MRS at 3.0 T was used to study neurochemical abnormalities in the motor cortex in patients with ALS. Relative representations of NAA and Ins were evaluated as the NAA/Cr, NAA/Cho, Ins/Cr, and NAA/Ins ratios. We hypothesized that NAA/Ins would be the most accurate at detecting disease given that previous reports5,6 have revealed decreased NAA and increased Ins in ALS. Indeed, NAA/Ins was the most abnormal, with a 22% decrease. Decreased NAA/Cr and increased Ins/Cr had high sensitivity but low specificity. Conversely, decreased NAA/Cho had low sensitivity but high specificity. The NAA/Ins ratio had moderate sensitivity (72%), the highest specificity (93%), and the best sensitivity and specificity profile among the 4 metabolite ratios. The NAA/Ins ratio has been evaluated in other neurodegenerative disorders14; however, to our knowledge, this is the first report of NAA/Ins measurement in ALS.

The best correlation with the ALSFRS, a validated clinical rating scale and end point in clinical trials,15 was with NAA/Ins. Although this result only approached statistical significance, it would suggest that cerebral degeneration contributes to disability as measured by the ALSFRS. Correlation was not found with tapping rates, contrary to a previous report,16 or with the Modified Ashworth Scale spasticity score, as has been described elsewhere.17

Whereas NAA is an established marker of neuronal integrity, the pathophysiological basis for an increase in Ins in ALS is unknown. The popularity of Ins as a putative spectroscopic glial marker is based on a cerebral distribution that strongly favors glial cells4 and on the observation of increased Ins in several disorders in which astrogliosis is prominent. This has particular relevance in ALS where motor neuron degeneration is commonly accompanied by astrogliosis.18 Evidence is emerging that astrocytes may play an active role in the pathogenesis of ALS. Glial glutamate transporters are decreased in the motor cortex of patients with ALS.19 In SOD1 transgenic mouse models of ALS, proliferating astrocytes interact intimately with neurons.20 Mutant SOD1 expression in motor neurons or astrocytes alone does not lead to neurodegeneration,21,22 implicating an apparent necessity of an interaction between neuronal and glial or other nonneuronal cells for degeneration to occur.23

Myo-inositol is a precursor to the phosphatidylinositol second messenger system3; altered signal transduction in ALS is supported by the observation of increased phosphatidylinositol 3–kinase activity24 and an elevated protein kinase C level.25 Increased Ins may also be a consequence of glutamate-mediated excitotoxicity, for which there is considerable evidence as a pathogenetic process in ALS. Glutamate activates the phosphatidylinositol cycle by stimulation of metabotropic receptors. This, in addition to cell depolarization and increased cellular calcium, up-regulates neuronal and astrocytic cell surface expression of a proton-coupled Ins transporter.26

Myo-inositol also functions as an osmolyte,27 with increased cellular uptake occurring as a protective response to hypertonicity. Because this is absent in ALS, it would be an unlikely mechanism leading to increased Ins.

We sought to specifically evaluate the NAA/Ins ratio because of the greater experimental accuracy28 and technical ease of measurement associated with ratio determination that permits easier application of our results to further clinical investigation. Although absolute quantitation allows measurement of individual metabolite concentrations, this may reduce precision and limit application to clinical evaluation. Future studies could address the role of individual metabolites in ALS. Assessment of metabolite relaxation times could also be considered to explore their effect on observed changes in and the pathophysiological relevance of neurochemical perturbations in ALS.29 Measurement of glutamine, an astrocyte marker, concurrent to Ins may help clarify the cellular specificity of Ins. With further inclusion of glutamate, such studies would contribute valuable knowledge to in vivo derangements in glutamate and glutamine metabolism, involvement of astrocytes, and glutamate-mediated excitotoxicity. However, the protocols will need to be tailored to minimize the duration of data acquisition because patients with ALS cannot tolerate protracted studies.

This study amplifies previous investigations of spectroscopic markers of disease in ALS. The metabolites studied could provide insight into aberrant intracellular signaling and astrogliosis, and they were significantly abnormal so as to accurately differentiate patients with an established clinical diagnosis from healthy controls. The utility of the NAA/Ins as a biomarker will require further investigation. Specifically, to determine its disease specificity and predictive ability with early diagnosis of ALS, a study is required that includes patients with progressive lower motor neuron syndromes in whom UMN signs are absent (ie, progressive muscular atrophy) or insufficient (ie, “possible ALS” by El Escorial criteria) to make a firm clinical diagnosis. A longitudinal study with sequential MRS examinations will be essential to establish the sensitivity of the NAA/Ins ratio to disease progression.

Correspondence: Sanjay Kalra, MD, Division of Neurology, Department of Medicine, University of Alberta, 2E3.18 Walter C. Mackenzie Health Sciences Centre, 8440 112th St, Edmonton, Alberta, Canada T6G 2B7 (sanjay.kalra@ualberta.ca).

Accepted for Publication: March 9, 2006.

Author Contributions:Study concept and design: Kalra. Acquisition of data: Kalra, Hanstock, Allen, and Johnston. Analysis and interpretation of data: Kalra, Hanstock, and Martin. Drafting of the manuscript: Kalra. Critical revision of the manuscript for important intellectual content: Kalra, Hanstock, Martin, Allen, and Johnston. Statistical analysis: Kalra. Obtained funding: Kalra and Allen. Administrative, technical, or material support: Hanstock and Johnston. Supervision: Martin, Allen, and Johnston.

Funding/Support: This study was supported by the University of Alberta Hospital Foundation, the MSI Foundation of Alberta, and the Canadian Institutes of Health Research.

Acknowledgment: We thank the subjects for their participation, Kevin Harris and Christie Sorochuk for their assistance with coordinating the study, and Richard Camicioli, MD, for helpful comments in preparing the manuscript.

Additional Information: The eFigure is available.

Ince  PGEvans  JKnopp  M  et al.  Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS. Neurology 2003;601252- 1258
PubMed Link to Article
Pioro  EPAntel  JPCashman  NRArnold  DL Detection of cortical neuron loss in motor neuron disease by proton magnetic resonance spectroscopic imaging in vivo. Neurology 1994;441933- 1938
PubMed Link to Article
Berridge  MJIrvine  RF Inositol phosphates and cell signalling. Nature 1989;341197- 205
PubMed Link to Article
Brand  ARichter-Landsberg  CLeibfritz  D Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 1993;15289- 298
PubMed Link to Article
Block  WKaritzky  JTraber  F  et al.  Proton magnetic resonance spectroscopy of the primary motor cortex in patients with motor neuron disease: subgroup analysis and follow-up measurements. Arch Neurol 1998;55931- 936
PubMed Link to Article
Bowen  BCPattany  PMBradley  WG  et al.  MR imaging and localized proton spectroscopy of the precentral gyrus in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol 2000;21647- 658
PubMed
Srinivasan  RVigneron  DSailasuta  NHurd  RNelson  S A comparative study of myo-inositol quantification using LCModel at 1.5 T and 3.0 T with 3 D 1H proton spectroscopic imaging of the human brain. Magn Reson Imaging 2004;22523- 528
PubMed Link to Article
Kim  HThompson  RBHanstock  CCAllen  PS Variability of metabolite yield using STEAM or PRESS sequences in vivo at 3.0 T, illustrated with myo-inositol. Magn Reson Med 2005;53760- 769
PubMed Link to Article
Brooks  BRMiller  RGSwash  MMunsat  TL El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1293- 299
PubMed Link to Article
Kent-Braun  JAWalker  CHWeiner  MWMiller  RG Functional significance of upper and lower motor neuron impairment in amyotrophic lateral sclerosis. Muscle Nerve 1998;21762- 768
PubMed Link to Article
Thompson  RBAllen  PS A new multiple quantum filter design procedure for use on strongly coupled spin systems found in vivo: its application to glutamate. Magn Reson Med 1998;39762- 771
PubMed Link to Article
Hanstock  CCAllen  PS Segmentation of brain from a PRESS localized single volume using double inversion recovery for simultaneous T1nulling.  In: Program and abstracts of the 8th Scientific Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine; April 3-7, 2000; Denver, Colo. Abstract 1964
Provencher  SW Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 1993;30672- 679
PubMed Link to Article
Martinez-Bisbal  MCArana  EMarti-Bonmati  LMolla  ECelda  B Cognitive impairment: classification by 1H magnetic resonance spectroscopy. Eur J Neurol 2004;11187- 193
PubMed Link to Article
ALS CNTF Treatment Study (ACTS) Phase I-II Study Group, The Amyotrophic Lateral Sclerosis Functional Rating Scale: assessment of activities of daily living in patients with amyotrophic lateral sclerosis. Arch Neurol 1996;53141- 147
PubMed Link to Article
Rooney  WDMiller  RGGelinas  D  et al.  Decreased N-acetylaspartate in motor cortex and corticospinal tract in ALS. Neurology 1998;501800- 1805
PubMed Link to Article
Ellis  CMSimmons  AAndrews  C  et al.  A proton magnetic resonance spectroscopic study in ALS: correlation with clinical findings. Neurology 1998;511104- 1109
PubMed Link to Article
Nagy  DKato  TKushner  PD Reactive astrocytes are widespread in the cortical gray matter of amyotrophic lateral sclerosis. J Neurosci Res 1994;38336- 347
PubMed Link to Article
Rothstein  JDVan Kammen  MLevey  AIMartin  LJKuncl  RW Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995;3873- 84
PubMed Link to Article
Levine  JBKong  JNadler  MXu  Z Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS). Glia 1999;28215- 224
PubMed Link to Article
Gong  YHParsadanian  ASAndreeva  ASnider  WDElliott  JL Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J Neurosci 2000;20660- 665
PubMed
Pramatarova  ALaganiere  JRoussel  JBrisebois  KRouleau  GA Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci 2001;213369- 3374
PubMed
Clement  AMNguyen  MDRoberts  EA  et al.  Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 2003;302113- 117
PubMed Link to Article
Wagey  RPelech  SLDuronio  VKrieger  C Phosphatidylinositol 3–kinase: increased activity and protein level in amyotrophic lateral sclerosis. J Neurochem 1998;71716- 722
PubMed Link to Article
Hu  JHZhang  HWagey  RKrieger  CPelech  SL Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord. J Neurochem 2003;85432- 442
PubMed Link to Article
Uldry  MSteiner  PZurich  MG  et al.  Regulated exocytosis of an H+/myo-inositol symporter at synapses and growth cones. EMBO J 2004;23531- 540
PubMed Link to Article
Thurston  JHSherman  WRHauhart  REKloepper  RF Myo-inositol: a newly identified nonnitrogenous osmoregulatory molecule in mammalian brain. Pediatr Res 1989;26482- 485
PubMed Link to Article
Kreis  R Issues of spectral quality in clinical 1H-magnetic resonance spectroscopy and a gallery of artifacts. NMR Biomed 2004;17361- 381
PubMed Link to Article
Hanstock  CCCwik  VAMartin  WR Reduction in metabolite transverse relaxation times in amyotrophic lateral sclerosis. J Neurol Sci 2002;19837- 41
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Voxel placement and magnetic resonance spectrum. Axial (A) and sagittal (B) gradient-echo images demonstrating placement of the volume of interest in the left motor cortex of a healthy subject. C, A proton magnetic resonance spectrum acquired at 3.0 T from this region is shown on the right. Cho indicates choline; Cr, creatine plus phosophocreatine; Ins, myo-inositol; and NAA, N-acetylaspartate plus N-acetylaspartylglutamate.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Distribution of metabolite ratios. Ratios of N-acetylaspartate plus N-acetylaspartylglutamate (NAA) are reduced in amyotrophic lateral sclerosis (ALS). The myo-inositol (Ins)– creatine plus phosphocreatine (Cr) ratio is increased. The greatest abnormality is a decrease in NAA/Ins. The mean for each group is indicated by a horizontal bar. Cho indicates choline; open circles, control subjects; and solid circles, subjects with ALS.

Graphic Jump Location
Place holder to copy figure label and caption
eFigure.

Receiver operating characteristic curves for the metabolite ratios. The N-acetylaspartate plus N-acetylaspartylglutamate (NAA)–myo-inositol (Ins) ratio has the greatest area under the curve, reflecting its superior sensitivity and specificity profile. Cho indicates choline; Cr, creatine plus phosphocreatine.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinical Characteristics of Patients With Amyotrophic Lateral Sclerosis (ALS) and Healthy Control Subjects*
Table Graphic Jump LocationTable 2. Spectroscopy Results and Accuracy Profiles*

References

Ince  PGEvans  JKnopp  M  et al.  Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS. Neurology 2003;601252- 1258
PubMed Link to Article
Pioro  EPAntel  JPCashman  NRArnold  DL Detection of cortical neuron loss in motor neuron disease by proton magnetic resonance spectroscopic imaging in vivo. Neurology 1994;441933- 1938
PubMed Link to Article
Berridge  MJIrvine  RF Inositol phosphates and cell signalling. Nature 1989;341197- 205
PubMed Link to Article
Brand  ARichter-Landsberg  CLeibfritz  D Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 1993;15289- 298
PubMed Link to Article
Block  WKaritzky  JTraber  F  et al.  Proton magnetic resonance spectroscopy of the primary motor cortex in patients with motor neuron disease: subgroup analysis and follow-up measurements. Arch Neurol 1998;55931- 936
PubMed Link to Article
Bowen  BCPattany  PMBradley  WG  et al.  MR imaging and localized proton spectroscopy of the precentral gyrus in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol 2000;21647- 658
PubMed
Srinivasan  RVigneron  DSailasuta  NHurd  RNelson  S A comparative study of myo-inositol quantification using LCModel at 1.5 T and 3.0 T with 3 D 1H proton spectroscopic imaging of the human brain. Magn Reson Imaging 2004;22523- 528
PubMed Link to Article
Kim  HThompson  RBHanstock  CCAllen  PS Variability of metabolite yield using STEAM or PRESS sequences in vivo at 3.0 T, illustrated with myo-inositol. Magn Reson Med 2005;53760- 769
PubMed Link to Article
Brooks  BRMiller  RGSwash  MMunsat  TL El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1293- 299
PubMed Link to Article
Kent-Braun  JAWalker  CHWeiner  MWMiller  RG Functional significance of upper and lower motor neuron impairment in amyotrophic lateral sclerosis. Muscle Nerve 1998;21762- 768
PubMed Link to Article
Thompson  RBAllen  PS A new multiple quantum filter design procedure for use on strongly coupled spin systems found in vivo: its application to glutamate. Magn Reson Med 1998;39762- 771
PubMed Link to Article
Hanstock  CCAllen  PS Segmentation of brain from a PRESS localized single volume using double inversion recovery for simultaneous T1nulling.  In: Program and abstracts of the 8th Scientific Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine; April 3-7, 2000; Denver, Colo. Abstract 1964
Provencher  SW Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 1993;30672- 679
PubMed Link to Article
Martinez-Bisbal  MCArana  EMarti-Bonmati  LMolla  ECelda  B Cognitive impairment: classification by 1H magnetic resonance spectroscopy. Eur J Neurol 2004;11187- 193
PubMed Link to Article
ALS CNTF Treatment Study (ACTS) Phase I-II Study Group, The Amyotrophic Lateral Sclerosis Functional Rating Scale: assessment of activities of daily living in patients with amyotrophic lateral sclerosis. Arch Neurol 1996;53141- 147
PubMed Link to Article
Rooney  WDMiller  RGGelinas  D  et al.  Decreased N-acetylaspartate in motor cortex and corticospinal tract in ALS. Neurology 1998;501800- 1805
PubMed Link to Article
Ellis  CMSimmons  AAndrews  C  et al.  A proton magnetic resonance spectroscopic study in ALS: correlation with clinical findings. Neurology 1998;511104- 1109
PubMed Link to Article
Nagy  DKato  TKushner  PD Reactive astrocytes are widespread in the cortical gray matter of amyotrophic lateral sclerosis. J Neurosci Res 1994;38336- 347
PubMed Link to Article
Rothstein  JDVan Kammen  MLevey  AIMartin  LJKuncl  RW Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995;3873- 84
PubMed Link to Article
Levine  JBKong  JNadler  MXu  Z Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS). Glia 1999;28215- 224
PubMed Link to Article
Gong  YHParsadanian  ASAndreeva  ASnider  WDElliott  JL Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J Neurosci 2000;20660- 665
PubMed
Pramatarova  ALaganiere  JRoussel  JBrisebois  KRouleau  GA Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci 2001;213369- 3374
PubMed
Clement  AMNguyen  MDRoberts  EA  et al.  Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 2003;302113- 117
PubMed Link to Article
Wagey  RPelech  SLDuronio  VKrieger  C Phosphatidylinositol 3–kinase: increased activity and protein level in amyotrophic lateral sclerosis. J Neurochem 1998;71716- 722
PubMed Link to Article
Hu  JHZhang  HWagey  RKrieger  CPelech  SL Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord. J Neurochem 2003;85432- 442
PubMed Link to Article
Uldry  MSteiner  PZurich  MG  et al.  Regulated exocytosis of an H+/myo-inositol symporter at synapses and growth cones. EMBO J 2004;23531- 540
PubMed Link to Article
Thurston  JHSherman  WRHauhart  REKloepper  RF Myo-inositol: a newly identified nonnitrogenous osmoregulatory molecule in mammalian brain. Pediatr Res 1989;26482- 485
PubMed Link to Article
Kreis  R Issues of spectral quality in clinical 1H-magnetic resonance spectroscopy and a gallery of artifacts. NMR Biomed 2004;17361- 381
PubMed Link to Article
Hanstock  CCCwik  VAMartin  WR Reduction in metabolite transverse relaxation times in amyotrophic lateral sclerosis. J Neurol Sci 2002;19837- 41
PubMed Link to Article

Correspondence

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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