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September 21, 2011

Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS

October 4, 2011 issue
77 (14) 1370-1375

Abstract

Objective:

It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neurodegeneration precedes the appearance of clinical manifestations. Magnetic resonance spectroscopy (MRS) was used to measure ratios of neurometabolites in the cervical spine of asymptomatic individuals with a mutation in the SOD1 gene (SOD1+) and compare their neurometabolic ratios to patients with ALS and healthy controls.

Methods:

A cross-sectional study of 1H-MRS of the cervical spine was performed on 24 presymptomatic SOD1+ volunteers, 29 healthy controls, and 23 patients with ALS. All presymptomatic subjects had no symptoms of disease, normal forced vital capacity, and normal electromyographic examination. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and N-acetylaspartate (NAA) were determined.

Results:

NAA/Cr and NAA/Myo ratios are reduced in both SOD1+ subjects (39.7%, p = 0.001 and 18.0%, p = 0.02) and patients with ALS (41.2%, p < 0.001 and 24.0%, p = 0.01) compared to controls. Myo/Cr is reduced (10.3%, p = 0.02) in SOD1+ subjects compared to controls, but no difference was found between patients with ALS and controls. By contrast, NAA/Cho is reduced in patients with ALS (24.0%, p = 0.002), but not in presymptomatic SOD1+ subjects compared to controls.

Conclusions:

Changes in neurometabolite ratios in the cervical spinal cord are evident in presymptomatic SOD1+ individuals in advance of symptoms and clinical or electromyographic signs of disease. These changes reflect a reduction in NAA/Cr and NAA/Myo. Neurometabolic changes in this population resemble changes observed in patients with clinically apparent ALS. This suggests that neurometabolic changes occur early in the course of the disease process.

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REFERENCES

1.
Shefner JM. MUNE studies in mouse models of motor neuron disease. Clin Neurophysiol Suppl 2003;55:301–307.
2.
Aggarwal A, Nicholson G. Detection of preclinical motor neurone loss in SOD1 mutation carriers using motor unit number estimation. J Neurol Neurosurg Psychiatry 2002;73:199–201.
3.
Vucic S, Nicholson GA, Kiernan MC. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 2008;131:1540–1550.
4.
Ng MC, Ho JT, Ho SL, et al. Abnormal diffusion tensor in nonsymptomatic familial amyotrophic lateral sclerosis with a causative superoxide dismutase 1 mutation. J Magn Reson Imaging 2008;27:8–13.
5.
Pioro EP, Majors AW, Mitsumoto H, Nelson DR, Ng TC. 1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla. Neurology 1999;53:71–79.
6.
Pioro E. Proton magnetic resonance spectroscopy (1H-MRS) in ALS. Amyotroph Lateral Scler 2000;5:S7–S16.
7.
Kalra S, Arnold DL. ALS surrogate markers. MRS Amyotroph Lateral Scler 2004;5:S111–S114.
8.
Grehl T, Fischer S, Muller K, Malin J, Zange J. A prospective study to evaluate the impact of 31P-MRS to determine mitochondrial dysfunction in skeletal muscle of ALS patients. Amyotroph Lateral Scler 2007;8:4–8.
9.
Khiat A, D'Amour M, Souchon F, Boulanger Y. MRS study of the effects of minocycline on markers of neuronal and microglial integrity in ALS. Magn Reson Med 2010;28:1456–1460.
10.
Carew JD, Nair G, Pineda-Alonso N, Usher S, Hu X, Benatar M. Magnetic resonance spectroscopy of the cervical cord in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2011;12:185–191.
11.
Sarchielli P, Pelliccioli GP, Tarducci R, et al. Magnetic resonance imaging and 1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis. Neuroradiology 2001;43:189–197.
12.
Schuff N, Rooney WD, Miller R, et al. Reanalysis of multislice (1)H MRSI in amyotrophic lateral sclerosis. Magn Reson Med 2001;45:513–516.
13.
Abe K, Takanashi M, Watanabe Y, et al. Decrease in N-acetylaspartate/creatine ratio in the motor area and the frontal lobe in amyotrophic lateral sclerosis. Neuroradiology 2001;43:537–541.
14.
Chan S, Shungu DC, Douglas-Akinwande A, Lange DJ, Rowland LP. Motor neuron diseases: comparison of single-voxel proton MR spectroscopy of the motor cortex with MR imaging of the brain. Radiology 1999;212:763–769.
15.
Cwik VA, Hanstock CC, Allen PS, Martin WR. Estimation of brainstem neuronal loss in amyotrophic lateral sclerosis with in vivo proton magnetic resonance spectroscopy. Neurology 1998;50:72–77.
16.
Kalra S, Cashman NR, Caramanos Z, Genge A, Arnold DL. Gabapentin therapy for amyotrophic lateral sclerosis: lack of improvement in neuronal integrity shown by MR spectroscopy. AJNR Am J Neuroradiol 2003;24:476–480.
17.
Pioro EP, Antel JP, Cashman NR, Arnold DL. Detection of cortical neuron loss in motor neuron disease by proton magnetic resonance spectroscopic imaging in vivo. Neurology 1994;44:1933–1938.
18.
Rule RR, Suhy J, Schuff N, Gelinas DF, Miller RG, Weiner MW. Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study. Amyotroph Lateral Scler Other Motor Neuron Disord 2004;5:141–149.
19.
Suhy J, Miller RG, Rule R, et al. Early detection and longitudinal changes in amyotrophic lateral sclerosis by (1)H MRSI. Neurology 2002;58:773–779.
20.
Kalra S, Cashman NR, Genge A, Arnold DL. Recovery of N-acetylaspartate in corticomotor neurons of patients with ALS after riluzole therapy. Neuroreport 1998;9:1757–1761.
21.
Block W, Karitzky J, Traber 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;55:931–936.
22.
Jones AP, Gunawardena WJ, Coutinho CM, Gatt JA, Shaw IC, Mitchell JD. Preliminary results of proton magnetic resonance spectroscopy in motor neurone disease (amyotrophic lateral sclerosis). J Neurol Sci 1995;129(suppl):85–89.
23.
Rooney WD, Miller RG, Gelinas D, Schuff N, Maudsley AA, Weiner MW. Decreased N-acetylaspartate in motor cortex and corticospinal tract in ALS. Neurology 1998;50:1800–1805.
24.
Kalra S, Hanstock CC, Martin WR, Allen PS, Johnston WS. Detection of cerebral degeneration in amyotrophic lateral sclerosis using high-field magnetic resonance spectroscopy. Arch Neurol 2006;63:1144–1148.
25.
Bradley WG, Bowen BC, Pattany PM, Rotta F. 1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis. J Neurol Sci 1999;169:84–86.
26.
Gredal O, Rosenbaum S, Topp S, Karlsborg M, Strange P, Werdelin L. Quantification of brain metabolites in amyotrophic lateral sclerosis by localized proton magnetic resonance spectroscopy. Neurology 1997; 48:878–881.
27.
Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293–299.
28.
Provencher SW. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed 2001;14:260–264.
29.
Banjamini Y, Hochberg Y. Controlling the false discovery rate: a piratical and powerful approach to multiple testing. J R Stat Soc Ser B 1995;57:289–300.
30.
Morrish PK, Rakshi JS, Bailey DL, Sawle GV, Brooks DJ. Measuring the rate of progression and estimating the preclinical period of Parkinson's disease with [18F]dopa PET. J Neurol Neurosurg Psychiatry 1998;64:314–319.
31.
Aylward EH, Sparks BF, Field KM, et al. Onset and rate of striatal atrophy in preclinical Huntington disease. Neurology 2004;63:66–72.
32.
Jack CR, Lowe VJ, Weigand SD, et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain 2009;132:1355–1365.
33.
Ellis CM, Simmons A, Andrews C, Dawson JM, Williams SC, Leigh PN. A proton magnetic resonance spectroscopic study in ALS: correlation with clinical findings. Neurology 1998;51:1104–1109.

Information & Authors

Information

Published In

Neurology®
Volume 77Number 14October 4, 2011
Pages: 1370-1375
PubMed: 21940617

Publication History

Received: March 5, 2011
Accepted: June 14, 2011
Published online: September 21, 2011
Published in print: October 4, 2011

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Disclosure

Dr. Carew receives research support from the NIH, AHRQ, the Cardiovascular Research Foundation, and the Carolinas HealthCare Foundation. Dr. Nair and Ms. Gronka report no disclosures. Dr. Andersen receives research support from the Swedish Science Council, the Swedish Hållsten's Brain Research Foundation and Swedish Brain Power; Dr. Andersen has served as a paid consultant for Hoffman La Roche. Ms. Wuu receives research support from NIH, FDA, CDC, MDA, ALS Association, Consolidated Anti-Aging Foundation and the Woodruff Health Sciences Center (Emory University). Dr. Hu has received research support from the NIH/NHLBI. Dr. Benatar is funded by FDA grants FD003517 and FD003710, ALS Association grants 1491, 1712, and 1862, and Muscular Dystrophy Association grant 172123; and is a paid consultant for Cytokinetics and Bayhill Therapeutics. Dr. Benatar receives publishing royalties for Neuromuscular Disease: Evidence and Analysis in Clinical Neurology (Humana Press, 2006), BluePrints in Neurology (Lippincott Williams & Wilkins, 2002), and Field of Vision: A Manual and Atlas of Perimetry (Humana Press, 2010); and has received research support from CytRx Corporation, the Centers for Disease Control and Prevention, the Woodruff Health Sciences Center (Emory University), and the NIH; he has participated in medico-legal cases.

Authors

Affiliations & Disclosures

J.D. Carew, PhD
From the Carolinas HealthCare System (J.D.C.), Charlotte, NC; Emory University (G.N., X.H.), Atlanta, GA; Umeå University (P.M.A.), Umeå, Sweden; and University of Miami (J.W., S.G., M.B.), Miami, FL.
G. Nair, PhD
From the Carolinas HealthCare System (J.D.C.), Charlotte, NC; Emory University (G.N., X.H.), Atlanta, GA; Umeå University (P.M.A.), Umeå, Sweden; and University of Miami (J.W., S.G., M.B.), Miami, FL.
P.M. Andersen, MD
From the Carolinas HealthCare System (J.D.C.), Charlotte, NC; Emory University (G.N., X.H.), Atlanta, GA; Umeå University (P.M.A.), Umeå, Sweden; and University of Miami (J.W., S.G., M.B.), Miami, FL.
J. Wuu, ScM
From the Carolinas HealthCare System (J.D.C.), Charlotte, NC; Emory University (G.N., X.H.), Atlanta, GA; Umeå University (P.M.A.), Umeå, Sweden; and University of Miami (J.W., S.G., M.B.), Miami, FL.
S. Gronka, RN
From the Carolinas HealthCare System (J.D.C.), Charlotte, NC; Emory University (G.N., X.H.), Atlanta, GA; Umeå University (P.M.A.), Umeå, Sweden; and University of Miami (J.W., S.G., M.B.), Miami, FL.
X. Hu, PhD
From the Carolinas HealthCare System (J.D.C.), Charlotte, NC; Emory University (G.N., X.H.), Atlanta, GA; Umeå University (P.M.A.), Umeå, Sweden; and University of Miami (J.W., S.G., M.B.), Miami, FL.
M. Benatar, MBChB, DPhil
From the Carolinas HealthCare System (J.D.C.), Charlotte, NC; Emory University (G.N., X.H.), Atlanta, GA; Umeå University (P.M.A.), Umeå, Sweden; and University of Miami (J.W., S.G., M.B.), Miami, FL.

Notes

Study funding: Supported by the Muscular Dystrophy Association (grants 4365 and 172123), the ALS Association (grants 1491 and 1712), the Swedish Brain Research Foundation, the Hållsten's Brain Research Foundation, the Swedish Science Council, and the Swedish Association for the Neurologically Disabled.
Address correspondence and reprint requests to Dr. Michael Benatar, Department of Neurology, University of Miami, Miller School of Medicine, 1120 NW 14th Street, Room 1318, Miami, FL 33136 E-mail: [email protected]

Author Contributions

Dr. Carew: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis, study supervision, obtaining funding. Dr. Nair: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data. Dr. Andersen: analysis or interpretation of data, acquisition of data. Ms. Wuu: study concept or design, analysis or interpretation of data. Ms. Gronka: study concept or design, acquisition of data, study supervision. Dr. Hu: study concept or design, analysis or interpretation of data, study supervision. Dr. Benatar: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, study supervision, obtaining funding.

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