1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla.
OBJECTIVE
To determine whether short echo-time (TE) proton magnetic resonance spectroscopic imaging (1H-MRSI) can detect in vivo differences in signal intensities of specific metabolites in the medulla of patients with ALS compared with healthy individuals and whether these metabolites could be useful surrogate markers of disease.


BACKGROUND
1H-MRSI can detect N-acetylaspartate + N-acetylaspartylglutamate (abbreviated NAx), which is localized to neurons, and glutamate (Glu) + glutamine (Gln), abbreviated Glx, which may be important in ALS pathogenesis. The medulla is an ideal region to study ALS because of its high density of nuclei and fiber tracts that frequently undergo degeneration, even when more rostral brain regions show minimal pathology.


METHODS
Ten patients with ALS and seven healthy control subjects underwent short TE 1H-MRSI on a 1.5 T clinical imaging system. Signal intensities of NAx and Glx were normalized to creatine-phosphocreatine and compared between groups.


RESULTS
Compared with normal subjects, the medulla of patients with ALS had 17% lower NAx (p = 0.03) and 55% higher Glx (p = 0.02) signals. Bulbar symptoms, represented by the ALS Functional Rating Scale, correlated with Glx (r = -0.68, p = 0.03) but not NAx (r = 0.22, p = 0.53).


CONCLUSIONS
There is in vivo 1H-MRSI evidence of neuronal degeneration or loss and excess Glu + Gln in the medulla of patients with ALS. Although this cross-sectional study cannot identify which change occurred first, the higher Glx signal in the medulla of patients with more dysarthria and dysphagia is consistent with the hypothesis of Glu excitotoxicity in ALS pathogenesis. Longitudinal 1H-MRSI studies of the medulla (and other brain regions) in more patients with ALS are required to confirm these findings and to determine whether such metabolite changes will be useful in monitoring disease progression, in clinical diagnosis, and in understanding the pathogenesis of ALS.
Department of Neurology and Neurosciences, The Cleveland Clinic Foundation, OH 44195, USA. pioroe@ccf.org
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D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000473:pathology*; D005260:Female; D018698:Glutamic Acid / Q000032:analysis / Q000378:metabolism*; D005973:Glutamine / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D006859:Hydrogen; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009410:Nerve Degeneration / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D012016:Reference Values
D015415:Biomarkers; D005973:Glutamine; D001224:Aspartic Acid; D018698:Glutamic Acid; D006859:Hydrogen; C000179:N-acetylaspartate