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. 2011 Oct 4;77(14):1370-5.
doi: 10.1212/WNL.0b013e318231526a. Epub 2011 Sep 21.

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

J D Carew  1 , G Nair, P M Andersen, J Wuu, S Gronka, X Hu, M Benatar
Affiliations

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

J D Carew et al. Neurology. .

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 (1)H-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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Figures

Figure 1
Figure 1
Magnetic resonance spectroscopy voxels placed to cover the spinal cord at the level of the C1-C2 vertebral body.
Figure 2
Figure 2. Magnetic resonance spectroscopy metabolite ratios in the cervical cord from healthy controls, presymptomatic SOD1-positive subjects (Pre-fALS), and patients with amyotrophic lateral sclerosis (ALS)
The line segments connect the group medians. In Pre-fALS subjects, relative to healthy individuals, there are significant decreases in myo-inositol (Myo)/creatine (Cr) (10.3%), N-acetylaspartate (NAA)/Cr (39.7%), and NAA/Myo (18.0%). The metabolic patterns of NAA/Cho, NAA/Cr, and NAA/Myo among SOD1+ subjects fit between healthy controls and patients with ALS. Statistical significance of differences was assessed using Wilcoxon rank tests to mitigate outlier effects.
Figure 3
Figure 3. N-acetylaspartate (NAA)/creatine (Cr) and myo-inositol (Myo)/Cr metabolite measurements showing a clustering pattern among the 3 subject types
Despite some overlap, there is a clear distinction between healthy subjects and patients with amyotrophic lateral sclerosis (ALS). Pre-familial ALS (Pre-fALS) subjects tend to predominantly cluster near the patients with ALS, although a minority of Pre-fALS subjects tend to cluster among healthy controls.
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