Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study

Abstract

Objectives: After replication of previous findings we aimed to: 1) determine if previously reported (1)H MRSI differences between ALS patients and control subjects are limited to the motor cortex; and 2) determine the longitudinal metabolic changes corresponding to varying levels of diagnostic certainty.

Methods: Twenty-one patients with possible/suspected ALS, 24 patients with probable/definite ALS and 17 control subjects underwent multislice (1)H MRSI co-registered with tissue-segmented MRI to obtain concentrations of the brain metabolites N-acetylaspartate (NAA), creatine, and choline in the left and right motor cortex and in gray matter and white matter of non-motor regions in the brain.

Results: In the more affected hemisphere, reductions in the ratios, NAA/Cho and NAA/Cre+Cho were observed both within (12.6% and 9.5% respectively) and outside (9.2% and 7.3% respectively) the motor cortex in probable/definite ALS. However, these reductions were significantly greater within the motor cortex (P<0.05 for NAA/Cho and P<0.005 for NAA/Cre+Cho). Longitudinal changes in NAA were observed at three months within the motor cortex of both possible/suspected ALS patients (P<0.005) and at nine months outside the motor cortex of probable/definite patients (P<0.005). However, there was no clear pattern of progressive change over time.

Conclusions: NAA ratios are reduced in the motor cortex and outside the motor cortex in ALS, suggesting widespread neuronal injury. Longitudinal changes of NAA are not reliable, suggesting that NAA may not be a useful surrogate marker for treatment trials.

Figure 1

(A) Position of ¹H MRS multislice volumes of interest. Examples of the (B) top; (C) middle; and bottom slice (D). On the top and middle slice white arrows indicate the motor region, non-motor frontal areas are colored red and parietal regions are colored blue. Motor cortex marking did not extend to the lower slice on this subject.

Figure 2

Mean concentrations of (a) NAA (b) creatine and (c) choline at 3-month intervals. Significant values are relative to mean concentrations at the time of the initial scan. Comparisons were made using single df comparisons within a mixed linear model with months from initial scan as a repeated measure (* P≤0.05, ^◆P≤0.01, ^†P≤0.005, ^‡P≤0.0005, ^‡‡P≤0.0001). Error bars represent standard error of the mean.

Figure 2

Mean concentrations of (a) NAA (b) creatine and (c) choline at 3-month intervals. Significant values are relative to mean concentrations at the time of the initial scan. Comparisons were made using single df comparisons within a mixed linear model with months from initial scan as a repeated measure (* P≤0.05, ^◆P≤0.01, ^†P≤0.005, ^‡P≤0.0005, ^‡‡P≤0.0001). Error bars represent standard error of the mean.

Figure 3

NAA concentrations in each of the 12 possible/suspected ALS patients tracked longitudinally. Each colored line represents an individual subject. During the first three months NAA either decreases or remains stable in all of these subjects. Subsequent to the 3-month time point, this tendency is no longer present.