NAA is a Marker of Disability in Secondary-Progressive MS: A Proton MR Spectroscopic Imaging Study

Abstract

Background and purpose: The secondary progressive phase of multiple sclerosis is characterised by disability progression due to processes that lead to neurodegeneration. Surrogate markers such as those derived from MRI are beneficial in understanding the pathophysiology that drives disease progression and its relationship to clinical disability. We undertook a 1H-MRS imaging study in a large secondary progressive MS (SPMS) cohort, to examine whether metabolic markers of brain injury are associated with measures of disability, both physical and cognitive.

Materials and methods: A cross-sectional analysis of individuals with secondary-progressive MS was performed in 119 participants. They underwent ¹H-MR spectroscopy to obtain estimated concentrations and ratios to total Cr for total NAA, mIns, Glx, and total Cho in normal-appearing WM and GM. Clinical outcome measures chosen were the following: Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Nine-Hole Peg Test, Timed 25-foot Walk Test, and the Expanded Disability Status Scale. The relationship between these neurometabolites and clinical disability measures was initially examined using Spearman rank correlations. Significant associations were then further analyzed in multiple regression models adjusting for age, sex, disease duration, T2 lesion load, normalized brain volume, and occurrence of relapses in 2 years preceding study entry.

Results: Significant associations, which were then confirmed by multiple linear regression, were found in normal-appearing WM for total NAA (tNAA)/total Cr (tCr) and the Nine-Hole Peg Test (ρ = 0.23; 95% CI, 0.06-0.40); tNAA and tNAA/tCr and the Paced Auditory Serial Addition Test (ρ = 0.21; 95% CI, 0.03-0.38) (ρ = 0.19; 95% CI, 0.01-0.36); mIns/tCr and the Paced Auditory Serial Addition Test, (ρ = -0.23; 95% CI, -0.39 to -0.05); and in GM for tCho and the Paced Auditory Serial Addition Test (ρ = -0.24; 95% CI, -0.40 to -0.06). No other GM or normal-appearing WM relationships were found with any metabolite, with associations found during initial correlation testing losing significance after multiple linear regression analysis.

Conclusions: This study suggests that metabolic markers of neuroaxonal integrity and astrogliosis in normal-appearing WM and membrane turnover in GM may act as markers of disability in secondary-progressive MS.

FIG 1.

Proton MR spectroscopy slice placement and mask. The upper panel demonstrates slice placement in the sagittal, coronal, and axial planes. The lower panel shows an example of the chemical shift mask for normal-appearing white matter and gray matter.

FIG 2.

Sample spectra and the chemical shift grid show the position where representative spectra originate, including a lesion (A), accepted spectra in red and lesion in black (B), and spectra from a rejected voxel (C). The position is shown in green in A.

FIG 3.

Associations between neurometabolites and clinical disability measures. The scatterplots with the line of best fit and 95% confidence intervals are shown for the associations in normal-appearing white matter among the following: A, tNAA/tCr and 9HPT (ρ = 0.23; 95% CI, 0.06–0.40). B, tNAA and Paced Auditory Serial Addition Test (ρ  = 0.21; 95% CI, 0.03–0.38). C, tNAA/tCr and Paced Auditory Serial Addition Test (ρ  = 0.19; 95% CI, 0.01–0.36). D, mIns/tCr and Paced Auditory Serial Addition Test (ρ = –0.23; 95% CI,–0.39 to −0.05) and in gray matter between tCho and Paced Auditory Serial Addition Test (ρ = –0.24; 95% CI, –0.40 to −0.06) (E).