Longitudinal Metabolite Changes in Progressive Multiple Sclerosis: A Study of 3 Potential Neuroprotective Treatments

Background 1 H‐magnetic resonance spectroscopy ( 1 H‐MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total N ‐acetyl‐aspartate (tNAA), total creatine (tCr), myo‐inositol (mIns), total‐choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS). Purpose To assess the effect on neurometabolites from three candidate drugs after 96‐weeks as seen by 1 H‐MRS and their association with clinical disability in SPMS. Study‐Type Longitudinal. Population 108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%]. Field Strength/Sequence 3‐Tesla. Chemical‐shift‐imaging 2D‐point‐resolved‐spectroscopy (PRESS), 3DT1. Assessment Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine‐hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96‐weeks. Statistical Tests Paired t ‐test was used to analyze metabolite changes in the placebo arm over 96‐weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96‐weeks assessed using multiple linear regression models. P ‐value<0.05 was considered statistically significant. Results In the placebo arm, tCho increased in GM (mean difference = −0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm , mIns/tCr was lower ( β = −0.21); in the riluzole arm , GM Glx ( β = −0.25) and Glx/tCr ( β = −0.29) were reduced. Baseline tNAA( β = 0.22) and tNAA/tCr ( β = 0.23) in NAWM were associated with 9HPT scores at 96‐weeks. Data Conclusion 1 H‐MRS demonstrated altered membrane turnover over 96‐weeks in the placebo group. It also distinguished changes in neuro‐metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function. Level of Evidence 1 Technical Efficacy Stage 4