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

Background 1H‐magnetic resonance spectroscopy (1H‐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 1H‐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