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

Abstract

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<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:

1H-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.

• Authors: Nevin A John, Bhavana S Solanky, Floriana De Angelis, Richard A Parker, Christopher J Weir, Jonathan Stutters, Ferran Prados Carrasco, Torben Schneider, Anisha Doshi, Alberto Calvi, Thomas Williams, Domenico Plantone, Anita Monteverdi, David MacManus, Ian Marshall, Frederik Barkhof, Claudia A M Gandini Wheeler-Kingshott, Jeremy Chataway, MS‐SMART Investigators
• Journal: Journal of magnetic resonance imaging : JMRI (J Magn Reson Imaging) Vol. 59 Issue 6 Pg. 2192-2201 (Jun 2024) ISSN: 1522-2586 [Electronic] United States
• PMID: 37787109 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.

Chemical References

• Neuroprotective Agents
• Riluzole
• Fluoxetine
• Inositol
• Creatine
• Aspartic Acid
• Choline
• N-acetylaspartate
• Glutamine
• Glutamic Acid

Topics

• Humans
• Female
• Male
• Middle Aged
• Neuroprotective Agents
• Longitudinal Studies
• Multiple Sclerosis, Chronic Progressive (diagnostic imaging, drug therapy, metabolism)
• Riluzole
• Adult
• Fluoxetine
• Brain (diagnostic imaging, metabolism)
• Inositol (metabolism)
• Creatine (metabolism)
• Aspartic Acid (analogs & derivatives, metabolism)
• Choline (metabolism)
• Magnetic Resonance Spectroscopy
• Proton Magnetic Resonance Spectroscopy
• Glutamine (metabolism)
• Glutamic Acid (metabolism)
• Magnetic Resonance Imaging (methods)
• Gray Matter (diagnostic imaging, metabolism)