Background

Neurometabolites measured by proton magnetic resonance spectroscopic imaging (MRSI) can be used to examine the relationship between metabolic markers of brain injury and clinical disability in secondary progressive multiple sclerosis (SPMS). Current work has shown an association between normal appearing white matter (NAWM) total N-acetyl aspartate plus N-acetyl aspartyl glutamate (tNAA) and both arm function and measures of processing speed.

Objectives

To determine if baseline tNAA and tNAA/tCr in NAWM are associated with upper limb function (9-hole peg test) and information processing speed (Paced auditory serial addition test) after 96 weeks of follow-up.

Methods

108 participants from the recently reported MS-SMART trial were included.¹ All participants had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR = 35/2000ms) at 3T and metabolite levels were determined for grey matter and NAWM. Absolute concentrations and ratios to total creatine (tCr) were calculated with LCModel, using an unsuppressed water scan as the internal reference. Along with MRSI, baseline T2 lesion volume (T2LV) and normalised brain volume (NBV) were calculated. Clinical measures were acquired as per MS-SMART protocol at baseline and 96 weeks.² To determine the association between baseline neurometabolites and 9-hole peg test (9HPT) and Paced auditory serial addition test (PASAT) scores at 96 weeks, multiple regression analysis was used with trial arm, age, sex, disease duration, relapses preceding study entry, T2LV and NBV at baseline as the covariates.

Results

At baseline, mean age of the cohort was 55 years (sd 7.1) and 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (IQR 1.0), mean PASAT score 42.8, 95% CI [40.4-45.2], mean 9HPT (sec^-1) 0.036, 95% CI [0.034-0.037] and median T2LV 9.0mL (IQR 13.6). At 96 weeks, mean 9HPT (sec^-1) was 0.034, 95% CI [0.032-0.036] and mean PASAT3 score was 43.6, 95% CI [40.8-46.3]. Baseline tNAA (β = 0.22, 95% CI [0.02-0.41], p = 0.03) and tNAA/tCr (β = 0.23, 95% CI [0.5-0.42], p = 0.02) in NAWM were associated with 9HPT at 96 weeks. Baseline NAWM tNAA and tNAA/tCr were not significantly associated with 96-week PASAT scores.

Conclusions

Baseline neuroaxonal integrity in NAWM as measured by tNAA and tNAA/tCr are associated with upper limb function at 96-weeks. Baseline neuroaxonal integrity in NAWM was not associated with a measure of processing speed at 96 weeks.

1. Chataway J et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol 2020

2. Connick P et al. Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis. BMJ Open 2018

Background

MS-SMART is a recently reported phase 2b randomised placebo controlled multi-arm study of the neuroprotective potential of amiloride, fluoxetine and riluzole in secondary progressive multiple sclerosis [NCT01910259]. No change in atrophy rate was observed in any arm compared to placebo. We obtained brain metabolic data using proton magnetic resonance spectroscopic imaging (MRSI) at baseline and 96 weeks to explore postulated candidate drug mechanisms of action for the three interventions. Fluoxetine has previously shown an increase in total N-acetyl aspartate plus N-acetyl aspartyl glutamate [tNAA]; myoinositol was also examined as a marker of astrogliosis. Amiloride blocks the acid sensing ion channel-1 receptor that mediates sodium and calcium and therefore could increase neuroaxonal integrity (tNAA). It is known that riluzole decreases glutaminergic transmission.

Objectives

MRSI data at baseline and then 96 weeks was used to interrogate drug specific effects of fluoxetine on tNAA and myoinositol (mIns); riluzole on Glx (glutamate + glutamine); and amiloride on tNAA levels, all compared to placebo.

Methods

108 participants from the MS-SMART trial were included and had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR =35/2000ms) at 3T. Metabolite levels and ratios to creatine (tCr) were determined for normal appearing white matter (NAWM) and grey matter (GM) with LCModel using an unsuppressed water scan as the internal reference. Multiple regression models adjusting for age, sex and baseline Expanded Disability Status Scale (EDSS) were used.

Results

Mean age of the entire cohort was 55 (sd 7.1) years, 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (range 4.0-6.5) and median T2 lesion volume 9.0mL (IQR 6.0).

In the fluoxetine arm, there was no significant change in tNAA (or tNAA/Cr) in NAWM or GM; mIns/tCr (but not mIns) was lower at 96 weeks (β = -0.21, 95% CI [-0.40 to -0.02], p = 0.03) in NAWM (but not GM).

In the riluzole arm, there was a reduction in GM Glx (β = -0.25, 95% CI [-0.47 to -0.04], p = 0.02) and Glx/tCr (β = -0.29, 95% CI [-0.50 to -0.08], p = 0.007), but no change was seen in NAWM.

In the amiloride arm, there was no change in tNAA (or tNAA/tCr) in NAWM or GM.

Conclusions

Neither fluoxetine nor amiloride had any effect on proposed measures of neuroaxonal integrity in NAWM or GM as reflected in tNAA levels. There was a fluoxetine reduction in NAWM mIns/tCr perhaps reflecting some decrease in astrogliosis. Riluzole decreased GM Glx levels as anticipated. However, despite these target effects for these drugs, ultimately they did not translate into a reduction in atrophy rate in the trial.

Background

Cognitive dysfunction is common in multiple sclerosis (MS) and is particularly prevalent in patients with progressive forms of the disease [1]. Exploring neurofilament associations has clear value in trying to develop treatments for cognition.

Objectives

To perform a post-hoc analysis of the MS-STAT trial [2], assessing serum neurofilament light (sNFL) and heavy (sNFH) as predictive biomarkers of future cognitive performance.

Methods

Serum samples were analysed for sNFL and sNFH using Single Molecule Array (Simoa). Cognition was assessed at months 0, 12 and 24 with a detailed neuropsychometric battery including the Wechsler Abbreviated Scale of Intelligence (WASI) and Brain Injury Rehabilitation Trust Memory and Information Processing Battery (BMIPB), as previously described [3]. Multivariate regression models were used for cross-sectional analysis, and linear mixed models were used to assess the predictive value of dichotomised baseline sNFL and sNFH on changes in cognition. All analyses controlled for the established MRI variables of whole brain volume (WBV) and T2 lesion volume (T2LV) in order to assess the extent to which sNFL and sNFH provided additional prognostic value.

Results

Cross-sectional analyses:

After adjusting for demographics, T2LV and WBV, neither sNFL nor sNFH demonstrated cross-sectional associations with current cognitive performance.

Longitudinal analyses:

Patients with high baseline sNFL experienced significantly greater cognitive decline from 0 to 24 months in WASI full-scale IQ (95% CI of coefficient -0.238 to -0.024), WASI Verbal IQ (-0.281 to -0.011), and in both immediate and delayed BMIPB figure recall (-0.489 to -0.046 and -0.399 to -0.025, respectively). sNFH was not associated with changes in cognitive performance.

Conclusions

Our results demonstrate the prognostic value of sNFL on future changes in cognitive performance in SPMS, assessed through a detailed neuropsychometric battery. sNFL remained significantly associated with future cognitive decline whilst controlling for established MRI biomarkers, suggesting that it may provide additional utility in identifying those who may benefit most from interventions aimed at preventing cognitive decline.

1. Sumowski JF et al (2018) Cognition in multiple sclerosis: State of the field and priorities for the future. Neurology

2. Chataway J et al (2014) Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet

3. Chan D et al (2017) Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol