Characterisation of tissue-type metabolic content in secondary progressive multiple sclerosis: a magnetic resonance spectroscopic imaging study

Marshall, Ian; Thrippleton, Michael J.; Bastin, Mark E.; Mollison, Daisy; Dickie, David Alexander; Chappell, Francesca M; Semple, Scott; Cooper, Annette; Pavitt, Sue; Giovannoni, Gavin; Wheeler-Kingshott, C; Solanky, Bhavana; Weir, Christopher J.; Stallard, Nigel; Hawkins, Clive; Sharrack, Basil; Chataway, Jeremy; Connick, Peter; Chandran, Siddharthan

doi:10.1007/s00415-018-8903-y

Cited by 9 publications

(6 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 1 H-MRS and MRSI methods allow quantitative measurements of brain metabolites that provide useful markers for disease investigation and longitudinal evaluations. MRS techniques have been applied to study numerous brain conditions and disorders, including brain development, 7,115 drug discovery and evaluation, 14 and several diseases and disorders, such as human immunodeficiency virus/acquired immunodeficiency syndrome, 10,[116][117][118][119] Alzheimer's disease and mild cognitive impairment, 120 multiple sclerosis, 121,122 schizophrenia, 123 Parkinson's disease, 124,125 amyotrophic lateral sclerosis, 126 fetal alcohol spectrum disorders, 127 Tourette syndrome, 128 and autism. 129,130 As discussed earlier, MRS/MRSI acquisitions are necessarily long to attain data with sufficient SNR, rendering these acquisitions susceptible to subject and scanner instabilities.…”

Section: Clinical Investigationsmentioning

confidence: 99%

Motion correction in magnetic resonance spectroscopy

Saleh

Edden

Chang

et al. 2020

Magnetic Resonance in Med

View full text Add to dashboard Cite

In vivo proton magnetic resonance spectroscopy and spectroscopic imaging (MRS/MRSI) are valuable tools to study normal and abnormal human brain physiology. However, they are sensitive to motion, due to strong crusher gradients, long acquisition times, reliance on high magnetic field homogeneity, and particular acquisition methods such as spectral editing. The effects of motion include incorrect spatial localization, phase fluctuations, incoherent averaging, line broadening, and ultimately quantitation errors. Several retrospective methods have been proposed to correct motion‐related artifacts. Recent advances in hardware also allow prospective (real‐time) correction of the effects of motion, including adjusting voxel location, center frequency, and magnetic field homogeneity. This article reviews prospective and retrospective methods available in the literature and their implications for clinical MRS/MRSI. In combination, these methods can attenuate or eliminate most motion‐related artifacts and facilitate the acquisition of high‐quality data in the clinical research setting.

show abstract

Section: Clinical Investigationsmentioning

confidence: 99%

Motion correction in magnetic resonance spectroscopy

Saleh

Edden

Chang

et al. 2020

Magnetic Resonance in Med

View full text Add to dashboard Cite

show abstract

“…% standard deviations) of the fitted spectra exceeded 20% for any metabolite or 40% for myoinositol. 88 At the London site, the participating patients underwent a standardised MRS sequence on a Philips Achieva 3T MRI scanner (Philips Healthcare, Best, the Netherlands) using a 16-channel neurovascular coil. A 15-mm single-slice-thick volume of interest (VOI) was selected for MRS placed superior to the lateral ventricles.…”

Section: Magnetic Resonance Spectroscopymentioning

confidence: 99%

Amiloride, fluoxetine or riluzole to reduce brain volume loss in secondary progressive multiple sclerosis: the MS-SMART four-arm RCT

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability accrual in secondary progressive multiple sclerosis. Amiloride, fluoxetine and riluzole are repurposed drugs with potential neuroprotective effects. Objectives To assess whether or not amiloride, fluoxetine and riluzole can reduce the rate of brain volume loss in people with secondary progressive multiple sclerosis over 96 weeks. The secondary objectives that were assessed were feasibility of a multiarm trial design approach, evaluation of anti-inflammatory effects, clinician- and patient-reported efficacy and three mechanistic substudies. Design A multicentre, multiarm, randomised, double-blind, placebo-controlled, parallel-group Phase IIb trial with follow-up at 4, 8, 12, 24, 36, 48, 72 and 96 weeks. Patients, investigators (including magnetic resonance imaging analysts), and treating and independent assessing neurologists were blinded to the treatment allocation. The target sample size was 440 patients. Setting Thirteen UK clinical neuroscience centres. Participants Participants were aged 25–65 years, had secondary progressive multiple sclerosis with evidence of disease progression independent of relapses in the previous 2 years, and had an Expanded Disability Status Scale score of 4.0–6.5. Patients were ineligible if they could not have a magnetic resonance imaging scan; had a relapse or steroids in the previous 3 months; or had epilepsy, depression, bipolar disorder, glaucoma, bleeding disorders or significant organ comorbidities. Exclusion criteria were concurrent disease-modified treatments, immunosuppressants or selective serotonin reuptake inhibitors. Interventions Participants received amiloride (5 mg), fluoxetine (20 mg), riluzole (50 mg) or placebo (randomised 1 : 1 : 1 : 1) twice daily. Main outcome measures The primary end point was magnetic resonance imaging-derived percentage brain volume change at 96 weeks. Secondary end points were new/enlarging T2 lesions, pseudoatrophy, and clinician- and patient-reported measures (including the Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Symbol Digit Modalities Test, low-contrast letter visual acuity, Multiple Sclerosis Impact Scale 29 items, version 2, Multiple Sclerosis Walking Scale, version 2, and questionnaires addressing pain and fatigue). The exploratory end points included measures of persistent new T1 hypointensities and grey matter volume changes. The substudies were advanced magnetic resonance imaging, optical coherence tomography and cerebrospinal fluid analyses. Results Between December 2014 and June 2016, 445 patients were randomised (analysed) to amiloride [n = 111 (99)], fluoxetine [n = 111 (96)], riluzole [n = 111 (99)] or placebo [n = 112 (99)]. A total of 206 randomised patients consented to the advanced magnetic resonance imaging substudy, 260 consented to the optical coherence tomography substudy and 70 consented to the cerebrospinal fluid substudy. No significant difference was seen between the active drugs and placebo in percentage brain volume change at week 96 as follows (where negative values mean more atrophy than placebo): amiloride minus placebo 0.0% (Dunnett-adjusted 95% confidence interval –0.4% to 0.5%), fluoxetine minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.5% to 0.3%); riluzole minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.6% to 0.3%). There was good adherence to study drugs. The proportion of patients experiencing adverse events was similar in the treatment and placebo groups. There were no emergent safety issues. Limitations There was a lower than expected uptake in the cerebrospinal fluid substudy. Conclusions A multiarm Phase II paradigm is efficient in determining which neuroprotective agents to take through to Phase III trials. Amiloride, fluoxetine and riluzole were not effective in reducing the brain atrophy rate in people with secondary progressive multiple sclerosis. Mechanistic pathobiological insight was gained. Future work To use the information gained from the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) to inform future trial design as new candidate agents are identified. Trial registration Current Controlled Trials ISRCTN28440672, NCT01910259 and EudraCT 2012-005394-31. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 3. See the NIHR Journals Library website for further project information. This trial also received funding from the UK MS Society and the US National Multiple Sclerosis Society.

show abstract

“…Recently, we and others showed that MS lesion characteristics in autopsy tissue are associated with the clinical disease course of MS, in which the proportion of mixed active/inactive (chronic active) lesions was significantly associated with disease progression . This chronic lesion activity is not identifiable with commonly used MRI techniques, although recent 7T MRI and PET‐MRI studies have shown the prognostic potential of these approaches for detection and quantification of these mixed active/inactive lesions in living MS patients .…”

Section: Introductionmentioning

confidence: 98%

Post‐mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms

et al. 2019

View full text Add to dashboard Cite

Over the last few decades, several common single nucleotide polymorphisms (SNPs) have been identified that correlate with clinical outcome in multiple sclerosis (MS), but the pathogenic mechanisms underlying the clinical effects of these SNPs are unknown. This is in part because of the difficulty in the functional translation of genotype into disease‐relevant mechanisms. Building on our recent work showing the association of clinical disease course with post‐mortem MS lesion characteristics, we hypothesized that SNPs that correlate with clinical disease course would also correlate with specific MS lesion characteristics in autopsy tissue. To test this hypothesis, 179 MS brain donors from the Netherlands Brain Bank MS autopsy cohort were genotyped for 102 SNPs, selected based on their reported associations with clinical outcome or their associations with genes that show differential gene expression in MS lesions. Three SNPs linked to MS clinical severity showed a significant association between the genotype and either the proportion of active lesions (rs2234978/FAS and rs11957313/KCNIP1) or the proportion of mixed active/inactive lesions (rs8056098/CLEC16A). Three SNPs linked to MS pathology‐associated genes showed a significant association with either proportion of active lesions (rs3130253/MOG), incidence of cortical gray matter lesions (rs1064395/NCAN) or the proportion of remyelinated lesions (rs5742909/CTLA4). In addition, rs2234978/FAS T‐allele carriers showed increased FAS gene expression levels in perivascular T cells and perilesional oligodendrocytes, cell types that have been implicated in MS lesion formation. Thus, by combining pathological characterization of MS brain autopsy tissue with genetics, we now start to translate genotypes linked to clinical outcomes in MS into mechanisms involved in MS lesion pathogenesis.

show abstract

Characterisation of tissue-type metabolic content in secondary progressive multiple sclerosis: a magnetic resonance spectroscopic imaging study

Cited by 9 publications

References 19 publications

Motion correction in magnetic resonance spectroscopy

Motion correction in magnetic resonance spectroscopy

Amiloride, fluoxetine or riluzole to reduce brain volume loss in secondary progressive multiple sclerosis: the MS-SMART four-arm RCT

Post‐mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms

Contact Info

Product

Resources

About