Imperial College London
Alternate

ProfessorRichardNicholas

Faculty of Medicine, Department of Brain Sciences

Professor of Practice (Neurology)
 
 
 
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Contact

 

r.nicholas

 
 
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Location

 

12L12CLab BlockCharing Cross Campus

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Summary

 

Publications

Citation

BibTex format

@article{Gafson:2019:10.1212/NXI.0000000000000562,
author = {Gafson, AR and Savva, C and Thorne, T and David, MJ and Gomez-Romero, B and Lewis, M and Nicholas, R and Heslegrave, A and Zetterberg, H and Matthews, P},
doi = {10.1212/NXI.0000000000000562},
journal = {Neurology, Neuroimmunology and Neuroinflammation},
title = {Breaking the cycle: reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate},
url = {http://dx.doi.org/10.1212/NXI.0000000000000562},
volume = {6},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - ObjectiveTo infer possible molecular effectors of therapeutic effects and adverse events for the pro-drug dimethyl fumarate (DMF, Tecfidera) in the plasma of relapsing-remitting MS patients (RRMS) based on untargeted blood plasma metabolomics. MethodsBlood samples were collected from 27 RRMS patients at baseline and six weeks after initiation of treatment with DMF (BG-12; Tecfidera). Patients were separated into a discovery (n=15) and a validation cohort (n=12). Ten healthy controls were also recruited and blood samples were collected over the same time intervals. Untargeted metabolomic profiling using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was performed on plasma samples from the discovery cohort and healthy controls at Metabolon Inc. (Durham, NC). UPLC-MS was then performed on samples from the validation cohort at the National Phenome Centre (Imperial College, UK). Plasma neurofilament concentration (NfL) was also assayed for all subjects using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional statistical analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events. Results       In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine were increased 6-weeks after the start of treatment (q < 0.05). We confirmed that methyl succinyl carnitine was also increased in the validation cohort 6-weeks after the start of treatment (q < 0.05). Changes in concentrations of these metabolites were not seen over a similar time period in blood from the untreated healthy control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing, abdominal symptoms. The mean plasma NfL concentration before treatment was higher in the RRMS patients than in the healthy contro
AU  - Gafson,AR
AU  - Savva,C
AU  - Thorne,T
AU  - David,MJ
AU  - Gomez-Romero,B
AU  - Lewis,M
AU  - Nicholas,R
AU  - Heslegrave,A
AU  - Zetterberg,H
AU  - Matthews,P
DO  - 10.1212/NXI.0000000000000562
PY  - 2019///
SN  - 2332-7812
TI  - Breaking the cycle: reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate
T2  - Neurology, Neuroimmunology and Neuroinflammation
UR  - http://dx.doi.org/10.1212/NXI.0000000000000562
UR  - http://hdl.handle.net/10044/1/68184
VL  - 6
ER  -
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