Evidence map›Paper›PMID 31086805›Full record

ArticleNeurology(R) neuroimmunology & neuroinflammation2019

Breaking the cycle: Reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate.

Arie R Gafson, Constantinos Savva, Tom Thorne, Mark David, Maria Gomez-Romero, Matthew R Lewis, Richard Nicholas, Amanda Heslegrave, Henrik Zetterberg, Paul M Matthews

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurology(R) neuroimmunology & neuroinflammation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed, 1 pooled it
1.5field-weighted citation impact, top 18% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

17 citing papers in PubMed, 1 synthesis or guideline pooled it, 20 citations in OpenAlex.

  1. Pooled it
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  11. Review
  12. Emerging Therapeutic Applications for Fumarates.Trends in pharmacological sciences · 2021
    Review
  13. Effect of Fluorofenidone Against Paraquat-Induced Pulmonary Fibrosis Based on Metabolomics and Network Pharmacology.Medical science monitor : international medical journal of experimental and clinical research · 2021
    Article
  14. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 4 institutions in 2 countries.

Arie R GafsonDivision of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.
Constantinos SavvaDivision of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.
Tom ThorneDivision of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.
Mark DavidDivision of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.
Maria Gomez-RomeroDivision of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.
Matthew R LewisDivision of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.
Richard NicholasDivision of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.
Amanda HeslegraveDivision of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.
Henrik ZetterbergDivision of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.
Paul M MatthewsDivision of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.
Imperial College London · GBUniversity of Gothenburg · SENational Hospital for Neurology and Neurosurgery · GBUniversity of Oxford · GB

Funding

Medical Research Council MC_PC_12025Medical Research Council MC_PC_17114Medical Research Council MR/N026934/1Wellcome Trust
6 · The paper itself

Abstract

Objective: To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in patients with relapsing-remitting MS (RRMS) using untargeted plasma metabolomics. Methods: Plasma from 27 patients with RRMS was collected at baseline and 6 weeks after initiating DMF. Patients were separated into discovery (n = 15) and validation cohorts (n = 12). Ten healthy controls were also recruited. Metabolomic profiling using ultra-high-performance liquid chromatography mass spectrometry (UPLC-MS) was performed on the discovery cohort and healthy controls at Metabolon Inc (Durham, NC). UPLC-MS was performed on the validation cohort at the National Phenome Centre (London, UK). Plasma neurofilament concentration (pNfL) was assayed using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional 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 increased 6 weeks following treatment (q < 0.05). Methyl succinyl-carnitine increased in the validation cohort (q < 0.05). These changes were not observed in the control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing and abdominal symptoms). pNfL concentration was higher in patients with RRMS than in controls and reduced over 15 months of treatment. Conclusion: TCA cycle intermediates and metabolites are increased in patients with RRMS treated with DMF. The results suggest reversal of flux through the succinate dehydrogenase complex. The contribution of succinyl-carnitine ester agonism at hydroxycarboxylic acid receptor 2 to both therapeutic effects and adverse events requires investigation.

Indexed as

MetabolomeAdultCitric Acid CycleCohort StudiesDimethyl FumarateFemaleHumansImmunologic FactorsMaleMiddle AgedMultiple Sclerosis, Relapsing-RemittingDimethyl FumarateImmunologic Factors

Identifiers

PMID31086805
PMCPMC6481230
OpenAlexW2941923295

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.