Dysregulation of energy metabolism in multiple sclerosis measured in vivo with diffusion-weighted spectroscopy

Abstract

Objective:

We employed diffusion-weighted magnetic resonance spectroscopy (DW-MRS), which allows to measure in vivo the diffusion properties of metabolites, to explore the functional neuro-axonal damage and the ongoing energetic dysregulation in multiple sclerosis (MS).

Methods:

Twenty-five patients with MS and 18 healthy controls (HC) underwent conventional magnetic resonance imaging (MRI) and DW-MRS. The apparent diffusion coefficient (ADC) of total N-acetyl-aspartate (tNAA) and creatine–phosphocreatine (tCr) were measured in the parietal normal-appearing white matter (NAWM) and in the thalamic grey matter (TGM). Multiple regressions were used to compare metabolite ADCs between groups and to explore clinical correlations.

Results:

In patients compared with HCs, we found a reduction in ADC(tNAA) in the TGM, reflecting functional and structural neuro-axonal damage, and in ADC(tCr) in both NAWM and TGM, possibly reflecting a reduction in energy supply in neurons and glial cells. Metabolite ADCs did not correlate with tissue atrophy, lesional volume or metabolite concentrations, while in TGM metabolite ADCs correlated with clinical scores.

Conclusion:

DW-MRS showed a reduction in tCr diffusivity in the normal-appearing brain of patients with MS, which might reflect a state of ongoing energy dysregulation affecting neurons and/or glial cells. Reversing this energy dysregulation before neuro-axonal degeneration arises may become a key objective in future neuroprotective strategies.

Keywords

Multiple sclerosis diffusion-weighted spectroscopy energy dysregulation

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References

Simons

Misgeld

Kerschensteiner

A unified cell biological perspective on axon-myelin injury. J Cell Biol 2014; 206: 335–345.

Nave

KA.

Myelination and support of axonal integrity by glia. Nature 2010; 468: 244–252.

Trapp

Stys

PK.

Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 2009; 8: 280–291.

Stys

PK.

General mechanisms of axonal damage and its prevention. J Neurol Sci 2005; 233: 3–13.

Nikic

Merkler

Sorbara

et al . A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 2011; 17: 495–499.

Campbell

Mahad

DJ.

Mitochondrial changes associated with demyelination: Consequences for axonal integrity. Mitochondrion 2012; 12: 173–179.

Nicolay

Braun

Graaf

et al . Diffusion NMR spectroscopy. NMR Biomed 2001; 14: 94–111.

Ronen

Valette

Diffusion-weighted magnetic resonance spectroscopy. eMagRes 2015; 4: 733–750.

Wood

Ronen

Techawiboonwong

et al . Investigating axonal damage in multiple sclerosis by diffusion tensor spectroscopy. J Neurosci 2012; 32: 6665–6669.

10.

Branzoli

Techawiboonwong

Kan

et al . Functional diffusion-weighted magnetic resonance spectroscopy of the human primary visual cortex at 7 T. Magn Reson Med 2013; 69: 303–309.

11.

Lublin

Reingold

Cohen

et al . Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014; 83: 278–286.

12.

Polman

Reingold

Edan

et al . Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘McDonald Criteria’. Ann Neurol 2005; 58: 840–846.

13.

Kurtzke

JF.

Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983; 33: 1444–1452.

14.

Chard

Jackson

Miller

et al . Reducing the impact of white matter lesions on automated measures of brain gray and white matter volumes. J Magn Reson Imaging 2010; 32: 223–228.

15.

Provencher

SW.

Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed 2001; 14: 260–264.

16.

Rovira

Alonso

1H magnetic resonance spectroscopy in multiple sclerosis and related disorders. Neuroimaging Clin N Am 2013; 23: 459–474.

17.

Bates

Strangward

Keelan

et al . Inhibition of N-acetylaspartate production: Implications for 1H MRS studies in vivo. Neuroreport 1996; 7: 1397–1400.

18.

Ciccarelli

Toosy

De Stefano

et al . Assessing neuronal metabolism in vivo by modeling imaging measures. J Neurosci 2010; 30: 15030–15033.

19.

Bjartmar

Kidd

Mork

et al . Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 2000; 48: 893–901.

20.

Tachikawa

Fukaya

Terasaki

et al . Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis. Eur J Neurosci 2004; 20: 144–160.

21.

Beard

Braissant

Synthesis and transport of creatine in the CNS: Importance for cerebral functions. J Neurochem 2010; 115: 297–313.

22.

Baroncelli

Alessandri

Tola

et al . A novel mouse model of creatine transporter deficiency. F1000Res 2014; 3: 228.

23.

Steen

Wilczak

Hoogduin

et al . Reduced creatine kinase B activity in multiple sclerosis normal appearing white matter. PLoS ONE 2010; 5: e10811.

24.

Ercan

Magro Checa

Valabregue

et al . Glial and axonal changes in systemic lupus erythematosus evidenced by metabolite diffusion. Brain 2016; 139: 1447–1457.

25.

Popescu

Klaver

Voorn

et al . What drives MRI-measured cortical atrophy in multiple sclerosis? Mult Scler 2015; 21: 1280–1290.

26.

Geurts

Kooi

Witte

et al . Multiple sclerosis as an ‘inside-out’ disease. Ann Neurol 2010; 68: 767–768 (author reply 768).

27.

Stys

Zamponi

van Minnen

et al . Will the real multiple sclerosis please stand up? Nat Rev Neurosci 2012; 13: 507–514.

28.

Tewarie

Schoonheim

Schouten

et al . Functional brain networks: Linking thalamic atrophy to clinical disability in multiple sclerosis, a multimodal fMRI and MEG study. Hum Brain Mapp 2015; 36: 603–618.