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Published on: July 28, 2013
Diffuse white matter pathology in multiple sclerosis during treatment with dimethyl fumarate-An observational study
Anders Tisell1,2, Kristina Söderberg3, Yumin Link4
1Department of Medical Radiation Physics in Linköping, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
Background:
Multiple sclerosis (MS) is an inflammatory demyelinating disease with neurodegenerative features causing risk for neurologic irreversible disability over time. Examination of normal-appearing white matter (NAWM) changes in MS by proton magnetic resonance spectroscopy (1H-MRS), may detect diffuse white matter pathology that is associated with neurodegeneration.
Methods:
In this observational study of in total twenty-six patients with MS, starting treatment with dimethyl fumarate (DMF), we measured the absolute concentration of metabolites in periventricular NAWM using 1H-MRS at baseline and after one and three years of treatment. Metabolite concentrations were analyzed both cross-sectionally, in relation to 10 controls and longitudinally in relation to disease activity.
Results:
Patients with MS had higher concentrations of myo-inositol (mIns) in NAWM at baseline compared with controls (mean 5.98 ± 1.37 (SD) and 4.32 ± 1.16 (SD), p<0.01, independent samples t-test). The disease duration was inversely correlated with concentrations of total N-acetylaspartate and N-acetylaspartylglutamate (tNA) (r = -0.62, p<0.01) in NAWM as well as positively to the ratio of mIns and tNA (r = 0.51, p = 0.03). Metabolite concentrations during one-year (n = 19) and three-years (n = 11) follow-up were generally stable. The dropouts were caused by treatment switch after one year, mainly due to new MRI activity. Cross-sectional analyses showed that there was an inverse correlation between concentrations of tNA and mIns at both baseline and at 1 and 3-years follow-up (r = -0.44 to -0.65, p = 0.04 to 0.004). Metabolite concentrations were stable during 1-year follow-up independently of disease activity.
Conclusions:
Higher concentrations of the astrogliosis marker mIns in MS compared to controls, the inverse relation between MS disease duration and the neuroaxonal integrity marker tNA, as well as the consistent inverse relation between these two metabolites during follow-up, showed that non-lesional white matter pathology is present in this cohort of MS patients in early disease stages. However, metabolite concentrations during follow-up were generally stable and did not reflect differences in disease activity among patients.
Insights
Multiple sclerosis (MS) shows elevated myo-inositol (mIns) in normal-appearing white matter (NAWM). Neuroaxonal integrity marker tNA decreases with disease duration, indicating early white matter pathology in MS patients.
Area of Science:
- Neuroimaging
- Neurology
- Biochemistry
Background:
- Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease with progressive neurodegeneration.
- Normal-appearing white matter (NAWM) in MS patients exhibits subtle pathology contributing to irreversible disability.
- Proton magnetic resonance spectroscopy (1H-MRS) can detect diffuse white matter changes associated with neurodegeneration in MS.
Purpose of the Study:
- To investigate white matter metabolite concentrations in MS patients treated with dimethyl fumarate (DMF).
- To assess changes in periventricular NAWM using 1H-MRS at baseline, one year, and three years.
- To correlate metabolite levels with disease duration and activity.
Main Methods:
- Observational study of 26 MS patients starting DMF treatment.
- 1H-MRS used to measure absolute metabolite concentrations in NAWM.
- Cross-sectional analysis with 10 controls and longitudinal analysis of disease activity.
Main Results:
- MS patients had higher myo-inositol (mIns) in NAWM versus controls (p<0.01).
- Disease duration inversely correlated with tNA (neuroaxonal integrity marker) and positively with mIns/tNA ratio (p<0.01).
- Metabolite concentrations remained stable over three years, irrespective of disease activity.
Conclusions:
- Elevated mIns suggests astrogliosis, and decreased tNA with disease duration indicates neuroaxonal damage in early MS.
- Non-lesional white matter pathology is present in early MS.
- Metabolite levels were stable during follow-up and did not correlate with disease activity.
