Exploratory trials (phase II)

Definitive trials (phase III)

Outcome measure



Sampling frequency



Main carrier

Gadolinium T1

Unenhanced T2

Principal target

Individual lesion

Lesion load

Method of detection


Computer assisted

Required resolution



Outcome parameter

Number (volume) of lesion

Change in lesion volume

Source: From Ref. 239.

Source: From Ref. 239.

White Matter Study Group of the International Society for MR in Medicine has indeed recommended the use of MT MRI in the context of MS clinical trials as an adjunctive outcome measure (260). Several recent MS clinical trials have already incorporated MT MRI, with a view to assess the impact of treatment on demyelina-tion and axonal loss. To our knowledge, MT MRI has been used in phase II and phase III trials for RRMS (injectable and oral IFN beta-1a, IFN beta-1b, oral gla-tiramer acetate) and SPMS (IFN beta-1b and immunoglobulins). In these trials, MT MRI acquisition has been limited to highly specialized MR centers and only subgroups of patients (about 50-100 per trial) have been studied using MT MRI. The results of two of these trials have been published and have shown a lack of an effect of IFN beta-1b (261) and intravenous immunoglobulins (262) on MT MRI-derived quantities of the whole brain tissue and NAWM from patients with SPMS. Few studies were conducted at single centers with small numbers of patients (263-265) and have achieved conflicting results. Two of these studies have shown that treatment with IFN beta-1a (264) or IFN beta-1b (265) favorably modifies the recovery of MTR values which follows the ceasement of enhancement in newly formed lesions from RRMS patients. On the contrary, Richert et al. (265) did not find any significant difference in the MTR values of NAWM before and during IFN beta-1b therapy, as well as in the parameters derived from whole brain MTR histograms (263).

Only a few studies have been conducted to evaluate the effect of disease-modifying MS treatments on 1H-MRS-derived parameters (266-269). Using monthly 1H-MRS scans, Sarchielli et al. (266) found that treatment with IFN beta-1a has an impact on Cho peaks in spectra of lesions from RRMS patients, suggesting an increase in lesion membrane turnover during the first period of treatment. Narayanan et al. (267) found increased NAA levels in a small group of RRMS patients after one year of treatment with IFN beta-1b, suggesting a potential effect of treatment in preventing chronic, sublethal axonal injury. Schubert et al. (268) showed a stability of metabolite concentration over time in patients with RRMS treated with IFN beta-1b. More recently, Parry et al. (269) monitored with serial single-voxel 1H-MRS 11 patients treated with various formulations of IFN beta and found that the central white matter NAA/Cr ratio continued to decrease over the follow-up, suggesting that reduction of new inflammatory activity with IFN beta does not invariably halt progression of axonal injury.

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