Multiple sclerosis (MS) is commonly regarded as an inflammatory disease, but it also has a neurodegenerative component, which represents an additional target for treatment. The use of MRI to evaluate the inflammatory disease component in 'proof-of concept' clinical trials is well established, but no systematic assessment of imaging outcomes to evaluate neuroprotection or repair in MS has been performed. In this Review, we examine the potential of traditional and novel imaging parameters to serve as primary outcomes in phase II clinical trials of neuroprotective and reparative strategies in MS. We present the conclusions of an international meeting of imaging, clinical and statistical experts, as well as a review of relevant literature. The available imaging techniques are appraised in five categories of performance: pathological specificity, reproducibility, sensitivity to change, clinical relevance, and response to treatment. At present, the three most promising primary outcomes in phase II trials of neuroprotective and/or reparative strategies in MS are: changes in whole-brain volume to gauge general cerebral atrophy; T1 hypointensity and magnetization transfer ratio to monitor the evolution of lesion damage; and optical coherence tomography findings to evaluate the anterior visual pathway. Power calculations show that these outcome measures can be applied with attainable sample sizes.
Multiple sclerosis (MS) is not only an inflammatory demyelinating disease; it also involves neurodegeneration, which starts early in the disease process
Development of new neuroprotective and reparative treatments for MS has been hampered by lack of sensitive clinical response criteria
Imaging outcomes provide the best current in vivo measures of neuroprotection, and possibly also of repair, in MS
Brain-volume change on serial MRI provides a sensitive overall measure of neuroprotection in MS trials over the course of a year
Magnetization transfer ratio and T1 hypointensity provide lesional measures of neuroprotection and repair over the course of 6–9 months
Optical coherence tomography is a robust measure of axonal damage in the anterior visual pathways
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The workshop on Imaging Outcomes for Protection and Repair in Multiple Sclerosis in Amsterdam, The Netherlands (28–29 August 2008) was supported by the National Multiple Sclerosis Society (New York, USA) as an activity of its International Advisory Committee on Clinical Trials in Multiple Sclerosis. The Amsterdam MS Center is supported by the Dutch Foundation for MS Research (Voorschoten, The Netherlands). The Johns Hopkins Multiple Sclerosis Center is supported by the National MS Society (USA), the Nancy Davis Foundation and the National Institute of Neurological Disorders and Stroke, NIH (Bethesda, MD, USA). The NMR Research Unit at the Institute of Neurology, London, UK is supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland. We thank Hanneke Hulst for providing Figure 2 and Paul Matthews for providing a template from which Figure 4 was adapted. We also thank Douglas Arnold and Laura Balcer for providing details about the power calculations.
The authors declare no competing financial interests.
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Barkhof, F., Calabresi, P., Miller, D. et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 5, 256–266 (2009). https://doi.org/10.1038/nrneurol.2009.41
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