Abstract
BackgroundQuantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([11C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS.MethodsPatients with active relapsing‐remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [11C]PiB and magnetic resonance imaging. Voxel‐wise maps of [11C]PiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination.ResultsAt baseline, there was a progressive reduction in [11C]PiB binding from the normal‐appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow‐up, high between‐patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta‐coefficient = –0.67 with the Expanded Disability Status Scale; p = 0.003 and beta‐coefficient = –0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index.Interpretation[11C]PiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726–738
Highlights
As the leading cause of onset of neurological disability in young adulthood, multiple sclerosis (MS) presents an enormous social and economic burden in the western world[1]
Demyelination at baseline: a gradient of [11C]Pittsburgh Compound B (PIB) binding decreases from normal-appearing tissue to the center of the lesion Compared to normal-appearing WM (NAWM) in patients, mean distribution volume ratio (DVR) values were significantly lower in perilesional white matter (WM), in T2 lesions, in Gd+ lesions, and in black holes (percent reduction in mean DVR= -30.95% (p
No significant effect on either the index of dynamic demyelination or the index of dynamic remyelination was found for gender, disease duration, temporal distance between the two positron emission tomography (PET) scans, volume of Gd+ lesions, and diseasemodifying treatment (Table 5 in the Supplementary Material), whereas age was a significant contributor to the index of dynamic demyelination only, with older patients showing more extensive dynamic demyelination (p=0.014, beta-coefficient=0.73; Table 5 in the Supplementary Material). In this longitudinal study, for the first time to our knowledge, we used highresolution [11C]PIB-PET images quantified with a novel non-invasive approach to visualize and measure lesional myelin loss and regeneration developing over a few months in a cohort of patients with active relapsingremitting MS
Summary
As the leading cause of onset of neurological disability in young adulthood, multiple sclerosis (MS) presents an enormous social and economic burden in the western world[1]. Advanced MRI sequences, such as magnetization transfer imaging, diffusion-weighted imaging, and T2 relaxometry, which are able to generate quantitative images exploiting physical properties of the brain parenchyma, have been proposed to gain indirect information about the myelin compartment in the human brain 5 These techniques are not specific for myelin because they are affected to various extents by intracellular and extracellular water, axons, edema, and inflammatory infiltration. Following the pilot demonstration indicating that the stilbene Congo red derivative BMB could be used as a myelin tracer suitable for PET imaging[6], a similar affinity for myelin was reported for other stilbene derivatives[7,8,9,10] These tracers, all previously known as amyloid markers, were hypothesized to bind to proteins characterized by a similar conformation contained in amyloid plaques and myelin[11, 12]. Dynamic remyelination was inversely correlated with clinical disability (p=0.006 and beta-coefficient=-0.67 with the Expanded Disability Status Scale; p=0.003 and beta-coefficient=-0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index
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