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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

Objectives:To explore in-vivo innate immune cell activation as a function of the distance from ventricular CSF in patients with Multiple Sclerosis (MS) using [18F]-DPA714 PET, and to investigate its relationship with periventricular microstructural damage, evaluated by magnetization transfer ratio (MTR), and with trajectories of disability worsening.Methods:Thirty-seven MS patients and nineteen healthy controls underwent MRI and [18F]-DPA714 TSPO dynamic PET, from which individual maps of voxels characterized by innate immune cell activation (DPA+) were generated. White matter (WM) was divided in 3mm-thick concentric rings radiating from the ventricular surface toward the cortex, and the percentage of DPA+ voxels and mean MTR were extracted from each ring. Two-year trajectories of disability worsening were collected to identify patients with and without recent disability worsening.Results:The percentage of DPA+ voxels was higher in patients compared to controls in the periventricular WM (p=6.10e-6), and declined with increasing distance from ventricular surface, with a steeper gradient in patients compared to controls (p=0.001). This gradient was found both in periventricular lesions and normal-appearing WM. In the total WM, it correlated with a gradient of microstructural tissue damage measured by MTR (rs=-0.65, p=1.0e-3). When compared to clinically stable patients, patients with disability worsening were characterized by a higher percentage of DPA+ voxels in the periventricular normal-appearing WM (p=0.025).Conclusions:Our results demonstrate that in MS the innate immune cell activation predominates in periventricular regions and associates with microstructural damage and disability worsening. This could result from the diffusion of pro-inflammatory CSF-derived factors into surrounding tissues.