Quantification of [¹¹C]PIB PET for Imaging Myelin in the Human Brain: A Test—Retest Reproducibility Study in High-Resolution Research Tomography

Abstract

An accurate in vivo measure of myelin content is essential to deepen our insight into the mechanisms underlying demyelinating and dysmyelinating neurological disorders, and to evaluate the effects of emerging remyelinating treatments. Recently [(11)C]PIB, a positron emission tomography (PET) tracer originally conceived as a beta-amyloid marker, has been shown to be sensitive to myelin changes in preclinical models and humans. In this work, we propose a reference-region methodology for the voxelwise quantification of brain white-matter (WM) binding for [(11)C]PIB. This methodology consists of a supervised procedure for the automatic extraction of a reference region and the application of the Logan graphical method to generate distribution volume ratio (DVR) maps. This approach was assessed on a test-retest group of 10 healthy volunteers using a high-resolution PET tomograph. The [(11)C]PIB PET tracer binding was shown to be up to 23% higher in WM compared with gray matter, depending on the image reconstruction. The DVR estimates were characterized by high reliability (outliers <1%) and reproducibility (intraclass correlation coefficient (ICC) >0.95). [(11)C]PIB parametric maps were also found to be significantly correlated (R(2)>0.50) to mRNA expressions of the most represented proteins in the myelin sheath. On the contrary, no correlation was found between [(11)C]PIB imaging and nonmyelin-associated proteins.

Optimizing PiB-PET SUVR change-over-time measurement by a large-scale analysis of longitudinal reliability, plausibility, separability, and correlation with MMSE

“…One potential caveat of WM-containing references for longitudinal analyses is the potential for a confound by changes in WM myelination, which have been shown to affect uptake of β-amyloid PET ligands (Stankoff et al, 2011; Veronese et al, 2015). It is possible that such WM changes over long periods of time could affect the value of a WM-containing reference ROI.…”

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

“…A supervised clustering method already validated for [ 11 C]PiB was used for the extraction of the reference region time activity curve (TAC). 14,20,21 Briefly, this method consists of the multiple regression of all PET image voxel TACs on a predefined set of kinetic classes. After regression, all the voxels associated with the reference class with probability >90% are combined and the average of their TACs defines the reference input function.…”

“…13 A noninvasive parametric voxel-wise quantification procedure based on the extraction of reference regions using a supervised clustering algorithm showing higher reproducibility compared to previously used semiquantitative methods, has recently been shown to allow reliable longitudinal evaluation of [ 11 C]PiB binding in the white matter (WM) of healthy volunteers. 14 Here, we report the results of the first longitudinal study in which PET with [ 11 C]PiB was used to quantify in vivo myelin loss and regeneration in the WM lesions of patients with MS and to explore the clinical relevance of these processes.…”

Exploring the heterogeneity of MS lesions using positron emission tomography: a reappraisal of their contribution to disability

“…This approach allowed to generate voxel‐wise maps of [ 11 C]PIB distribution volume ratio (DVR), reflecting myelin density. Test–retest analyses in healthy controls have shown a more accurate reproducibility of DVR compared to SUV . Further supporting the [ 11 C]PIB selective binding to myelin in vivo , [ 11 C]PIB DVR maps of the WM generated from a group of healthy controls showed a remarkable correlation with the mRNA maps of the Allen Brain Atlas for those genes coding for the major proteins composing the structure of human myelin .…”