KCNA2 mutations are rare in hereditary spastic paraplegia

ing good reproducibility of this radiotracer. Raffel et al questioned our normalization method that used a pseudoreference clustering approach based on the identification of voxels with similar C-PBR28 values in MS and controls, located in the central brain normal-appearing white matter. Because pathological and imaging studies reported frequent and diffuse brain microglia/macrophage activation in MS, the use of a consistent anatomical region for normalization would require the assumption that this brain region would be devoid of microglia pathology in all patients. Global brain normalization would also not be optimal in the context of a multifocal disease such as MS. For this reason, a supervised clustering method for normalizing PET data has been previously employed for C-PK11195 TSPO imaging. Although their algorithm was different from ours, both select as reference regions a set of voxels (in the gray matter in their case) in different anatomical areas, which might differ within each individual. Raffel et al made the following assumptions: (1) MS subjects show, relative to controls, higher C-PBR28 plasma concentrations; and (2) this would translate into a global increase in C-PBR28 standardized uptake values (SUV). Hence, the observed increased C-PBR28 uptake in MS would not reflect higher TSPO expression in the brain, and thereby neuroinflammation. Currently, we are not aware of any evidence of peripheral blood inflammation associated with increased plasma TSPO binding in MS. MS subjects and controls showed similar levels of C-PBR28 plasma concentrations, and no differences in the area under the blood curves (Fig). With the exception of the pseudoreference region, volumes of distribution were generally increased in MS relative to healthy subjects. Finally, relative to controls, only secondary progressive MS subjects had globally increased SUV, but not relapsing–remitting MS cases, which, however, exhibited higher C-PBR28 uptake in cortex and cortical lesions. We conclude that our C-PBR28 findings in MS reflect increased brain TSPO expression, suggesting neuroinflammation.