Ion channels and pain in Fabry disease.

Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A (α-Gal A) activity which results in progressive accumulation of globotriaosylceramide (Gb3) and related metabolites. One prominent feature of Fabry disease is neuropathic pain. Accumulation of Gb3 has been documented in dorsal root ganglia (DRG) as well as other neurons, and has lately been associated with the mechanism of pain though the pathophysiology is still unclear. Small fiber (SF) neuropathy in FD differs from other entities in several aspects related to the perception of pain, alteration of fibers as well as drug therapies used in the practice with patients, with therapies far from satisfying. In order to develop better treatments, more information on the underlying mechanisms of pain is needed. Research in neuropathy has gained momentum from the development of preclinical models where different aspects of pain can be modelled and further analyzed. This review aims at describing the different in vitro and FD animal models that have been used so far, as well as some of the insights gained from their use. We focus especially in recent findings associated with ion channel alterations -that apart from the vascular alterations-, could provide targets for improved therapies in pain.

Evaluation of early microstructural changes in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MR imaging.

Diffusion MRI (dMRI) has been able to detect early structural changes related to neurological symptoms present in Huntington's disease (HD). However, there is still a knowledge gap to interpret the biological significance at early neuropathological stages. The purpose of this study is two-fold: (i) establish if the combination of Ultra-High Field Diffusion MRI (UHFD-MRI) techniques can add a more comprehensive analysis of the early microstructural changes observed in HD, and (ii) evaluate if early changes in dMRI microstructural parameters can be linked to cellular biomarkers of neuroinflammation. Ultra-high field magnet (16.7T), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) techniques were applied to fixed ex-vivo brains of a preclinical model of HD (R6/1 mice). Fractional anisotropy (FA) was decreased in deep and superficial grey matter (GM) as well as white matter (WM) brain regions with well-known early HD microstructure and connectivity pathology. NODDI parameters associated with the intracellular and extracellular compartment, such as intracellular ventricular fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fractions (IsoVF) were altered in R6/1 mice GM. Further, histological studies in these areas showed that glia cell markers associated with neuroinflammation (GFAP & Iba1) were consistent with the dMRI findings. dMRI can be used to extract non-invasive information of neuropathological events present in the early stages of HD. The combination of multiple imaging techniques represents a better approach to understand the neuropathological process allowing the early diagnosis and neuromonitoring of patients affected by HD.