Microglia activation in cerebellum increases with proximity to the fourth ventricle in progressive MS.

Text: Introduction. Cerebellar pathology contributes to disease progression in multiple sclerosis (MS). Neuroimaging studies show that demyelination in the normal appearing brain and cerebellum tends to occur mainly close to the inner (periventricular) and/or outer (subpial) surfaces, possibly driven by cerebro-spinal fluid inflammatory factors. Aims. To investigate the periventricular distribution of neuroinflammat ion in the cerebellum in relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) relative to healthy controls (HC) using integrated 3 Tesla Magnetic Resonance/Positron Emission Tomography (MR-PET) with C-PBR28, a tracer for activated microglia. Methods. Sixteen RRMS, 15 SPMS and 16 HC underwent 90' C-PBR28 MR-PET scan to obtain 60-90' standardized uptake values normalized by a pseudo-reference region (SUVR), at different distances from the IV ventricle. Fourth ventricle masks were segmented with Freesurfer from anatomical T1 images and concentric periventricular slices were extracted from normal appearing cerebellar tissue underlying the cerebellar cortex at 3-6, 6-9 and 9-12 mm from the IV ventricle. To avoid partial volume effects, the first slice extending 0 to 3 mm from the ventricle was excluded. Mean SUVR values from each slice were obtained with FSL in RRMS, SPMS and HC. Matched pairs t-test was used to estimate uptake differences among the three slices in each group. Multiple linear regression was applied to compare tracer uptake at similar distance among the three groups, age and radiotracer binding affinity being covariates of no interest. Results. Each group (RRMS, SPMS, HC) showed a gradient in PBR SUVR decreasing from the IV ventricle towards the cortex (p< 0.05). At similar distance from IV ventricle, a significant difference in SUVR was present only when comparing SPMS to HC. This difference was more marked close to the IV ventricle (p= 0.03 at 3-6 mm, p= 0.04 at 6-9 mm, p= 0.05 at 9-12 mm). This pattern was present also when comparing SPMS to RRMS though the uptake did not significantly differ between them. Conclusion. Cerebellar C-PBR 28 tracer uptake showed, relative to HC, a mild decreasing gradient from the IV ventricle in SPMS but not in RRMS. This finding suggests that neuroinflammation, although diffuse, tends to be higher near the inner cerebellar surface, at least in progressive disease. Further investigation is needed to clarify the role of neuroinflammation in the pathogenesis of cerebellar demyelination.