Magnetic resonance elastography (MRE) is an imaging method that reveals the mechanical properties of tissue, modelled as a combination of " viscosity" and " elasticity" . We recently showed reduced brain viscoelasticity in multiple sclerosis (MS) patients compared with healthy controls, and in the relapsing-remitting disease model experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which these intrinsic tissue properties become altered remain unclear. This study investigates whether distinct regions in the mouse brain differ in their native viscoelastic properties, and how these properties are affected during chronic EAE in C57Bl/6 mice and in mice lacking the cytokine interferon-gamma. IFN-γ(-/-) mice exhibit a more severe EAE phenotype, with amplified inflammation in the cerebellum and brain stem. Brain scans were performed in the sagittal plane using a 7 T animal MRI scanner, and the anterior (cerebral) and posterior (cerebellar) regions analyzed separately. MRE investigations were accompanied by contrast-enhanced MRI scans, and by histopathology and gene expression analysis ex vivo. Compared with the cerebrum, the cerebellum in healthy mice has a lower viscoelasticity, i.e. it is intrinsically " softer" . This was seen both in the wild-type mice and the IFNγ(-/-) mice. During chronic EAE, C57Bl/6 mice did not show altered brain viscoelasticity. However, as expected, the IFNγ(-/-) mice showed a more severe EAE phenotype, and these mice did show altered brain elasticity during the course of disease. The magnitude of the elasticity reduction correlated with F4/80 gene expression, a marker for macrophages/microglia in inflamed central nervous system tissue. Together these results demonstrate that MRE is sensitive enough to discriminate between viscoelastic properties in distinct anatomical structures in the mouse brain, and to confirm a further relationship between cellular inflammation and mechanical alterations of the brain. This study underscores the utility of MRE to monitor pathological tissue alterations in vivo.

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Based on our previous data on the presence of very small superparamagnetic iron oxide nanoparticles (VSOP) on brain endothelial structures during experimental autoimmune encephalomyelitis (EAE), we investigated the mechanisms of VSOP binding on inflamed brain endothelial cells in vivo and in vitro. After intravenous application, VSOP were detected in brain endothelial cells of EAE animals at peak disease and prior to clinical onset. In vitro, inflammatory stimuli increased VSOP uptake by brain endothelial bEnd.3 cells, which we confirmed in primary endothelial cells and in bEnd.3 cells cultured under shear stress. Transmission electron microscopy and blocking experiments revealed that during inflammation VSOP were endocytosed by bEnd.3. Modified sulfated glycosaminoglycans (GAG) on inflamed brain endothelial cells were the primary binding site for VSOP, as GAG degradation and inhibition of GAG sulfation reduced VSOP uptake. Thus, VSOP-based MRI is sensitive to visualize early neuroinflammatory processes such as GAG modifications on brain endothelial cells.

Purpose Bevacizumab, ranibizumab, and aflibercept are commonly used to treat neovascular age-related macular degeneration (nAMD). The results of various interventional, mostly randomized head-to-head studies, indicate statistical non-inferiority of these three drugs. The results of these studies are often interpreted as the three drugs being freely interchangeable, resulting in some health systems to pressure ophthalmologists to preferentially use the less expensive bevacizumab. This study analyzes switching from aflibercept or ranibizumab to bevacizumab and back under real-world conditions in order to investigate the assumption of interchangeability of the drugs. Methods Treatment data of IVT patients with diagnosed nAMD were extracted from the clinical Berlin Macular Registry database. Patients who underwent a drug switch from aflibercept or ranibizumab to bevacizumab were subject of this study. Statistical comparisons were pre-planned for best corrected visual acuity, central retinal thickness, macular volume, and length of injection interval. Additional endpoints were analyzed descriptively. Results Mean visual acuity decreased from 0.57 ± 0.05 under aflibercept/ranibizumab to 0.68 ± 0.06 logMAR after the switch (P = 0.001; N = 63). CRT increased from 308 ± 11 µm to 336 ± 16 µm (P = 0.011; N = 63). About half of the subjects were switched back: visual acuity increased from 0.69 ± 0.08 logMAR to 0.58 ± 0.09 logMAR (N = 26). CRT decreased from 396 ± 28 to 337 ± 20 µm (N = 28). Conclusion The data provides real-world evidence that there is loss of visual acuity and an increase in retinal edema after switching to bevacizumab. Thus, the assumption of free interchangeability cannot be confirmed in this cohort.