Effect of slight crosslinking on the mechanical relaxation behavior of poly(2-ethoxyethyl methacrylate) chains

The synthesis, thermal and mechanical characterizations of uncrosslinked and lightly crosslinked poly(2-ethoxyethyl methacrylate) are reported. The uncrosslinked poly(2-ethoxyethyl methacrylate) exhibits in the glassy state two relaxations called in increasing order of temperature, the gamma and beta processes respectively. These are followed by a prominent glass rubber or alpha relaxation. By decreasing the chains mobility by a small amount of crosslinking, the beta relaxation disappears and the peak maximum associated with the alpha relaxation is shifted from 268 K to 278 K, at 1 Hz. An investigation of the storage relaxation modulus of the crosslinked polymer indicates two inflexion points that presumably are related to segmental motions of dangling chains of the crosslinked networks and to cooperative motions of the chains between crosslinking points. Nanodomains formed by side-groups flanked by the backbone give rise to a Maxwell Wagner Sillars relaxation in the dielectric spectra that have no incidence in the mechanical relaxation spectra.We thank Dr. J. Guzman (Madrid) for providing us with the CEOEMA sample. This work was financially supported by the DGCYT and CAM through the Grant MAT2008-06725-C03 and MAT2012-33483. In memoriam of Professor Emeritus Evaristo Riande in recognition of his contribution to Polymer Science.Carsí Rosique, M.; Sanchis Sánchez, MJ.; Díaz Calleja, R.; Riande, E.; Nugent, MJD. (2013). Effect of slight crosslinking on the mechanical relaxation behavior of poly(2-ethoxyethyl methacrylate) chains. European Polymer Journal. 49(6):1495-1502. doi:10.1016/j.eurpolymj.2012.12.012S1495150249

Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease

Background Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. Methods To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Results Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Conclusion Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression

Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition

Neuroinflammation is a hallmark of Alzheimer’s disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aβ42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aβ when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity