Chronic neuroinflammation is thought to potentiate medial temporal lobe (MTL) atrophy and memory decline in Alzheimer’s disease (AD). It has become increasingly important to find novel immunological biomarkers of neuroinflammation or other processes that can track AD development and progression. Our study explored which pro- or anti-inflammatory cerebrospinal fluid (CSF) biomarkers best predicted AD neuropathology over 24 months. Using Alzheimer’s Disease Neuroimaging Initiative data (N=285), CSF inflammatory biomarkers from mass spectrometry and multiplex panels were screened using stepwise regression, followed up with 50%/50% model retests for validation. Neuronal Pentraxin 2 (NPTX2) and Chitinase-3-like-protein- 1 (C3LP1), biomarkers of glutamatergic synaptic plasticity and microglial activation respectively, were the only consistently significant biomarkers selected. Once these biomarkers were selected, linear mixed models were used to analyze their baseline and longitudinal associations with bilateral MTL volume, memory decline, global cognition, and established AD biomarkers including CSF amyloid and tau. Higher baseline NPTX2 levels corresponded to less MTL atrophy [R2= .287, p<.001] and substantially less memory decline [R2=.560, p<.001] by month 24. Conversely, higher C3LP1 modestly predicted more MTL atrophy [R2=.083, p<.001], yet did not significantly track memory decline over time. In conclusion, NPTX2 is a novel pro-inflammatory cytokine that predicts AD-related outcomes better than any immunological biomarker to date, substantially accounting for brain atrophy and especially memory decline. C3LP1 as the microglial biomarker, by contrast, performed modestly and did not predict longitudinal memory decline. This research may advance the current understanding of AD etiopathogenesis, while expanding early diagnostic techniques through the use of novel pro-inflammatory biomarkers, such as NPTX2. Future studies should also see if NPTX2 causally affects MTL morphometry and memory performance.

Neuroinflammation is a potential factor speculated to underlie Alzheimer’s disease (AD) etiopathogenesis and progression. The overwhelming focus in this area of research to date has been on the chronic upregulation of pro-inflammatory cytokines to understand how neuroinflammatory mechanisms contribute to neurodegeneration. Yet, it is important to understand the pleiotropic roles of these cytokines in modulating neuroinflammation in which they cannot be labeled as a strictly “good” or “bad” biomarker phenotype. As such, biomarkers with more precise functions are needed to better understand how neuroinflammation impacts the brain in AD. Neuronal pentraxins are a concentration- dependent group of pro- or anti- inflammatory cytokines. There is contradictory evidence of these pentraxins as being both neuroprotective and potentially detrimental in AD. Potential neuroprotective examples include their ability to predict AD-related outcomes such as cognition, memory function and synaptic refinement. This review will briefly outline the basis of AD and subsequently summarize findings for neuropathological mechanisms of neuroinflammation, roles for traditional pro-and anti-inflammatory cytokines, and data found thus far on the neuronal pentraxins.

This paper describes the effects of porosity and thermal ageing at 950°C for 4000 hr. in air on in-plane cracking behavior of plasma-sprayed thermal barrier coating (TBC) made up of 8 % yittria-stabilized zirconia. The in-plane TBC cracking was analyzed by a protruded TBC bend testing technique together with finite element stress analysis. As-deposited and aged TBC protruded specimens showed a large variation of porosity depending on the location of specimen extraction. The critical local tensile stress (s) necessary for the initiation of in-plane cracks for each specimen with different porosity was determined using elastic moduli (E) estimated from the porosity dependence of E. The s for in-plane cracking of the as-deposited TBC initially increased with increasing porosity and showed a peak when the porosity reached 0.23. It was shown that in-plane cracking at the interface of TBC and thermally grown oxides required much higher s than that at the interface of TBC and bond coatings. The thermal ageing led to a slight increase in s for away-from-interfacial TBC cracking. The dependence of in-plane TBC cracking behavior on the porosity is discussed in terms of effective critical stress via the Griffith criterion for porous materials.

No abstract