Intrathecal amyloid-beta oligomer administration increases tau phosphorylation in the medial temporal lobe in the African green monkey: A nonhuman primate model of Alzheimer's disease.

AIMS: An obstacle to developing new treatment strategies for Alzheimer's disease (AD) has been the inadequate translation of findings in current AD transgenic rodent models to the prediction of clinical outcomes. By contrast, nonhuman primates (NHPs) share a close neurobiology with humans in virtually all aspects relevant to developing a translational AD model. The present investigation used African green monkeys (AGMs) to refine an inducible NHP model of AD based on the administration of amyloid-beta oligomers (AßOs), a key upstream initiator of AD pathology. METHODS: AßOs or vehicle were repeatedly delivered over 4 weeks to age-matched young adult AGMs by intracerebroventricular (ICV) or intrathecal (IT) injections. Induction of AD-like pathology was assessed in subregions of the medial temporal lobe (MTL) by quantitative immunohistochemistry (IHC) using the AT8 antibody to detect hyperphosphorylated tau. Hippocampal volume was measured by magnetic resonance imaging (MRI) scans prior to, and after, intrathecal injections. RESULTS: IT administration of AßOs in young adult AGMs revealed an elevation of tau phosphorylation in the MTL cortical memory circuit compared with controls. The largest increases were detected in the entorhinal cortex that persisted for at least 12 weeks after dosing. MRI scans showed a reduction in hippocampal volume following AßO injections. CONCLUSIONS: Repeated IT delivery of AßOs in young adult AGMs led to an accelerated AD-like neuropathology in MTL, similar to human AD, supporting the value of this translational model to de-risk the clinical trial of diagnostic and therapeutic strategies.

Primate model of chronic retinal neovascularization and vascular leakage.

The purpose of this study was to characterize and develop a primate model of chronic retinal neovascularization and vascular leakage that can be employed to assess efficacy of experimental therapeutics targeting retinal ischemic and neovascular diseases. African green monkeys received bilateral intravitreal (IVT) injection of DL-alpha-aminoadipic acid (DLAAA; 5 mg) following ophthalmic examination, color fundus photography, fluorescein angiography (FA) and optical coherence tomography (OCT). Imaging was repeated to evaluate progression and subsequent stabilization of retinal vascular pathology elicited by DLAAA. Aflibercept (Eylea) was administered IVT (1.4 mg) to assess effects on vascular leakage. Ocular tissue was collected for histopathology and glial fibrillary acidic protein (GFAP), von Willebrand Factor (vWF), CD105/endoglin, VEGF and CD68 immunohistochemistry to study retinal degeneration and vascular remodeling. IVT DLAAA administration resulted in telangiectatic vessel formation as early as two-weeks post-injection, followed by retinal vascular leakage and inner retinal edema. Neovascular lesion progression was evident up to 8-10 weeks post-injection before stabilizing into a vascular leakage state that persisted beyond 90 weeks. Histopathology and immunostaining revealed retinal degeneration and neovascularization, increased expression of vWF, CD105/endoglin, VEGF and CD68 immunoreactivities in addition to Müller cell loss. Aflibercept significantly attenuated vascular leakage for 2-4 weeks before progressive return of leakage from weeks 4-8. Lesions remained responsive to anti-VEGF administration at 90 weeks after DLAAA injection. Findings support application of the primate DLAAA-induced retinal vascular leakage model for efficacy evaluations of candidate therapeutics and sustained release strategies targeting exudative AMD, diabetic retinopathy, macular telangiectasia and other retinal ischemic and neovascular diseases. Findings confirm relevance of the DLAAA primate phenotype to understanding shared retinal vascular disease mechanisms and macular susceptibility to vascular and metabolic insults.

Crystallinelike Ordering of Confined Liquids at the Moving Contact Line.

The friction between a liquid swollen soft elastomer and a solid surface depends on the state of a confined liquid. To measure the physical state of the confined liquid, an interface-sensitive sum frequency generation spectroscopy technique was used to probe the contact region. We find that during sliding (friction) and pull-off (adhesion) experiments of pentadecane-swollen poly(dimethyl siloxane) lenses submerged in linear alkane (pentadecane) on a sapphire substrate, crystallinelike ordering of the liquid occurs only at the contact line, where we anticipate the highest shear. This crystallinelike structure of pentadecane molecules is transient and shows Arrhenius temperature dependence with unusually long relaxation times (hundreds of seconds) and an activation energy (50 kJ/mole), which is twice that of the bulk pentadecane liquid, at temperatures that are 14-70 °C higher than the bulk melting temperature (T_{m}=9 °C). This unusual long-lived crystallinelike ordering may explain why these systems show higher friction coefficients (boundary lubrication) compared to values predicted using bulk viscosity of pentadecane (hydrodynamic lubrication).

Individual Differences in Reading Skill Are Related to Trial-by-Trial Neural Activation Variability in the Reading Network.

Recent work has suggested that variability in levels of neural activation may be related to behavioral and cognitive performance across a number of domains and may offer information that is not captured by more traditional measures that use the average level of brain activation. We examined the relationship between reading skill in school-aged children and neural activation variability during a functional MRI reading task after taking into account average levels of activity. The reading task involved matching printed and spoken words to pictures of items. Single trial activation estimates were used to calculate the mean and standard deviation of children's responses to print and speech stimuli; multiple regression analyses evaluated the relationship between reading skill and trial-by-trial activation variability. The reliability of observed findings from the discovery sample (n = 44; ages 8-11; 18 female) was then confirmed in an independent sample of children (n = 32; ages 8-11; 14 female). Across the two samples, reading skill was positively related to trial-by-trial variability in the activation response to print in the left inferior frontal gyrus pars triangularis. This relationship held even when accounting for mean levels of activation. This finding suggests that intrasubject variability in trial-by-trial fMRI activation responses to printed words accounts for individual differences in human reading ability that are not fully captured by traditional mean levels of brain activity. Furthermore, this positive relationship between trial-by-trial activation variability and reading skill may provide evidence that neural variability plays a beneficial role during early reading development.SIGNIFICANCE STATEMENT Recent work has suggested that neural activation variability, or moment-to-moment changes in the engagement of brain regions, is related to individual differences in behavioral and cognitive performance across multiple domains. However, differences in neural activation variability have not yet been evaluated in relation to reading skill. In the current study, we analyzed data from two independent groups of children who performed an fMRI task involving reading and listening to words. Across both samples, reading skill was positively related to trial-by-trial variability in activation to print stimuli in the left inferior frontal gyrus pars triangularis, even when accounting for the more conventional measure of mean levels of brain activity. This finding suggests that neural variability could be beneficial in developing readers.

Neural correlates of language and non-language visuospatial processing in adolescents with reading disability.

Despite anecdotal evidence of relative visuospatial processing strengths in individuals with reading disability (RD), only a few studies have assessed the presence or the extent of these putative strengths. The current study examined the cognitive and neural bases of visuospatial processing abilities in adolescents with RD relative to typically developing (TD) peers. Using both cognitive tasks and functional magnetic resonance imaging (fMRI) we contrasted printed word recognition with non-language visuospatial processing tasks. Behaviorally, lower reading skill was related to a visuospatial processing advantage (shorter latencies and equivalent accuracy) on a geometric figure processing task, similar to findings shown in two published studies. FMRI analyses revealed key group by task interactions in patterns of cortical and subcortical activation, particularly in frontostriatal networks, and in the distributions of right and left hemisphere activation on the two tasks. The results are discussed in terms of a possible neural tradeoff in visuospatial processing in RD.

Interfacial segregation in polymer blends driven by acid-base interactions.

Infrared-visible sum frequency generation spectroscopy (SFG) was used to measure the interfacial concentrations of poly(methyl methacrylate) (PMMA)/polystyrene (PS) blends next to a sapphire substrate. The acid-base interactions of carbonyl groups of PMMA with the hydroxyl groups on the sapphire drive the interfacial segregation of PMMA next to the sapphire substrate. Using the shift of sapphire surface OH peaks, we have determined the difference in interfacial energy between the PMMA/sapphire and the PS/sapphire to be ~44-45 mJ/m(2). These results highlight the importance of acid-base interactions and their role in controlling the interfacial segregation next to solid substrates in polymer blends.

Direct measurement of acid-base interaction energy at solid interfaces.

We have studied acid-base interactions at solid-liquid and solid-solid interfaces using interface-sensitive sum frequency generation (SFG) spectroscopy. The shift of the sapphire hydroxyl peak in contact with several polar and nonpolar liquids and polymers was used to determine the interaction energy. The trend in the interaction energies cannot be explained by measuring only water contact angles. Molecular rearrangements at the sapphire interface, to maximize the interaction of the acid-base groups, play a dominant role, and these effects are not accounted for in the current theoretical models. These results provide important insights into understanding adhesion, friction, and wetting on solid interfaces.