No abstract

We examined if baseline level of cognitive reserve (CR) and of Alzheimer’s disease (AD) biomarkers modify the rate of change in cognition among individuals with normal cognition at baseline (n=303, mean baseline age = 57 years, mean follow-up = 12 years); 66 participants subsequently developed Mild Cognitive Impairment (MCI) or dementia due to AD. CR was indexed by years of education, reading, and vocabulary measures. AD biomarkers were measured with a composite score composed of measures of amyloid, phosphorylated tau and neurodegeneration. Higher CR scores were associated with better cognitive performance, but did not modify the rate of change in cognition among those who remained cognitively normal, nor among those who progressed to MCI prior to symptom onset, independent of baseline biomarker levels. However, higher CR scores were associated with faster cognitive decline after symptom onset of MCI. These results suggest that the mechanism by which CR mediates the relationship between pathology and cognitive function is by delaying the onset of symptoms rather than reducing the rate of cognitive decline.

Objective Assess the impact of false positives (FPs), false negatives (FNs), fixation losses (FLs) and test duration (TD) on visual field (VF) reliability at different stages of glaucoma severity. Participants 10,262 VFs from 1,538 eyes of 909 subjects with suspect or manifest glaucoma and ≥5 VF examinations. Design Retrospective. Methods Predicted mean deviation (MD) was calculated with multilevel modeling of longitudinal data (>5 non-initial VFs). Differences between predicted and observed MD (ΔMD) were calculated as a reliability measure. The impact of FPs, FNs, FLs and TD on ΔMD was assessed using multi-level modelling. Main outcome measure ΔMD associated with a 10% increment in FPs, FNs, and FLs, or a 1-minute change in test duration. Results FLs had little impact on ΔMD (<0.2 dB per 10% abnormal catch trials) and no level of FL produced ≥ 1 dB of ΔMD at any disease stage. FPs yielded greater than expected MD, with a 10% increment in abnormal catch trials associated with a ΔMD=0.42, 0.73, and 0.66 dB in mild (MD>−6 dB), moderate (−6≤MD<−12 dB), and severe (−12≤MD≤−20 dB) disease, respectively, up to 20% abnormal catch trials, and a ΔMD=1.57, 2.06, and 3.53 dB beyond 20% abnormal catch trials. FNs generally produced observed MDs below expected MDs. FNs were minimally impactful up to 20% abnormal catch trials (ΔMD per 10% increment >−0.14 dB at all levels of severity). Beyond 20% abnormal catch trials, each 10% increment in abnormal FN catch trials was associated with a ΔMD=−1.27, −0.53, and −0.51 dB in mild, moderate and severe disease. |ΔMD|≥1dB occurred with 22% FPs and 26% FNs in early, 14% FPs and 34% FNs in moderate, and 16% FPs and 51% FNs in severe disease. A 1-minute increment in TD produced a ΔMD between −0.35 and −0.40 depending on disease severity. Conclusion FLs have little impact on test reliability in established glaucoma patients. FPs, and to a lesser extent FNs and test duration, impact reliability significantly. The impact of FP and FN varies with disease severity and over the range of abnormal catch trials. Based on our findings, we present evidence-based severity-specific standards for classifying VF reliability are presented for clinical or research applications.

Corneal inflammation is often encountered as a key pathological event in many corneal diseases. Current treatments involve topical corticosteroids which require frequent instillations due to rapid tear turnover, causing side-effects such as corneal toxicity and elevated intraocular pressure (IOP). Hence, new interventions that can reduce side effects, dosing frequency, and increase patient compliance can be highly beneficial. In this study, we explore a subconjunctival injectable gel based on G4-PAMAM dendrimer and hyaluronic acid, cross-linked using thiol-ene click chemistry, incorporated with dendrimer dexamethasone (D-Dex) conjugates as a potential strategy for sustained delivery and enhanced bioavailability of corticosteroids. The efficacy of the injectable gel formulation was evaluated in a rat mild alkali burn model. Fluorescently-labelled dendrimers (D-Cy5) incorporated in the gel release D-Cy5 in vivo. The released D-Cy5 selectively targets and localizes within corneal macrophages in inflamed rat cornea but not in healthy controls. This pathology dependent biodistribution was exploited for drug delivery, by incorporating D-Dex in the injectable gel. The attenuation of corneal inflammation by D-Dex gels was assessed using various clinical and biochemical parameters over a 2-week period. Subconjunctival D-Dex gel treatment resulted in favorable clinically-relevant outcomes with reduced central corneal thickness and improved corneal clarity compared to free-Dex and placebo gel controls. The extent of corneal neovascularization was significantly reduced in the D-Dex group. These findings suggest that D-Dex attenuates corneal inflammation more effectively than free-Dex by attenuating macrophage infiltration and pro-inflammatory cytokines expression. A significant elevation in IOP was not observed in the D-Dex group but was observed in the free-Dex group. This novel injectable D-Dex gel may be a potential drug delivery platform for the treatment of many inflammatory ocular surface disorders such as dry eye, autoimmune keratitis and post-surnical complications where frequent steroid administration is required.

Background An association between visual impairment and cognitive outcomes has been documented, but there is limited research examining this relationship using multiple measures of vision. Methods Participants included non-demented individuals in Year 3 of the Visual impairment was assessed using visual acuity, contrast sensitivity, and stereo acuity. Cognitive function was defined using the digit symbol test and the Modified Mini-Mental State Examination (3MS). Incident cognitive impairment was defined as a 3MS score <80 or a decline >5 points following Year 3. Linear mixed effects models examined longitudinal associations adjusting for year, age, sex, race, education, smoking, depression, diabetes, study site, as well as interaction terms between the vision parameters and years in study, between baseline age and years in study, and quadratic terms of baseline age and years in study. Discrete Cox regression models examined the risk of incident cognitive impairment. Results Analyses included 2,444 participants (mean age = 74). Visual acuity, contrast sensitivity, and stereo acuity impairments were not associated with statistically significant changes in annual digit symbol test scores over 7 years of follow-up, as compared to those without these impairments. However, visual acuity, contrast sensitivity, and stereo acuity impairments were associated with greater declines in annual 3MS scores over 9 years. Participants with impaired visual acuity, contrast sensitivity, and stereo acuity had a greater risk of incident cognitive impairment. Conclusions Our results suggest that visual acuity, contrast sensitivity, and stereo acuity impairments may be risk factors for cognitive decline.

Background: Comparative studies of characteristics of optic neuritis (ON) associated with myelin oligodendrocyte glycoprotein-IgG (MOG-ON) and aquaporin-4-IgG (AQP4-ON) seropositivity are limited. Objective: To compare visual and optical coherence tomography (OCT) measures following AQP4-ON, MOG-ON, and multiple sclerosis associated ON (MS-ON). Methods: In this cross-sectional study, 48 AQP4-ON, 16 MOG-ON, 40 MS-ON, and 31 healthy control participants underwent monocular letter-acuity assessment and spectral-domain OCT. Eyes with a history of ON >3 months prior to evaluation were analyzed. Results: AQP4-ON eyes exhibited worse high-contrast letter acuity (HCLA) compared to MOG-ON (−22.3 ± 3.9 letters; p < 0.001) and MS-ON eyes (−21.7 ± 4.0 letters; p < 0.001). Macular ganglion cell + inner plexiform layer (GCIPL) thickness was lower, as compared to MS-ON, in AQP4-ON (−9.1 ± 2.0 µm; p < 0.001) and MOG-ON (−7.6 ± 2.2 µm; p = 0.001) eyes. Lower GCIPL thickness was associated with worse HCLA in AQP4-ON (−16.5 ± 1.5 letters per 10 µm decrease; p < 0.001) and MS-ON eyes (−8.5 ± 2.3 letters per 10 µm decrease; p < 0.001), but not in MOG-ON eyes (−5.2 ± 3.8 letters per 10 µm decrease; p = 0.17), and these relationships differed between the AQP4-ON and other ON groups ( p < 0.01 for interaction). Conclusion: AQP4-IgG seropositivity is associated with worse visual outcomes after ON compared with MOG-ON and MS-ON, even with similar severity of macular GCIPL thinning.

The authors report the first independent replication of rs613872 conferring risk of late-onset FCD. Their data suggest that this risk factor is likely independent of the FCD2 locus, whose causality remains unknown.

The PIVENS [Pioglitazone versus Vitamin E versus Placebo for the Treatment of Non-diabetic Patients with Nonalcoholic Steatohepatitis (NASH)] trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees but mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological end points. Adipo-IR [fasting non-esterified fatty acids (NEFA) × fasting insulin] was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either vitamin E group (p=0.34) or pioglitazone group (p=0.29).). Baseline Adipo-IR was significantly associated with fibrosis score (p=0.017) but not with other histological features or NAFLD activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had significant reduction in Adipo-IR (−15.7 vs. −1.91, p=0.02) but this effect did not persist at 96 weeks (−3.25 vs. −4.28, p=0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (p=0.70) or after 96 weeks (p=0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (p=0.02), fibrosis (p=0.004), and NAFLD activity score (p=0.01). Conclusion Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis.