Quantifying Putative Retinal Gliosis in Preclinical Alzheimer's Disease.

Purpose: Neuroinflammation plays a significant role in the pathology of Alzheimer's disease (AD). Mouse models of AD and postmortem biopsy of patients with AD reveal retinal glial activation comparable to central nervous system immunoreactivity. We hypothesized that the surface area of putative retinal gliosis observed in vivo using en face optical coherence tomography (OCT) imaging will be larger in patients with preclinical AD versus controls. Methods: The Spectralis II instrument was used to acquire macular centered 20 × 20 and 30 × 25-degrees spectral domain OCT images of 76 participants (132 eyes). A cohort of 22 patients with preclinical AD (40 eyes, mean age = 69 years, range = 60-80 years) and 20 control participants (32 eyes, mean age = 66 years, range = 58-82 years, P = 0.11) were included for the assessment of difference in surface area of putative retinal gliosis and retinal nerve fiber layer (RNFL) thickness. The surface area of putative retinal gliosis and RNFL thickness for the nine sectors of the Early Treatment Diabetic Retinopathy Study (ETDRS) map were compared between groups using generalized linear mixed models. Results: The surface area of putative retinal gliosis was significantly greater in the preclinical AD group (0.97 ± 0.55 mm2) compared to controls (0.68 ± 0.40 mm2); F(1,70) = 4.41, P = 0.039; Cohen's d = 0.61. There was no significant difference between groups for RNFL thickness in the 9 ETDRS sectors, P > 0.05. Conclusions: Our analysis shows greater putative retinal gliosis in preclinical AD compared to controls. This demonstrates putative retinal gliosis as a potential biomarker for AD-related neuroinflammation.

Ten-year safety and clinical benefit from open-label etanercept treatment in children and young adults with juvenile idiopathic arthritis.

OBJECTIVES: CLIPPER2 was an 8-year, open-label extension of the phase 3b, 2-year CLIPPER study on the safety and efficacy of etanercept in patients with JIA, categorized as extended oligoarticular arthritis (eoJIA), enthesitis-related arthritis (ERA) or PsA. METHODS: Participants with eoJIA (2-17 years old), ERA or PsA (each 12-17 years old) who received ≥1 etanercept dose (0.8 mg/kg weekly; maximum 50 mg) in CLIPPER could enter CLIPPER2. Primary end point was occurrence of malignancy. Efficacy assessments included proportions achieving JIA ACR 30/50/70/90/100 criteria and ACR inactive disease criteria, and clinical remission (ACR criteria) or Juvenile Arthritis DAS (JADAS) ≤1. RESULTS: Overall, 109/127 (86%) CLIPPER participants entered CLIPPER2 [n = 55 eoJIA, n = 31 ERA, n = 23 PsA; 99 (78%) on active treatment]; 84 (66%) completed 120 months' follow-up [32 (25%) on active treatment]. One malignancy (Hodgkin's disease in 18-year-old patient with eoJIA treated with methotrexate for 8 years) was reported; there were no cases of active tuberculosis or deaths. Numbers and incidence rates (events per 100 patient-years) of TEAEs (excluding infections/ISRs) decreased from 193 (173.81) in Year 1 to 9 (27.15) in Year 10; TE infections and serious infections also decreased. Over 45% of participants (n = 127) achieved JIA ACR50 responses from Month 2 onwards; 42 (33%) and 34 (27%) participants achieved JADAS and ACR clinical remission, respectively. CONCLUSIONS: Etanercept treatment up to 10 years was well tolerated, consistent with the known safety profile, with durable response in the participants still on active treatment. The benefit-risk assessment of etanercept in these JIA categories remains favourable. TRIAL REGISTRATION: ClinicalTrials.gov IDs: CLIPPER (NCT00962741); CLIPPER2 (NCT01421069).

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aß-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval.

BACKGROUND: Abnormal beta-amyloid (Aß) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1-4, 2017). Previously, we established the scopolamine challenge test (SCT) as a "cognitive stress test" screening measure to identify individuals at risk for AD (Alzheimer's & Dementia 10(2):262-7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval. METHODS: Older adults (N = 63, aged 55-75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam. RESULTS: Significant differences in both cognitive performance and in Aß neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period. CONCLUSIONS: Cognitive response to the SCT (Alzheimer's & Dementia 10(2):262-7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.

Developing retinal biomarkers for the earliest stages of Alzheimer's disease: What we know, what we don't, and how to move forward.

The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.

Central Macular Thickness in Diabetic Patients: A Sex-based Analysis.

SIGNIFICANCE: The pathological changes in clinically significant diabetic macular edema lead to greater retinal thickening in men than in women. Therefore, male sex should be considered a potential risk factor for identifying individuals with the most severe pathological changes. Understanding this excessive retinal thickening in men may help preserve vision. PURPOSE: The purpose of this study was to investigate the sex differences in retinal thickness in diabetic patients. We tested whether men with clinically significant macular edema had even greater central macular thickness than expected from sex differences without significant pathological changes. This study also aimed to determine which retinal layers contribute to abnormal retinal thickness. METHODS: From 2047 underserved adult diabetic patients from Alameda County, CA, 142 patients with clinically significant macular edema were identified by EyePACS-certified graders using color fundus images (Canon CR6-45NM). First, central macular thickness from spectral domain optical coherence tomography (iVue; Optovue Inc.) was compared in 21 men versus 21 women without clinically significant macular edema. Then, a planned comparison contrasted the greater values of central macular thickness in men versus women with clinically significant macular edema as compared with those without. Mean retinal thickness and variability of central macular layers were compared in men versus women. RESULTS: Men without clinically significant macular edema had a 12-µm greater central macular thickness than did women (245 ± 21.3 and 233 ± 13.4 µm, respectively; t40 = -2.18, P = .04). Men with clinically significant macular edema had a 67-µm greater central macular thickness than did women (383 ± 48.7 and 316 ± 60.4 µm, P < .001); that is, men had 55 µm or more than five times more (t20 = 2.35, P = .02). In men, the outer-nuclear-layer thickness was more variable, F10,10 = 9.34. CONCLUSIONS: Underserved diabetic men had thicker retinas than did women, exacerbated by clinically significant macular edema.

Postoperative Corneal and Surgically Induced Astigmatism following Superior Approach Manual Small Incision Cataract Surgery in Patients with Preoperative Against-the-Rule Astigmatism.

The aim of the study was to report postoperative corneal and surgically induced astigmatism (SIA) in patients with preoperative against-the-rule (ATR) astigmatism who underwent superior approach manual small incision cataract surgery (MSICS). 58 eyes of 58 cataract patients with preoperative ATR astigmatism were involved in this study. All patients had operable cataracts and underwent superior approach MSICS. Keratometric (K) readings were taken prior to surgery and at 12 weeks after surgery. Centroid values of SIA, preoperative astigmatism, and postoperative astigmatism were calculated using Cartesian coordinates based analysis. Wilcoxon signed rank test was used to compute statistical significance between mean preoperative and postoperative corneal astigmatism. Cohen's d was used as effect size measure. Centroid values of 1.42 D × 179, 2.48 D × 0, and 1.07 D × 1 were recorded, respectively, for preoperative astigmatism, postoperative astigmatism, and SIA. Wilcoxon signed rank test indicated that mean ± SD postoperative corneal astigmatism (2.80 ± 1.40 D) was statistically significantly greater than preoperative corneal astigmatism (1.49 ± 1.34 D), Z = -6.263, p < 0.0001. A high Cohen's d of 1.32 was found. Our results suggest statistical and clinically significant greater postoperative corneal astigmatism than preoperative corneal astigmatism for ATR astigmatism cataract patients who underwent superior approach MSICS.