Teleophthalmology: Evaluation of Phone-based Visual Acuity in a Pediatric Population.

PURPOSE: With the recent rise of teleophthalmology due to coronavirus disease, health care needs accurate and reliable methods of checking visual acuity remotely. The visual acuity as measured by the GoCheck Kids application was compared with that of the Amblyopia Treatment Study (ATS) and the authors' clinic protocol. DESIGN: This was a prospective, comparison of visual acuity assessment methods. METHODS: Established patients (3-18 years of age) in the practice of a single pediatric ophthalmologist were eligible. Visual acuity was measured 1) by GoCheck Kids mobile application, by the patient's family member; 2) by HOTV-ATS, by study personnel; and 3) by regular clinic protocol, by an ophthalmic technician. To assess agreement between measurement of acuity, intraclass correlations with 95% confidence intervals (CI) were computed. RESULTS: A total of 53 children participated. The mean differences between GoCheck Kids and HOTV-ATS acuities (0.094) were significantly different (P < .001). The intraclass correlation coefficient (ICC) was 0.55 (95% CI: 0.40-0.68). The mean differences between GoCheck Kids and chart acuities (0.010) were not significantly different (P = .319; ICC: 0.59; 95% CI: 0.45-0.71). The mean differences between HOTV-ATS and chart acuities (0.084) were significantly different (P < .001; ICC: 0.66; 95% CI: 0.53-0.76). The percentages of eyes with visual acuity measured by GoCheck Kids within 1 line of the HOTV-ATS and chart acuity were 65.3% and 86.7%, respectively. CONCLUSIONS: GoCheck Kids as checked by a family member provided a modest correlation of visual acuity compared to the chart screen and a fair correlation of visual acuity compared to HOTV-Amblyopia Treatment Study protocol, although most were within 1 line.

Amyloid-ß42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer's disease.

The relationship between amyloid-ß (Aß) species and tau pathology in Alzheimer's disease (AD) is not fully understood. Here, we provide direct evidence that Aß42/40 ratio, not total Aß level, plays a critical role in inducing neurofibrillary tangles (NTFs) in human neurons. Using 3D-differentiated clonal human neural progenitor cells (hNPCs) expressing varying levels of amyloid ß precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with Aß42/40 ratio. Roles of Aß42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential Aß42/40 ratios without mutant PS1. Moreover, naïve hNPCs co-cultured with APP TMD I45F (high Aß42/40) cells, not with I47F cells (low Aß42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the Aß42/40 ratio in AD therapy.

Blood-Brain Barrier Dysfunction in a 3D In Vitro Model of Alzheimer's Disease.

Harmful materials in the blood are prevented from entering the healthy brain by a highly selective blood-brain barrier (BBB), and impairment of barrier function has been associated with a variety of neurological diseases. In Alzheimer's disease (AD), BBB breakdown has been shown to occur even before cognitive decline and brain pathology. To investigate the role of the cerebral vasculature in AD, a physiologically relevant 3D human neural cell culture microfluidic model is developed having a brain endothelial cell monolayer with a BBB-like phenotype. This model is shown to recapitulate several key aspects of BBB dysfunction observed in AD patients: increased BBB permeability, decreased expression of claudin-1, claudin-5, and VE-cadherin, increased expression of matrix-metalloproteinase-2 and reactive oxygen species, and deposition of ß-amyloid (Aß) peptides at the vascular endothelium. Thus, it provides a well-controlled platform for investigating BBB function as well as for screening of new drugs that need to pass the BBB to gain access to neural tissues.

BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice.

ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of ß-amyloid (Aß), one of the major pathogenic molecules of Alzheimer's disease (AD), and is therefore being actively pursued as a drug target for AD. Adult hippocampal neurogenesis (AHN) is a lifelong process that is known to be important for learning and memory and may have the potential to regenerate damaged neural tissue. In this study, we examined whether BACE1 regulates AHN, which holds important implications for its suitability as a drug target in AD. Cohorts of 2-month-old wild-type (BACE1+/+), heterozygous, and homozygous BACE1 knockout mice (BACE1+/- and BACE1-/-, respectively) were injected with 5-bromo-2'-deoxyuridine (BrdU) and sacrificed 1 day later to examine the impact of loss of BACE1 on neural precursor cell (NPC) proliferation in the adult brain. Parallel cohorts of mice were sacrificed 4 weeks after BrdU injection to determine the effects of BACE1 on survival and differentiation of newborn NPCs. We found that NPC proliferation was increased in BACE1-/- mice compared to BACE1+/+ mice, while no difference was observed in NPC survival across genotypes. Differentiation of NPCs to neuronal lineage was impaired in BACE1-/- mice. However, no differences were observed in astrogenesis, the proportion of immature neurons, or the production of oligodendrocytes across genotypes. Importantly, corresponding with a decrease in neuronal differentiation in the absence of a complementary increase in an alternate cell fate, BACE1-/- mice were found to have a pool of undifferentiated NPCs in the hippocampus compared to BACE1+/+ and BACE1+/- mice.

Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model.

Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer's disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.

Soluble Gamma-secretase Modulators Attenuate Alzheimer's ß-amyloid Pathology and Induce Conformational Changes in Presenilin 1.

A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aß42 peptide, which is generated from amyloid-ß precursor protein (APP) via cleavages by ß- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aß42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Aß42 levels without affecting either α- and ß-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD.

A 3D human neural cell culture system for modeling Alzheimer's disease.

Stem cell technologies have facilitated the development of human cellular disease models that can be used to study pathogenesis and test therapeutic candidates. These models hold promise for complex neurological diseases such as Alzheimer's disease (AD), because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the characterization of a novel 3D culture system that exhibits key events in AD pathogenesis, including extracellular aggregation of amyloid-ß (Aß) and accumulation of hyperphosphorylated tau. Here we provide instructions for the generation and analysis of 3D human neural cell cultures, including the production of genetically modified human neural progenitor cells (hNPCs) with familial AD mutations, the differentiation of the hNPCs in a 3D matrix and the analysis of AD pathogenesis. The 3D culture generation takes 1-2 d. The aggregation of Aß is observed after 6 weeks of differentiation, followed by robust tau pathology after 10-14 weeks.