Metabolic Syndromes as Important Comorbidities in Patients of Inherited Retinal Degenerations: Experiences from the Nationwide Health Database and a Large Hospital-Based Cohort.

This study aimed to evaluate the medical and socioeconomic impacts of IRDs using the nationwide health database and a large hospital-based cohort. This retrospective cross-sectional cohort study used data from the nationwide National Health Insurance Research Database (NHIRD). All patients with IRD from January 2012 to December 2016 were selected from the NHIRD and matched with the general population at a ratio of 1:4. All variables, including comorbidities, medications, service utilization, and medical costs, within 1 year from the date of the IRD diagnosis, were analyzed. Disability data were retrieved from the Taiwan Inherited retinal degeneration Project (TIP), a medical center-based database. A total of 4447 and 17,788 subjects from the nationwide database were included in the IRD and control groups, respectively. The Charlson comorbidity index score was higher in the IRD group (0.74:0.52, p < 0.001). Yearly visits to the ophthalmology clinic were more frequent in the IRD group (6.80:1.06, p < 0.001), particularly to tertiary medical centers (p < 0.001). The IRD group showed greater odds ratios (OR) for metabolic syndrome-related comorbidities, including hypertension (OR = 1.18, 95% confidence interval (CI) 1.10 to 1.26) and diabetes (OR = 1.32, 95% CI 1.21 to 1.45), and double the average yearly medical cost (2104.3 vs. 1084.6 USD, p < 0.001) and ten times the yearly ophthalmology cost (369.1 vs. 36.1 USD, p < 0.001). The average disability level was 54.17% for all subjects. This study revealed the large medical and socioeconomic impacts of IRD on not only patients with IRD, but also their family members and the whole society.

Genetic characteristics and epidemiology of inherited retinal degeneration in Taiwan.

Inherited retinal degenerations (IRDs) are a group of phenotypically and genotypically heterogeneous disorders with substantial socioeconomic impact. In this cohort study, we tried to address the genetic characteristics and epidemiology of IRDs in Taiwan. Totally, 312 families with IRDs were identified and recruited and genetic testing was performed via probe capture-based NGS targeting 212 IRD-related genes. Statistical analysis was based on the proband of each affected family. Disease-causing genotypes were identified in 178 families (57.1%). ABCA4 variants were the most common cause of disease in this cohort (27 families, 15.2%), whereas CYP4V2 variants were the most common cause for the single phenotype-Bietti's crystalline dystrophy (12 families, 3.8%). Some variants such as ABCA4:c.1804C>T, CYP4V2:c.802-8_810delinsGC, and EYS:c6416G>A were population-specific disease-causing hotspots. Probands affected by ABCA4, RPGR, RP1L1, and CEP290 sought medical help earlier while patients affected by EYS and CYP4V2 visited our clinic at an older age. To evaluate the representativeness of our cohort in the genetic epidemiology of IRDs in Taiwan, our demographic data were compared with that of the total IRD population in Taiwan, obtained from the National Health Insurance Research Database. This is currently the largest-scale, comprehensive study investigating the genetic characteristics and epidemiology of IRD in Taiwan. These data could help patients and caregivers to adopt precision genomic medicine and novel gene therapies in near future.

Genotypes Predispose Phenotypes-Clinical Features and Genetic Spectrum of ABCA4-Associated Retinal Dystrophies.

The ABCA4 gene is one of the most common disease-causing genes of inherited retinal degeneration. In this study, we report different phenotypes of ABCA4-associated retinal dystrophies in the Taiwanese population, its clinical progression, and its relationship with genetic characteristics. Thirty-seven subjects were recruited and all patients underwent serial ophthalmic examinations at a single medical center. Fundus autofluorescence (FAF) images were quantified for clinical evaluation, and panel-based next-generation sequencing testing was performed for genetic diagnosis. Visual preservation, disease progression, and genotype-phenotype correlation were analyzed. In this cohort, ABCA4-associated retinal degeneration presented as Stargardt disease 1 (STGD1, 62.16%), retinitis pigmentosa (32.43%), and cone-rod dystrophy (5.41%). STGD1 could be further divided into central and dispersed types. In each phenotype, the lesion areas quantified by FAF increased with age (p < 0.01) and correlated with poorer visual acuity. However, three patients had the foveal sparing phenotype and had relatively preserved visual acuity. Forty-two ABCA4 variants were identified as disease-causing, with c.1804C>T (p.Arg602Trp) the most frequent (37.84%). Patients with a combination of severe/null variants could have more extensive phenotypes, such as arRP and dispersed STGD1. This is the first cohort study of ABCA4-associated retinal degeneration in Taiwan with wide spectrums of both genotypic and phenotypic characteristics. An extremely high prevalence of c.1804C>T, which has not been reported in East Asia before, was noted. The extensiveness of retinal involvement might be regarded as a spectrum of ABCA4-associated retinal dystrophies. Different types of genetic variations could lead to distinctive phenotypes, according to the coding impact of variants.

Connectivity between nidopallium caudolateral and visual pathways in color perception of zebra finches.

Researchers demonstrated an elegant ability for red discrimination in zebra finches. It is interested to understand whether red activates exhibit much stronger response than other colors in neural network levels. To reveal the question, local field potentials (LFPs) was recorded and analyzed in two visual pathways, the thalamofugal and the tectofugal pathways, of zebra finches. Human studies demonstrate visual associated telencephalons communicate with higher order brain areas such as prefrontal cortex. The present study determined whether a comparable transmission occurs in zebra finches. Telencephalic regions of the thalamofugal (the visual Wulst) and the tectofugal pathway (the entopallium) with their higher order telencephalon, nidopallium caudolateral (NCL) were simultaneously recorded. LFPs of relay nuclei (the nucleus rotundus, ROT) of tectofugal pathway were also acquired. We demonstrated that LFP powers in the tectofugal pathway were higher than those in the thalamofugal pathway when illuminating blue lights. In addition, the LFP synchronization was stronger between the entopallium and NCL. LFPs also revealed a higher Granger causality from the direction of entopallium to NCL and from ROT to entopallium. These results suggest that zebra finches' tectofugal pathway predominately processing color information from ROT to NCL, relayed by entopallium, and blue could trigger the strongest response.

Polybenzyl Glutamate Biocompatible Scaffold Promotes the Efficiency of Retinal Differentiation toward Retinal Ganglion Cell Lineage from Human-Induced Pluripotent Stem Cells.

Optic neuropathy is one of the leading causes of irreversible blindness caused by retinal ganglion cell (RGC) degeneration. The development of induced pluripotent stem cell (iPSC)-based therapy opens a therapeutic window for RGC degeneration, and tissue engineering may further promote the efficiency of differentiation process of iPSCs. The present study was designed to evaluate the effects of a novel biomimetic polybenzyl glutamate (PBG) scaffold on culturing iPSC-derived RGC progenitors. The iPSC-derived neural spheres cultured on PBG scaffold increased the differentiated retinal neurons and promoted the neurite outgrowth in the RGC progenitor layer. Additionally, iPSCs cultured on PBG scaffold formed the organoid-like structures compared to that of iPSCs cultured on cover glass within the same culture period. With RNA-seq, we found that cells of the PBG group were differentiated toward retinal lineage and may be related to the glutamate signaling pathway. Further ontological analysis and the gene network analysis showed that the differentially expressed genes between cells of the PBG group and the control group were mainly associated with neuronal differentiation, neuronal maturation, and more specifically, retinal differentiation and maturation. The novel electrospinning PBG scaffold is beneficial for culturing iPSC-derived RGC progenitors as well as retinal organoids. Cells cultured on PBG scaffold differentiate effectively and shorten the process of RGC differentiation compared to that of cells cultured on coverslip. The new culture system may be helpful in future disease modeling, pharmacological screening, autologous transplantation, as well as narrowing the gap to clinical application.

Protective Effects of Wogonin against Alzheimer's Disease by Inhibition of Amyloidogenic Pathway.

One of the pathogenic systems of Alzheimer's disease (AD) is the formation of ß-amyloid plaques in the brains of patients, and amyloidogenic activity becomes one of the therapeutic targets. Here, we report wogonin, one of the major active constituting components in Scutellaria baicalensis, which has the neuroprotective effects on amyloid-ß peptides- (Aß-) induced toxicity. Oral wogonin treatment improved the performance of triple transgenic AD mice (h-APPswe, h-Tau P301L, and h-PS1 M146V) on the Morris water maze, Y-maze, and novel object recognition. Furthermore, wogonin activated the neurite outgrowth of AD cells by increasing neurite length and complexity of Tet-On Aß42-GFP SH-SY5Y neuroblastoma cells (AD cells) and attenuated amyloidogenic pathway by decreasing the levels of ß-secretase, APP ß-C-terminal fragment, Aß-aggregation, and phosphorylated Tau. Wogonin also increased mitochondrial membrane potential (∆ψm) and protected against apoptosis by reducing the expression of Bax and cleaved PARP. Collectively, these results conclude that wogonin may be a promising multifunctional drug candidate for AD.

Treatment with a Ginkgo biloba extract, EGb 761, inhibits excitotoxicity in an animal model of spinocerebellar ataxia type 17.

Spinocerebellar ataxia type 17 (SCA 17) is a polyglutamine disease caused by the expansion of CAG/CAA repeats in the TATA box-binding protein (TBP) gene. The Ginkgo biloba extract, EGb 761, contains flavonoids and terpenoids with a potential use for the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The neuroprotective effects of EGb 761 are obvious, but whether the EGb 761 has therapeutic effects in SCA 17 is still unclear. To manage our issues, we have generated TBP/79Q-expressing SH-SY5Y cells and SCA 17 transgenic mice with the mutant hTBP gene. In in vitro experiment, we observed that the EGb 761 treatment decreased the amount of sodium dodecyl sulfate-insoluble proteins in the TBP/79Q-expressing SH-SY5Y cells. We further found that the EGb 761 treatment could inhibit excitotoxicity and calcium influx and reduce the expression of apoptotic markers in glutamate-treated SH-SY5Y neuroblastoma cells. In in vivo experiment, we observed that the EGb 761 treatment (100 mg/kg intraperitoneal injection per day) could relieve the motor deficiencies of the SCA 17 transgenic mice. Our findings provide evidence that the EGb 761 treatment can be a remedy for SCA 17 via suppressing excitotoxicity and apoptosis in SCA 17 cell and animal models. Therefore, we suggest that EGb 761 may be a potential therapeutic agent for treating SCA 17.