The APOE E4 allele is associated with faster rates of neuroretinal thinning in a prospective cohort study of suspect and early glaucoma

Purpose: To investigate the association between the apolipoprotein E (APOE) E4 dementia-risk allele and prospective longitudinal retinal thinning in a cohort study of suspect and early manifest glaucoma. Design: Retrospective analysis of prospective cohort data. Participants: This study included all available eyes from participants recruited to the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study with genotyping data from which APOE genotypes could be determined. Methods: Apolipoprotein E alleles and genotypes were determined in PROGRESSA, and their distributions were compared with an age-matched and ancestrally matched normative cohort, the Blue Mountains Eye Study. Structural parameters of neuroretinal atrophy measured using spectral-domain OCT were compared within the PROGRESSA cohort on the basis of APOE E4 allele status. Main Outcome Measures: Longitudinal rates of thinning in the macular ganglion celleinner plexiform layer (mGCIPL) complex and the peripapillary retinal nerve fiber layer (pRNFL). Results: Rates of mGCIPL complex thinning were faster in participants harboring ≥1 copies of the APOE E4 allele (b ¼ e0.13 mm/year; P ≤0.001). This finding was strongest in eyes affected by normal-tension glaucoma (NTG; b ¼ e0.20 mm/year; P ¼ 0.003). Apolipoprotein E E4 allele carriers were also more likely to be lost to followup (P ¼ 0.01) and to demonstrate a thinner average mGCIPL complex (70.9 mm vs. 71.9 mm; P ¼ 0.011) and pRNFL (77.6 mm vs. 79.2 mm; P ¼ 0.045) after a minimum of 3 years of monitoring. Conclusions: The APOE E4 allele was associated with faster rates of mCGIPL complex thinning, particularly in eyes with NTG. These results suggest that the APOE E4 allele may be a risk factor for retinal ganglion cell degeneration in glaucoma.Sean Mullany, Henry Marshall, Santiago Diaz-Torres, Ella C. Berry, Joshua M. Schmidt, Daniel Thomson, Ayub Qassim, Minh-Son To, David Dimasi, Abraham Kuot, Lachlan S.W. Knight, Georgina Hollitt, Antonia Kolovos, Angela Schulz, Stewart Lake, Richard A. Mills, Ashish Agar, Anna Galanopoulos, John Landers, Paul Mitchell, Paul R. Healey, Stuart L. Graham, Alex W. Hewitt, Emmanuelle Souzeau, Mark M. Hassall, Sonja Klebe, Stuart MacGregor, Puya Gharahkhani, Robert J. Casson, Owen M. Siggs, Jamie E. Crai

RNA Sequencing of Lens Capsular Epithelium Implicates Novel Pathways in Pseudoexfoliation Syndrome

Published: March 29, 2022PURPOSE. Pseudoexfoliation syndrome (PEX) is a common systemic disease that results in severe and often irreversible vision loss. Despite considerable research effort, PEX remains incompletely understood. This study sought to perform the first RNAseq study in elucidate the pathophysiology of PEX, and contribute a publicly available transcriptomic data resource for future research. METHODS. Human ocular lens capsular epithelium samples were collected from 25 patients with PEX and 39 non-PEX controls undergoing cataract surgery. RNA extracted from these specimens was subjected to polyadenylated (mRNA) selection and deep bulk RNA sequencing. Differential expression analysis investigated protein-coding gene transcripts. Exploratory analyses used pathway analysis tools, and curated class- and disease-specific gene sets. RESULTS. Differential expression analysis demonstrated that 2882 genes were differentially expressed according to PEX status. Genes associated with viral gene expression pathways were among the most upregulated, alongside genes encoding ribosomal and mitochondrial respiratory transport chain proteins. Cell adhesion protein transcripts including type 4 collagen subunits were downregulated. CONCLUSIONS. This comparative transcriptomic dataset highlights novel and previously recognized pathogenic pathways in PEX and provides the first comprehensive transcriptomic resource, adding an additional layer to build further understanding of PEX pathophysiology.Sean Mullany, Henry Marshall, Tiger Zhou, Daniel Thomson, Joshua M. Schmidt, Ayub Qassim, Lachlan S. W. Knight, Georgina Hollitt, Ella C. Berry, Thi Nguyen, Minh-Son To, David Dimasi, Abraham Kuot, Joshua Dubowsky, Rhys Fogarty, Michelle Sun, Luke Chehade, Shilpa Kuruvilla, Devaraj Supramaniam, James Breen, Shiwani Sharma, John Landers, Stewart Lake, Richard A. Mills, Mark M. Hassall, Weng O. Chan, Sonja Klebe, Emmanuelle Souzeau, Owen M. Siggs, and Jamie E. Crai

Personalised Music for Residents With Dementia in an Australian Rural Aged-care Setting

OBJECTIVE: Personalised music reportedly has a positive effect on behaviour and mood in people living with dementia. This intervention has not been conducted in low-resourced or rural aged-care settings. We evaluated the effect of a non-therapist-led personalised music listening intervention on residents with dementia and workplace culture in a rural aged-care facility in South Australia. DESIGN: Qualitative pilot study. SETTING: Rural aged-care home in South Australia. PARTICIPANTS: Ten residents with dementia and 15 aged-care staff participated in this study. INTERVENTIONS: Ten residents participated in an 8-week music program. Four focus groups were conducted with aged-care staff post-intervention. A thematic analysis was used to identify emerging themes. MAIN OUTCOME MEASURE: Personalised music positively influenced resident\u27s behaviour and well-being, social interaction and the workplace environment and culture, and served as a useful tool for personalised care. RESULTS: Three themes emerged: quality of life, personalised care and better aged-care environment. Personalised music positively influenced resident\u27s behaviour and well-being, social interaction and the workplace environment and culture, and served as a useful tool for personalised care. CONCLUSION: Personalised music program is an effective, low-cost intervention to improve quality of life and personalised care of residents living with dementia, staff well-being, and a workplace and culture in low-resourced or rural aged-care settings

Differential gene expression analysis of corneal endothelium indicates involvement of phagocytic activity in Fuchs’ endothelial corneal dystrophy

Fuchs' endothelial corneal dystrophy (FECD) is a progressive vision impairing disease caused by thickening of Descemet's membrane and gradual degeneration and loss of corneal endothelial cells. The aim of this study was to identify differentially expressed genes between FECD-affected and unaffected corneal endothelium to gain insight into the pathophysiological mechanisms underlying this disease. Microarray gene expression analysis was performed on total RNA from FECD-affected and unaffected corneal endothelium-Descemet's membrane (CE-DM) specimens using the Illumina HumanHT-12 v4.0 expression array. RNA from pools of FECD-affected (n = 3 per pool) and individual unaffected (n = 3) specimens was used for comparison. Altered expression of a sub-set of differentially expressed genes was validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in independent specimens. Bioinformatics analysis was performed using InnateDB to reveal functional relationships among the differentially expressed genes and molecular pathways involved in the disease. A total of 16,513 genes were found expressed in the corneal endothelium of which 142 genes were differentially expressed between FECD-affected and unaffected endothelium (log2 fold-change ≥1.5, corrected p-value ≤0.05). Most of the genes were up-regulated (126) and a small proportion down-regulated (16) in affected corneal endothelium. Of the twelve genes prioritised for validation, differential expression of 10 genes, including those ranked 57th and 81st by significance validated by qRT-PCR (8 up-regulated and 2 downregulated, corrected p ≤ 0.05), one gene showed a trend for up-regulation in affected endothelium, consistent with the microarray analysis and another was up-regulated in an independent study indicating robustness of the differential expression dataset. Bioinformatic analysis revealed significant over-representation of differentially expressed genes in extracellular matrix reorganisation, cellular remodelling, immune response, and inflammation. Network analysis showed functional inter-relatedness of the majority of the dysregulated genes and revealed known direct functional relationships between 20 of the genes; many of these genes have roles in macrophage differentiation, phagocytosis and inflammation. This is the second report of microarray gene expression analysis in FECD. This study revealed a set of highly dysregulated genes in the corneal endothelium in FECD. More than a third of the dysregulated genes in the disease have been discovered for the first time and thus are novel. The dysregulated genes strongly suggest the presence of phagocytic cells, most likely immune cells, and inflammation in corneal endothelium in the disease. This study provides a molecular framework for delineating the mechanisms underlying these cellular processes in FECD

Reduced expression of apolipoprotein E and immunoglobulin heavy constant gamma 1 proteins in Fuchs endothelial corneal dystrophy

Background Fuchs endothelial corneal dystrophy (FECD) is a progressive and potentially a sight threatening disease, and a common indication for corneal grafting in the elderly. Aberrant thickening of Descemet's membrane, formation of microscopic excrescences (guttae) and gradual loss of corneal endothelial cells are the hallmarks of the disease. The aim of this study was to identify differentially abundant proteins between FECD-affected and unaffected Descemet's membrane. Methods Label-free quantitative proteomics using nanoscale ultra-performance liquid chromatography-mass spectrometry (nUPLC-MSE) was employed on affected and unaffected Descemet's membrane extracts, and interesting findings were further investigated using quantitative reverse transcription-polymerase chain reaction and immunohistochemical techniques. Results Quantitative proteomics revealed significantly lower abundance of apolipoprotein E (APOE) and immunoglobulin heavy constant gamma 1 protein (IGHG1) in affected Descemet's membrane. The difference in the distribution of APOE between affected and unaffected Descemet's membrane and of IGHG1 detected by immunohistochemistry support their down-regulation in the disease. Comparative gene expression analysis showed significantly lower APOE mRNA levels in FECD-affected than unaffected corneal endothelium. IGHG1 gene is expressed at extremely low levels in the corneal endothelium, precluding relative expression analysis. Conclusions This is the first study to report comparative proteomics of Descemet's membrane tissue, and implicates dysregulation of APOE and IGHG1 proteins in the pathogenesis of Fuchs endothelial corneal dystrophy

The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort

Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF, TMEM98, MFRP, and PRSS56. Two of four PRSS56 families harboured the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.Owen M. Siggs, Mona S. Awadalla, Emmanuelle Souzeau, Sandra E. Staffieri, Lisa S. Kearns, Kate Laurie, Abraham Kuot, Ayub Qassim, Thomas L. Edwards, Michael A. Coote, Erica Mancel, Mark J. Walland, Joanne Dondey, Anna Galanopoulous, Robert J. Casson, Richard A. Mills, Daniel G. MacArthur, Jonathan B. Ruddle, Kathryn P. Burdon, Jamie E. Crai