Retinal thickness study with optical coherence tomography in patients with diabetes

To quantitatively assess retinal thickness by optical coherence tomography (OCT) in normal subjects and patients with diabetes. This study was intended to determine which retinal thickness value measured with OCT best discriminates between diabetic eyes, with and without macular edema. METHODS: OCT retinal thickness was measured by a manual technique in a total of 26 healthy volunteers (44 control eyes) and 85 patients with diabetes (148 eyes) with the clinical diagnosis of no diabetic retinopathy (45 eyes), nonproliferative diabetic retinopathy without clinically significant macular edema (CSME; 54 eyes), proliferative diabetic retinopathy without CSME (21 eyes), and 28 eyes with diabetic retinopathy with CSME. Independent predictors of the presence of CSME were quantified by using univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curves were generated to evaluate and compare the predictor variables. The correlation of retinal thickness measurements and visual acuity was calculated. RESULTS: There were statistically significant differences in foveal thickness between control eyes and all the other eye groups (P = 0.001). Diabetic eyes with CSME had a statistically significant greater thickness in each of the areas compared with the other groups. In a multivariate logistic regression model, foveal thickness was a strong and independent predictor of CSME (odds ratio [OR], 1.037; 95% confidence interval [CI] 1.02-1.05). The area under the ROC curve of this predictor variable was 0.94 (P = 0.001). For a cutoff point of 180 microm, the sensitivity was 93%, and specificity was 75%. Foveal thickness correlated with visual acuity in a log minimum angle of resolution (logMAR) scale (Spearman's rho = 0.9, P = 0.001). CONCLUSIONS: These results suggest that foveal thickening over 180 microm measured by OCT may be useful for the early detection of macular thickening and may be an indicator for a closer follow-up of the patient with diabetes

Termoterapia transpupilar en neovascularización subretiniana oculta secundaria a degeneración macular asociada a la edad. Primeros resultados

To determine the efficacy of transpupillary thermotherapy (TTT) to treat choroidal neovascularization (CNV) in patients with age-related macular degeneration (ARMD). Patients and Methods: Eight patients (ten eyes) with occult CNV were treated by TTT. A 810 nm diode laser was used to perform TTT. The diode laser was delivered through a panfunduscopic contact lens. Results: Three eyes showed a visual acuity improvement and a decrease in exudation on fluorescein angiography. Four eyes remained stable. Nevertheless, lesions worsened after treatment in three cases. One of these cases suffered an overtreatment. Conclusions: TTT may be a useful therapy in some cases of CNV in patients with age-related macular degeneration. Randomized and multicentric studies are necessary to stablish precise indications of this therap

Age effect on retina and optic disc normal values

Purpose: To investigate retinal thickness and optic disc parameters by the Retinal Thickness Analyzer (RTA) glaucoma program in older normal subjects and to determine any age effect. Methods: Subjects over 40 years of age without any prior history of eye diseases were recruited. Only subjects completely normal on clinical ophthalmologic examination and on visual field testing by Humphrey Field Analyzer (HFA) using the SITA 24-2 program were included. A total of 74 eyes from 74 subjects with even age distribution over the decades were enrolled and underwent topographic measurements of the posterior pole and of the optic disc by RTA. The `glaucoma full' program in software version 4.11B was applied. Results: Mean patient age was 59.9 +/- 10.3 years with a range from 40 to 80 years. The only parameter intraocular pressure (IOP) correlated with was retinal posterior pole asymmetry (r=0.27, p=0.02). IOP itself increased significantly with age (r=0.341, p=0.003). Mean defect and pattern standard deviation of the HFA did not correlate with any of the retinal or optic disc measurements. Increasing age correlated significantly with some of the morphologic measurements of the RTA: decreasing perifoveal minimum thickness (r=-0.258, p=0.026), increased cup-to-disc area ratio (r=0.302, p=0.016) and increased cup area (r=0.338 p=0.007). Conclusions: An age effect exists for some of the retina and optic disc measurements obtained by the RTA. Copyright (C) 2005 S. Karger AG, Basel

Laser treatment in diabetic retinopathy

Diabetic retinopathy is a leading cause of visual impairment and blindness in developed countries due to macular edema and proliferative diabetic retinopathy (PDR). For both complications laser treatment may offer proven therapy: the Diabetic Retinopathy Study demonstrated that panretinal scatter photocoagulation reduces the risk of severe visual loss by >= 50% in eyes with high-risk characteristics. Pan-retinal scatter coagulation may also be beneficial in other PDR and severe nonproliferative diabetic retinopathy (NPDR) under certain conditions. For clinically significant macular edema the Early Treatment of Diabetic Retinopathy Study could show that immediate focal laser photocoagulation reduces the risk of moderate visual loss by at least 50%. When and how to perform laser treatment is described in detail, offering a proven treatment for many problems associated with diabetic retinopathy based on a high evidence level. Copyright (c) 2007 S. Karger AG, Basel

Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD

Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Identification of candidate Parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies