Publications by authors named "John Landers"

172 Publications

Laponite-Incorporated UiO-66-NH-Polyethylene Oxide Composite Membranes for Protection against Chemical Warfare Agent Simulants.

ACS Appl Mater Interfaces 2021 Mar 19;13(8):10500-10512. Epub 2021 Feb 19.

DEVCOM Chemical Biological Center, 8198 Blackhawk Rd., Aberdeen Proving Ground, Maryland 21010, United States.

A strategy is developed to enhance the barrier protection of polyethylene oxide (PEO)-metal-organic framework (MOF) composite films against chemical warfare agent simulants. To achieve enhanced protection, an impermeable high-aspect-ratio filler in the form of Laponite RD (LRD) clay platelets was incorporated into a composite PEO film containing MOF UiO-66-NH. The inclusion of the platelets aids in mitigating permeation of inert hydrocarbons (octane) and toxic chemicals (2-chloroethyl ethyl sulfide, 2-CEES) of dimensions/chemistry similar to prominent vesicant threats while still maintaining high water vapor transport rates (WVTR). By utilizing small-angle neutron scattering, small-angle X-ray scattering, and wide-angle X-ray scattering, the LRD platelet alignment of the films was determined, and the structure of the films was correlated with performance as a barrier material. Performance of the membranes against toxic chemical threats was assessed using permeation testing of octane and 2-CEES, a common simulant for the vesicant mustard gas, and breathability of the membranes was assessed using WVTR measurements. To assess their robustness, chemical exposure ( diffuse reflectance infrared Fourier transform spectroscopy) and mechanical (tensile strength) measurements were also performed. It was demonstrated that the barrier performance of the film upon inclusion of the LRD platelets exceeds that of other MOF-polymer composites found in the literature and that this approach establishes a new path for improving permselective materials for chemical protection applications.
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http://dx.doi.org/10.1021/acsami.1c00397DOI Listing
March 2021

Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types.

Sci Adv 2021 Jan 15;7(3). Epub 2021 Jan 15.

Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (, , , , , and ) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.
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http://dx.doi.org/10.1126/sciadv.abd9036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810371PMC
January 2021

The Effect of SMN Gene Dosage on ALS Risk and Disease Severity.

Ann Neurol 2021 Apr 15;89(4):686-697. Epub 2021 Jan 15.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA.

Objective: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency.

Methods: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data.

Results: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63).

Interpretation: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.
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http://dx.doi.org/10.1002/ana.26009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048961PMC
April 2021

A Polygenic Risk Score Predicts Intraocular Pressure Readings Outside Office Hours and Early Morning Spikes as Measured by Home Tonometry.

Ophthalmol Glaucoma 2020 Dec 11. Epub 2020 Dec 11.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Australia.

Purpose: Intraocular pressure (IOP) elevations may occur in early morning or outside office hours and can be missed during routine in-clinic IOP measurements. Such fluctuations or peaks likely contribute to glaucoma progression. We sought to investigate the relationship between an IOP polygenic risk score (PRS) and short-term IOP profile.

Design: Cross-sectional study.

Participants: Four hundred seventy-three eyes from 239 participants with suspected or established primary open-angle glaucoma sampled from 4 outpatient clinics in Australia between August 2016 and December 2019.

Methods: Participants underwent Icare HOME (Icare Oy, Vanda, Finland) tonometer measurements to record IOP 4 times daily for 5 days. Unreliable measurements were excluded. A minimum of 2 days with at least 3 reliable measurements were required. We used a validated IOP PRS derived from 146 IOP-associated variants in a linear regression model adjusted for central corneal thickness and age.

Main Outcome Measures: Highest recorded early morning IOP and mean IOP within and outside office hours. Early morning IOP spikes were defined by a higher early morning IOP than the maximum in-office hours IOP.

Results: Reliable measurements were obtained from 334 eyes of 176 participants (mean age, 64 ± 9 years). Eyes in the highest IOP PRS quintile showed an early morning IOP increase of 4.3 mmHg (95% confidence interval [CI], 1.4-7.3; P = 0.005) and mean increase in IOP outside office hours of 2.7 mmHg (95% CI, 0.61-4.7; P = 0.013) than the lowest quintile, which were significant independently after accounting for a recent in-clinic IOP measured by Goldmann applanation tonometry. Eyes in the highest PRS quintile were 5.4-fold more likely to show early morning IOP spikes than the lowest quintile (odds ratio 95% CI, 1.3-23.6; P = 0.023).

Conclusions: A validated IOP PRS was associated with higher early morning IOP and mean IOP outside office hours. These findings support a role for genetic risk prediction of susceptibility to elevated IOP that may not be apparent during in-clinic hours, requiring more detailed clinical phenotyping using home tonometry, the results of which may guide additional interventions to improve IOP control.
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http://dx.doi.org/10.1016/j.ogla.2020.12.002DOI Listing
December 2020

Corneal Stiffness Parameters Are Predictive of Structural and Functional Progression in Glaucoma Suspect Eyes.

Ophthalmology 2020 Nov 25. Epub 2020 Nov 25.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Australia.

Purpose: To investigate corneal stiffness parameters (SPs) as predictors of future progression risk in glaucoma suspect eyes.

Design: Prospective, longitudinal study.

Participants: Three hundred seventy-one eyes from 228 primary open-angle glaucoma suspects, based on optic disc appearance, with normal baseline Humphrey Visual Field (HVF; Carl Zeiss Meditec) results.

Methods: Baseline corneal SPs were measured using Corvis ST (Oculus Optikgeräte GmbH). Participants were followed up every 6 months with clinical examination, HVF testing, and OCT. The baseline SP at first applanation (SP-A1) and highest concavity predicted the prospective outcome measures.

Main Outcome Measures: Structural progression was measured by the OCT rate of thinning of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL). Functional progression was assessed by permutation analysis of pointwise linear regression criteria on HVF testing.

Results: Stiffness parameters correlated positively with central corneal thickness (CCT), which was adjusted for in all analyses. A higher SP-A1, suggestive of a stiffer cornea, was associated with a faster rate of RNFL thinning (P < 0.001), synergistic with thinner CCT (P = 0.004) over a mean follow-up of 4.2 years. Eyes with higher SP-A1 and thinner CCT (thin and stiff corneas) showed accelerated RNFL thinning by 0.72 μm/year relative to eyes with lower SP-A1 and thicker CCT (95% confidence interval [CI], 0.17-1.28; P = 0.011) and were at 2.9-fold higher likelihood of fast RNFL progression of more than 1 μm/year (95% CI, 1.4-6.1; P = 0.006). Consistent results also were observed with GCIPL thinning. Furthermore, a higher SP-A1 was associated with a greater risk of visual field progression (P = 0.002), synergistic with thinner CCT (P = 0.010). Eyes with higher SP-A1 and thinner CCT were at 3.7-fold greater risk of visual field progression relative to eyes with thicker CCT and lower SP-A1 (95% CI, 1.3-10.5; P = 0.014).

Conclusions: Glaucoma suspect eyes with higher corneal SPs and lower CCT, suggestive of thin and stiff corneas, are at greater risk of progression. Corneal SPs seem to act synergistically with CCT as risk factors for glaucoma progression.
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http://dx.doi.org/10.1016/j.ophtha.2020.11.021DOI Listing
November 2020

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

Neuron 2021 02 26;109(3):448-460.e4. Epub 2020 Nov 26.

Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy; MAC Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
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http://dx.doi.org/10.1016/j.neuron.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864894PMC
February 2021

repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

Brain Commun 2020 19;2(2):fcaa064. Epub 2020 May 19.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King's College London, London SE5 9NU, UK.

Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in , polyglutamine expansions in and polyalanine expansions in . Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in , suggested a similar disease association for the repeat expansion in . We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate repeat expansions and amyotrophic lateral sclerosis (=3.33 × 10). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in , further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425293PMC
May 2020

Telemedicine Proof of Concept and Cost Savings During Underway Naval Operations.

Telemed J E Health 2020 Jul 28. Epub 2020 Jul 28.

Otolaryngology-Head and Neck Surgery, Indo-Pacific Command, Naval Medical Center San Diego, San Diego, California, USA.

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http://dx.doi.org/10.1089/tmj.2020.0181DOI Listing
July 2020

Cardiovascular Disease Predicts Structural and Functional Progression in Early Glaucoma.

Ophthalmology 2021 01 28;128(1):58-69. Epub 2020 Jul 28.

Department of Ophthalmology, Flinders University, Adelaide, Australia.

Purpose: To investigate the association between cardiovascular disease and baseline structural defects and disease progression in glaucoma.

Design: Prospective, longitudinal study of preperimetric and perimetric glaucoma.

Participants: Two thousand six hundred twenty-eight eyes from 1314 participants recruited to the Progression Risk of Glaucoma: Relevant SNPs with Significant Association (PROGRESSA) study were evaluated for baseline and longitudinal structural thinning using spectral-domain OCT and for visual field progression on Humphrey visual field (HVF) assessment.

Methods: Patients were classified as either predominantly macula ganglion cell-inner plexiform layer (mGCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL), or both mGCIPL and pRNFL structural change at enrollment, and then evaluated for longitudinal OCT or HVF progression. Cardiovascular disease and medication characteristics of the participants were compared with a reference group of stable patients.

Main Outcome Measures: OCT and HVF baseline status and longitudinal progression.

Results: After accounting for age and cardiovascular characteristics, patients with predominantly mGCIPL thinning at baseline showed a higher prevalence of hypertension (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.66-4.41; P < 0.001), antihypertensive use (OR, 2.03; 95% CI, 1.20-3.46; P = 0.008), and statin use (OR, 1.98; 95% CI, 1.07-3.66; P = 0.029) than reference patients. Patients with predominantly pRNFL thinning exhibited a comparable prevalence of cardiovascular disease or medication with reference patients. Review of longitudinal OCT and HVF data (mean follow-up, 5.34 ± 1.29 years) showed that hypertension was associated with an increased risk of both OCT (OR, 1.79; 95% CI, 1.17-2.75; P = 0.006) and HVF progression (OR, 1.92; 95% CI, 1.18-3.15; P = 0.013). A 1-standard deviation (approximately 21 mmHg) increase in systolic blood pressure at baseline was associated with a greater risk of OCT progression (OR, 1.27; 95% CI, 1.01-1.63; P = 0.041) and HVF progression (OR, 1.32; 95% CI, 1.01-1.73; P = 0.043). The association between systolic blood pressure and structural progression was comparable to that observed between intraocular pressure and structural progression (OR, 1.30; 95% CI, 1.01-1.67; P = 0.039).

Conclusions: Cardiovascular disease is an important risk factor for glaucoma progression.
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http://dx.doi.org/10.1016/j.ophtha.2020.06.067DOI Listing
January 2021

CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis.

Brain 2020 03;143(3):783-799

UK Dementia Research Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London SE5 9RX, UK.

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/brain/awaa039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089666PMC
March 2020

An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity.

Ophthalmology 2020 07 7;127(7):901-907. Epub 2020 Jan 7.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Australia.

Purpose: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification.

Design: Cross-sectional study.

Participants: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients.

Methods: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group.

Main Outcome Measures: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity.

Results: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01).

Conclusions: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.
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http://dx.doi.org/10.1016/j.ophtha.2019.12.025DOI Listing
July 2020

Effect of phacoemulsification cataract surgery on intraocular pressure in early glaucoma: A prospective multi-site study.

Clin Exp Ophthalmol 2020 05 13;48(4):442-449. Epub 2020 Feb 13.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

Importance: Cataract and primary open-angle glaucoma (POAG) commonly co-exist, and cataract surgery is thought to reduce intraocular pressure (IOP), the major modifiable risk factor of POAG.

Background: Previous studies exploring the effect of cataract surgery on IOP are limited by retrospective design, lack of a control group, medication use and washout and loss to follow up.

Design: Prospective, multicentre, matched case-control Australian study.

Participants: 171 eyes of 108 POAG patients who underwent cataract surgery, matched to 171 control eyes.

Methods: Serial longitudinal IOP measurements were compared before and after cataract surgery, and relative to the controls. A mixed-effect model was used for the longitudinal data.

Main Outcome Measures: Change in IOP.

Results: The mean follow-up time was 4.8 (1.4) years. Cataract surgery reduced mean IOP by 2.22 mmHg (95% confidence interval: 1.93-2.52 mmHg, P < .001) with 59 eyes (34%) achieving at least 3 mmHg reduction. Compared to matched controls, the mean reduction in IOP was 1.75 mmHg (95% confidence interval 1.15-2.33 mmHg; P < .001). Higher preoperative IOP and being on fewer topical glaucoma medications preoperatively were strongly predictive of a larger IOP reduction in a multivariable model. Anterior chamber depth was not associated with IOP reduction. Eyes with preoperative IOP ≥24 mmHg had a mean IOP reduction of 4.03 mmHg with 81% experiencing at least 3 mmHg reduction. Sub-analysis of medication naïve and pseudoexfoliation patients showed similar results.

Conclusions And Relevance: Cataract surgery has a confirmed effect in reducing IOP in a "real world" setting of early glaucoma patients.
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http://dx.doi.org/10.1111/ceo.13724DOI Listing
May 2020

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression.

Nat Genet 2020 02 20;52(2):160-166. Epub 2020 Jan 20.

Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
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http://dx.doi.org/10.1038/s41588-019-0556-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056672PMC
February 2020

Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology.

Sci Transl Med 2019 12;11(523)

Project MinE ALS Sequencing Consortium.

Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.
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http://dx.doi.org/10.1126/scitranslmed.aav5264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057809PMC
December 2019

Using Icare HOME tonometry for follow-up of patients with open-angle glaucoma before and after selective laser trabeculoplasty.

Clin Exp Ophthalmol 2020 04 2;48(3):328-333. Epub 2019 Dec 2.

Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.

Importance: Monitoring the results of selective laser trabeculoplasty (SLT) on intraocular pressure (IOP) using a home rebound tonometry.

Background: To evaluate the role of Icare HOME tonometry in open-angle glaucoma patients being treated with SLT.

Design: A clinic-based prospective case study.

Participants: Fourteen eyes from 14 patients diagnosed with primary open-angle glaucoma were recruited.

Methods: The trabecular meshwork of each eye was treated 360° with a frequency-doubled Q-switched Nd:YAG laser. IOP was measured four times a day for a week before and after SLT. On the day of SLT, the patients were required to measure the IOP in the evening to record any IOP spikes.

Main Outcome Measures: The use of Icare HOME in following up patients post-laser trabeculoplasty without the need for clinic attendance.

Results: Icare HOME recorded a significant reduction of 5.12 mmHg in the mean IOP post-SLT (95% confidence interval [CI] 3.75-6.50 mmHg, P < .001). The maximum IOP was also reduced by 6.14 mmHg (95% CI 3.07-9.21, P < .001) with no IOP spikes recorded post-SLT. There was a reduction in IOP fluctuation post-SLT by 1.07 mmHg (95% CI 0.24-1.89 mmHg, P = .021). No adverse effects for using the Icare HOME were reported by the study participants.

Conclusions And Relevance: This methodology could be highly useful for facilitating safe follow-up of patients residing in remote and rural areas, thus reducing healthcare cost with better information on IOP.
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http://dx.doi.org/10.1111/ceo.13686DOI Listing
April 2020

Differential Expression in Blood-Brain Barrier Is Responsible for Strain Specific Central Nervous System Transduction Profile of AAV-PHP.B.

Hum Gene Ther 2020 01 13;31(1-2):90-102. Epub 2019 Dec 13.

Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts.

Adeno-associated virus (AAV) gene therapy for neurological diseases was revolutionized by the discovery that AAV9 crosses the blood-brain barrier (BBB) after systemic administration. Transformative results have been documented in various inherited diseases, but overall neuronal transduction efficiency is relatively low. The recent development of AAV-PHP.B with ∼60-fold higher efficiency than AAV9 in transducing the adult mouse brain was the major first step toward acquiring the ability to deliver genes to the majority of cells in the central nervous system (CNS). However, little is known about the mechanism utilized by AAV to cross the BBB, and how it may diverge across species. In this study, we show that AAV-PHP.B is ineffective for systemic CNS gene transfer in the inbred strains BALB/cJ, BALB/cByJ, A/J, NOD/ShiLtJ, NZO/HILtJ, C3H/HeJ, and CBA/J mice, but it is highly potent in C57BL/6J, FVB/NJ, DBA/2J, 129S1/SvImJ, and AKR/J mice and also the outbred strain CD-1. We used the power of classical genetics to uncover the molecular mechanisms AAV-PHP.B engages to transduce CNS at high efficiency, and by quantitative trait locus mapping we identify a 6 Mb region in chromosome 15 with an logarithm of the odds (LOD) score ∼20, including single nucleotide polymorphisms in the coding region of 9 different genes. Comparison of the publicly available data on the genome sequence of 16 different mouse strains, combined with RNA-seq data analysis of brain microcapillary endothelia, led us to conclude that the expression level of is likely the determining factor for differential efficacy of AAV-PHP.B in transducing the CNS across different mouse strains.
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http://dx.doi.org/10.1089/hum.2019.186DOI Listing
January 2020

Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis.

Nat Commun 2019 08 23;10(1):3827. Epub 2019 Aug 23.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other neurodegenerative diseases, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here we show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity, nuclear import, and downstream pathways such as mRNA post-transcriptional regulation. Importantly, we demonstrate that modulation of actin homeostasis can rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansion, the most common mutation in ALS patients. Collectively, our data link NCT defects to ALS-associated cellular pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.
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http://dx.doi.org/10.1038/s41467-019-11837-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707192PMC
August 2019

TDP-43 and NOVA-1 RNA-binding proteins as competitive splicing regulators of the schizophrenia-associated TNIK gene.

Biochim Biophys Acta Gene Regul Mech 2019 09 2;1862(9):194413. Epub 2019 Aug 2.

Istituto Auxologico Italiano, IRCCS, Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Via Zucchi 18, 20095, Cusano Milanino, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Via Fratelli Cervi 93, 20090, Segrate, Milan, Italy. Electronic address:

The RNA-binding protein TDP-43, associated to amyotrophic lateral sclerosis and frontotemporal dementia, regulates the alternative splicing of several genes, including the skipping of TNIK exon 15. TNIK, a genetic risk factor for schizophrenia and causative for intellectual disability, encodes for a Ser/Thr kinase regulating negatively F-actin dynamics. Here we show that in the human adult nervous system TNIK exon 15 is mostly included compared to the other tissues and that, during neuronal differentiation of human induced pluripotent stem cells and of human neuroblastoma cells, TNIK exon 15 inclusion increases independently of TDP-43 protein content. By studying the possible molecular interplay of TDP-43 with brain-specific splicing factors, we found that the neuronal NOVA-1 protein competitively inhibits both TDP-43 and hnRNPA2/B1 skipping activity on TNIK by means of a RNA-dependent interaction and that this competitive mechanism is common to other TDP-43 RNA targets. We also show that the TNIK protein isoforms including/excluding exon 15 differently regulate cell spreading in non-neuronal cells and neuritogenesis in primary cortical neurons. Our data suggest a complex regulation between the ubiquitous TDP-43 and the neuron-specific NOVA-1 splicing factors in the brain that may help better understand the pathobiology of both neurodegenerative diseases and schizophrenia.
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http://dx.doi.org/10.1016/j.bbagrm.2019.194413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818381PMC
September 2019

The intravitreal injection pain study: a randomized control study comparing subjective pain with injection technique.

Acta Ophthalmol 2019 Dec 11;97(8):e1153-e1154. Epub 2019 Jun 11.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1111/aos.14142DOI Listing
December 2019

The RNA-binding protein FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for mRNA processing.

J Biol Chem 2019 06 15;294(26):10194-10210. Epub 2019 May 15.

From the Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease-linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function, and disease have not been explored. Here, using primary cortical and motor neurons, we found that excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by excitotoxicity included TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS). We noted that FUS is translocated through a calcium-dependent mechanism and that its translocation coincides with striking alterations in nucleocytoplasmic transport. Furthermore, glutamate-induced up-regulation of glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type subunit 2 () in neurons depended on FUS expression, consistent with a functional role for FUS in excitotoxic stress. These findings reveal molecular links among prominent factors in neurodegenerative diseases, namely excitotoxicity, disease-associated RBPs, and nucleocytoplasmic transport.
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http://dx.doi.org/10.1074/jbc.RA118.005933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664169PMC
June 2019

Long-term survival rates of patients undergoing vitrectomy for diabetic retinopathy in an Australian population: A population-based audit-Response.

Clin Exp Ophthalmol 2019 08 21;47(6):817-818. Epub 2019 May 21.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1111/ceo.13531DOI Listing
August 2019

Rare variants in MYH15 modify amyotrophic lateral sclerosis risk.

Hum Mol Genet 2019 07;28(14):2309-2318

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive muscular atrophy and respiratory failure. The G4C2 repeat expansion in the C9orf72 gene is the most prevalent genetic risk for ALS. Mutation carriers (C9ALS) display variability in phenotypes such as age-at-onset and duration, suggesting the existence of additional genetic factors. Here we introduce a three-step gene discovery strategy to identify genetic factors modifying the risk of both C9ALS and sporadic ALS (sALS) using limited samples. We first identified 135 candidate genetic modifiers of C9ALS using whole-genome sequencing (WGS) of extreme C9ALS cases diagnosed ~30 years apart. We then performed an unbiased genetic screen using a Drosophila model of the G4C2 repeat expansion with the genes identified from WGS analysis. This genetic screen identified the novel genetic interaction between G4C2 repeat-associated toxicity and 18 genetic factors, suggesting their potential association with C9ALS risk. We went on to test if 14 out of the 18 genes, those which were not known to be risk factors for ALS previously, are also associated with ALS risk in sALS cases. Gene-based-statistical analyses of targeted resequencing and WGS were performed. These analyses together reveal that rare variants in MYH15 represent a likely genetic risk factor for ALS. Furthermore, we show that MYH15 could modulate the toxicity of dipeptides produced from expanded G4C2 repeat. Our study presented here demonstrates the power of combining WGS with fly genetics to facilitate the discovery of fundamental genetic components of complex traits with a limited number of samples.
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http://dx.doi.org/10.1093/hmg/ddz063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606848PMC
July 2019

Disordered Mesoporous Zirconium (Hydr)oxides for Decomposition of Dimethyl Chlorophosphate.

ACS Appl Mater Interfaces 2019 May 30;11(19):17931-17939. Epub 2019 Apr 30.

Chemical and Biochemical Engineering Department , Rutgers University , Piscataway , New Jersey 08854 , United States.

A facile method for the formation of mesoporosity within nonporous zirconium hydr(oxides) (ZrO/Zr(OH)) is presented and their detoxifying capabilities against dimethyl chlorophosphate (DMCP) are investigated. Nanoaggregates of ZrO/Zr(OH) appear to be deposited on larger thin flakes of the same material. HO is used to induce surface oxygen vacancies of synthesized ZrO/Zr(OH) and, as a consequence, mesopores with an average diameter of 3.1 nm were formed. A surface area of HO-treated ZrO/Zr(OH) was increased by an order of magnitude and shows enhanced reactivity toward DMCP. DRIFTS spectroscopy is employed to assess the reactivity differences between the HO-treated and untreated ZrO/Zr(OH). Peaks at 1175 and 1144 cm indicate the presence of asymmetric stretching of the O-P-O moiety within dimethyl phosphonate (DMHP), a decomposition product from DMCP, and a zirconium-bound methoxy group, respectively. It is suggested that the decomposition of DMCP proceeds through the consumption of bridged hydroxyl groups (b-OH) for both the untreated and HO-treated samples, as well as an additional hydrolytic decomposition pathway for the HO-treated sample.
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http://dx.doi.org/10.1021/acsami.9b00843DOI Listing
May 2019

Macular Ganglion Cell-Inner Plexiform Layer Loss Precedes Peripapillary Retinal Nerve Fiber Layer Loss in Glaucoma with Lower Intraocular Pressure.

Ophthalmology 2019 08 22;126(8):1119-1130. Epub 2019 Mar 22.

Department of Ophthalmology, Flinders University, Bedford Park, Australia. Electronic address:

Purpose: To investigate which clinical measures influence whether an individual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fiber layer (pRNFL) or macular ganglion cell-inner plexiform layer (mGCIPL).

Design: Prospective, longitudinal cohort study.

Participants: Two hundred seventy-one eyes from 207 individuals with statistically significant evidence of glaucomatous progression on OCT Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 individuals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance.

Methods: Individuals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared with individuals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis.

Main Outcome Measures: Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL.

Results: Intraocular pressure, baseline pRNFL thickness, baseline mGCIPL thickness, and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pretreatment IOP (mean difference, 3.90 mmHg; 95% confidence interval [CI], 2.37-5.43 mmHg; P < 0.001). The interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5-mmHg increase in IOP (95% CI, 10.32-15.72 months). Eyes demonstrating earliest longitudinal progression on mGCIPL showed significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference, 7.07 μm; 95% CI, 4.38-9.77 μm; P < 0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to demonstrate a new paracentral field defect than eyes progressing first on pRNFL parameters (odds ratio, 3.03; 95% CI, 1.26-7.28; P = 0.01).

Conclusions: Clinical features, particularly pretreatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the usefulness of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.
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http://dx.doi.org/10.1016/j.ophtha.2019.03.016DOI Listing
August 2019

Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis.

Cell Rep 2019 02;26(9):2298-2306.e5

Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have linked ALS pathophysiology to inherited mutations that diminish the activity of a glycosyltransferase enzyme.
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http://dx.doi.org/10.1016/j.celrep.2019.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003067PMC
February 2019

Quantitative proteomics identifies proteins that resist translational repression and become dysregulated in ALS-FUS.

Hum Mol Genet 2019 07;28(13):2143-2160

Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.

Aberrant translational repression is a feature of multiple neurodegenerative diseases. The association between disease-linked proteins and stress granules further implicates impaired stress responses in neurodegeneration. However, our knowledge of the proteins that evade translational repression is incomplete. It is also unclear whether disease-linked proteins influence the proteome under conditions of translational repression. To address these questions, a quantitative proteomics approach was used to identify proteins that evade stress-induced translational repression in arsenite-treated cells expressing either wild-type or amyotrophic lateral sclerosis (ALS)-linked mutant FUS. This study revealed hundreds of proteins that are actively synthesized during stress-induced translational repression, irrespective of FUS genotype. In addition to proteins involved in RNA- and protein-processing, proteins associated with neurodegenerative diseases such as ALS were also actively synthesized during stress. Protein synthesis under stress was largely unperturbed by mutant FUS, although several proteins were found to be differentially expressed between mutant and control cells. One protein in particular, COPBI, was downregulated in mutant FUS-expressing cells under stress. COPBI is the beta subunit of the coat protein I (COPI), which is involved in Golgi to endoplasmic reticulum (ER) retrograde transport. Further investigation revealed reduced levels of other COPI subunit proteins and defects in COPBI-relatedprocesses in cells expressing mutant FUS. Even in the absence of stress, COPBI localization was altered in primary and human stem cell-derived neurons expressing ALS-linked FUS variants. Our results suggest that Golgi to ER retrograde transport may be important under conditions of stress and is perturbed upon the expression of disease-linked proteins such as FUS.
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http://dx.doi.org/10.1093/hmg/ddz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586143PMC
July 2019

Long-term survival rates of patients undergoing vitrectomy for diabetic retinopathy in an Australian population: a population-based audit.

Clin Exp Ophthalmol 2019 07 20;47(5):598-604. Epub 2019 Feb 20.

Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia.

Importance: Five-year survival rates in patients undergoing vitrectomy for diabetic retinopathy (DR) vary from 68% to 95%. No study has been conducted in an Australian population.

Background: We aimed to determine the survival rates of patients undergoing diabetic vitrectomy in an Australian population.

Design: Retrospective audit, tertiary centre hospitals and private practices.

Participants: All individuals in South Australia and the Northern Territory who underwent their first vitrectomy for diabetic complications between January 1, 2007 and December 31, 2011.

Methods: An audit of all eligible participants has been completed previously. Survival status as of July 6, 2018 and cause of death were obtained using SA/NT DataLink. Kaplan-Meier survival curves and multivariate cox-regressions were used to analyse survival rates and identify risk factors for mortality.

Main Outcome Measures: Five-, seven- and nine-year survival rates.

Results: The 5-, 7- and 9-year survival rates were 84.4%, 77.9% and 74.7%, respectively. The most common cause of death was cardiovascular disease. Associated with increased mortality independent of age were Indigenous ethnicity (HR = 2.04, 95% confidence interval [CI]: 1.17-3.57, P = 0.012), chronic renal failure (HR = 1.76, 95% CI: 1.07-2.89, P = 0.026) and renal failure requiring dialysis (HR = 2.32, 95% CI: 1.25-4.32, P = 0.008).

Conclusions And Relevance: Long-term survival rates after diabetic vitrectomy in Australia are similar to rates reported in other populations. Indigenous ethnicity and chronic renal failure were the most significant factors associated with long-term mortality. This information can guide allocation of future resources to improve the prognosis of these high risk groups.
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http://dx.doi.org/10.1111/ceo.13466DOI Listing
July 2019

Prevalence and type of artefact with spectral domain optical coherence tomography macular ganglion cell imaging in glaucoma surveillance.

PLoS One 2018 5;13(12):e0206684. Epub 2018 Dec 5.

Flinders University, Department of Ophthalmology, South Australia, Australia.

Purpose: The ganglion cell analysis (GCA) of the CIRRUSTM HD-OCT (Carl Zeiss, Meditec; Dublin, CA) provides measurement of the macular ganglion cell-inner plexiform layer (GCIPL) thickness. This study determined the frequency of scan artefacts and errors in GCIPL imaging in individuals undergoing HD-OCT surveillance for glaucoma.

Method: A total of 1439 eyes from 721 subjects enrolled in a prospective study assessing predictors of glaucoma progression underwent macular GCIPL imaging with the CIRRUS HD-OCT at recruitment. The prevalence of acquisition errors, segmentation errors, and co-morbid macular pathology was determined.

Results: A total of 87 (6.0%) of the 1439 scans had either acquisition errors, segmentation artefacts, or other macular pathology. The most common co-morbid macular pathology was epiretinal membrane in 2.2% of eyes.

Conclusion: The macular GCIPL scan was artefact free in 94% of eyes. However, epiretinal membrane and high myopia can cause scan artefact and should be considered when interpreting the results.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206684PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281246PMC
April 2019

Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort.

Neurobiol Aging 2019 02 22;74:234.e9-234.e15. Epub 2018 Sep 22.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893598PMC
February 2019

Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies.

JAMA Ophthalmol 2019 01;137(1):28-35

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Importance: The p.Gln368Ter (rs74315329) risk allele in the myocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom.

Objectives: To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT).

Design, Setting, And Participants: This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018.

Main Outcomes And Measures: The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT.

Results: A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%.

Conclusions And Relevance: The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.
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http://dx.doi.org/10.1001/jamaophthalmol.2018.4477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439786PMC
January 2019