Showing papers by "Ronald Klein published in 2018"
TL;DR: GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss, and the genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA.
112 citations
TL;DR: SINE compounds modestly extend cellular survival in neuronal ALS/FTD models and mitigate motor symptoms in an in vivo rat ALS model, and overexpression of XPO1, XPO7 and NXF1 are each sufficient to promote nuclear TDP43 egress.
Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders marked in most cases by the nuclear exclusion and cytoplasmic deposition of the RNA binding protein TDP43. We previously demonstrated that ALS-associated mutant TDP43 accumulates within the cytoplasm, and that TDP43 mislocalization predicts neurodegeneration. Here, we sought to prevent neurodegeneration in ALS/FTD models using selective inhibitor of nuclear export (SINE) compounds that target exportin-1 (XPO1). SINE compounds modestly extend cellular survival in neuronal ALS/FTD models and mitigate motor symptoms in an in vivo rat ALS model. At high doses, SINE compounds block nuclear egress of an XPO1 cargo reporter, but not at lower concentrations that were associated with neuroprotection. Neither SINE compounds nor leptomycin B, a separate XPO1 inhibitor, enhanced nuclear TDP43 levels, while depletion of XPO1 or other exportins had little effect on TDP43 localization, suggesting that no single exporter is necessary for TDP43 export. Supporting this hypothesis, we find overexpression of XPO1, XPO7 and NXF1 are each sufficient to promote nuclear TDP43 egress. Taken together, our results indicate that redundant pathways regulate TDP43 nuclear export, and that therapeutic prevention of cytoplasmic TDP43 accumulation in ALS/FTD may be enhanced by targeting several overlapping mechanisms.
106 citations
TL;DR: Significant barriers exist for rural patients that affect their ability to adhere with yearly diabetic eye screening, and strategies targeted specifically to environmental barriers such as long travel distances may fill crucial gaps in diabetic eye Screening in rural communities.
Abstract: Objective Diabetic retinopathy remains the leading cause of blindness among working-age U.S. adults largely due to low screening rates. Rural populations face particularly greater challenges to screening because they are older, poorer, less insured, and less likely to receive guideline-concordant care than those in urban areas. Current patient education efforts may not fully address multiple barriers to screening faced by rural patients. We sought to characterize contextual factors affecting rural patient adherence with diabetic eye screening guidelines. Research design and methods We conducted semi-structured interviews with 29 participants (20 adult patients with type 2 diabetes and 9 primary care providers) in a rural, multi-payer health system. Both inductive and directed content analysis were performed. Results Factors influencing rural patient adherence with diabetic eye screening were categorized as environmental, social, and individual using the Ecological Model of Health. Major themes included limited access to and infrequent use of healthcare, long travel distances to obtain care, poverty and financial tradeoffs, trusting relationships with healthcare providers, family members’ struggles with diabetes, anxiety about diabetes complications, and the burden of diabetes management. Conclusions Significant barriers exist for rural patients that affect their ability to adhere with yearly diabetic eye screening. Many studies emphasize patient education to increase adherence, but current patient education strategies fail to address major environmental, social, and individual barriers. Addressing these factors, leveraging patient trust in their healthcare providers, and strategies targeted specifically to environmental barriers such as long travel distances (e.g. teleophthalmology) may fill crucial gaps in diabetic eye screening in rural communities.
51 citations
University of Dundee1, University of Chicago2, Harvard University3, University of Helsinki4, University of Oxford5, Wellcome Trust Centre for Human Genetics6, Churchill Hospital7, Lund University8, Royal Melbourne Hospital9, Flinders University10, University of Sydney11, University of Washington12, University of Mississippi Medical Center13, Los Angeles Biomedical Research Institute14, UCLA Medical Center15, University of Wisconsin-Madison16, National University of Singapore17, University of Edinburgh18, Western General Hospital19, Menzies Research Institute20, University of Illinois at Chicago21, Massachusetts Eye and Ear Infirmary22
TL;DR: The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy and establish a smoking cessation strategy for patients with diabetes.
Abstract: Purpose: Diabetic retinopathy is the most common eye complication in patients with diabetes The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy Methods: A genome-wide association approach was applied In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts Results: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 405 × 10−9 Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 741 × 10−8 and 123 × 10−8, respectively) In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0003 and 0007, respectively), while the p value of rs3913535 was not significant (p = 0429) Conclusion: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene (Less)
49 citations
TL;DR: Prevalence of MD in this cohort of Chinese Americans was higher than that observed in other East Asian populations and in people of other ethnicities, indicating that a high proportion of Chinese American might be at risk for MD and associated visual complications.
42 citations
TL;DR: This work characterized the relatively novel AAV PHP.B.EB vector for expansive gene transfer in the CNS of adult rats at three doses and found it to be one of the most efficient AAV vectors in the field for CNS gene transfer.
Abstract: Engineered recombinant adeno-associated virus (AAV) vectors have advanced the transduction of neurons in the CNS on an expansive, wide-scale basis since the papers first using AAV9 for this purpose Wide-scale CNS expression is relevant to gene therapy as well as indispensable for basic studies such as disease modeling For example, the wide-scale gene transfer approach could expedite hypothesis testing in vivo relative to the generation of germ-line transgenic mice for all of the genes of interest Wide-scale gene transfer is more efficient in neonates than in adults, so improving gene transfer efficiency in adults is an important goal Here we characterized the relatively novel AAV PHPEB vector for expansive gene transfer in the CNS of adult rats at three doses The dose–response data were consistent; expression levels can be controlled in a reproducible manner in the rat from moderate to robust levels Within the CNS, the AAV PHPEB-derived expression was neuron-selective to neuron-specific, while outside the CNS, organs such as the liver and heart were transduced by the parenteral gene delivery Though we demonstrated graded expression levels, only the high dose, 12 × 1014 vector genomes/kg, yielded efficient expression in spinal cord motor neurons of the adult rat, so this vector dose would be required for models of spinal cord motor neuron disease The neuronal expression in the rat CNS was greater with AAV PHPEB than the previous engineered vector AAV PHPB AAV PHPEB is thus one of the most efficient AAV vectors in the field for CNS gene transfer
39 citations
TL;DR: The data indicate that loss of NNT increases vascular ROS production and exacerbates atherosclerotic plaque development.
Abstract: Background Mitochondrial reactive oxygen species (ROS) contribute to inflammation and vascular remodeling during atherosclerotic plaque formation. C57BL/6N (6N) and C57BL/6J (6J) mice display distinct mitochondrial redox balance due to the absence of nicotinamide nucleotide transhydrogenase (NNT) in 6J mice. We hypothesize that differential NNT expression between these animals alters plaque development. Methods 6N and 6J mice were treated with AAV8-PCSK9 (adeno-associated virus serotype 8/proprotein convertase subtilisin/kexin type 9) virus leading to hypercholesterolemia, increased low-density lipoprotein, and atherosclerosis in mice fed a high-fat diet (HFD). Mice were co-treated with the mitochondria-targeted superoxide dismutase mimetic MitoTEMPO to assess the contribution of mitochondrial ROS to atherosclerosis. Results Baseline and HFD-induced vascular superoxide is increased in 6J compared to 6N mice. MitoTEMPO diminished superoxide in both groups demonstrating differential production of mitochondrial ROS among these strains. PCSK9 treatment and HFD led to similar increases in plasma lipids in both 6N and 6J mice. However, 6J animals displayed significantly higher levels of plaque formation. MitoTEMPO reduced plasma lipids but did not affect plaque formation in 6N mice. In contrast, MitoTEMPO surprisingly increased plaque formation in 6J mice. Conclusion These data indicate that loss of NNT increases vascular ROS production and exacerbates atherosclerotic plaque development.
28 citations
TL;DR: The findings support the exploration of more sensitive measures in the eye such as optical coherence tomography angiography, which may provide surrogate indexes of microvascular lesions relevant to cognitive decline in older adults.
Abstract: Objective To test the hypothesis that retinal vascular signs are associated with greater cognitive decline over 20 years in 12,317 men and women 50 to 73 years of age at baseline. Methods A composite cognitive score was created with 3 neuropsychological tests measured at 3 time points (1990–1992 to 2011–2013). Retinal signs were measured with fundus photography (1993–1995). Differences in cognitive change by retinal signs status were estimated with linear mixed models. Cognitive scores were imputed for living participants with incomplete cognitive testing. Results In multivariable-adjusted analyses that controlled for attrition, loss of vascular integrity (retinopathy and its components) was associated with greater 20-year decline (difference in 20-year cognitive change for moderate/severe vs no retinopathy −0.53 SD, 95% confidence interval −0.74 to −0.33). Estimated differences were similar in participants with and without diabetes mellitus and in white and black participants. Conclusions Retinopathy was associated with accelerated rates of 20-year cognitive decline. These findings support the exploration of more sensitive measures in the eye such as optical coherence tomography angiography, which may provide surrogate indexes of microvascular lesions relevant to cognitive decline in older adults.
27 citations
Case Western Reserve University1, University of Toronto2, Lunenfeld-Tanenbaum Research Institute3, McMaster University4, University of Utah5, Joslin Diabetes Center6, Harvard University7, Anschutz Medical Campus8, Stanford University9, University of Wisconsin-Madison10, University of Pittsburgh11, University of Exeter12, National Institute for Health Research13
TL;DR: A locus on chromosome 1 and multiple variants in the MHC region, at least some of which were distinct from type 1 diabetes risk loci, that were associated with C-peptide were identified, suggesting partly non-overlapping mechanisms for the development and progression of type 1 Diabetes.
Abstract: The aim of this study was to identify genetic variants associated with beta cell function in type 1 diabetes, as measured by serum C-peptide levels, through meta-genome-wide association studies (meta-GWAS). We performed a meta-GWAS to combine the results from five studies in type 1 diabetes with cross-sectionally measured stimulated, fasting or random C-peptide levels, including 3479 European participants. The p values across studies were combined, taking into account sample size and direction of effect. We also performed separate meta-GWAS for stimulated (n = 1303), fasting (n = 2019) and random (n = 1497) C-peptide levels. In the meta-GWAS for stimulated/fasting/random C-peptide levels, a SNP on chromosome 1, rs559047 (Chr1:238753916, T>A, minor allele frequency [MAF] 0.24–0.26), was associated with C-peptide (p = 4.13 × 10−8), meeting the genome-wide significance threshold (p T, MAF 0.07–0.10, p = 8.43 × 10−8). In the stimulated C-peptide meta-GWAS, rs61211515 (Chr6:30100975, T/–, MAF 0.17–0.19) in the MHC region was associated with stimulated C-peptide (β [SE] = − 0.39 [0.07], p = 9.72 × 10−8). rs61211515 was also associated with the rate of stimulated C-peptide decline over time in a subset of individuals (n = 258) with annual repeated measures for up to 6 years (p = 0.02). In the meta-GWAS of random C-peptide, another MHC region, SNP rs3135002 (Chr6:32668439, C>A, MAF 0.02–0.06), was associated with C-peptide (p = 3.49 × 10−8). Conditional analyses suggested that the three identified variants in the MHC region were independent of each other. rs9260151 and rs3135002 have been associated with type 1 diabetes, whereas rs559047 and rs61211515 have not been associated with a risk of developing type 1 diabetes. We identified a locus on chromosome 1 and multiple variants in the MHC region, at least some of which were distinct from type 1 diabetes risk loci, that were associated with C-peptide, suggesting partly non-overlapping mechanisms for the development and progression of type 1 diabetes. These associations need to be validated in independent populations. Further investigations could provide insights into mechanisms of beta cell loss and opportunities to preserve beta cell function.
26 citations
TL;DR: Retinal vessel geometric characteristics of the retinal venules were associated with progression ofDR; however, most of the RVGCs measured from digitized fundus photographs added little to the assessment of risk of incidence and progression of DR when other risk factors were considered in T1DM and T2DM.
26 citations
TL;DR: These differences in PCSK9 expression and hypercholesterolemia development between male and female mice using the AAV8-PCSK9 model do not hinder the use of female mice, however, localization to and production in organs besides the liver in mice may introduce confounding factors into studies and should be considered during experimental design.
TL;DR: It is suggested that incident CS impairment was common in the 10-year follow-up, with cadmium, but not lead, exposure associated with increased risk, and associations of diminished CS with other modifiable risk factors found appear to imply that changes in behavior may reduce future incidence of CS impairment.
Abstract: Importance Contrast sensitivity (CS) is an important indicator of visual function that affects daily life, including mobility, visually intensive tasks, safety, and autonomy. Understanding the risk factors for CS impairment could prevent decreases in visual function. Objective To determine the incidence of and factors associated with CS impairment in a large cohort. Design, Setting, and Participants The Beaver Dam Offspring Study is an ongoing longitudinal cohort study of aging involving adults in Beaver Dam, Wisconsin. Participants who were free of CS impairment in both eyes at baseline were included (N = 1983). Baseline data collection occurred from June 8, 2005, through August 4, 2008, when the participants ranged from 21 to 84 years of age. Two follow-up examinations occurred at 5-year intervals: one was conducted between July 12, 2010, and March 21, 2013, and the other between July 1, 2015, and November 13, 2017. Data analysis was performed from November 27, 2017, to February 27, 2018. Main Outcomes and Measures Contrast sensitivity testing was conducted with Pelli-Robson letter sensitivity charts, and incident impairment was defined as a log CS score less than 1.55 in either eye at any follow-up examination. Cadmium and lead levels were measured in whole blood with inductively coupled plasma mass spectrometry. Associations between baseline characteristics and CS impairment incidence were examined using Cox proportional hazard models and quantified as hazard ratios (HRs) with 95% CI. Results Of the 1983 participants included, 1028 (51.8%) were female and 955 (48.2%) were male, with a mean (SD) age of 48 (9.3) years. The 10-year cumulative incidence of CS impairment was 24.8% (95% CI, 22.9-26.8), similar in women (24.9%) and men (24.6%), and highest in the oldest age group (65-84 years) at 66.3%. In multivariable models, cadmium level in the highest quintile (HR, 1.35; 95% CI, 1.02-1.78), older age (HR, 1.36; 95% CI, 1.25-1.47), larger waist circumference (HR, 1.06; 95% CI, 1.01-1.11), and more plaque sites (1-3 sites: HR, 1.43; 95% CI, 1.07-1.92; 4-6 sites: HR, 2.75; 95% CI, 1.26-6.05) were among the factors associated with increased risk, while male sex (HR, 0.77; 95% CI, 0.60-0.98) and any alcohol consumption (HR, 0.61; 95% CI, 0.43-0.88) were associated with decreased risk. Results were similar when smoking status replaced cadmium exposure in the models. Lead level was not associated with increased risk. Conclusions and Relevance This study’s findings suggest that incident CS impairment was common in the 10-year follow-up, with cadmium, but not lead, exposure associated with increased risk. The associations of diminished CS with other modifiable risk factors found appear to imply that changes in behavior may reduce future incidence of CS impairment.
TL;DR: Nuclear cataract is the primary contributor to the myopic shift among older individuals, and changes in refraction measured over a 20-year period among adults over age 40 from the Beaver Dam Eye Study are summarized.
Abstract: Purpose Hyperopic shifts in refraction have been consistently reported in adults over 40, followed by myopic shifts after age 70 Although potential factors underlying these changes in refraction in older adults have been investigated previously, the studies were restricted by the limited longitudinal data available The authors of this study sought to better characterize the long-term trajectory of refraction in older adults using 20 years of prospective data Methods The impact of cohort effects on refraction over 20 years was examined Generalized estimating equations were used to evaluate the etiologic factors underlying refraction and changes in refraction measured over a 20-year period (1988-2010) among adults over age 40 from the Beaver Dam Eye Study Results Only individuals with nuclear cataract experienced a myopic shift in refraction, showing a 025 diopter (D) decrease (95% confidence interval [CI]: -044 D to -007 D) over a five-year period Individuals with mild and moderate nuclear sclerosis showed varying degrees of hyperopic shifts over five years (022 D: 95% CI: 020 D-025 D; 023 D: 95% CI: 020 D-027 D, respectively) Conclusions Nuclear cataract is the primary contributor to the myopic shift among older individuals Birth cohort effects on baseline refraction but not change in refraction were observed
TL;DR: Retinal microvascular signs and pure geographic atrophy may be associated with deep and exclusively lobar CMBs, respectively, in older people, and have implications for further research to define the role of small vessel disease in cognitive impairment.
Abstract: Objective To test the hypothesis that age-related macular degeneration (AMD) and retinal microvascular signs are differentially associated with lobar and deep cerebral microbleeds (CMBs). Methods CMBs in lobar regions indicate cerebral amyloid angiopathy (CAA). β-Amyloid deposits are implicated in both CAA and AMD. Deep CMBs are associated with hypertension, a major risk factor for retinal microvascular damage. This population-based cohort study included 2,502 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study who undertook binocular digital retinal photographs at baseline (2002–2006) to assess retinal microvascular signs and AMD and brain MRI scan at both baseline and follow-up (2007–2011) to assess CMBs. We assessed retinal microvascular lesion burden by counting the 3 retinal microvascular signs (focal arteriolar narrowing, arteriovenous nicking, and retinopathy) concurrently present in the participant. We used multiple logistic models to examine the association of baseline retinal pathology to incident CMBs detected at follow-up. Results During an average 5.2 years of follow-up, 461 people (18.3%) developed new CMBs, including 293 in exclusively lobar regions and 168 in deep regions. Pure geographic atrophy was significantly associated with strictly lobar CMBs (multivariable-adjusted odds ratio 2.59, 95% confidence interval [CI] 1.01–6.65) but not with deep CMBs. Concurrently having ≥2 retinal microvascular signs was associated with a 3-fold (95% CI 1.73–5.20) increased likelihood for deep CMBs but not exclusively lobar CMBs. Conclusions Retinal microvascular signs and pure geographic atrophy may be associated with deep and exclusively lobar CMBs, respectively, in older people. These results have implications for further research to define the role of small vessel disease in cognitive impairment.
University of California, San Diego1, Boston Children's Hospital2, Harvard University3, Broad Institute4, University of Helsinki5, University of Virginia6, University College Dublin7, University of Utah8, University of Edinburgh9, Hospital for Sick Children10, University of Pennsylvania11, University of Michigan12, Joslin Diabetes Center13, Wellcome Trust Centre for Human Genetics14, University of Oxford15, Lund University16, Steno Diabetes Center17, Boehringer Ingelheim18, National Institutes of Health19, University of Wisconsin-Madison20, George Washington University21, University of Minnesota22, University of Washington23, University of Pittsburgh24, Institute of Chartered Accountants of Nigeria25, University of Paris26, University of Colorado Denver27, Stanford University28, University of Toronto29, McMaster University30, University of Dundee31, Paracelsus Private Medical University of Salzburg32, University of Latvia33, Latvian Biomedical Research and Study centre34, Lithuanian University of Health Sciences35, Carol Davila University of Medicine and Pharmacy36, Karolinska University Hospital37, China Pharmaceutical University38, Umeå University39, Karolinska Institutet40, University of Copenhagen41, Paris Diderot University42, New York City Fire Department43, French Institute of Health and Medical Research44, University of Poitiers45, Queen's University Belfast46
TL;DR: The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.
Abstract: Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD (BMP7) or renal biology (COLEC11 and DDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.
TL;DR: Vascular health-related factors may play a role in central auditory function in people with a history of cardiovascular disease or higher PWV, and after multivariable adjustment, participants with diabetes had a significantly lower mean DDT-free recall total score.
Abstract: BACKGROUND Associations between vascular health-related factors and hearing loss defined using audiometric pure-tone thresholds have been found. Studies have not focused on a potential relationship between vascular health-related factors and central auditory processing. PURPOSE The aim of this study was to evaluate, on a population level, the relationship of vascular health-related factors with central auditory function. RESEARCH DESIGN A cross-sectional, population study. STUDY SAMPLE Subjects were participants in the Epidemiology of Hearing Loss Study (EHLS) or the Beaver Dam Offspring Study (BOSS)-prospective studies of aging and sensory loss. BOSS participants were the adult offspring of participants in the EHLS. Participants who completed the Dichotic Digits Test (DDT) during the fourth examination period of the EHLS (2008-2010) or the second examination period of the BOSS (2010-2013) were included (n = 3,655, mean age = 61.1 years). DATA COLLECTION AND ANALYSIS The DDT-free recall test was conducted using 25 sets of triple-digit pairs at a 70 dB HL presentation level. The total number of correctly repeated digits from the right and left ears was converted to a percentage correct and used as an outcome. The percentage correct in the left ear was subtracted from the percentage correct in the right ear and used as an outcome. Vascular health-related measures obtained during the examination included blood pressure, mean carotid intima-media thickness, femoral pulse wave velocity (PWV), hemoglobin A1C, and non-high-density lipoprotein (HDL) cholesterol, and, in the EHLS participants, C-reactive protein and interleukin-6. Information on vascular health-related history and behaviors was self-reported. General linear modeling produced estimates of the age- and sex-adjusted least squares means for each vascular factor, and multiple linear regression was used for multivariable modeling of each outcome. RESULTS After multivariable adjustment, participants with diabetes had a significantly lower (worse) mean DDT-free recall total score (-2.08 percentage points, p < 0.001) than those without diabetes. Participants who exercised at least once per week had a significantly higher (better) mean DDT-free recall total score (+1.07 percentage points, p < 0.01) than those who did not exercise at least once per week. Alcohol consumption was associated with a higher DDT-free recall total score (+0.15 percentage points per +25 g ethanol, p < 0.01). In multivariable modeling of the right-left ear difference in DDT-free recall scores, participants with a history of cardiovascular disease (CVD) or higher PWV demonstrated significantly larger differences (CVD: +3.11 percentage points, p = 0.02; PWV: +0.36 percentage points per 1 m/sec, p < 0.01). Higher levels of non-HDL cholesterol were associated with smaller right-left ear differences (-0.22 percentage points per 10 mg/dL, p = 0.01). Adjustment for handedness did not affect the results. CONCLUSIONS Vascular health-related factors may play a role in central auditory function.
01 Jan 2018
TL;DR: A genome-wide association study for HbA1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane, found three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with Hb a 1c in FinnD Diane at genome- wide significance.
TL;DR: Investigation of the association between cystatin C, both as an independent biomarker and as a marker of kidney function, and the 20-year cumulative incidence of HI suggested that some age-related HI may occur in conjunction with or as the result of reduced kidney function.
Abstract: Importance Hearing impairment (HI) is one of the most common conditions affecting older adults. Identification of factors associated with the development of HI may lead to ways to reduce the incidence of this condition. Objective To investigate the association between cystatin C, both as an independent biomarker and as a marker of kidney function, and the 20-year incidence of HI. Design, Setting, and Participants Data were obtained from the Epidemiology of Hearing Loss Study (EHLS), a longitudinal, population-based study in Beaver Dam, Wisconsin. Baseline examinations began in 1993 and continued through 1995, and participants were examined approximately every 5 years, with the most recent examination phase completed in 2015. The EHLS participants with serum cystatin C concentration data and without HI at the baseline examination were included in this study. Main Outcomes and Measures Participants without HI were followed up for incident HI (pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz >25 dB hearing level in either ear) for 20 years. Cystatin C was analyzed as a biomarker (concentration) and used to determine estimated glomerular filtration rate (eGFRCysC). Discrete-time Cox proportional hazards regression models were used to analyze the association between cystatin C concentration and eGFRCysCand the 20-year cumulative incidence of HI. Results There were 863 participants aged 48 to 86 years with cystatin C data and without HI at baseline. Of these, 599 (69.4%) were women. In models adjusted for age and sex, cystatin C was associated with an increased risk of developing HI (hazard ratio [HR], 1.20; 95% CI, 1.07-1.34 per 0.2-mg/L increase in cystatin C concentration), but the estimate was attenuated after further adjusting for educational level, current smoking, waist circumference, and glycated hemoglobin (HR, 1.11; 95% CI, 0.98-1.27 per 0.2-mg/L increase in cystatin C concentration). Low eGFRCysCwas significantly associated with the 20-year cumulative incidence of HI in both the age- and sex-adjusted model (HR, 1.70; 95% CI, 1.16-2.48; Conclusions and Relevance Reduced kidney function as estimated using cystatin C, but not cystatin C alone, was associated with the 20-year cumulative incidence of HI, suggesting that some age-related HI may occur in conjunction with or as the result of reduced kidney function.
TL;DR: By combining Cre recombinase‐dependent AAVs in Cre‐driver rats in which Cre is expressed only in the tyrosine hydroxylase neurons, the refined targeting foreshadows a next‐generation disease modeling system for expressing neurodegenerative disease‐related proteins in a disease‐relevant manner.
Abstract: Recombinant adeno-associated virus (AAV) vectors are a popular genetic approach in neuroscience because they confer such efficient transgene expression in the brain and spinal cord. A number of studies have used AAV to express pathological disease-related proteins in the dopaminergic neurons of the substantia nigra in situ ( e.g., α-synuclein to model aspects of Parkinson's disease). The neuropathology and neurodegeneration of Parkinson's disease occur in a circumscribed pattern in the brain, and one of the most important goals of any gene transfer study is accurate, pinpoint targeting. By combining Cre recombinase-dependent AAVs in Cre-driver rats in which Cre is expressed only in the tyrosine hydroxylase neurons, we have achieved more highly targeted expression of several disease-relevant neuropathological proteins in the substantia nigra pars compacta than using constitutive expression AAV vectors. Alpha-synuclein, tau, transactive response DNA-binding protein of 43 kDa, or the control fluorescent protein yellow fluorescent protein was individually expressed to induce highly targeted, dopaminergic neuron-specific neurodegeneration models. The refined targeting foreshadows a next-generation disease modeling system for expressing neurodegenerative disease-related proteins in a disease-relevant manner. We foresee specific utilities of this in vivo AAV vector targeting of pathological proteins to a well-defined and well-demarcated cell population.-Grames, M. S., Dayton, R. D., Jackson, K. L., Richard, A. D., Lu, X., Klein, R. L. Cre-dependent AAV vectors for highly targeted expression of disease-related proteins and neurodegeneration in the substantia nigra.
University of Chicago1, Centers for Disease Control and Prevention2, National Institutes of Health3, KPMG4, Institute for Health Metrics and Evaluation5, Johns Hopkins University6, Uniformed Services University of the Health Sciences7, University of Illinois at Chicago8, University of Wisconsin-Madison9, University of Michigan10
TL;DR: Known ototoxic medications are widely used among older adults and any subsequent ototoxicity may interact with age changes and a more severe hearing loss than that associated with only age.
Abstract: Background and purpose Drug-related ototoxicity may exacerbate presbycusis (age-related hearing loss); yet, few data are available on the prevalence of ototoxic medication use by older adults. The purposes of this study were to assess the impact of aging and ototoxicity on hearing loss, the prevalence of ototoxic medication use, and select characteristics associated with ototoxic medication use among older adults. Methods Cross-sectional analyses were conducted using select variables extracted from the baseline and 10-year follow-up assessments of the two population-based epidemiological studies to compare two points in time. Results Ninety-one percent of the sample was taking a medication reported to be ototoxic. Nonsteroidal anti-inflammatory drugs were the most commonly used (75.2%), followed by acetaminophen (39.9%) and diuretics (35.6%). Hypertension, diabetes, cardiovascular disease, and history of smoking were associated with ototoxic medication use. Participants with hearing loss were taking a significantly greater number of ototoxic medications than those without hearing loss. Conclusion Known ototoxic medications are widely used. Any subsequent ototoxicity may interact with age changes and a more severe hearing loss than that associated with only age. Implications for practice Nurse practitioners should inform older adults about the possibility of drug-related ototoxicity and monitor hearing acuity of all older adults taking known ototoxic medications.
TL;DR: The data indicate that the impact of increasing HbA1c and SBP on DR probability is incrementally the same in both populations, however, increasing T2DM duration is associated with higher DR probability in Latinos than Chinese Americans, even after controlling for other known predictors.
TL;DR: Long-term arterial retinal changes could indicate type 1 diabetes–related cognitive impairment and studies examining longitudinal central retinal arteriolar equivalent changes as early biomarkers of cognitive impairment risk are warranted.
Abstract: Objective:To assess associations between cognitive impairment and longitudinal changes in retinal microvasculature, over 18 years, in adults with type 1 diabetes.Research design and methods:Participants of the Pittsburgh Epidemiology of Diabetes Complications Study received ≥3 fundus photographs between baseline (1986–1988) and time of cognitive assessment (2010–2015: N = 119; 52% male; mean age and type 1 diabetes duration 43 and 34 years, respectively). Central retinal arteriolar equivalent and central retinal venular equivalent were estimated via computer-based methods; overall magnitude and speed of narrowing were quantified as cumulative average and slope, respectively. Median regression models estimated associations of central retinal arteriolar equivalent and central retinal venular equivalent measures with cognitive impairment status, adjusted for type 1 diabetes duration. Interactions with HbA1c, proliferative retinopathy and white matter hyperintensities were assessed.Results:Compared with parti...
TL;DR: The presence of AMD in a diverse population without known clinical CVD independently predicted higher 10-year CAC progression in participants with baseline CAC >0.01, suggesting the retinal exam might be a useful tool for pre-clinical assessment and prevention of CVD events.
Abstract: Background Age-related macular degeneration (AMD) shares many similarities with cardiovascular disease (CVD) pathophysiology. We sought to determine the relationship of AMD to the progression of coronary artery calcium (CAC) using data from the Multi-Ethnic Study of Atherosclerosis (MESA). Methods Our cohort consisted of 5803 adults aged 45 to 84 years free of known cardiovascular disease (CVD). Retinal photographs were taken during visit 2 (Aug 2002-Jan 2004). CAC was measured with computed tomography at visit 1 (July 2000-Aug 2002) and visit 5 (April 2010-Dec 2011) and changes between visits were determined. Results Participants were categorized as with (n = 244) and without AMD (n = 5559) at visit 2. At visit 5, 92 participants with and 2684 without AMD had CAC scores. Among those with detectable CAC at baseline (>0 at visit 1), CAC progression was greater in persons with compared to those without AMD after multivariable adjustment (530 ± 537 vs. 339 ± 426 Agatston units, P 0. The retinal exam might be a useful tool for pre-clinical assessment and prevention of CVD events.
TL;DR: This study did not find a significant genetic association with nuclear sclerosis, but the possible association with the RNF149 gene highlights a potential candidate gene for future studies that aim to understand the genetic architecture of nuclear sclerosis.
Abstract: Purpose: Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data.Methods: We analyzed Illumina Human Exome Array data for 1,488 participants of European ancestry in the Beaver Dam Eye Study who were without cataract surgery for association with nuclear sclerosis grade, controlling for age and sex. We performed single-variant regression analysis for 32,138 variants with minor allele frequency (MAF) ≥0.003. In addition, gene-based analysis of 11,844 genes containing at least two variants with MAF < 0.05 was performed using a gene-based unified burden and non-burden sequence kernel association test (SKAT-O). Addition...
Journal Article•
TL;DR: Genetic susceptibility to AMD was higher in European compared to Chinese samples and explained more of the AMD risk difference between the two samples than the dietary factors investigated.
Abstract: ABSTRACT Aims To assess contributions of dietary and genetic factors to ethnic differences in AMD prevalence. Design Population-based analytical study. Methods In the Blue Mountains Eye Study, Australia (European ancestry n = 2826) and Multi-Ethnic Cohort Study, Singapore (Asian ancestry, n = 1900), AMD was assessed from retinal photographs. Patterns of dietary composition and scores of the Alternative Healthy Eating Index were computed using food frequency questionnaire data. Genetic susceptibility to AMD was determined using either single nucleotide polymorphisms (SNPs) of the complement factor H and age-related maculopathy susceptibility 2 genes, or combined odds-weighted genetic risk scores of 24 AMD-associated SNPs. Associations of AMD with ethnicity, diet, and genetics were assessed using logistic regression. Six potential mediators covering genetic, diet and lifestyle factors were assessed for their contributions to AMD risk difference between the two samples using mediation analyses. Results Age-standardized prevalence of any (early or late) AMD was higher in the European (16%) compared to Asian samples (9%, p < .01). Mean AMD-related genetic risk scores were also higher in European (33.3 ± 4.4) than Asian (Chinese) samples (31.7 ± 3.7, p < .001). In a model simultaneously adjusting for age, ethnicity, genetic susceptibility and Alternative Healthy Eating Index scores, only age and genetic susceptibility were significantly associated with AMD. Genetic risk scores contributed 19% of AMD risk difference between the two samples while intake of polyunsaturated fatty acids contributed 7.2%. Conclusion Genetic susceptibility to AMD was higher in European compared to Chinese samples and explained more of the AMD risk difference between the two samples than the dietary factors investigated.
TL;DR: A genetic association analysis with three ocular phenotypes in 1,871 European–Americans from the Beaver Dam Eye Study confirmed two previous loci associated with corneal curvature and spherical equivalent in a European–American population highlighting the potential biological role of those regions in these traits.
Abstract: Refractive errors, myopia, and hyperopia are common visual disorders greatly affecting older individuals Refraction is determined by genetic factors but only a small percentage of its variation has been explained We performed a genetic association analysis with three ocular phenotypes: spherical equivalent (a continous measure of refraction), axial length, and corneal curvature in 1,871 European-Americans from the Beaver Dam Eye Study Individuals were genotyped on the Illumina exome array and imputed to the Haplotype Reference Consortium reference panel After increasing the number of analyzed variants in targeted protein-coding regions 10-fold via imputation, we confirmed associations for two previously known loci with corneal curvature (chr4q12, rs2114039; g55092626T > C, β = -003 (95% confidence interval [CI]): -006, -001, P value = 001) and spherical equivalent (chr15q14, rs634990; g35006073T > C, β = -027, 95% CI: -045, -009, P value = 379 × 10-3 ) Despite increased single nucleotide polymorphism (SNP) density, we did not detect any novel significant variants after correction for multiple comparisons In summary, we confirmed two previous loci associated with corneal curvature and spherical equivalent in a European-American population highlighting the potential biological role of those regions in these traits
TL;DR: Cortical event-related potentials during differential associative learning are sensitive to asymptomatic brain abnormality associated with AD.
Abstract: Trace eyeblink conditioning is a hippocampus-dependent associative learning paradigm which is impaired in patients with Alzheimer's disease (AD) and animal AD models. Learning in this paradigm accompanies changes in oscillatory activity in forebrain regions, some of which are loci of pathogenic changes in prodromal AD stages. These observations motivated us to examine how cortical event-related potentials (ERPs) during this paradigm are affected by two features of the asymptomatic, AD-related brain abnormality, entorhinal tau accumulation and mild cholinergic deficit. Adult rats received viral overexpression of P301L mutant human tau in the entorhinal cortex, low-dose scopolamine treatment, or both. Electroencephalograms were recorded with epidural electrodes on the surface of the frontal, parietal, and temporal cortices during differential and reversal trace eyeblink conditioning. All rats developed conditioned responses to one of two stimuli (auditory or visual) paired with mild eyelid shock (CS+), but not to the other stimulus presented alone (CS-). They were also able to adjust the response when the stimulus contingency was reversed. With learning, the amplitude of several ERP components in the frontal and temporal cortices came to differentiate the CS+ from CS-. Scopolamine affected the learning-related change in temporal P2 and other learning-unrelated components in three regions. Entorhinal tau overexpression primary affected the amplitude of temporal visual ERPs and learning-unrelated frontal and temporal auditory ERP components. The double manipulation only affected two components of temporal auditory ERPs. Thus, cortical ERPs during differential associative learning are sensitive to asymptomatic brain abnormality associated with AD.
TL;DR: This prospective study found that retinal vascular diameters and retinopathy are not associated with incidence of abdominal aortic aneurysm.
Abstract: Purpose: To test the hypothesis that retinal microvascular abnormalities known to predict other cardiovascular diseases are associated prospectively with risk of abdominal aortic aneurysm. ...
TL;DR: Retinal microvascular diameter measurements are valid and present moderate to high intra and intergrader reproducibility in ELSA-Brasil.
Abstract: BACKGROUND: Investigation of alterations to retinal microvasculature may contribute towards understanding the role of such changes in the pathophysiology of several chronic non-communicable diseases. The objective here was to evaluate the validity and reproducibility of retinal arteriole and venule diameter measurements made by Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) graders. DESIGN AND SETTING: Cross-sectional study at six teaching and research institutions. METHODS: To evaluate validity, each of 25 retinal images from the University of Wisconsin (gold standard) was measured by five ELSA-Brasil graders. To evaluate reproducibility, 105 images across the spectrum of vessel diameters were selected from 12,257 retinal images that had been obtained between 2010 and 2012, and each image was reexamined by the same grader and by an independent grader. All measurements were made using the Interactive Vessel Analysis (IVAN) software. Bland-Altman plots, paired t tests and intraclass correlation coefficients (ICCs) were analyzed. RESULTS: Mean differences between ELSA-Brasil and gold-standard readings were 0.16 µm (95% CI -0.17-0.50; P = 0.31) for central retinal artery equivalent (CRAE), -0.21 µm (95% CI -0.56-0.14; P = 0.22) for central retinal vein equivalent (CRVE) and 0.0005 (95% CI -0.008-0.009; P = 0.55) for arteriole/venule ratio (AVR). Intragrader ICCs were 0.77 (95% CI 0.67-0.86) for CRAE, 0.90 (95% CI 0.780.96) for CRVE and 0.70 (0.55-0.83) for AVR. Intergrader ICCs were 0.75 (95% CI 0.64-0.85) for CRAE, 0.90 (95% CI 0.79-0.96) for CRVE and 0.68 (95% CI 0.55-0.82) for AVR. CONCLUSIONS: Retinal microvascular diameter measurements are valid and present moderate to high intra and intergrader reproducibility in ELSA-Brasil.