Showing papers by "Ronald Klein published in 2019"
TL;DR: It is suggested that more high-quality population-based studies capturing data on the incidence and progression of diabetic retinopathy with stratification by age and sex are needed to consolidate the evidence base.
258 citations
University of California, San Diego1, Broad Institute2, Boston Children's Hospital3, University of Helsinki4, University of Virginia5, University College Dublin6, University of Utah7, University of Pennsylvania8, Joslin Diabetes Center9, University of Edinburgh10, University of Oxford11, Lund University12, Steno Diabetes Center13, University of Michigan14, Boehringer Ingelheim15, National Institutes of Health16, University of Wisconsin-Madison17, George Washington University18, University of Minnesota19, University of Washington20, University of Pittsburgh21, University of Paris22, Institute of Chartered Accountants of Nigeria23, University of Colorado Denver24, Stanford University25, Lunenfeld-Tanenbaum Research Institute26, McMaster University27, University of Dundee28, Paracelsus Private Medical University of Salzburg29, University of Latvia30, Latvian Biomedical Research and Study centre31, Lithuanian University of Health Sciences32, Carol Davila University of Medicine and Pharmacy33, China Pharmaceutical University34, Umeå University35, Karolinska Institutet36, Karolinska University Hospital37, University of Copenhagen38, French Institute of Health and Medical Research39, Queen's University Belfast40
TL;DR: In this paper, a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes were assembled through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, and 16 genome-wide significant risk loci were identified.
Abstract: Background Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. Methods To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. Results Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk 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). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1). Conclusions The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
122 citations
Harvard University1, Case Western Reserve University2, University of Washington3, UCLA Medical Center4, National University of Singapore5, Wake Forest University6, University of Iceland7, Massachusetts Eye and Ear Infirmary8, Princeton University9, University of Dundee10, University of the Ryukyus11, University of Southern California12, University of Texas Health Science Center at Houston13, New Generation University College14, University of Chicago15, Seoul National University Bundang Hospital16, University of California, Los Angeles17, Los Angeles Biomedical Research Institute18, French Institute of Health and Medical Research19, Paris Diderot University20, University of Paris21, Churchill Hospital22, University of Oxford23, Lund University24, University of Bergen25, University of Edinburgh26, Western General Hospital27, University of Helsinki28, University of Mississippi Medical Center29, University of Sydney30, Flinders University31, National Institutes of Health32, University of Toronto33, University of Illinois at Chicago34, Genentech35, New York Academy of Medicine36, Menzies Research Institute37, University of Wisconsin-Madison38
TL;DR: Findings suggest that genetic variation in NVL, as well as variation within a protein–protein interaction network that includes genes implicated in inflammation, may influence risk for DR.
Abstract: To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value <1 × 10-5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10-9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.
45 citations
TL;DR: A model is developed that maps where key patient and PCP barriers occur in the teleophthalmology referral process and suggests system-based implementation strategies primarily targetingPCP barriers in conjunction with improved patient and provider education may increase telephthalmology use in rural, US multipayer primary care clinics.
Abstract: Objective Teleophthalmology for diabetic eye screening is an evidence-based intervention substantially underused in US multipayer primary care clinics, even when equipment and trained personnel are readily available. We sought to identify patient and primary care provider (PCP) barriers, facilitators, as well as strategies to increase teleophthalmology use. Design We conducted standardised open-ended, individual interviews and analysed the transcripts using both inductive and directed content analysis to identify barriers and facilitators to teleophthalmology use. The Chronic Care Model was used as a framework for the development of the interview guide and for categorising implementation strategies to increase teleophthalmology use. Setting A rural, US multipayer primary care clinic with an established teleophthalmology programme for diabetic eye screening. Participants We conducted interviews with 29 participants (20 patients with diabetes and 9 PCPs). Results Major patient barriers to teleophthalmology use included being unfamiliar with teleophthalmology, misconceptions about diabetic eye screening and logistical challenges. Major patient facilitators included a recommendation from the patient’s PCP and factors related to convenience. Major PCP barriers to referring patients for teleophthalmology included difficulty identifying when patients are due for diabetic eye screening and being unfamiliar with teleophthalmology. Major PCP facilitators included the ease of the referral process and the communication of screening results. Based on our results, we developed a model that maps where these key patient and PCP barriers occur in the teleophthalmology referral process. Patients and PCPs also identified implementation strategies to directly address barriers and facilitators to teleophthalmology use. Conclusions Patients and PCPs have limited familiarity with teleophthalmology for diabetic eye screening. PCPs were expected to initiate teleophthalmology referrals, but reported significant difficulty identifying when patients are due for diabetic eye screening. System-based implementation strategies primarily targeting PCP barriers in conjunction with improved patient and provider education may increase teleophthalmology use in rural, US multipayer primary care clinics.
36 citations
TL;DR: The genetic associations of drusenoid pigment epithelial detachment associated with age-related macular degeneration are consistent with genes associated with AMD progression, and progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD.
35 citations
TL;DR: It is reported that neurons in the brains of Msut2 knockout mice are protected from abnormal tau pathology, and it is proposed that MSUT2 and PABPN1 may act together in a macromolecular complex bound to poly(A) RNA.
Abstract: Brain lesions composed of pathological tau help to drive neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Here, we identified the mammalian suppressor of tauopathy 2 (MSUT2) gene as a modifier of susceptibility to tau toxicity in two mouse models of tauopathy. Transgenic PS19 mice overexpressing tau, a model of AD, and lacking the Msut2 gene exhibited decreased learning and memory deficits, reduced neurodegeneration, and reduced accumulation of pathological tau compared to PS19 tau transgenic mice expressing Msut2 Conversely, Msut2 overexpression in 4RTauTg2652 tau transgenic mice increased pathological tau deposition and promoted the neuroinflammatory response to pathological tau. MSUT2 is a poly(A) RNA binding protein that antagonizes the canonical nuclear poly(A) binding protein PABPN1. In individuals with AD, MSUT2 abundance in postmortem brain tissue predicted an earlier age of disease onset. Postmortem AD brain tissue samples with normal amounts of MSUT2 showed elevated neuroinflammation associated with tau pathology. We observed co-depletion of MSUT2 and PABPN1 in postmortem brain samples from a subset of AD cases with higher tau burden and increased neuronal loss. This suggested that MSUT2 and PABPN1 may act together in a macromolecular complex bound to poly(A) RNA. Although MSUT2 and PABPN1 had opposing effects on both tau aggregation and poly(A) RNA tail length, we found that increased poly(A) tail length did not ameliorate tauopathy, implicating other functions of the MSUT2/PABPN1 complex in tau proteostasis. Our findings implicate poly(A) RNA binding proteins both as modulators of pathological tau toxicity in AD and as potential molecular targets for interventions to slow neurodegeneration in tauopathies.
31 citations
TL;DR: Long‐term associations of retinal vessel calibres with incident HF, in those with and without prevalent macrovascular disease, and how they relate to cardiac structure and function are described.
Abstract: AIMS Narrower retinal arterioles and wider retinal venules have been associated with macrovascular forms of cardiovascular disease (CVD). However, whether they are predictive of the development of heart failure (HF) independent of atherosclerotic CVD is unclear. We aimed to describe long-term associations of retinal vessel calibres with incident HF, in those with and without prevalent macrovascular disease, and how they relate to cardiac structure and function. METHODS AND RESULTS This analysis included Atherosclerosis Risk in Communities Study participants who underwent retinal photography between 1993 and 1995. HF outcomes were followed in these participants until the end of 2013. Returning participants underwent echocardiography between 2011 and 2013. Participants with retinal vessel measurements who were free of CVD at baseline (n = 10 692) were followed for a mean of 16 years (baseline mean age 60 ± 6 years). Wider central retinal venular equivalent (CRVE) and narrower central retinal arteriolar equivalent (CRAE), adjusted for age, gender, and race, were significantly linearly associated with incident HF; however, a non-linear association was detected with CRVE and incident HF (P-value for overall trend < 0.001; P-value for non-linearity = 0.002). After adjustment with clinical risk factors, CRVE association with incident HF remained significant (P-value for overall trend = 0.025). Adjusted for age, gender, and race, CRVE widening and CRAE narrowing were associated with larger left ventricular size, higher prevalence of left ventricular hypertrophy, and worse measures of diastolic and systolic function. CONCLUSION Retinal vessel calibre imaging, which characterizes retinal microvasculature, is a simple, non-invasive test that predicts incident HF and adverse cardiac structure/function 18 years in the future, thereby providing insight into systemic cardiovascular health.
28 citations
TL;DR: The easily‐imaged retinal microvasculature may reflect the brain microvasulature and therefore be related to dementia.
Abstract: Introduction The easily-imaged retinal microvasculature may reflect the brain microvasculature and therefore be related to dementia. Methods In a population-based study of 12,482 adults aged 50-73 years (22% African American), we estimated the relationship of retinal characteristics from fundus photography (1993-1995) with incident all-cause dementia (1993-1995 to 2011-2013) and with etiologic subtype of dementia/mild cognitive impairment (2011-13). Results A total of 1259 (10%) participants developed dementia over a mean 15.6 years. Moderate/severe (vs. no) retinopathy (hazard ratio [HR], 1.86; 95% confidence interval [CI]: 1.36–2.55) and central retinal arteriolar equivalent (narrowest quartile vs. widest three quartiles; HR, 1.26; 95% CI: 1.09–1.45) were associated with all-cause dementia. Results were qualitatively stronger (but not statistically significantly different) in participants with diabetes. Retinopathy was associated with a joint outcome of cerebrovascular-related, but not Alzheimer's disease–related, dementia/mild cognitive impairment (HR, 2.29; 95% CI: 1.24–4.23). Discussion Exploration of measures in the eye may provide surrogate indices of microvascular lesions relevant to dementia.
27 citations
TL;DR: Visual and olfactory impairments, CVRF and CVD were associated with the 10-year cumulative incidence of cognitive impairment and decline in middle-aged adults.
Abstract: Background Sensorineural impairments and cardiovascular risk factors (CVRF) and disease (CVD) in midlife may be important predictors of future cognitive health, but longitudinal studies that include multiple sensorineural measures in middle-aged adults are lacking. Methods Hearing, vision, and olfaction, and CVRF and CVD were measured at the Beaver Dam Offspring Study baseline (2005-2008) examination. The Mini-Mental State Examination and Trail Making Tests A and B were administered at all phases and additional cognitive function measures were obtained at 5 (2010-2013) and 10 years (2015-2017). Cox proportional hazards models were used to evaluate associations between baseline sensorineural impairments, CVRF, CVD, and 10-year cumulative incidence of cognitive impairment and decline. Results There were 2,556 participants (22-84 years) without cognitive impairment at baseline and data from at least one follow-up. In a multivariable model including age, sex, education, and head injury, visual impairment (hazard ratio = 2.59, 95% confidence interval = 1.34, 5.02), olfactory impairment (hazard ratio = 3.18, 95% confidence interval = 1.53, 6.59), CVD (hazard ratio = 2.37, 95% confidence interval = 1.24, 4.52), and not consuming alcohol in the past year (hazard ratio = 2.21, 95% confidence interval = 1.16, 4.19) were associated with the 10-year cumulative incidence of cognitive impairment. Current smoking and diabetes were associated with increased risk, and exercise with decreased risk, of 10-year decline in cognitive function. Conclusions Visual and olfactory impairments, CVRF, and CVD were associated with the 10-year cumulative incidence of cognitive impairment and decline in middle-aged adults. Identifying modifiable factors associated with cognitive decline and impairment in midlife may provide opportunities for prevention or treatment and improve cognitive health later in life.
26 citations
TL;DR: Factors associated with a novel measure of brain aging in middle‐aged and older adults are evaluated to help identify ways to preserve brain function with aging.
Abstract: Objectives Middle age has been identified as a critical time period for health later in life. Identifying factors associated with worse brain function in middle-aged adults may help identify ways to preserve brain function with aging. Our objective was to evaluate factors associated with a novel measure of brain aging in middle-aged and older adults. Design Longitudinal cohort study. Setting Beaver Dam Offspring Study (BOSS) baseline (2005-2008), 5-year (2010-2013), and 10-year examinations (2015-2017). Participants A total of 2285 adults, 22 to 84 years of age, with complete sensorineural and neurocognitive data at the 5-year examination. Measurements Principal component analysis (PCA) was performed combining 5-year sensorineural (hearing, vision, olfaction) and cognitive (Trail Making Test A and B, Digit Symbol Substitution Test, Verbal Fluency Test, Auditory Verbal Learning Test) test data. Participants with a standardized PCA score less than -1 were classified as having brain aging. Incident brain aging was defined as a PCA score less than -1 at 10 years among participants who had a PCA score of -1 or higher at 5 years. Logistic regression and Poisson models were used to estimate associations between baseline factors and prevalent or incident brain aging, respectively. Results Older age, being male, current smoking, larger waist circumference, not consuming alcohol, cardiovascular disease, and interleukin-6 were associated with greater odds of prevalent brain aging, whereas more education and exercise were associated with decreased odds. In addition to age and sex, less than a college education, higher levels of soluble intercellular adhesion molecule-1, diabetes, depressive symptoms, and history of head injury were associated with an increased 5-year risk of incident brain aging. Conclusion In the current study, vascular and inflammatory factors were associated with a new brain aging marker in middle-aged and older adults. Many of these factors are modifiable, highlighting the importance of addressing health and lifestyle factors in midlife to potentially preserve function for better brain health later in life. J Am Geriatr Soc 67:1610-1616, 2019.
20 citations
TL;DR: The results provide further evidence to support the GWAS studies that the dosage sensitivity intolerance of VIPR2 is disease causative to manifest schizophrenia-like dopamine, cognitive, and social behavioral deficits in mice.
Abstract: Recent genome-wide association studies (GWAS) have identified copy number variations (CNVs) at chromosomal locus 7q36.3 that significantly contribute to the risk of schizophrenia, with all of the microduplications occurring within a single gene: vasoactive intestinal peptide receptor 2 (VIPR2). To confirm disease causality and translate such a genetic vulnerability into mechanistic and pathophysiological insights, we have developed a series of conditional VIPR2 bacterial artificial chromosome (BAC) transgenic mouse models of VIPR2 CNV. VIPR2 CNV mouse model recapitulates gene expression and signaling deficits seen in human CNV carriers. VIPR2 microduplication in mice elicits prominent dorsal striatal dopamine dysfunction, cognitive, sensorimotor gating, and social behavioral deficits preceded by an increase of striatal cAMP/PKA signaling and the disrupted early postnatal striatal development. Genetic removal of VIPR2 transgene expression via crossing with Drd1a-Cre BAC transgenic mice rescued the dopamine D2 receptor abnormality and multiple behavioral deficits, implicating a pathogenic role of VIPR2 overexpression in dopaminoceptive neurons. Thus, our results provide further evidence to support the GWAS studies that the dosage sensitivity intolerance of VIPR2 is disease causative to manifest schizophrenia-like dopamine, cognitive, and social behavioral deficits in mice. The conditional BAC transgenesis offers a novel strategy to model CNVs with a gain-of -copies and facilitate the genetic dissection of when/where/how the genetic vulnerabilities affect development, structure, and function of neural circuits. Our findings have important implications for therapeutic development, and the etiology-relevant mouse model provides a useful preclinical platform for drug discovery.
TL;DR: The findings do not provide evidence for statistically significant relationships between ox-LDL and AMD disease development or worsening of AMD.
TL;DR: In this paper, the authors performed a genome-wide association study (GWAS) for HbA1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane.
Abstract: Glycated hemoglobin (HbA1c) is an important measure of glycemia in diabetes. HbA1c is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA1c in FinnDiane at genome-wide significance (P < 5 × 10-8). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA1c also in the meta-analysis with RASS (P < 5 × 10-8), where these variants had minor allele frequencies ≥1%. Furthermore, these SNPs were associated with HbA1c in an East Asian population without diabetes (P ≤ 0.013). A weighted genetic risk score created from 55 HbA1c-associated variants from the literature was associated with HbA1c in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA1c may lead to better prevention of diabetes complications.
TL;DR: High 25(OH)D concentrations, approximately >70 nM, may be associated with decreased odds of incident early AMD, suggesting these associations may be biased by loss to follow-up and sampling for retinal photographs at visit 5.
Abstract: Purpose To investigate the association between serum 25-hydroxyvitamin D (25[OH]D) concentrations at visit 2 (1990-1992) and the 18-year incidence of age-related macular degeneration (AMD) between visit 3 (1993-1995) and visit 5 (2011-2013). Methods This prospective analysis was conducted in a subset of participants (n = 1225) from the Atherosclerosis Risk in Communities Study. We evaluated the incidence of any, early, and late AMD from visit 3 to 5. The 25(OH)D concentrations were assessed in 2012-2013 by using stored serum from visit 2. Retinal fundus photographs taken at both visits were graded side by side to determine the incidence of AMD. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for incident AMD outcomes during 18 years of follow-up (1993-1995 to 2011-2013) by tertile of 25(OH)D adjusted for age, race, and smoking status. P for linear trend was estimated by using continuous 25(OH)D concentrations. Sensitivity analyses applied inverse probability weights to account for selection to have eye photographs, death, and loss to follow-up. Results There was a decreased odds of any incident AMD (n = 139) and large, soft drusen (n = 80) in 25(OH)D tertile 3 versus 1, with OR (95% CI) = 0.57 (0.36-0.90), P trend = 0.11 and with 0.52 (0.28-0.93), P trend = 0.18, respectively. Applying sampling weights attenuated these results to 0.66 (0.38-1.16), P trend = 0.32 (any incident AMD) and 0.54 (0.27-1.09), P trend = 0.36 (large, soft drusen), respectively, suggesting these associations may be biased by loss to follow-up and sampling for retinal photographs at visit 5. No statistically significant results were observed with pigmentary abnormalities (n = 46) or incident late AMD (n = 26). Conclusions High 25(OH)D concentrations, approximately >70 nM, may be associated with decreased odds of incident early AMD.
TL;DR: Late AMD was not characterized by alterations in systemic lipids compared with normal controls, and findings suggest that there may be differences in the LPC pathway between adults with neovascular AMD and geographic atrophy.
Abstract: Lipids are implicated in the pathogenesis of age-related macular degeneration (AMD). The relationship between systemic lipids and AMD has not been well characterized. The objective was to investigate the relationship between serum lipids and AMD in older adults using a lipidomic approach. In a case-control study, 240 adults, aged ≥66 years, a third each having geographic atrophy, neovascular AMD, or no signs of AMD, were selected from a population-based sample of participants in the Age Gene/Environment Susceptibility-Reykjavik Study. The exposure was serum lipids and risk factors for AMD. The outcome was late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for neovascular AMD and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. Of 177 serum lipid species measured, there were no significant differences in serum lipids between controls and those with geographic atrophy or neovascular AMD, respectively. Adults with neovascular AMD had higher total serum lysophosphatidylcholine (LPC) (P = 0.004) and serum LPC 18:0 (P = 0.0002) compared to those with geographic atrophy. Late AMD was not characterized by alterations in systemic lipids compared with normal controls. These findings suggest that there may be differences in the LPC pathway between adults with neovascular AMD and geographic atrophy.
TL;DR: Venular narrowing in hand OA in women was an unexpected finding and is in contrast with the venular widening usually observed in cardiovascular diseases.
Abstract: To investigate the association between osteoarthritis (OA) and microvascular pathology, we examined the relationship between retinal microvascular caliber and osteoarthritis of the hand and knee in an elderly population. The AGES-Reykjavik is a population-based, multidisciplinary longitudinal cohort study of aging. Retinal vessel caliber, hand osteoarthritis and total knee joint replacements due to OA were examined in 4757 individuals (mean age 76 ± 5 years; 57% female). Incident knee joint replacements during 5-year follow-up (n = 2961, mean age 75 ± 5 years; 58% female) were also assessed. Logistic regression analysis, adjusting for age, sex, and body mass index, showed an association between narrow arteriolar caliber and hand OA, as well as knee replacement. After adjustment for other covariates, including statin therapy, this association was significant for both hand OA in men and women [OR 1.10(1.03–1.17), p < 0.01] (per unit standard deviation decrease in CRAE) and TKR prevalence [OR 1.15 (1.01–1.32), p = 0.04], especially for men [OR 1.22 (1.00–1.51) p = 0.04] and also for incident TKRs in men [OR 1.50 (1.07–2.10), p = 0.04]. Narrow venular caliber was associated with hand OA in women [OR 1.10 (1.01–1.21), p = 0.03]. Retinal arterial narrowing in hand and knee OA is present in males as well as females. Venular narrowing in hand OA in women was an unexpected finding and is in contrast with the venular widening usually observed in cardiovascular diseases.
TL;DR: Wider retinal venular diameter was associated with sex-specific changes in RVEDM and RVEDV in adults without clinical cardiovascular disease and this was of borderline significance after adjusting for the LVEF.
Abstract: Retinal vessel diameters have been associated with left ventricular morphology and function but their relationship with the right ventricle (RV) has not been studied. We hypothesized that wider ret...
TL;DR: The main effect was observed on working memory which was significantly impaired in Abeta‐Tau group only 3 months post injections, and on EEG, as early as the 3rd week, an overall decrease of the EEG bands power was observed in the treated groups, particularly the theta waves during the rapid eye movement (REM) sleep.
TL;DR: The present study aims to investigate relationships between Aldosterone, insulin‐like growth factor (IGF1), and brain‐derived neurotrophic factor (BDNF) and hearing impairment in aging adults.
Abstract: Objective Hearing impairment (HI) is common in aging adults. Aldosterone, insulin-like growth factor (IGF1), and brain-derived neurotrophic factor (BDNF) have been identified as potentially protective of hearing. The present study aims to investigate these relationships. Methods The Epidemiology of Hearing Loss Study is a longitudinal population-based study of aging in Beaver Dam, Wisconsin, that began in 1993. Baseline for the present investigation is the 1998 to 2000 phase. Follow-up exams occurred approximately every 5 years, with the most recent occurring from 2013 to 2016. Hearing was measured by pure-tone audiometry. HI was defined as a pure tone average (PTA) > 25 decibels hearing level in either ear. Change in PTA was the difference between follow-up examinations and baseline. Baseline serum samples were used to measure biomarkers in 2017. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to assess the effect of biomarker levels in the lowest quintile (Q1) versus the highest (Q5) on incident HI and PTA change. Results There were 1,088 participants (69.3% women) at risk of HI included in analyses. The mean baseline age was 63.8 years (standard deviation = 7.0). The 16-year incidence of HI was 54.9% and was higher in men (61.1%) than women (52.1%). In age- and sex-adjusted models, aldosterone (HR = 1.06, 95% CI = 0.82-1.37), IGF1 (HR = 0.92, 95% CI = 0.71-1.19), and BDNF (HR = 0.86, 95% CI = 0.66-1.12) levels were not associated with risk of HI. PTA change was similarly not affected by biomarker levels. Conclusion Aldosterone, IGF1, and BDNF were not associated with decreased risk of age-related hearing loss in this study. Level of evidence 2b Laryngoscope, 129:2178-2183, 2019.
TL;DR: A modest association between the post-illumination pupil response and cognitive function was demonstrated, warranting longitudinal studies to evaluate the role of the PIPR in predicting cognitive function in the middle-aged and older adults.
Abstract: We conducted a cross-sectional study on 403 participants in the 10-year follow-up examination of the Beaver Dam Offspring Study. The participants included 172 male and 231 female, with age ranging from 33 to 81 years (mean ± SD, 60.7 ± 9.3). The post-illumination pupil response (PIPR) was recorded using binocular infrared pupillometer (Neur-Optics, Inc., Irvine, CA). Cognitive testing consisted of Trail Making Test (TMT) Parts A and B, Rey Auditory Verbal Learning Test (AVLT), Digit Symbol Substitution Test (DSST), and Verbal Fluency Test (VFT) (F, A, and S). Principal component analysis (PCA) was used to calculate an overall cognitive function score. There was a significant reduction in the mean baseline pupil diameter by 0.21 mm for every 5-year increase in age (95% CI: -0.25, -0.17). There was also a significant increase in the PCA cognitive score by 0.20 (linear regression, 95% CI: 0.08, 0.32) for every 0.1 unit increase in the PIPR. The association remained significant after adjusting for age, sex, education, medications, systemic and ocular disease, and short form-12 physical and mental component score. The results of this study demonstrated a modest association between the PIPR and cognitive function, warranting longitudinal studies to evaluate the role of the PIPR in predicting cognitive function in the middle-aged and older adults.
Journal Article•
TL;DR: Pregnancy is associated with worsening DR in women with T1D, and DR severity in early pregnancy isassociated with severe adverse outcome in the infant.
Abstract: Objectives To determine whether: 1) retinal vessel diameters in pregnant and non-pregnant women with type 1 diabetes (T1D) alter the relationship of pregnancy to severity of diabetic retinopathy (DR); and 2) retinal vessel diameters in early pregnancy alter the relationship of severity of DR in the mother to severe adverse outcome in the infant. Methods Two cohorts of women with T1D, one composed of pregnant women and the other of non-pregnant women of child-bearing age, were recruited in Wisconsin. Baseline examinations (including retinal photography and collection of diabetes-related characteristics) were conducted, with follow-up approximately one year later. Retinal images were graded according to the modified Airlie House classification protocol, and retinal vessel diameters were measured from digitized images. The latter were included in analyses as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE). Results In multivariate models: 1) Pregnancy was significantly associated with both incidence (OR = 4.43, CI = 1.42–13.79) and progression (OR = 2.62, CI = 1.52–4.51) of DR. Neither CRAE nor CRVE were significant, but their addition modestly altered the associations of pregnancy to worsening DR; 2) Baseline retinopathy (OR = 1.28, CI = 1.05–1.57) was associated with severe adverse outcome in the infant. This association was unchanged by adjustment for retinal vessel diameters. Conclusions Pregnancy is associated with worsening DR in women with T1D. DR severity in early pregnancy is associated with severe adverse outcome in the infant. The retinal vessel diameters CRAE and CRVE were not associated with these outcomes but were modest confounders of the association of pregnancy to worsening DR.
TL;DR: Skin intrinsic fluorescence provides easily obtained markers of age-related functional outcomes, suggesting SIF measurements may be useful to identify persons who may benefit from more frequent medical scrutiny to decrease morbidity and mortality.
Abstract: Purpose: Functional, structural and metabolic decline in many systems and in combination contribute to biologic aging and may be manifest as increased risk of morbid events such as neuropat...