The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease.

Disruption of retromer-dependent endosomal trafficking is considered pathogenic in late-onset Alzheimer's disease (AD). Here, to investigate this disruption in the intact brain, we turn to a genetic mouse model where the retromer core protein VPS35 is depleted in hippocampal neurons, and then we replete VPS35 using an optimized viral vector protocol. The VPS35 depletion-repletion studies strengthen the causal link between the neuronal retromer and AD-associated neuronal phenotypes, including the acceleration of amyloid precursor protein cleavage and the loss of synaptic glutamate receptors. Moreover, the studies show that the neuronal retromer can regulate a distinct, dystrophic, microglia morphology, phenotypic of hippocampal microglia in AD. Finally, the neuronal and, in part, the microglia responses to VPS35 depletion were found to occur independent of tau. Showing that the neuronal retromer can regulate AD-associated pathologies in two of AD's principal cell types strengthens the link, and clarifies the mechanism, between endosomal trafficking and late-onset sporadic AD.

Incidence and progression of diabetic retinopathy in a multi-ethnic US cohort: the Multi-Ethnic Study of Atherosclerosis.

AIM: To provide contemporary longitudinal data on the incidence and progression of diabetic retinopathy (DR) in a multi-ethnic population of whites, African Americans, Chinese and Hispanics in the United States. METHODS: A prospective, multi-region, multi-ethnic population-based cohort study that included 498 participants with diabetes, aged 45-84 years at baseline, from the Multi-Ethnic Study of Atherosclerosis with retinal images obtained twice, on average 8 years apart. Presence and severity of DR were graded from these retinal images according to the modified Airlie House classification system. Main outcome measures were 8-year incidence, progression and improvement of DR, and their associated risk factors. RESULTS: Over the 8 years, the cumulative rates were 19.2% for incident DR, 17.3% for DR progression, 23.3% for DR improvement, 2.7% for incident vision-threatening DR, 1.8% for incident proliferative DR and 2.2% for incident macular oedema. In multivariate analysis, significant risk factors associated with incident DR were higher glycosylated haemoglobin (relative risk (RR) 1.28; 95% CI: 1.16 to 1.41) and higher systolic blood pressure (RR 1.14; 95% CI: 1.04 to 1.25). Significant factors associated with DR progression were higher glycosylated haemoglobin (RR 1.20; 95% CI: 1.00 to 1.43) and higher low-density lipoprotein cholesterol (RR 1.01; 95% CI: 1.00 to 1.03). CONCLUSION: Over an 8-year period, approximately one in five participants with diabetes developed DR, while almost a quarter of those with DR at baseline showed improvement, possibly reflecting the positive impact of clinical and public health efforts in improving diabetes care in the United States over the last two decades.

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

BACKGROUND: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. METHODS: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (n=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (n=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. RESULTS: Protein coding variants in the hydroxysteroid 17-ß dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n=4196; P value=3.3 × 10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. CONCLUSIONS: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.

Relation between Retinopathy and Progression of Coronary Artery Calcium in Individuals with Versus Without Diabetes Mellitus (From the Multi-Ethnic Study of Atherosclerosis).

Retinopathy is a microvascular complication of diabetes mellitus (DM); however, it is also increasingly recognized in persons without DM. The microvascular diseases may play a prominent role in coronary heart disease (CHD) development in individuals with DM. We performed the study to evaluate the relation between non-DM retinopathy and CHD and also the association between baseline retinopathy and incidence and progression of CHD in individuals with and without DM. We included 5709 subjects with and without DM from the Multi-Ethnic Study of Atherosclerosis, who had retinal photos and coronary artery calcium score (CACS) available. We studied the association between baseline retinopathy and incidence and progression of coronary artery calcification (CAC) in subjects with and without DM. In DM group, the presence of retinopathy was significantly associated with an increased rate of CAC (RR 1.3 (95% CI [1.02, 1.66]) after adjusting for age, sex, race, follow-up time, and CHD risk factors. In non-DM group, the presence of retinopathy was not significantly associated with increased risk of CAC, however, the interaction between presence of retinopathy and DM status was not statistically significant. Within the DM group with CAC present at baseline, the presence of retinopathy was significantly associated with greater CAC progression (113 Agatson units (AU) greater, (95% CI [51-174]). In the non-DM group with present CAC at baseline; the presence of retinopathy was associated with 24 (95% CI [-0.69, 48.76]) AU higher CAC progression. All findings were adjusted for CHD risk factors. In conclusion, after adjustment for major CHD risk factors, retinopathy was associated with progression of CAC in both DM and non-DM individuals. However, the association was stronger in those with DM.

Clinical, diagnostic, and epidemiological features of a community-wide outbreak of canine leptospirosis in a low-prevalence region (Maricopa County, Arizona).

OBJECTIVE: To describe clinical, diagnostic, and epidemiological features of an outbreak of leptospirosis in dogs in Maricopa County, Ariz, from January 2016 through June 2017. ANIMALS: 71 case and 281 control dogs. PROCEDURES: Cases were classified as confirmed, probable, suspect, or not a case on the basis of medical record data that fulfilled clinical, diagnostic, and epidemiological criteria. Potential exposures were assessed by owner survey. For the case-control investigation, control dogs were recruited through owner completion of a July 2017 survey. Summary statistics and ORs for case dog lifestyle factors were reported. RESULTS: 54 dogs were classified as confirmed and 17 as probable cases. For 4 dogs of a household cluster (5 confirmed and 3 probable), the highest microscopic agglutination titer was for serovar Djasiman (Leptospira kirschneri detected by PCR assay), and for 13 dogs of a community outbreak (49 confirmed and 14 probable cases), the highest titer was for serovar Canicola (Leptospira interrogans detected by PCR assay). The 44 case dogs included in the case-control investigation were 7.7 (95% CI, 3.5 to 16.7) and 2.9 times (95% CI, 1.3 to 6.6) as likely as control dogs to have visited dog daycare or to have been kenneled overnight at a boarding facility, respectively, 30 days prior to the onset of clinical signs or diagnosis. CONCLUSIONS AND CLINICAL RELEVANCE: Diagnostic and epidemiological findings indicated 2 outbreaks. Transmission where dogs congregated likely propagated the community outbreak. Outbreaks of leptospiral infections can occur in regions of low prevalence, and a dog's exposure to areas where dogs congregate should be considered when making Leptospira vaccination recommendations.

Diabetes subgroups and risk for complications: The Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: To characterize diabetes subgroups among a multi-ethnic cohort and assess risk for incident complications. METHODS: We included 1587 participants from the Multi-Ethnic Study of Atherosclerosis with diabetes. We characterized eight diabetes subgroups according to absolute thresholds for disease characteristics: age at diabetes diagnosis (≤45 years), fasting glucose (FG ≥7.7 mmol/L; ≥140 mg/dL), and waist circumference (women ≥105 cm; men ≥110 cm). We estimated risk for mortality, incident cardiovascular disease, chronic kidney disease, heart failure, dementia, and retinopathy, respectively, over 17 years after adjustment for demographics, behavioral, clinical risk factors, and cohort attrition. RESULTS: The subgroup with both high FG and early age at onset was associated with higher risk for death, CVD, heart failure, CKD, and retinopathy and the subgroup with both early age at onset and high waist circumference was associated CVD, heart failure, CKD, and retinopathy. The subgroup that met all three high-risk thresholds had greater risk for death, heart failure, CKD, and retinopathy. We did not observe evidence for synergistic or antagonistic joint effects of the high-risk characteristics for any outcome. CONCLUSIONS: Our work supports differential risk for various diabetes complications among exclusive subgroups defined by age at diabetes onset, fasting glucose, and central adiposity.

Generational Differences in the 10-year Incidence of Impaired Contrast Sensitivity.

PURPOSE: To determine if incidence of contrast sensitivity (CS) impairment differs by generation and identify factors to explain these differences. METHODS: The Beaver Dam Eye Study (BDES) and Beaver Dam Offspring Study (BOSS) are cohort studies of aging adults in Beaver Dam, Wisconsin. Baseline examinations occurred from 1993 to 1995 (BDES) and 2005-2008 (BOSS). Follow-up examinations occurred in five-year intervals. CS testing was conducted with Pelli-Robson letter sensitivity charts; Incident impairment was a log CS score <1.55 in either eye at follow-up. Associations of incidence with generation were investigated using estimated hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Participants (N = 3185) had a mean age of 51.9 years at baseline (standard deviation = 9.9) and 51.9% were female. Ten-year cumulative incidence of CS impairment was 40.1%, was higher among women (41.7%) than men (38.8%), and increased by age group. The risk of incident CS impairment decreased by 39% per generation. In multivariable models, the Baby Boom Generation (HR = 0.42, 95%CI = 0.31, 0.58) and Generation X (HR = 0.56, 95%CI = 0.34, 0.91) had a significantly decreased risk of CS impairment compared to the Greatest Generation. Results were similar in sensitivity analyses excluding those with cataract, age-related macular degeneration, or visual acuity impairment. CONCLUSION: The risk of incident CS impairment decreased by birth cohort, with the greatest reduction in the Baby Boom Generation. The difference in risk suggests that there are unknown modifiable risk factors that may help to further explain the etiology of CS impairment and provide potential pathways for prevention in the future.

A systematic review and participant-level meta-analysis found little association of retinal microvascular caliber with reduced kidney function.

Previously, variation in retinal vascular caliber has been reported in association with chronic kidney disease (CKD) but findings remain inconsistent. To help clarify this we conducted individual participant data meta-analysis and aggregate data meta-analysis on summary estimates to evaluate cross-sectional associations between retinal vascular caliber and CKD. A systematic review was performed using Medline and EMBASE for articles published until October 2018. The aggregate analysis used a two-stage approach combining summary estimates from eleven studies (44,803 patients) while the individual participant analysis used a one-stage approach combining raw data from nine studies (33,222 patients). CKD stages 3-5 was defined as an estimated glomerular filtration rate under 60 mL/min/1.73m2. Retinal arteriolar and venular caliber (central retinal arteriolar and venular equivalent) were assessed from retinal photographs using computer-assisted methods. Logistic regression estimated relative risk of CKD stages 3-5 associated with a 20 µm decrease (approximately one standard deviation) in central retinal arteriolar and venular equivalent. Prevalence of CKD stages 3-5 was 11.2% of 33,222 and 11.3% of 44,803 patients in the individual participant and aggregate data analysis, respectively. No significant associations were detected in adjusted analyses between central retinal arteriolar and venular equivalent and CKD stages 3-5 in the aggregate analysis for central retinal arteriolar relative risk (0.98, 95% confidence interval 0.94-1.03); venular equivalent (0.99, 0.95-1.04) or individual participant central retinal arteriolar (0.99, 0.95-1.04) or venular equivalent (1.01, 0.97-1.05). Thus, meta-analysis provided little evidence to suggest that cross sectional direct measurements of retinal vascular caliber was associated with CKD stages 3-5 in the general population. Hence, meta-analyses of longitudinal studies evaluating the association between retinal parameters and CKD stages 3-5 may be warranted.

Exploring Factors Underlying Ethnic Difference in Age-related Macular Degeneration Prevalence.

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.

Prevalence of Age-related Maculopathy: The Beaver Dam Eye Study.

PURPOSE: The relationships of retinal drusen, retinal pigmentary abnormalities, and macular degeneration to age and sex were studied in 4926 people between the ages of 43 and 86 years who participated in the Beaver Dam Eye Study. METHODS: The presence and severity of various characteristics of drusen and other lesions typical of age-related maculopathy were determined by grading stereoscopic color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. RESULTS: One or more drusen were present in the macular area of at least 1 eye in 95.5% of the population. People 75 years of age or older had significantly higher frequencies (P < 0.01) of the following characteristics than people 43 to 54 years of age: larger sized drusen (>125 /µm, 24.0% versus 1.9%), soft indistinct drusen (23.0% versus 2.1%), retinal pigment abnormalities (26.6% versus 7.3%), exudative macular degeneration (5.2% versus 0.1%), and geographic atrophy (2.0% versus 0%). CONCLUSION: These data indicate signs of age-related maculopathy are common in people 75 years of age or older and may pose a substantial public health problem.

Associations between omega-6 polyunsaturated fatty acids, hyperinsulinemia and incident diabetes by race/ethnicity: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND & AIMS: Omega-6 polyunsaturated fatty acids (PUFAs) have been shown to relate to insulin resistance and type 2 diabetes (T2D), but influence of race/ethnicity has not been investigated. The aim of this study was to determine whether omega-6 PUFAs, and estimated desaturase enzyme activity, are associated with fasting glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and incident T2D, and whether associations differ by race/ethnicity. METHODS: This study was conducted in the Multi-Ethnic Study of Atherosclerosis (MESA) (N = 6282). Associations between baseline plasma phospholipid fatty acids (LA, Linoleic Acid; GLA, γ-linoleic acid; DGLA, Dihomo-γ-linolenic acid; AA, arachidonic acid; D5D, delta-5 desaturase; D6D, delta-6 desaturase), fasting glucose, insulin, and HOMA-IR [(fasting insulin - fasting glucose)/22.5] were evaluated using linear regression. Associations between omega-6 PUFAs (N = 5508 after excluding diabetics at baseline) and T2D incidence were assessed using Cox proportional hazards regression. Analyses were replicated/stratified by race/ethnicity (White, Black, Chinese, Hispanic) and tests for interaction were assessed by inclusion of a cross-product term in models. RESULTS: In fully adjusted models, insulin and HOMA-IR were positively associated with LA (insulin: 0.213 per SD, p = 0.01; HOMA-IR: 0.252 per SD, p < 0.001), GLA (insulin: 0.010 per SD, p < 0.001; HOMA-IR: 0.006 per SD, p < 0.001), DGLA (insulin: 0.279 per SD, p < 0.001; HOMA-IR: 0.175 per SD, p < 0.001) and D6D activity (insulin: 0.001 per SD, p < 0.001; HOMA-IR: 0.006 per SD, p < 0.001), and inversely associated with AA (insulin -0.272 per SD, p < 0.001; HOMA-IR: -0.125 per SD, p = 0.03) and D5D activity (insulin: -0.530 per SD, p < 0.001; HOMA-IR: -0.322 per SD, p < 0.001), while weak or no associations were observed with fasting glucose, and associations appeared to differ by race/ethnicity. After accounting for HOMA-IR at baseline, LA was inversely (HR: 0.87, p = 0.003) and DGLA (HR: 1.17, p < 0.001) and AA (HR: 1.15, p = 0.001) were positively associated with T2D in the overall population, but associations were attenuated or no longer present when stratified by race/ethnicity (P-interaction >0.05). CONCLUSIONS: Results confirm previous reports that omega-6 PUFAs are associated with hyperinsulinemia. Findings suggest omega-6 PUFAs are more likely markers of hyperinsulinemia rather than a protective/risk factor for T2D and indicate racial/ethnic differences in associations, but further research is needed to confirm findings.

Central arterial stiffness and retinal vessel calibers: the Atherosclerosis Risk in Communities Study-Neurocognitive Study.

BACKGROUND: The retinal microvasculature provides a window to the cerebral vasculature and enables examination of changes in retinal caliber that may mimic those occurring in cerebrovascular disease. The association of central arterial stiffness and retinal vessel caliber in a population sample is not fully understood. METHODS: In 1706 older adults (mean age 76.3, 58.1% women) from the population-based Atherosclerosis Risk in Communities Study, we examined the cross-sectional association of central arterial stiffness [carotid-femoral pulse wave velocity (cfPWV)] with retinal vessel calibers [central retinal arteriolar equivalent (CRAE) and central retinal vein equivalent (CRVE)]. We estimated the association of cfPWV with CRAE narrowing (<25th percentile) and CRVE widening (>75th percentile) after adjustment for age, sex, race-field center, BMI, smoking, and type 2 diabetes. We tested for effect modification by sex, hypertension, and type 2 diabetes. RESULTS: Carotid-femoral PWV (m/s) was not associated with the odds of CRAE narrowing [odds ratio (OR): 0.99; 95% CI: 0.95-1.03]. The association of cfPWV with CRVE widening was stronger in those without hypertension (OR: 1.10; 95% CI: 1.01-1.20) versus those with hypertension (OR: 1.01 95% CI: 0.96-1.05) and slightly stronger in those with type 2 diabetes (OR: 1.07; 95% CI: 1.00-1.14) versus without type 2 diabetes (OR: 1.01; 95% CI: 0.96-1.06). CONCLUSIONS: In older adults, cfPWV was associated with wider retinal venular caliber, particularly in individuals without hypertension. Central arterial stiffening may be associated with cerebral microvascular changes, as exhibited in its retinal vasculature component.

Cadmium, obesity, and education, and the 10-year incidence of hearing impairment: The beaver dam offspring study.

OBJECTIVES/HYPOTHESIS: To determine the 10-year incidence of hearing impairment (HI) and associated risk factors in the Beaver Dam Offspring Study (BOSS; 2004-present), a large middle-aged cohort followed for 10 years. STUDY DESIGN: Prospective cohort study. METHODS: Hearing thresholds were measured at baseline (2005-2008) and 5- (2010-2013) and 10-year (2015-2017) follow-up examinations. HI was defined as a pure-tone average >25 dB HL in either ear. BOSS participants free of HI at baseline with at least one follow-up examination (N = 2,065) were included. Potential risk factors evaluated included cardiovascular measures, health history, lifestyle factors, inflammatory markers, vitamins D and B12, lead, and cadmium. RESULTS: Participants were 21 to 79 years (mean age = 47.9 years) at baseline. The 10-year cumulative HI incidence was 17.4% (95% confidence interval [CI]: 15.7-19.2) and was twice as likely in men (24.4%, 95% CI: 21.5-27.7) than in women (12.2%, 95% CI: 10.3-14.3). In a multivariable adjusted model, age (hazard ratio [HR] = 1.48, 95% CI: 1.38-1.59, per 5 years), male sex (HR = 2.47, 95% CI: 1.91-3.18), less than a college education (HR = 1.35, 95% CI: 1.02-1.79), body mass index (HR = 1.03, 95% CI: 1.01-1.05, per kg/m2 ), and higher cadmium levels (HR = 1.42, 95% CI: 1.05-1.92, quintile 5 vs. quintiles 1-4) were associated with the 10-year cumulative incidence of HI. There was no association between high lead levels, vitamins D or B12, and 10-year incidence of HI. CONCLUSIONS: In addition to age and sex, obesity, education, and blood cadmium levels were associated with increased incidence of HI. These prospective results add to evidence that age-related HI is a multifactorial preventable disorder. LEVEL OF EVIDENCE: 2b Laryngoscope, 130:1396-1401, 2020.

Chronic kidney disease and the risk of incident hearing loss.

OBJECTIVES: There is a strikingly high prevalence of sensorineural hearing loss among patients with chronic kidney disease, with estimates ranging from 36% to 77%; however, longitudinal data are limited. We assessed whether lower baseline estimated glomerular filtration rate calculated using creatinine (eGFRCr ), as well as decline in eGFRCr over time, were associated with incident hearing loss. METHODS: Serum creatinine was measured in 1,843 individuals aged 48 to 80 years without hearing loss at the start of the Epidemiology of Hearing Loss Study in 1993. Follow-up creatinine assessments were conducted at 5 (n = 1,526) and 10 (n = 1,095) years. Hearing tests were conducted at baseline and at 5-, 10-, and 15-year follow-up visits. The risk of hearing loss was assessed as a function of baseline eGFRCr as well as a function of a 20% decline in eGFRCr between baseline and 5 years and between 5 and 10 years. Cox proportional hazards regression was used to examine the risk of incident speech-frequency hearing loss, defined as pure tone average (PTA) > 25 decibels hearing loss for thresholds at 0.5, 1, 2, and 4 kHz (PTA0.5,1,2,4 ) in either ear. RESULTS: During 15,676 person-years of follow up, there were 802 cases of incident hearing loss. There was no statistically significant association between lower baseline eGFRCr and risk of incident hearing loss. Decline in eGFRCr was also not associated with incident hearing loss at speech frequencies. CONCLUSION: Overall, there was no significant association between eGFRCr or decline in eGFRCr using the serum creatinine-based equation and risk of incident hearing loss. LEVEL OF EVIDENCE: 2 Laryngoscope, 130:E213-E219, 2020.

The Contribution of Ototoxic Medications to Hearing Loss Among Older Adults.

BACKGROUND: Ototoxicity may interact with the effects of aging, leading to a more severe hearing loss than that associated with age alone. The purpose of this study was to explore the associations between ototoxic medication use and the incidence and progression of hearing loss in older adults with a population-based longitudinal study. METHODS: Epidemiology of Hearing Loss Study participants (n = 3,753) were examined. Medication use was assessed using a standardized questionnaire by the examiners at each examination every 5 year. The ototoxic medications include loop diuretics, nonsteroidal anti-inflammatory drugs, antibiotics, chemotherapeutic agents, quinine, and acetaminophen in this study. Generalized estimating equations model was used as a proportional hazard discrete time analysis. RESULTS: Number of ototoxic medications was associated with the risk of developing hearing loss during the 10-year follow-up period (hazard ratio [HR] = 1.15, 95% confidence interval [CI] = 1.06, 1.25) after adjusting for age, sex, smoking, and body mass index. Loop diuretics (HR = 1.40, 95% CI = 1.05, 1.87) were associated with the 10-year incidence of hearing loss. Nonsteroidal anti-inflammatory drugs (HR = 1.45, 95% CI = 1.22, 1.72) and loop diuretics (HR = 1.33 95% CI = 1.08, 1.63) were associated with risk of progressive hearing loss over 10 years. CONCLUSION: These ototoxic medications are commonly used in older adults and should be considered as potentially modifiable contributors to the incidence and severity of age-related hearing loss.

Neuroprotective Biomarkers and Cognitive Function in a Long-Term Prospective Population-based Study of Aging US Adults.

BACKGROUND: Relationships between brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1), aldosterone, and cognition in aging were evaluated in the population-based Epidemiology of Hearing Loss Study (1993 to present). METHODS: Beginning in 1998 to 2000, cognitive impairment was assessed by report of physician diagnoses and the Mini-Mental State Examination. In 2009 to 2010 and 2013 to 2016, information was collected on diagnosis of mild cognitive impairment/dementia. Decline in cognitive function was assessed by principal component analysis from additional tests administered during 2009 to 2010 and 2013 to 2016. BDNF, IGF-1, and aldosterone were measured in serum collected in 1998 to 2000. RESULTS: There were 1970 participants (mean age=66.9 y; 59.1% female) without cognitive impairment at baseline. Among women, low BDNF was associated with 16-year incident cognitive impairment [hazard ratio=1.76; 95% confidence interval (CI)=1.04, 2.98]. Among men, increasing IGF-1 was associated with decreased risk [per SD: relative risk (RR)=0.57; 95% CI=0.35, 0.92], whereas increasing aldosterone levels were associated with increased risk (per SD: RR=1.28; 95% CI=1.01, 1.62) for 5-year incident mild cognitive impairment/dementia. Overall, low BDNF was associated with increased risk (RR=1.52; 95% CI=1.02, 2.26) for 5-year cognitive decline. CONCLUSION: Low levels of serum BDNF and IGF-1 were associated with poorer cognition during aging. There may be differential biomarker effects by sex.

Diet patterns and the incidence of age-related macular degeneration in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among the elderly. OBJECTIVE: This study aimed to determine the association between dietary patterns and food groups (used to make them) with the 18-year incidence of AMD. METHODS: ARIC (Atherosclerosis Risk in Communities) participants who showed change in AMD lesions between retinal photographs taken at visit 3 and visit 5 were graded side by side to determine incident AMD (any=144; early=117; late=27). A 66-line item food frequency questionnaire, administered at visit 1 and visit 3, was used to identify 29 food groups. Principal component analysis was used to derive dietary patterns from average food group servings. Logistic regression was used to estimate ORs and 95% CIs for incident AMD (any, early and late) by tertiles of dietary pattern scores, adjusted for age, race, education, total calories and smoking status. P-trend was estimated using continuous scores. RESULTS: Western (unhealthy) and Prudent (healthy) dietary patterns were identified. No significant associations were observed between either dietary pattern and incident any or incident early AMD. However, a threefold higher incidence of late AMD was observed among participants with a Western pattern score above, as compared with below, the median (OR=3.44 (95% CI 1.33 to 8.87), p-trend=0.014). The risk of developing late AMD was decreased, but not statistically significant, among participants with a Prudent pattern score above, as compared with below, the median (OR=0.51 (95% CI 0.22 to 1.18), p-trend=0.054). CONCLUSIONS: Diet patterns were not significantly associated with incident any or incident early AMD. However, consumption of a Western pattern diet may be a risk factor for development of late AMD.

Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain.

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.

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen.

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.

The association of retinal vessel calibres with heart failure and long-term alterations in cardiac structure and function: the Atherosclerosis Risk in Communities (ARIC) Study.

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.