Association of fractal dimension and other retinal vascular network parameters with cognitive performance and neuroimaging biomarkers: The Multi-Ethnic Study of Atherosclerosis (MESA).

INTRODUCTION: Retinal vascular network changes may reflect the integrity of the cerebral microcirculation, and may be associated with cognitive impairment. METHODS: Associations of retinal vascular measures with cognitive function and MRI biomarkers were examined amongst Multi-Ethnic Study of Atherosclerosis (MESA) participants in North Carolina who had gradable retinal photographs at Exams 2 (2002 to 2004, n = 313) and 5 (2010 to 2012, n = 306), and detailed cognitive testing and MRI at Exam 6 (2016 to 2018). RESULTS: After adjustment for covariates and multiple comparisons, greater arteriolar fractal dimension (FD) at Exam 2 was associated with less isotropic free water of gray matter regions (ß = -0.0005, SE = 0.0024, p = 0.01) at Exam 6, while greater arteriolar FD at Exam 5 was associated with greater gray matter cortical volume (in mm3 , ß = 5458, SE = 20.17, p = 0.04) at Exam 6. CONCLUSION: Greater arteriolar FD, reflecting greater complexity of the branching pattern of the retinal arteries, is associated with MRI biomarkers indicative of less neuroinflammation and neurodegeneration.

Sequential hybridization may have facilitated ecological transitions in the Southwestern pinyon pine syngameon.

Multispecies interbreeding networks, or syngameons, have been increasingly reported in natural systems. However, the formation, structure, and maintenance of syngameons have received little attention. Through gene flow, syngameons can increase genetic diversity, facilitate the colonization of new environments, and contribute to hybrid speciation. In this study, we evaluated the history, patterns, and consequences of hybridization in a pinyon pine syngameon using morphological and genomic data to assess genetic structure, demographic history, and geographic and climatic data to determine niche differentiation. We demonstrated that Pinus edulis, a dominant species in the Southwestern US and a barometer of climate change, is a core participant in the syngameon, involved in the formation of two drought-adapted hybrid lineages including the parapatric and taxonomically controversial fallax-type. We found that species remain morphologically and genetically distinct at range cores, maintaining species boundaries while undergoing extensive gene flow in areas of sympatry at range peripheries. Our study shows that sequential hybridization may have caused relatively rapid speciation and facilitated the colonization of different niches, resulting in the rapid formation of two new lineages. Participation in the syngameon may allow adaptive traits to be introgressed across species barriers and provide the changes needed to survive future climate scenarios.

Inflammation, metabolic dysregulation and environmental neurotoxins and risk of cognitive decline and impairment in midlife.

BACKGROUND: Age-related declines in cognitive function may begin in midlife. PURPOSE: To determine whether blood-based biomarkers of inflammation, metabolic dysregulation and neurotoxins are associated with risk of cognitive decline and impairment. METHODS: Baseline blood samples from the longitudinal Beaver Dam Offspring Study (2005-2008) were assayed for markers of inflammation, metabolic dysregulation, and environmental neurotoxins. Cognitive function was measured at baseline, 5-year (2010-2013) and 10-year (2015-2017) examinations. Participants without cognitive impairment at baseline and with cognitive data from at least one follow-up were included. Cox proportional hazards models were used to evaluate associations between baseline blood biomarkers and the 10-year cumulative incidence of cognitive impairment. Poisson models were used to estimate the relative risk (RR) of 5-year decline in cognitive function by baseline blood biomarkers. Models were adjusted for age, sex, education, and cardiovascular related risk factors. RESULTS: Participants (N = 2421) were a mean age of 49 years and 55% were women. Soluble vascular cell adhesion molecule-1 (sVCAM-1Tertile(T)3 vs T1-2 hazard ratio (HR) = 1.72, 95% confidence interval (CI) = 1.05,2.82) and hemoglobin A1C (HR = 1.75, 95% CI = 1.18,2.59, per 1% in women) were associated with the 10-year cumulative incidence of cognitive impairment. sVCAM-1 (RRT3 vs T1-2 = 1.45, 95% CI = 1.06,1.99) and white blood cell count (RR = 1.10, 95% CI = 1.02,1.19, per 103/µL) were associated with 5-year cognitive decline. CONCLUSIONS: Biomarkers related to inflammation and metabolic dysregulation were associated with an increased risk of developing cognitive decline and impairment. These results extend previous research in cognitive aging to early markers of cognitive decline in midlife, a time when intervention methods may be more efficacious.

OMEGA-3 FATTY ACIDS ARE ASSOCIATED WITH DECREASED PRESENCE AND SEVERITY OF DIABETIC RETINOPATHY: A Combined Analysis of MESA and GOLDR Cohorts.

PURPOSE: Inflammation is associated with diabetic retinopathy development and progression, and previous studies have demonstrated that omega-3 polyunsaturated fatty acids have anti-inflammatory properties. Therefore, the goal of this study was to determine if omega-3 polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are associated with decreased risk and severity of retinopathy in individuals with type 2 diabetes. METHODS: In a combined population of 1,356 individuals with type 2 diabetes from the Multi-Ethnic Study of Atherosclerosis and Genetics of Latino Diabetic Retinopathy cohorts, odds ratios using logistic regression were determined to assess the association between polyunsaturated fatty acids and retinopathy. RESULTS: In 1,356 participants with type 2 diabetes, individuals in the fourth quartile of DHA were 17% less likely to have retinopathy compared with the first quartile ( P = 0.009, CI: 0.72-0.95). Secondary analysis revealed 38% lower severity of retinopathy in individuals in the fourth quartile compared with the first quartile of DHA ( P = 0.006; CI: 0.44-0.87) and EPA + DHA ( P = 0.004; CI: 0.44-0.85). No significant associations were observed between EPA and retinopathy. CONCLUSION: DHA is inversely associated with the presence and severity of diabetic retinopathy. Increased intake of dietary sources of DHA may provide some protection against retinopathy in individuals with type 2 diabetes and warrants more research as a preventative option.

Retinal Microvascular Caliber and Incident Depressive Symptoms: The Multi-Ethnic Study of Atherosclerosis.

Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. The retina allows for visualization of a microvascular bed that shares similarities with the cerebral microvasculature. We investigated the associations between baseline retinal arteriolar and venular calibers (central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE), respectively) and incident depressive symptoms in the Multi-Ethnic Study of Atherosclerosis (MESA). We used longitudinal data on 4,366 participants (mean age = 63.2 years; 48.5% women, 28.4% Black) without baseline depressive symptoms. Depressive symptoms, defined as Center for Epidemiologic Studies Depression Scale score ≥16 and/or use of antidepressant medication, were determined between 2002 and 2004 (baseline; MESA visit 2) and at 3 follow-up examinations conducted every 1.5-2 years thereafter. Fundus photography was performed at baseline. After a mean follow-up period of 6.1 years, 21.9% (n = 958) had incident depressive symptoms. After adjustment for sociodemographic, lifestyle, and cardiovascular factors, a 1-standard-deviation larger baseline CRVE was associated with a higher risk of depressive symptoms (hazard ratio = 1.10, 95% confidence interval: 1.02, 1.17), and a 1-standard-deviation larger baseline CRAE was not statistically significantly associated with incident depressive symptoms (hazard ratio = 1.04, 95% confidence interval: 0.97, 1.11). In this study, larger baseline CRVE, but not CRAE, was associated with a higher incidence of depressive symptoms.

ASSOCIATION OF PLASMA ω-3 FATTY ACIDS WITH EARLY AGE-RELATED MACULAR DEGENERATION IN THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS.

PURPOSE: To examine the association between omega-3 polyunsaturated fatty acids, docosahexaenoic acid, and eicosapentaenoic acid and age-related macular degeneration (AMD) in the Multi-Ethnic Study of Atherosclerosis cohort. METHODS: Multi-Ethnic Study of Atherosclerosis is a multicenter, prospective cohort study designed to identify risk factors for cardiovascular disease in four ethnic groups. Six thousand eight hundred and fourteen participants of White, African American, Hispanic/Latino, and Chinese descent, aged 45-84 years, were recruited, with those found to have cardiovascular disease excluded. Our study population included all Multi-Ethnic Study of Atherosclerosis participants with baseline polyunsaturated fatty acid measurements and retinal photography at Examination 5 (n = 3,772). Fundus photographs were assessed for AMD using a standard grading protocol. Relative risk regression (log link) determined associations between polyunsaturated fatty acid levels and AMD. RESULTS: There was a significant association between increasing docosahexaenoic acid levels and increasing docosahexaenoic acid + eicosapentaenoic acid levels with reduced risk for early AMD (n = 214 participants with early AMD, of which n = 99 (46.3%) are non-White). Eicosapentaenoic acid levels alone were not significantly associated with AMD. CONCLUSION: Our analysis suggests increasing levels of docosahexaenoic acid are associated with reduced risk for early AMD in a multiethnic cohort. This represents the first racially diverse study demonstrating an association between omega-3 polyunsaturated fatty acids and AMD risk.

The pupil constriction to light is associated with cognitive measures in middle-aged and older adults.

AIMS: The evidence relating the pupil light reflex (PLR) and cognition have been inconsistent. In this cross-sectional study, we evaluated the association between the PLR and cognition in community-dwelling middle-aged and older individuals. METHODS: Pupil reactivity was recorded in a subgroup of 403 participants (mean age 60.7 years, 57.3% females) in an epidemiologic study of aging. Ten pupil parameters were calculated to describe pupil constriction to light stimuli. A principal component analysis (PCA) score was used to calculate an overall performance over four cognitive testings. Linear regression was used to assess the association between pupil parameters and PCA scores, adjusting for age, sex, education, medications, health-related quality of life questionnaire, and systemic and ocular comorbidities. RESULTS: The PCA scores decreased by 0.039 [95% CI (- 0.050, - 0.028)] per year increase in age and were lower in males than females by 0.76 [95% CI (- 0.96, - 0.55)] (p < 0.001). Pupil constriction amplitude in millimeters and the duration from stimulus onset to maximal constriction velocity were significantly associated with cognition after adjusting for (1) age and sex and (2) age, sex, and multiple covariates (p < 0.05). CONCLUSIONS: In this study, we provided moderate evidence suggesting the association between PLR and neuropsychological cognitive measures. The findings suggest the potential of pupil reactivity to serve as a biomarker of brain aging and warrant further longitudinal study to assess if changes in the PLR can predict cognitive decline over time.

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.

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.

Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: The REMOVAL trial.

AIM: To determine whether metformin's effects on carotid artery intima-media thickness (cIMT) in type 1 diabetes differ according to smoking status. METHODS: Regression model effect estimates for the effect of metformin versus placebo (double-blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial. RESULTS: In 428 randomized participants (227 never-smokers, 201 ever-smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.012 mm, 95% CI -0.021 to -0.002; p = .0137) but not in ever-smokers (0.003 mm, 95% CI -0.008 to 0.014; p = .5767); and similarly in non-current smokers (-0.008 mm, 95% CI -0.015 to -0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI -0.007 to 0.032; p = .1887). Three-way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non-current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.020 mm, 95% CI -0.034 to -0.006; p = .0067) but not in ever-smokers (-0.006 mm, 95% CI -0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three-way interaction term. CONCLUSIONS: This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes.

Factors Associated with the Macular Ganglion Cell-Inner Plexiform Layer Thickness in a Cohort of Middle-aged U.S. Adults.

SIGNIFICANCE: The macular ganglion cell-inner plexiform layer (mGCIPL) may serve as a quick and easily obtained measure of generalized neurodegeneration. Investigating factors associated with this thickness could help to understand neurodegenerative processes. PURPOSE: This study aimed to characterize and identify associated factors of the mGCIPL thickness in a Beaver Dam Offspring Study cohort of middle-aged U.S. adults. METHODS: Baseline examinations occurred from 2005 to 2008, with follow-up examinations every 5 years. Included participants had baseline data and measured mGCIPL at 10-year follow-up (N = 1848). The mGCIPL was measured using the Cirrus 5000 HD-OCT Macular Cube Scan. Associations between mean mGCIPL thickness and thin mGCIPL, defined as 1 standard deviation (SD) below the population mean, and baseline risk factors were investigated using generalized estimating equations. RESULTS: Participants (mean [SD] baseline age, 48.9 [9.3] years; 54.4% women) had mean (SD) mGCIPL thicknesses of 78.4 (8.1) µm in the right eye and 78.1 (8.5) µm in the left (correlation coefficient = 0.76). In multivariable models, age (-1.07 µm per 5 years; 95% confidence interval [CI], -1.28 to -0.86 µm), high alcohol consumption (-1.44 µm; 95% CI, -2.72 to -0.16 µm), higher interleukin 6 levels (50% increase in level: -0.23 µm; 95% CI, -0.45 to 0.00 µm), myopia (-2.55 µm; 95% CI, -3.17 to -1.94 µm), and glaucoma (-1.74 µm; 95% CI, -2.77 to -0.70 µm) were associated with thinner mGCIPL. Age (per 5 years: odds ratio [OR], 1.38; 95% CI, 1.24 to 1.53), diabetes (OR, 1.89, 95% CI, 1.09 to 3.27), myopia (OR, 2.11; 95% CI, 1.63 to 2.73), and increasing and long-term high C-reactive protein (ORs, 1.46 [95% CI, 1.01 to 2.11] and 1.74 [95% CI, 1.14 to 2.65], respectively) were associated with increased odds of thin mGCIPL. CONCLUSIONS: Factors associated cross-sectionally with mGCIPL thickness, older age, high alcohol consumption, inflammation, diabetes, myopia, and glaucoma may be important to neural retina structure and health and neuronal health system-wide.

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.

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.

Severe pressure ulcers requiring surgery impair the functional outcome after acute spinal cord injury.

STUDY DESIGN: Retrospective matched cohort study. OBJECTIVES: Assessing the influence of surgically managed grade 3 and 4 pressure ulcers (PU) in the acute phase after spinal cord injury (SCI) on the neurological and functional outcome after 1 year. SETTING: Specialized SCI-unit within a level 1 trauma center in Murnau, Germany. METHODS: We performed a retrospective matched cohort study. For every patient with acute SCI and a PU requiring surgery, we identified matched controls within our database in a 1:3 ratio. Matching criteria were: AIS-grade (American Spinal Injury Association Impairment Scale), neurological level and age. The scores of the SCIM-III (Spinal Cord Independence Measure) and the ISNCSCI (International Standards for Neurological Classification of Spinal Cord Injury) as well as the total length of stay (LOS) at the hospital were used as outcome parameters. We applied a stratified analysis using a conditional logistic regression to test for group differences in each outcome parameter of the study. RESULTS: In a 6-year period (2010-2015) 28 patients required flap surgery due to 3-4° PU in the acute phase after SCI. Of these patients, 15 had complete data sets according to the EMSCI (European Multicenter Study about Spinal Cord Injury) protocol. Patients with severe PUs during the acute SCI phase had a significantly impaired functional outcome. After 1 year the improvement of the SCIM score was significantly lower in the PU group compared to the control group (17.4 versus 30.5; p < 0.006). However, the change in AIS grade after 1 year was not significantly affected. The LOS was prolonged by a mean of 48 days in the PU group (p < 0.006). CONCLUSIONS: Severe PUs requiring surgery in the acute phase after SCI impair the functional outcome and increase LOS. Preventive measures should be applied to all acute SCI patients. Patients should be transferred to specialized SCI-centers as soon as possible.

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.

[Robotic assistance in activities of daily living exemplified by food intake]. / Robotische Assistenz bei den Aktivitäten des täglichen Lebens am Beispiel der Nahrungsaufnahme.

Carrying out activities of daily living (ADL, also called basic activities) is limited or even no longer possible due to functional limitations and functional losses associated with aging, (chronic) illness and disabilities. Nowadays, there are a variety of assistive technologies/devices and even robotic products. The aim of this article is to give an exemplary overview of the existing products for the basic activity of food intake for people with tetraplegia caused by accidents or neurological disorders, such as multiple sclerosis or amyotrophic lateral sclerosis (ALS). The dissemination and implementation of these products seems to be relatively low in Germany. Inhibiting and promoting factors for the dissemination and utilization are discussed.

Oxidized Low-density Lipoprotein and the Incidence of Age-related Macular Degeneration.

PURPOSE: To examine the relationship between serum oxidized low-density lipoprotein (ox-LDL) cholesterol and the incidence of age-related macular degeneration (AMD) over a 25-year period in a sample of persons from the population-based Beaver Dam Eye Study (BDES). DESIGN: Observational prospective cohort study. PARTICIPANTS: A total of 4972 people from the BDES (aged 43-84 years and living in Beaver Dam, Wisconsin in 1988) seen during at least 1 of 6 examination phases at approximately 5-year intervals between 1988 and 2016. METHODS: A 50% random sample of participants (N = 2468) was selected for ox-LDL measurements. Stored frozen specimens from every examination phase were processed using an enzyme-linked immunosorbent assay from a single batch. All available intervals were included for a person, resulting in 6586 person-visits. MAIN OUTCOME MEASURES: Age-related macular degeneration was assessed using the Wisconsin Age-related Maculopathy Grading System, and severity was defined using a 5-step severity scale. The severity of the worse eye at each examination was used for analyses. A multi-state Markov (MSM) model was fit to simultaneously assess the ox-LDL relationship to all AMD transitions, including incidence of any AMD, incidence of late AMD, and worsening and improvement of AMD over the 25 years of the study. RESULTS: The mean (standard deviation) level of ox-LDL was 75.3 (23.1) U/L at the baseline examination. When adjusting for age, sex, ARMS2 and CFH risk alleles, and examination phase, the ox-LDL at the beginning of a period was not statistically significantly associated with the incidence of any AMD (hazard ratio per 10 U/L ox-LDL was 1.03, 95% confidence interval 0.98,1.09). Furthermore, ox-LDL was not associated with worsening anywhere along the AMD severity scale, nor with incidence of late AMD. The lack of relationships of ox-LDL to the incidence of any AMD or worsening of AMD remained after adjustment for history of statin use, smoking status, body mass index, and history of cardiovascular disease (data not shown). CONCLUSIONS: Our findings do not provide evidence for statistically significant relationships between ox-LDL and AMD disease development or worsening of AMD.

Retinal signs and risk of incident dementia in the Atherosclerosis Risk in Communities study.

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.

Association analysis of exome variants and refraction, axial length, and corneal curvature in a European-American population.

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; g.55092626T > C, ß = -0.03 (95% confidence interval [CI]): -0.06, -0.01, P value = 0.01) and spherical equivalent (chr15q14, rs634990; g.35006073T > C, ß = -0.27, 95% CI: -0.45, -0.09, P value = 3.79 × 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.

Meta-genome-wide association studies identify a locus on chromosome 1 and multiple variants in the MHC region for serum C-peptide in type 1 diabetes.

AIMS/HYPOTHESIS: 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). METHODS: 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. RESULTS: 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 < 5 × 10-8). In the same meta-GWAS, a locus in the MHC region (rs9260151) was close to the genome-wide significance threshold (Chr6:29911030, C>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 (ß [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. CONCLUSIONS/INTERPRETATION: 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.