Development, characterization, and replication of proteomic aging clocks: Analysis of 2 population-based cohorts.

BACKGROUND: Biological age may be estimated by proteomic aging clocks (PACs). Previous published PACs were constructed either in smaller studies or mainly in white individuals, and they used proteomic measures from only one-time point. In this study, we created de novo PACs and compared their performance to published PACs at 2 different time points in the Atherosclerosis Risk in Communities (ARIC) study of white and black participants (around 75% white and 25% black). MEDTHODS AND FINDINGS: A total of 4,712 plasma proteins were measured using SomaScan in blood samples collected in 1990 to 1992 from 11,761 midlife participants (aged 46 to 70 years) and in 2011 to 2013 from 5,183 late-life participants (aged 66 to 90 years). The de novo ARIC PACs were constructed by training them against chronological age using elastic net regression in two-thirds of healthy participants in midlife and late life and validated in the remaining one-third of healthy participants at the corresponding time point. We also computed 3 published PACs. We estimated age acceleration for each PAC as residuals after regressing each PAC on chronological age. We also calculated the change in age acceleration from midlife to late life. We examined the associations of age acceleration and change in age acceleration with mortality through 2019 from all-cause, cardiovascular disease (CVD), cancer, and lower respiratory disease (LRD) using Cox proportional hazards regression in participants (irrespective of health) after excluding the training set. The model was adjusted for chronological age, smoking, body mass index (BMI), and other confounders. We externally validated the midlife PAC using the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 1 data. The ARIC PACs had a slightly stronger correlation with chronological age than published PACs in healthy participants at each time point. Associations with mortality were similar for the ARIC PACs and published PACs. For late-life and midlife age acceleration for the ARIC PACs, respectively, hazard ratios (HRs) per 1 standard deviation were 1.65 and 1.38 (both p < 0.001) for all-cause mortality, 1.37 and 1.20 (both p < 0.001) for CVD mortality, 1.21 (p = 0.028) and 1.04 (p = 0.280) for cancer mortality, and 1.68 and 1.36 (both p < 0.001) for LRD mortality. For the change in age acceleration, HRs for all-cause, CVD, and LRD mortality were comparable to the HRs for late-life age acceleration. The association between the change in age acceleration and cancer mortality was not significant. The external validation of the midlife PAC in MESA showed significant associations with mortality, as observed for midlife participants in ARIC. The main limitation is that our PACs were constructed in midlife and late-life participants. It is unknown whether these PACs could be applied to young individuals. CONCLUSIONS: In this longitudinal study, we found that the ARIC PACs and published PACs were similarly associated with an increased risk of mortality. These findings suggested that PACs show promise as biomarkers of biological age. PACs may be serve as tools to predict mortality and evaluate the effect of anti-aging lifestyle and therapeutic interventions.

Population Attributable Fraction of Total Stroke Associated with Modifiable Risk Factors in the United States.

Stroke is a leading cause of death in the United States across all race/ethnicity and sex groups, though disparities exist. We investigated the potential for primary prevention of total first stroke for Americans aged 20 and older, stratified by sex and race/ethnicity. Specifically, we calculated population attributable fractions (PAF) of first stroke for 7 potentially modifiable risk factors: smoking, physical inactivity, poor diet, obesity, hypertension, diabetes, and atrial fibrillation. PAFs are a function of (1) the relative risk of first stroke for people with the exposure and (2) the prevalence of the risk factor in the population. Relative risks came from recent meta-analyses and sex-race/ethnicity-specific prevalence estimates came from the 2015-2018 NHANES or Multi-Ethnic Study of Atherosclerosis (for atrial fibrillation only). Approximately 1/3 (35.7% [CI: 21.6%-49.0%]) for women, 32.7% [CI: 19.2%-45.1%] for men) of strokes were attributable to the 7 risk factors we considered. A 20% proportional reduction in stroke risk factors would result in approximately 37,000 fewer strokes annually in the United States. The estimated PAF was highest for non-Hispanic Black women (39.3% [CI: 24.8%-52.3%]) and lowest for non-Hispanic Asian men (25.5% [CI: 14.6%-36.2%]). For most groups, obesity and hypertension were the largest contributors to stroke rates.

Blood pressure, executive function, and network connectivity in middle-aged adults at risk of dementia in late life.

Midlife blood pressure is associated with structural brain changes, cognitive decline, and dementia in late life. However, the relationship between early adulthood blood pressure exposure, brain structure and function, and cognitive performance in midlife is not known. A better understanding of these relationships in the preclinical stage may advance our mechanistic understanding of vascular contributions to late-life cognitive decline and dementia and may provide early therapeutic targets. To identify resting-state functional connectivity of executive control networks (ECNs), a group independent components analysis was performed of functional MRI scans of 600 individuals from the Coronary Artery Risk Development in Young Adults longitudinal cohort study, with cumulative systolic blood pressure (cSBP) measured at nine visits over the preceding 30 y. Dual regression analysis investigated performance-related connectivity of ECNs in 578 individuals (mean age 55.5 ± 3.6 y, 323 female, 243 Black) with data from the Stroop color-word task of executive function. Greater connectivity of a left ECN to the bilateral anterior gyrus rectus, right posterior orbitofrontal cortex, and nucleus accumbens was associated with better executive control performance on the Stroop. Mediation analyses showed that while the relationship between cSBP and Stroop performance was mediated by white matter hyperintensities (WMH), resting-state connectivity of the ECN mediated the relationship between WMH and executive function. Increased connectivity of the left ECN to regions involved in reward processing appears to compensate for the deleterious effects of WMH on executive function in individuals across the burden of cumulative systolic blood pressure exposure in midlife.

Changes in Cardiovascular Health Across Midlife and Late-Life and Magnetic Resonance Imaging Markers of Cerebral Vascular Disease in Late-Life.

BACKGROUND: Cardiovascular health may be used for prevention of cerebral vascular disease; however, data on the association of cardiovascular health across midlife and late-life with late-life cerebral vascular disease are lacking. Our aim was to examine whether midlife or late-life cardiovascular health as well as changes of cardiovascular health within midlife and between midlife and late-life were associated with prevalence of magnetic resonance imaging markers of cerebral vascular disease at late-life. METHODS: Prospective cohort study including 1638 participants from the Atherosclerosis Risk in Communities Study who took part in 2 visits at midlife (mean ages, 53 and 59 years), and a late-life visit (mean age, 76 years). A cardiovascular health Life's Simple 7 score (range, 0-12/0-14, depending on diet availability) including 6 out of 7 items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Participants underwent 3T brain magnetic resonance imaging scans in late-life visit. Outcomes were white matter hyperintensity volume, microbleeds, and lacunar, subcortical, and cortical infarcts at late-life. Linear and logistic regression models were used to assess the associations of cardiovascular health in midlife and late-life, and improvement of cardiovascular health within midlife, and from midlife to late-life with magnetic resonance imaging markers of cerebral vascular disease, adjusting for potential confounders. RESULTS: A higher cardiovascular health in midlife, improvement of cardiovascular health within midlife, higher cardiovascular health at late-life, and improvement of cardiovascular health from midlife to late-life were associated with a lower prevalence of cerebral vascular disease markers. For example, improvement in cardiovascular health (per point) from midlife to late-life was associated with smaller white matter hyperintensity volume (ß, -0.07 [95% CI, -0.10 to -0.04]) and lower odds of microbleeds (odds ratio, 0.93 [0.90-0.97]), lacunar (odds ratio, 0.93 [0.89-0.97]), subcortical (odds ratio, 0.93 [0.89-0.97]), and cortical infarcts (odds ratio, 0.92 [0.87-0.97]). CONCLUSIONS: Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.

Association of change in cardiovascular risk factors with incident dementia.

INTRODUCTION: We evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk. METHODS: Two longitudinal population-based studies were used: Atherosclerosis Risk in Communities (ARIC) (n = 11,460/visits at ages 54 and 60), and Age, Gene/Environment Susceptibility (AGES)-Reykjavik (n = 3907/visit at age 51). A cardiovascular health score (range 0-12/0-14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Cardiovascular health was defined as low (score 0-4/0-5), intermediate (5-7/6-9), or high (8-12/10-14). Incident dementia was ascertained through linkage to health records and with neuropsychological examinations. RESULTS: Midlife high compared to low cardiovascular health (hazard ratios [HRs]: for ARIC: 0.60 [95% confidence interval: 0.52, 0.69]); for AGES-Reykjavik: 0.83 [0.66, 0.99] and improvement of cardiovascular health score within midlife (HR per one-point increase: ARIC: 0.94 [0.92, 0.96]) were associated with lower dementia risk. DISCUSSION: Better cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk. HIGHLIGHTS: Cardiovascular health and dementia were studied in two large cohort studies. Better cardiovascular health at midlife relates to lower dementia risk. Improvement of cardiovascular health within midlife relates to lower dementia risk. Promotion of cardiovascular health at midlife can help to reduce dementia risk.

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.

Cumulative Blood Pressure Exposure During Young Adulthood and Mobility and Cognitive Function in Midlife.

BACKGROUND: High blood pressure (BP) is a known risk factor for mobility and cognitive impairment in older adults. This study tested the association of cumulative BP exposure from young adulthood to midlife with gait and cognitive function in midlife. Furthermore, we tested whether these associations were modified by cerebral white matter hyperintensity (WMH) burden. METHODS: We included 191 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults), a community-based cohort of young individuals followed over 30 years. Cumulative BP was calculated as the area under the curve (mm Hg×years) from baseline up to year 30 examination. Gait and cognition were assessed at the year 30 examination. Cerebral WMH was available at year 30 in a subset of participants (n=144) who underwent magnetic resonance imaging. Multiple linear regression models were used to assess the association of cumulative BP exposure with gait and cognition. To test effect modification by WMH burden, participants were stratified at the median of WMH and tested for interaction. RESULTS: Higher cumulative systolic and diastolic BPs were associated with slower walking speed (both P=0.010), smaller step length (P=0.011 and 0.005, respectively), and higher gait variability (P=0.018 and 0.001, respectively). Higher cumulative systolic BP was associated with lower cognitive performance in the executive (P=0.021), memory (P=0.015), and global domains (P=0.010), and higher cumulative diastolic BP was associated with lower cognitive performance in the memory domain (P=0.012). All associations were independent of socio-demographics and vascular risk factors (body mass index, smoking, diabetes mellitus and total cholesterol). The association between cumulative BP and gait was moderated by WMH burden (interaction P<0.05). However, the relation between cumulative BP and cognitive function was not different based on the WMH burden (interaction P>0.05). CONCLUSIONS: Exposure to higher BP levels from young to midlife is associated with worse gait and cognitive performance in midlife. Furthermore, WMH moderates the association of cumulative BP exposure with gait, but not with cognitive function in midlife. The mechanisms underpinning the impact of BP exposure on brain structure and function must be investigated in longitudinal studies using a life course approach.

Plasma tau, neurofilament light chain and amyloid-ß levels and risk of dementia; a population-based cohort study.

CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-ß, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-ß40 and amyloid-ß42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer's disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ε4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer's disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer's disease dementia. A log2 higher baseline amyloid-ß42 plasma level was associated with a lower risk of developing all-cause or Alzheimer's disease dementia, adjusted hazard ratio (HR) 0.61 [95% confidence interval (CI), 0.47-0.78; P < 0.0001] and 0.59 (95% CI, 0.43-0.79; P = 0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia [adjusted HR 1.59 (95% CI, 1.38-1.83); P < 0.0001] or Alzheimer's disease [adjusted HR 1.50 (95% CI, 1.26-1.78); P < 0.0001]. Combining the lowest quartile group of amyloid-ß42 with the highest of NfL resulted in a stronger association with all-cause dementia [adjusted HR 9.5 (95% CI, 2.3-40.4); P < 0.002] and with Alzheimer's disease [adjusted HR 15.7 (95% CI, 2.1-117.4); P < 0.0001], compared to the highest quartile group of amyloid-ß42 and lowest of NfL. Total-tau and amyloid-ß40 levels were not associated with all-cause or Alzheimer's disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer's disease compared to those who remained dementia-free (P < 0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer's disease diagnosis. Amyloid-ß42 levels began to decrease in Alzheimer's disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-ß42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer's disease dementia. These data indicate that plasma NfL and amyloid-ß42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer's disease dementia.

Vascular health across young adulthood and midlife cerebral autoregulation, gait, and cognition.

INTRODUCTION: To test the association of vascular health (VH) across young adulthood with midlife dynamic cerebral autoregulation (dCA), gait, and cognition; and to test whether dCA is a modifying factor. METHODS: We studied 196 participants from the Coronary Artery Risk Development in Young Adults cohort who were followed over 30 years. VH was assessed at each visit according to American Heart Association recommendations. At year 30, dCA was measured using transcranial Doppler ultrasound and several gait and cognitive domains were assessed. RESULTS: Worse VH from baseline through year 7, but not at year 30, was associated with less efficient dCA (all P < .05). Worse VH at all visits was associated with slower gait speed, and at year 7 with worse executive and global cognition (all P < .05). The association of baseline VH and midlife gait, but not cognition, was moderated by dCA (interaction P < .05). CONCLUSIONS: VH as early as young adulthood may influence midlife brain health, and dCA may modify this relationship.

Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework. STUDY DESIGN: Cross-sectional individual participant-level analyses in a global consortium. SETTING & STUDY POPULATIONS: 17 CKD and 38 general population and high-risk cohorts. SELECTION CRITERIA FOR STUDIES: Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension. DATA EXTRACTION: Data were obtained and analyzed between July 2015 and January 2018. ANALYTICAL APPROACH: We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses. RESULTS: The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g). LIMITATIONS: Variations in study era, health care delivery system, typical diet, and laboratory assays. CONCLUSIONS: Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.

Quantification of biological age as a determinant of age-related diseases in the Rotterdam Study: a structural equation modeling approach.

Chronological age alone is not a sufficient measure of the true physiological state of the body. The aims of the present study were to: (1) quantify biological age based on a physiological biomarker composite model; (2) and evaluate its association with death and age-related disease onset in the setting of an elderly population. Using structural equation modeling we computed biological age for 1699 individuals recruited from the first and second waves of the Rotterdam study. The algorithm included nine physiological parameters (c-reactive protein, creatinine, albumin, total cholesterol, cytomegalovirus optical density, urea nitrogen, alkaline phosphatase, forced expiratory volume and systolic blood pressure). We assessed the association between biological age, all-cause mortality, all-cause morbidity and specific age-related diseases over a median follow-up of 11 years. Biological age, compared to chronological age or the traditional biomarkers of age-related diseases, showed a stronger association with all-cause mortality (HR 1.15 vs. 1.13 and 1.10), all-cause morbidity (HR 1.06 vs. 1.05 and 1.03), stroke (HR 1.17 vs. 1.08 and 1.04), cancer (HR 1.07 vs. 1.04 and 1.02) and diabetes mellitus (HR 1.12 vs. 1.01 and 0.98). Individuals who were biologically younger exhibited a healthier life-style as reflected in their lower BMI (P < 0.001) and lower incidence of stroke (P < 0.001), cancer (P < 0.01) and diabetes mellitus (P = 0.02). Collectively, our findings suggest that biological age based on the biomarker composite model of nine physiological parameters is a useful construct to assess individuals 65 years and older at increased risk for specific age-related diseases.

Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions.

BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0×10-3 (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P=1.3×10-16) in comparison with 5% in ever-smokers (P=2.5×10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

The AGES-Reykjavik Study suggests that change in kidney measures is associated with subclinical brain pathology in older community-dwelling persons.

Decreased glomerular filtration rate (GFR) and albuminuria may be accompanied by brain pathology. Here we investigated whether changes in these kidney measures are linked to development of new MRI-detected infarcts and microbleeds, and progression of white matter hyperintensity volume. The study included 2671 participants from the population-based AGES-Reykjavik Study (mean age 75, 58.7% women). GFR was estimated from serum creatinine, and albuminuria was assessed by urinary albumin-to-creatinine ratio. Brain MRI was acquired at baseline (2002-2006) and 5 years later (2007-2011). New MRI-detected infarcts and microbleeds were counted on the follow-up scans. White matter hyperintensity progression was estimated as percent change in white matter hyperintensity volumes between the two exams. Participants with a large eGFR decline (over 3 ml/min/1.73m2 per year) had more incident subcortical infarcts (odds ratio 1.53; 95% confidence interval 1.05, 2.22), and more marked progression of white matter hyperintensity volume (difference: 8%; 95% confidence interval: 4%, 12%), compared to participants without a large decline. Participants with incident albuminuria (over 30 mg/g) had 21% more white matter hyperintensity volume progression (95% confidence interval: 14%, 29%) and 1.86 higher odds of developing new deep microbleeds (95% confidence interval 1.16, 2.98), compared to participants without incident albuminuria. The findings were independent of cardiovascular risk factors. Changes in kidney measures were not associated with occurrence of cortical infarcts. Thus, larger changes in eGFR and albuminuria are associated with increased risk for developing manifestations of cerebral small vessel disease. Individuals with larger changes in these kidney measures should be considered as a high risk population for accelerated brain pathology.

Kidney function, gait pattern and fall in the general population: a cohort study.

Background: Gait disturbance is proposed as a mechanism for higher risk of fall in kidney disease patients. We investigated the association of kidney function with gait pattern in the general population and tested whether the association between impaired kidney function and fall is more pronounced in subjects with lower gait function. Methods: We included 1430 participants (mean age: 60 years) from the Rotterdam Study. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). We assessed global gait, gait velocity and seven independent gait domains: Rhythm, Phases, Variability, Pace, Tandem, Turning and Base of Support. Regression models adjusted for cardiometabolic and neurological factors were used. We evaluated whether participants with impaired kidney function and impaired gait fell more in the previous year. Results: The study population had a median (interquartile range) ACR of 3.6 (2.5-6.2) mg/g and mean ± SD eGFR of 87.6 ± 15 mL/min/1.73 m2. Higher ACR and lower eGFR were associated with lower global gait score [per doubling of ACR: -0.10, 95% confidence interval (CI): -0.14 to -0.06, and per SD eGFR:-0.09, 95% CI: -0.14 to -0.03] and slower gait speed (ACR: -1.44 cm/s, CI: -2.12 to -0.76; eGFR: -1.55 cm/s, CI: -2.43 to -0.67). Worse kidney function was associated with lower scores in Variability domain. The association between impaired kidney function and history of fall was present only in participants with lower gait scores [odds ratio (95% CI): ACR: 1.34 (1.09-1.65); eGFR: 1.58 (1.07-2.33)]. Conclusions: We observed a graded association between lower kidney function and impaired gait suggesting that individuals with decreased kidney function, even at an early stage, need to be evaluated for gait abnormalities and might benefit from fall prevention programmes.

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality.

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 × 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 × 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.

Coronary heart disease, heart failure, and the risk of dementia: A systematic review and meta-analysis.

INTRODUCTION: Cardiovascular risk factors are closely linked with dementia risk, but whether heart disease predisposes to dementia is uncertain. METHODS: We systematically reviewed the literature and meta-analyzed risk estimates from longitudinal studies reporting the association of coronary heart disease (CHD) or heart failure (HF) with risk of dementia. RESULTS: We identified 16 studies (1,309,483 individuals) regarding CHD, and seven studies (1,958,702 individuals) about HF. A history of CHD was associated with a 27% increased risk of dementia (pooled relative risk [RR] [95% confidence interval, CI]: 1.27 [1.07-1.50]), albeit with considerable heterogeneity across studies (I2 = 80%). HF was associated with 60% increased dementia risk (pooled RR 1.60 [1.19-2.13]) with moderate heterogeneity (I2 = 59%). Among prospective population-based cohorts, pooled estimates were similar (for CHD, RR 1.26 [1.06-1.49], nine studies; and HF, RR 1.80 [1.41-2.31], four studies) and highly consistent (I2 = 0%). CONCLUSION: CHD and HF are associated with an increased risk of dementia.

Kidney Function and Cerebral Blood Flow: The Rotterdam Study.

CKD is linked with various brain disorders. Whereas brain integrity is dependent on cerebral perfusion, the association between kidney function and cerebral blood flow has yet to be determined. This study was performed in the framework of the population-based Rotterdam Study and included 2645 participants with mean age of 56.6 years (45% men). We used eGFR and albumin-to-creatinine ratio to assess kidney function and performed phase-contrast magnetic resonance imaging of basilar and carotid arteries to measure cerebral blood flow. Participants had an average (SD) eGFR of 86.3 (13.4) ml/min per 1.73 m(2) and a median (interquartile range) albumin-to-creatinine ratio of 3.4 (2.2-6.1) mg/g. In age- and sex-adjusted models, a higher albumin-to-creatinine ratio was associated with lower cerebral blood flow level (difference in cerebral blood flow [milliliters per minute per 100 ml] per doubling of the albumin-to-creatinine ratio, -0.31; 95% confidence interval, -0.58 to -0.03). The association was not present after adjustment for cardiovascular risk factors (P=0.10). Each 1 SD lower eGFR was associated with 0.42 ml/min per 100 ml lower cerebral blood flow (95% confidence interval, 0.01 to 0.83) adjusted for cardiovascular risk factors. Thus, in this population-based study, we observed that lower eGFR is independently associated with lower cerebral blood flow.

von Willebrand Factor, ADAMTS13 Activity, and Decline in Kidney Function: A Population-Based Cohort Study.

BACKGROUND: Altered levels of von Willebrand factor (vWF) and ADAMTS13 can promote thrombosis and disturb blood flow in kidney microcirculations. We investigated the association of serum vWF:ADAMTS13 ratio in relation to decline in kidney function. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,479 individuals (mean age, 65.1±5.9 [SD] years; 43% men) from the population-based Rotterdam Study. PREDICTORS: vWF, ADAMTS13, and vWF:ADAMTS13 ratio. OUTCOMES & MEASUREMENTS: Annual decline in estimated glomerular filtration rate (eGFR), halving of eGFR, and new-onset eGFR<60mL/min/1.73m2 were assessed. RESULTS: During a median follow-up of 11 (range, 7.81-13.57) years, 500 cases of new-onset eGFR<60mL/min/1.73m2 occurred. The population had a mean eGFR decline of 0.96±0.92mL/min/1.73m2 per year. Higher vWF:ADAMTS13 ratio was associated with steeper annual decline in eGFR (difference, -0.06 [95% CI, -0.09 to -0.02] mL/min/1.73m2 per year) and higher risk for new-onset eGFR<60mL/min/1.73m2 (OR, 1.13; 95% CI, 1.01-1.27). Likewise, higher vWF:ADAMTS13 ratio was associated with higher risk for halving of eGFR (OR, 1.40; 95% CI, 1.02-1.93). After adjustment for cardiovascular risk factors and blood group, effect estimates remained the same. LIMITATIONS: No data available for albuminuria. Participants were classified based on a single measurement of vWF and ADAMTS13. CONCLUSIONS: In this population-based study, we showed that higher vWF:ADAMTS13 ratio is associated with decline in kidney function, suggesting a role of elevated prothrombotic factors in the development and progression of kidney disease.

EN-RAGE: a novel inflammatory marker for incident coronary heart disease.

OBJECTIVE: Inflammation plays a key role in atherosclerosis. We hypothesized that novel inflammatory markers may predict the risk of coronary heart disease (CHD). APPROACH AND RESULTS: We investigated the association of 16 inflammatory biomarkers with the risk of CHD in a random subset of 839 CHD-free individuals in a prospective population-based cohort study. A Bonferroni corrected P value of 3.1×10(-3) was used as a threshold of statistical significance. The mean age at baseline was 72.8 years. During a median follow-up of 10.6 years, 99 cases of incident CHD were observed. Among all inflammatory biomarkers, neutrophil-derived human s100a12 (extracellular newly identified receptor for advanced glycation end-products binding protein [EN-RAGE]) showed the strongest association with the risk of CHD (P value 2.0×10(-3)). After multivariable adjustment for established cardiovascular risk factors, each standard deviation increase in the natural log-transformed EN-RAGE was associated with 30% higher risk of incident CHD (hazard ratio, 1.30; 95% confidence interval, 1.06-1.59). Further adjustment for previously studied inflammatory markers did not attenuate the association. Excluding individuals with prevalent type 2 diabetes mellitus, impaired kidney function, or individuals using antihypertensive medication did not change the effect estimates. Cause-specific hazard ratios suggested a stronger association between EN-RAGE and CHD mortality compared with stable CHD. CONCLUSIONS: Our results highlight EN-RAGE as an inflammatory marker for future CHD in a general population, beyond traditional CHD risk factors and inflammatory markers.