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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 (β, −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.

Dementia spectrum disorders (DSDs) are a major cause of mortality and disability worldwide. DSDs encompass a large group of medical conditions that all ultimately lead to major functional and cognitive decline and disability. Demographic and comorbid conditions that are associated with DSDs have significant prognostic and preventive implications. In this article, we will discuss the global and regional burden of DSDs and cover key demographic and clinical conditions linked with DSDs. In the absence of disease-modifying treatments, the role of primary prevention has become more prominent. Implementation of preventive measures requires an understanding of predisposing and exacerbating factors.

We evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk.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.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.Better cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk.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.

Introduction: Leukocyte telomere length (LTL) is an important aging biomarker implicated in the pathogenesis of age-related conditions. We conducted a large-scale proteomics study to characterize the proteomic signatures of LTL and its genetic determinants measured by polygenic risk score (PRS). Hypothesis: We hypothesize that LTL and LTL PRS are associated with blood proteomic signatures linked to aging-related conditions. Methods: We used TelSeq to estimate LTL based on whole genome sequencing (WGS) data measured in samples collected in ARIC visits 1, 2, and 3 (i.e., the baseline for this study). TelSeq counted reads containing at least 12 TTAGGG repeats. This count was then normalized to the number of reads with GC content between 48% and 52%. Only samples with read lengths of 150 or 151 were included in subsequent analyses, and LTL estimates were inverse normalized within read length group and WGS group before being merged. We derived a PRS for LTL based on previously published genome-wide association study (GWAS) summary statistics for 150 significant autosomal SNPs and ARIC GWAS data. We then analyzed LTL or LTL PRS as a predictor and plasma levels of proteins as outcomes, measured at ARIC visit 2 (for the LTL PRS analysis) and visit 3 (for the LTL analysis) using SOMAscan v4 (~5,000 proteins). Race-specific linear regressions were performed to evaluate the association between LTL or LTL PRS and levels of each protein adjusting for potential confounders at baseline. We used a Bonferroni correction to account for multiple testing. The analysis in Whites served as a discovery (p≤1x10 -5 ) and that in Blacks as a replication. Results: The final sample sizes were as follows: LTL PRS analysis (n=7,587 Whites and 2,094 Blacks) and LTL analysis (n=5,014 Whites and 884 Blacks). In Whites, LTL PRS was significantly associated with five proteins (p≤1x10 -5 ) that also showed the same direction of association in Blacks: THPO, GP1Bα, PEAR1, KDR, and GP5, with the association for KDR reaching nominal significance in Blacks (p=0.02). For LTL as the predictor, GP1Bα, GDF15 and TXNDC5 were significant in Whites, with consistent direction of associations in Blacks (p>0.05). These proteins are linked to hemostasis (all), endothelial proliferation (KDR), heart disease and cancer (GDF15), and cancer and rheumatoid arthritis (TXNDC5) in the literature. Conclusion: This large-scale proteomic analysis reveals blood proteomic signatures for LTL PRS and LTL, which will likely improve the understanding of biological pathways and clinical conditions implicated by LTL.

Introduction: The number of copies of the mitochondrial genome, termed mitochondrial DNA copy number (MTCN), is a proxy for mitochondrial function and varies by cell. Critically, lower MTCN has been associated with aging and chronic diseases such as dementia and cancer. We conducted a large-scale proteomics analysis of leukocyte MTCN (L-MTCN) to elucidate pathways modulated by L-MTCN that may be involved in diseases of aging. Hypothesis: We hypothesize that L-MTCN is significantly associated to plasma proteins that have been implicated in biological pathways of L-MTCN and related diseases. Methods: Based on whole genome sequencing (WGS) data measured in samples collected in ARIC visits 1, 2, and 3 (i.e., baseline for the current study), L-MTCN was calculated as (2 * coverage of the mitochondrial genome) / coverage of the autosome, using the median coverage of 1000 base pair bins overlapping the mitochondrial genome (16 total) and the median coverage of ~142,000 higher quality autosomal bins. Only samples with read lengths of 150 or 151 were included in subsequent analyses, and L-MTCN estimates were inverse normalized within read length group and WGS group before being merged together. This normalized L-MTCN was then analyzed as a predictor for an association with 4,870 plasma proteins measured by SOMAscan v4 in ARIC visit 3 in race-specific generalized linear models, adjusting for the following covariates at baseline: WGS sample visit, age, gender, field center, smoking status, and a measure of kidney function. Bonferroni correction was applied to account for the number of proteins tested in 5,007 White participants (p≤1x10 -5 ). Associations were tested for replication in 1,178 Black participants and considered significant if protein estimates had the same direction of association as Whites at p-value ≤ 2.2x10 -4 . Results: Among White participants, 230 proteins were significantly associated with L-MTCN. Of these proteins S100A9, GP1Bα, EGFR, THBS2, and FCGR3B were significantly replicated among Black participants. Strongest associations with L-MTCN were seen with GP1Bα (Estimate: 0.121) and S100A9 (Estimate: -0.191). Biologically S100A9 is a calgranulin and together with S100A8 forms calprotectin, which have roles mediating inflammatory processes. GP1Bα helps mediate platelet activation and forms the glycoprotein Ib-IX-V complex which acts as a platelet surface receptor for von Willebrand factor facilitating platelet adhesion. Conclusion: This large proteomics analysis identified 230 plasma proteins significantly associated with L-MTCN. Some of the proteins have been connected to inflammatory diseases, cardiovascular disease, and cancer in the literature. These results provide insight into proteins involved in biological pathways related to L-MTCN.

Introduction: Cardiovascular health may be used for prevention of cerebral vascular disease. We evaluated whether improvement of cardiovascular health within midlife and from midlife to late-life were each associated with lower prevalence of MRI markers of cerebral vascular disease at late-life. Methods: 1,638 participants from the Atherosclerosis Risk in Communities (ARIC) Study took part in two visits at midlife (mean ages 53 at ARIC visit 1 and 59 at visit 3), and a late-life visit (mean age 76). A cardiovascular health Life’s Simple 7 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). Participants underwent 3T brain MRI scans in 2011-2013 (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 with MRI markers of cerebral vascular disease. Results: Thirty nine percent of participants had high cardiovascular health at midlife visit 1, 32% at midlife visit 3, and 33% at late-life. Improvement of cardiovascular health within midlife and from midlife to late-life were each 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 (Beta:-0.07 [95%CI:-0.10,-0.04]), and lower odds of microbleeds (OR:0.93 [0.90,0.97]), lacunar (OR:0.93 [0.89,0.97)], subcortical (OR:0.93 [0.89,0.97])], and cortical infarcts (OR:0.92 [0.87,0.97)] (Figure). Conclusions: Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.

Background: Reduced kidney function is related to brain atrophy and higher risk of dementia. It is not known whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition, which could contribute to elevated risk of dementia. Objective: To investigate whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition. Methods: This cross-sectional study was performed within the community–based Atherosclerosis Risk in Communities (ARIC) Study cohort. We used estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C levels and urine albumin-to-creatinine ratio (ACR) to assess kidney function. Amyloid positivity was defined as a standardized uptake value ratios > 1.2 measured with florbetapir positron emission tomography (PET) (n = 340). Plasma amyloid-β1 - 40 and amyloid-β1 - 42 were measured using a fluorimetric bead-based immunoassay (n = 2,569). Results: Independent of demographic and cardiovascular risk factors, a doubling of ACR was associated with 1.10 (95% CI: 1.01,1.20) higher odds of brain amyloid positivity, but not eGFR (odds ratio per 15 ml/min/1.73 m2 lower eGFR: 1.08; 95% CI: 0.95,1.23). A doubling of ACR was associated with a higher level of plasma amyloid-β1 - 40 (standardized difference: 0.12; 95% CI: 0.09,0.14) and higher plasma amyloid-β1 - 42 (0.08; 95% CI: 0.05,0.10). Lower eGFR was associated with higher plasma amyloid-β1 - 40 (0.36; 95% CI: 0.33,0.39) and higher amyloid-β1 - 42 (0.32; 95% CI: 0.29,0.35). Conclusion: Low clearance of amyloid-β and elevated brain amyloid positivity may link impaired kidney function with elevated risk of dementia. kidney function should be considered in interpreting amyloid biomarker results in clinical and research setting.

Identifying modifiable risk factors that are associated with dementia burden across racial and ethnic groups in the population can yield insights into the potential effectiveness of interventions in preventing dementia and reducing disparities.To calculate the population attributable fraction (PAF) of dementia associated with 12 established modifiable risk factors for all US adults, as well as separately by race and ethnicity.This cross-sectional study used survey data from nationally representative samples of US adults. PAFs were calculated using relative risks and prevalence estimates for 12 risk factors. Relative risks were taken from meta-analyses, as reported in a 2020 systematic review. Prevalence estimates for risk factors were derived from nationally representative cross-sectional survey data collected between 2011 and 2018. Combined PAFs were adjusted for risk factor communality using weights derived from the Atherosclerosis Risk in Communities (ARIC) study (1987-2018). Analyses were conducted May through October 2021.Low education, hearing loss, traumatic brain injury, hypertension, excessive alcohol consumption, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and air pollution.PAF for each dementia risk factor, a combined PAF, and the decrease in the number of prevalent dementia cases in 2020 that would be expected given a 15% proportional decrease in each exposure.Among all US adults, an estimated 41.0% (95% CI, 22.7%-55.9%) of dementia cases were attributable to 12 risk factors. A 15% proportional decrease in each risk factor would reduce dementia prevalence in the population by an estimated 7.3% (95% CI, 3.7%-10.9%). The estimated PAF was greater for Black and Hispanic than it was for White and Asian individuals. The greatest attributable fraction of dementia cases was observed for hypertension (PAF, 20.2%; 95% CI, 6.3%-34.4%), obesity (PAF, 20.9%; 95% CI, 13.0%-28.8%), and physical inactivity (PAF, 20.1%; 95% CI, 9.1%-29.6%). These factors were also highest within each racial and ethnic group, although the proportions varied.A large fraction of dementia cases in the US were associated with potentially modifiable risk factors, especially for Black and Hispanic individuals. Targeting and reducing these risk factors may curb the projected rise in dementia cases over the next several decades.

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

Introduction: Modifiable risk factors (including cardiovascular traits) are associated with dementia risk. However, it is unknown which risk factors have the greatest influence on dementia rates in the United States, or how that varies by race/ethnicity. Objective: For all Americans and separately by race and ethnicity, we calculated population attributable fractions (PAFs) of dementia for 12 potentially modifiable risk factors: low education, hearing loss, traumatic brain injury, hypertension, excessive alcohol consumption, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and air pollution. Methods: Assuming a causal relationship between risk factors and dementia, we calculated PAFs for dementia using relative risks and prevalence estimates for each risk factor. We used relative risks from recent meta-analyses and prevalence estimates from nationally representative cross-sectional survey data (e.g., NHANES). We estimated prevalence separately by race/ethnicity. We calculated the PAF (for all Americans and separately by race and ethnicity) for each dementia risk factor and a combined PAF accounting for correlations between exposures. Results: In the total population, 42.6% of dementia cases were attributable to the 12 risk factors we considered. The estimated PAF of these risk factors was greater for Black and Hispanic Americans (47.5% and 47.3%, respectively) than it was for White and Asian Americans (41.3% and 37.8%, respectively). The greatest fractions of dementia cases were attributable to key cardiovascular traits: hypertension (20.2%), obesity (20.9%), and physical inactivity (20.1%). These factors were highest within each racial and ethnic group, though the proportions varied (Figure 1). Conclusions: A large fraction of dementia cases are attributable to potentially modifiable factors, especially for Black and Hispanic Americans. Further research is needed to test whether intervening on these factors reduces dementia risk.

The proportion of aging populations affected by dementia is increasing. There is an urgent need to identify biological aging markers in mid-life before symptoms of age-related dementia present for early intervention to delay the cognitive decline and the onset of dementia. In this cohort study involving 1,676 healthy participants (mean age 40) with up to 15 years of follow up, we evaluated the associations between cognitive function and two classes of novel biological aging markers: blood-based epigenetic aging and neuroimaging-based brain aging. Both accelerated epigenetic aging and brain aging were prospectively associated with worse cognitive outcomes. Specifically, every year faster epigenetic or brain aging was on average associated with 0.19-0.28 higher (worse) Stroop score, 0.04-0.05 lower (worse) RAVLT score, and 0.23-0.45 lower (worse) DSST (all false-discovery-rate-adjusted p

ObjectiveTo test the hypothesis that end-stage renal disease (ESRD) risk exposure during young adulthood is related to worse cognitive performance in midlife.MethodsWe included 2,604 participants from the population-based Coronary Artery Risk Development in Young Adults (CARDIA) Study (mean age 35 years, 54% women, 45% Black). Estimated glomerular filtration rate and albumin-to-creatinine ratio were measured every 5 years at year (Y) 10 through Y30. At each visit, moderate/high risk of ESRD according to the Kidney Disease: Improving Global Outcomes guidelines (estimated glomerular filtration rate 2 or albumin-to-creatinine ratio >30 mg/g) was defined, totaled over examinations, and categorized into 0 episodes, 1 episode, and >1 episodes of ESRD risk. At Y30, participants underwent global and multidomain cognitive assessment. We used analysis of covariance to assess the association of ESRD risk categories with cognitive function, controlling for cardiovascular risk factors.ResultsOver the course of 20 years, 427 participants (16% of the study population) had ≥1 episodes of ESRD risk exposure. Individuals with more risk episodes had lower composite cognitive function (p < 0.001), psychomotor speed (p < 0.001), and executive function (p = 0.007). All these associations were independent of sociodemographic status and cardiovascular risk factors.ConclusionsIn this population-based longitudinal study, we show that episodes of decline in kidney function over the young-adulthood course are associated with worse cognitive performance at midlife. Preserving kidney function in young age needs to be investigated as a potential strategy to preserve cognitive function in midlife.

Adults with type 2 diabetes are at an increased risk of developing certain brain or mental disorders, including stroke, dementia, and depression. Although these disorders are not usually considered classic microvascular complications of diabetes, evidence is growing that microvascular dysfunction is one of the key underlying mechanisms. Microvascular dysfunction is a widespread phenomenon in people with diabetes, including effects on the brain. Cerebral microvascular dysfunction is also apparent in adults with prediabetes, suggesting that cerebral microvascular disease processes start before the onset of diabetes. The microvasculature is involved in the regulation of many cerebral processes that when impaired predispose to lacunar and haemorrhagic stroke, cognitive dysfunction, and depression. Main drivers of diabetes-related cerebral microvascular dysfunction are hyperglycaemia, obesity and insulin resistance, and hypertension. Increasing amounts of data from observational studies suggest that diabetes-related microvascular dysfunction is associated with a higher risk of stroke, cognitive dysfunction, and depression. Cerebral outcomes in diabetes might be itnproved following treatments targeting the pathways through which diabetes damages the microcirculation. These treatments might include drugs that reduce dicarbonyl compounds, augment cerebral insulin signalling, or imnprove blood-brain barrier permeability and cerebral vasoreactivity.

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped association between telomere length and risk of Alzheimer's disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13-2.23) for the lowest tertile and 1.47 (1.03-2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer's disease in the general population.

BackgroundDementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia.MethodsWe did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP

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.

IMPORTANCE Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions.OBJECTIVE To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR).DESIGN, SETTING, AND PARTICIPANTS Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540).EXPOSURES Demographic and clinical factors.MAIN OUTCOMES AND MEASURES Incident eGFR of less than 60 mL/min/1.73 m(2).RESULTS Among 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A(1c), and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25.CONCLUSIONS AND RELEVANCE Equations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.

Background Both education and cardiovascular risk factors are strongly associated with dementia risk. However, it is not clear whether these associations persist or vary among individuals with high genetic risk for Alzheimer’s disease. We examined the interactive relationship between lifestyle and genetic dementia risk factors in a prospective cohort study. Methods Our data came from the Atherosclerosis Risk in Communities study participants (n = 13 715; baseline age 45–64; 25% Black; 55% female), who were followed for incident dementia from 1987 through 2017. We used Cox proportional hazard models to estimate the risk of dementia (ascertained through in-person examination, telephone cognitive screeners, and/or hospital and death records) associated with baseline education and cardiovascular risk factors (measured using the American Heart Association’s “Life Simple 7”) among ε4 carriers and non-carriers separately. We also examined differences by race and sex. Results Two thousand two hundred and twenty-six incident dementia cases occurred over a median 25 years of follow-up. Lower educational attainment and poorer cardiovascular health were associated with greater risk of incident dementia. There was an education by apolipoprotein E (APOE) status interaction (p = .005) whereby the association of education and dementia was weaker for ε4 carriers (HR college graduates vs less than high school: 0.71 [0.59–0.84] than non-carriers (0.54 [0.47–0.63]). There was no interaction between APOE status and cardiovascular health on dementia risk. These relationships did not vary significantly by race or sex. Conclusions Education and cardiovascular health were associated with lower dementia risk regardless of APOE genotype, though the protective effects of education were somewhat diminished among ε4 carriers.

Longitudinal population-based data on effects of kidney dysfunction in the development of stroke and dementia remains inconclusive. We investigated associations of kidney function with risk of stroke and dementia in 5,993 community-dwelling individuals (mean age: 69.0 years, 57.2% women). We calculated estimated glomerular filtration rates based on creatinine, cystatin-C, and a combination of these two. During a mean follow-up of 11.6 years (69,790 person-years), 1,360 individuals suffered a stroke (n = 602) or developed dementia (n = 758). We found that an impaired kidney function was related to a higher risk of stroke, but not to dementia.

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.

Introduction: Microembolic signals (MES) identified by transcranial Doppler (TCD) reflect an ongoing embolic phenomenon with implications for the recurrence of cerebrovascular events and complications. In this study, we investigated the prevalence of MES detected after stroke or transient ischemic attack (TIA) and studied their relationship with future re-admissions. Method: This clinical cohort study is comprised of 961 consecutive patients (mean age 65 years, 59% male) admitted to Northwestern Memorial Hospital with the diagnosis of acute stroke (n: 872) or TIA (n: 89) and underwent TCD evaluation. TCD is performed within the first 48 hours of admission as a routine component of stroke etiology evaluation at our institution. After discharge, patients were followed for an average of 18 months for any hospital readmissions. Cox regression models were used to estimate risk of re-admissions in relation to MES. Results: MES were detected in 99 (10%, 95% CI; 8-12%) patients. During the follow up period, 356 patients had emergency room re-admissions. Compared to patients without MES, those with MES were younger ( p =0.007) and had longer index hospital stay ( p =0.008). Patients with MES, as compared to patients without MES, had 1.56-fold (hazard ratio 95% CI=1.15, 2.13; p =0.005) higher risk of readmission. This association was independent of age, sex, race, smoking, history of hyperlipidemia, diabetes, atrial fibrillation, history of pulmonary emboli, deep vein thrombosis, hypertension, coronary artery disease and heart failure. Conclusion: We show that MES are present in one tenth of patients admitted with stroke or TIA, and they are associated with higher risk of re-admission. These data highlight the importance of embolic signals in stroke complication risk stratification and suggest the need for prospective clinical trials targeting MES in secondary stroke risk and complication prevention.

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.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function., Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät; 19

High blood pressure (BP) negatively affects brain structure and function. Hypertension is associated with white matter hyperintensities, cognitive and mobility impairment in late-life. However, the impact of BP exposure from young adulthood on brain structure and function in mid-life is unclear. Identifying early brain structural changes associated with BP exposure, before clinical onset of cognitive dysfunction and mobility impairment, is essential for understanding mechanisms and developing interventions. We examined the effect of cumulative BP exposure from young adulthood on brain structure in a substudy of 144 (61 female) individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study. At year 30 (Y 30 , ninth visit), participants (56±4 years old) completed brain magnetic resonance imaging and gait measures (pace, rhythm, and postural control). Cumulative systolic and diastolic BP (cumulative systolic blood pressure, cDBP) over 9 visits were calculated, multiplying mean values between 2 consecutive visits by years between visits. Surface-based analysis of basal ganglia and thalamus was achieved using FreeSurfer-initiated Large Deformation Diffeomorphic Metric Mapping. Morphometric changes were regressed onto cumulative BP to localize regions of shape variation. Y 30 white matter hyperintensity volumes were small and positively correlated with cumulative BP but not gait. Negative morphometric associations with cumulative systolic blood pressure were seen in the caudate, putamen, nucleus accumbens, pallidum, and thalamus. A concave right medial putamen shape mediated the relationship between cumulative systolic blood pressure and stride width. Basal ganglia and thalamic morphometric changes, rather than volumes, may be earlier manifestation of gray matter structural signatures of BP exposure that impact midlife gait.

Introduction: Multiple studies demonstrated an independent and inverse association between cognitive function and mortality but little is known about the cause of death. Hypothesis: We hypothesized that lower cognitive function is related to higher mortality risk and this association is stronger for cardiovascular related deaths. Methods: We included 5569 persons (mean[SE] age 71[0.05], 52% women), from the Third National Health and Nutrition Examination Survey (NHANES III) with available cognitive function measurements and mortality follow-up. Cognitive domains include orientation, attention, immediate and delayed memory as well as global cognition. We used weighted Cox proportional regression models adjusted for age, sex, education, systolic and diastolic blood pressure, body mass index, smoking, history of diabetes and cardiovascular disorders. Results: During an average follow-up of 12 years, 1887 participants died from cardiovascular causes and 2675 died from non-cardiovascular causes. Each SD lower global cognitive performance (SD=6) was related to a 1.11 (95% CI: 1.05, 1.17) higher hazard of all-cause mortality. The associations were more prominent with cardiovascular mortality than with non- cardiovascular mortality (Table). Conclusion: Cognitive impairment in the absence of manifest dementia is an important independent predictor of mortality, in particular from cardiovascular causes.

CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-β, 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-β40 and amyloid-β42 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-β42 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

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.

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 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.

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 (I 2 = 80%). HF was associated with 60% increased dementia risk (pooled RR 1.60 [1.19–2.13]) with moderate heterogeneity (I 2 = 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 (I 2 = 0%). Conclusion CHD and HF are associated with an increased risk of dementia.

Introduction: As many as 20-50% of persons with chronic kidney disease have mild-to-moderate cognitive impairment or overt dementia. Shared risk factors, such as aging, sex, hypertension, and diabetes have been suggested to play a role in this association. Our objective was to examine the contribution of non-modifiable and modifiable risk factors to this association. Hypothesis: We hypothesize that non-modifiable and modifiable risk factors could explain part, but not all, of the association between worse kidney function with incidence of dementia. Methods: We included 6025 CVD free participants (mean age 62 yrs, 51% women, 38% white). Kidney function was assessed by estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Participants were followed for an average of 12±4 yrs for dementia ICD code hospitalization. Multiple Cox regression models, adjusted for baseline non-modifiable (age, sex, race, and APOE4 carriership) and modifiable risk factors (BMI, smoking, SBP, diabetes, cholesterol, alcohol intake, education, physical activity, and healthy diet score) were used to estimate the association of worse kidney function with incidence of dementia hospitalization. Results: During follow-up, 268 (4.4%) participants were hospitalized for dementia. Non-modifiable risk factors vs. modifiable risk factors were associated with greater reduction in HRs from a crude model for association between each SD lower eGFR and risk of dementia (70% vs. 8%). Non-modifiable risk factors explained a higher percentage of the association of doubling ACR with risk of dementia than modifiable risk factors (14% vs. 7%) (Figure). Adjusting for all factors, worse kidney function remained associated with incident dementia. Conclusions: Findings suggest that conventional modifiable and non-modifiable risk factors cannot fully explain higher risk of dementia in relation to worse kidney function. This finding warrants exploring other potential novel vascular and nonvascular mechanisms of this association.

Publisher's version (útgefin grein)., Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria., Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna Köttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests.

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10−56) and SLC2A9 (p = 4.5 × 10−7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10−3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout., Elevated serum urate levels are a risk factor for gout. Here, Tin et al. perform whole-exome sequencing in 19,517 individuals and detect low-frequency genetic variants in urate transporter genes, SLC22A12 and SLC2A9, associated with serum urate levels and confirm their damaging nature in vitro and in silico.

BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0,994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license.

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.

Background Carotid stiffening is considered a key element in the pathogenesis of stroke. However, results of studies evaluating the association between carotid stiffness and incident stroke have been inconsistent. Objectives This study investigated whether carotid stiffness (as determined by ultrasonography) is associated with incident stroke and whether this association is independent of aortic stiffness as estimated by carotid-femoral pulse wave velocity (cfPWV). Additionally, we evaluated the incremental value of carotid stiffness for stroke risk prediction beyond Framingham risk factors and cfPWV. Methods This study included a systematic review and meta-analyses of aggregate and individual participant data (IPD), the latter of which was obtained by requesting individual-level data of all cohort studies with available data on carotid stiffness and cfPWV. Results Ten studies (n = 22,472) were included in the aggregate data meta-analysis and 4 (n = 4,540) in the IPD meta-analysis. After adjusting for cardiovascular (CV) factors, the aggregate data meta-analysis showed that greater carotid stiffness (per SD) was associated with stroke (hazard ratio: 1.18; 95% confidence interval: 1.05 to 1.33). In addition, carotid stiffness was associated with total CV events and CV and all-cause mortality, but not with coronary heart disease events. In the IPD meta-analysis, additional adjustment for cfPWV did not materially change these associations. Carotid stiffness did improve stroke risk prediction beyond Framingham and cfPWV (integrative discrimination improvement: 0.4 percentage point [95% confidence interval: 0.1 to 0.6 percentage point] and continuous net reclassification improvement: 18.6% [95% confidence interval: 5.8% to 31.3%]). Conclusions Carotid stiffness is associated with incident stroke independently of CV factors and aortic stiffness. In addition, carotid stiffness improves stroke risk prediction beyond Framingham and aortic stiffness.