The contribution of kidney dysfunction, especially at mild-to-moderate stages, and bone-mineral metabolism (BMM) markers to vascular calcification remains controversial or unclear. We comprehensively ...evaluated the association of kidney and BMM markers with coronary artery calcification (CAC) and extra-coronary calcification (ECC).
In 1931 ARIC participants (age 73–95 years) without coronary heart disease at visit 7 (2018–19), we investigated the associations of estimated glomerular filtration rate (eGFR) (with creatinine, cystatin C, and both) and five serum BMM markers (calcium, fibroblast growth factor 23, magnesium, parathyroid hormone, and phosphorus) with high CAC and ECC (sex-race specific ≥75th vs. <75th percentile Agatston score) or any vs. zero CAC and ECC using multivariable logistic regression. For eGFR and BMM markers, we took their weighted cumulative averages from visit 1 (1987–89) to visit 5 (2011–13).
Lower eGFR, regardless of equations used, was not robustly associated with high CAC or ECC. Among BMM markers, only higher phosphorus levels, even within the normal range, showed robust associations with high CAC (only when modeled continuously) and ECC, independently of kidney function (e.g., odds ratio 1.94 95%CI 1.38–2.73 for high aortic valve calcification, in the highest vs. lowest quartile). Results were generally consistent when analyzing any CAC or ECC, although cystatin C-based eGFR <60 mL/min/1.73 m2 became significantly associated with mitral valve calcification (odds ratio 1.69 1.10–2.60).
Among kidney and BMM measures tested, only serum phosphorus demonstrated robust associations with both CAC and ECC, supporting a key role of phosphorus in the pathophysiology of vascular calcification.
•We tested 8 kidney and bone-mineral measures and vascular calcification.•Of those measures, phosphorus showed the most robust association.•The association was generally continuous and independent of kidney function.•The other measures showed no or weak associations.
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
, 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
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.
Objectives
Despite 3.8 million concussions occurring annually in the United States, the pathophysiological sequelae of the injury are still poorly understood. Animal and human studies have ...consistently reported deficits in cerebral blood flow (CBF) following concussion suggesting impairments in CBF regulation. Reductions in CBF are also associated with functional outcomes. The purpose of the study was to examine dynamic cerebral autoregulation (dCA) in an ongoing prospective cohort of collegiate athletes 3 days, 21 days, and 90 days following a concussion and compare them with non‐injured controls.
Materials and Methods
Twenty‐seven NCAA and recreational athletes (20±1 years) with a physician diagnosed sports‐related concussions were enrolled in the study. For the injured athletes, data was collected on days 3,21, and 90 following concussion. Twenty‐five age and sports matched non‐injured controls (20±1 years) were also enrolled. For non‐injured controls, data was collected at one time point. Symptom number and severity was measured using the Sports Concussion Assessment Tool (SCAT‐3). Depression scores were assessed with Patient Health Questionnaire‐9 (PHQ‐9). Continuous mean arterial blood pressure (MBP) was obtained with finger photoplethysmography and middle cerebral artery blood flow velocity (MCAV) was obtained with a 2 MHz transcranial Doppler ultrasonography while subjects were seated in an upright position. dCA was estimated from transfer function (Tf) analysis of beat‐to‐beat spontaneous fluctuations in MBP and MCAV within the low (LF, 0.07–0.20 Hz) and high (HF, 0.20–0.35 Hz) frequency ranges. Effective dCA would attenuate spontaneous changes in MCAV in response to variations in MBP, which would correspond to relatively low transfer function gain. Independent and paired t‐tests were used to compare dCA between days 3, 21, and 90 following concussion with the non‐injured controls.
Results
Compare to the controls, concussed athletes exhibited greater symptom number on day‐3 (12.2±6.8 vs. 2.4±3.4; p<0.001) and higher PHQ‐9 score (8.7±5.6 vs. 2.1±2.1; p<0.001). LF Tf gain was higher on day‐3 (1.26±0.34U vs. 1.04±0.28U; p=0.016) compared to the controls. LF Tf gain continued to be high on day‐21 (1.30±0.45U; p=0.025) compared to the non‐injured controls despite no differences in symptoms number or depression scores between the groups. LF Tf gain was comparable to the controls on day‐90.
Conclusions
Dynamic cerebral autoregulation appears to be impaired at least up to 21 days following concussion despite improvement in symptom and depression. Cerebral autoregulation estimated from transcranial Doppler ultrasonography may be useful as a potential vascular biomarker for return‐to‐play decisions following a concussion preventing the risk of second‐impact syndrome.
Support or Funding Information
This work was supported by SMU University Research Council Grant, Spring 2015 & Texas Institute for Brain Injury and Repair (TIBIR) Pilot Grant 2016.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
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.
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.
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).
Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.
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.
Aging is increasingly thought to involve dysregulation of metabolism in multiple organ systems that culminate in decreased functional capacity and morbidity. Here, we seek to understand complex ...interactions among metabolism, aging, and systems-wide phenotypes across the lifespan. Among 2469 adults (mean age 74.7 years; 38% Black) in the Health, Aging and Body Composition study we identified metabolic cross-sectionally correlates across 20 multi-dimensional aging-related phenotypes spanning seven domains. We used LASSO-PCA and bioinformatic techniques to summarize metabolome-phenome relationships and derive metabolic scores, which were subsequently linked to healthy aging, mortality, and incident outcomes (cardiovascular disease, disability, dementia, and cancer) over 9 years. To clarify the relationship of metabolism in early adulthood to aging, we tested association of these metabolic scores with aging phenotypes/outcomes in 2320 participants (mean age 32.1, 44% Black) of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We observed significant overlap in metabolic correlates across the seven aging domains, specifying pathways of mitochondrial/cellular energetics, host-commensal metabolism, inflammation, and oxidative stress. Across four metabolic scores (body composition, mental-physical performance, muscle strength, and physical activity), we found strong associations with healthy aging and incident outcomes, robust to adjustment for risk factors. Metabolic scores for participants four decades younger in CARDIA were related to incident cardiovascular, metabolic, and neurocognitive performance, as well as long-term cardiovascular disease and mortality over three decades. Conserved metabolic states are strongly related to domain-specific aging and outcomes over the life-course relevant to energetics, host-commensal interactions, and mechanisms of innate immunity.
Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we ...conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3ml/min per 1.73m2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.
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.
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.
To investigate whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition.
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).
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).
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.
Combining pertinent data from multiple studies can increase the robustness of epidemiological investigations. Effective “pre-statistical” data harmonization is paramount to the streamlined conduct of ...collective, multi-study analysis. Harmonizing data and documenting decisions about the transformations of variables to a common set of categorical values and measurement scales are time consuming and can be error prone, particularly for numerous studies with large quantities of variables. The psHarmonize R package facilitates harmonization by combining multiple datasets, applying data transformation functions, and creating long and wide harmonized datasets. The user provides transformation instructions in a “harmonization sheet” that includes dataset names, variable names, and coding instructions and centrally tracks all decisions. The package performs harmonization, generates error logs as necessary, and creates summary reports of harmonized data. psHarmonize is poised to serve as a central feature of data preparation for the joint analysis of multiple studies.
The psHarmonize R package assists users with pre-statistical data harmonization. Data harmonization combines data from multiple sources to create a unified dataset with a common data dictionary for downstream analysis. This process can be time consuming and error prone. psHarmonize allows users to create a set of coding instructions in a single “harmonization sheet.” The R package functionality pulls instructions from this sheet to manipulate the raw data, perform transformations as needed, and generate and summarize a harmonized dataset.
•Pre-statistical data harmonization can be error prone and time consuming•The psHarmonize R package performs data transformations useful in harmonization•Coding instructions are compiled in a unified “harmonization sheet”•After harmonization, psHarmonize generates summary R Markdown output
The number of statistical analyses relying on pooled data from studies that consider more than one group, or cohort, of participants measured on more than one occasion has greatly increased in recent years. There is a need for rigorous and reproducible methods to facilitate the harmonization of pooled data. Data harmonization refers to the combination of data from different studies in a way that users can compare them and use them. Harmonization of multiple datasets can require copious coding and can easily result in disjointed scripts that may not always guarantee reproducibility or result in a clean track record of research team decision-making. The psHarmonize R package facilitates the central compilation of all programming instructions, as well as the efficient generation of descriptive statistics of the harmonized data.
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