Psychometric reliability, validity, and generalizability of 3MSE scores among American Indian adults: the Strong Heart Study.

OBJECTIVE: Modified Mini-Mental State Examination (3MSE) is often used to screen for dementia, but little is known about psychometric validity in American Indians. METHODS: We recruited 818 American Indians aged 65-95 for 3MSE examinations in 2010-2013; 403 returned for a repeat examination in 2017-2019. Analyses included standard psychometrics inferences for interpretation, generalizability, and extrapolation: factor analysis; internal consistency-reliability; test-retest score stability; multiple indicator multiple cause structural equation models. RESULTS: This cohort was mean age 73, majority female, mean 12 years education, and majority bilingual. The 4-factor and 2nd-order models fit best, with subfactors for orientation and visuo-construction (OVC), language and executive functioning (LEF), psychomotor and working memory (PMWM), verbal and episodic memory (VEM). Factor structure was supported for both research and clinical interpretation, and factor loadings were moderate to high. Scores were generally consistent over mean 7 years. Younger participants performed better in overall scores, but not in individual factors. Males performed better on OVC and LEF, females better on PMWM. Those with more education performed better on LEF and worse on OVC; the converse was true for bilinguals. All differences were significant, but small. CONCLUSION: These findings support use of 3MSE for individual interpretation in clinic and research among American Indians, with moderate consistency, stability, reliability over time. Observed extrapolations across age, sex, education, and bilingual groups suggest some important contextual differences may exist.

Epidemiology and prevalence of dementia and Alzheimer's disease in American Indians: Data from the Strong Heart Study.

INTRODUCTION: Accurate epidemiologic estimates for dementia are lacking for American Indians, despite substantive social and health disparities. METHODS: The Strong Heart Study, a population-based cohort of 11 American Indian tribes, conducted detailed cognitive testing and examinations over two visits approximately 7 years apart. An expert panel reviewed case materials for consensus adjudication of cognitive status (intact; mild cognitive impairment [MCI]; dementia; other impaired/not MCI) and probable etiology (Alzheimer's disease [AD], vascular bain injury [VBI], traumatic brain injury [TBI], other). RESULTS: American Indians aged 70-95 years had 54% cognitive impairment including 10% dementia. VBI and AD were primary etiology approximately equal proportions (>40%). Apolipoprotein (APO) Eε4 carriers were more common among those with dementia (p = 0.040). Plasma pTau, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were higher among those with cognitive impairment, but not amyloid beta (Aß). Cognitive intact had mean 3MSE 92.2 (SD 6.4) and mean Montreal Cognitive Assessment (MoCA) score of 21.3 (SD 3.2). DISCUSSION: This is the first population-based study to estimate the prevalence of vascular and Alzheimer's dementias in a population-based study of American Indians. HIGHLIGHTS: The Strong Heart Study is a population-based cohort of American Indian tribes, conducted over 30+ years and three US geographic regions (Northern Plains, Southern Plains, Southwest). Our teams conducted detailed cognitive testing, neurological examination, and brain imaging over two visits approximately 7 years apart. An expert panel reviewed collected materials for consensus-based adjudication of cognitive status (intact; MCI; dementia; other impaired/not MCI) and probable underlying etiology (AD; VBI; TBI; other). In this cohort of American Indians aged 70-95, 54% were adjudicated with cognitive impairment, including approximately 35% MCI and 10% dementia. These data expand on prior reports from studies using electronic health records, which had suggested prevalence, and incidence of dementia in American Indians to be more comparable to the majority population or non-Hispanic White individuals, perhaps due to latent case undercounts in clinical settings. Vascular and neurodegenerative injuries were approximately equally responsible for cognitive impairment, suggesting that reduction of cardiovascular disease is needed for primary prevention. Traumatic injury was more prevalent than in other populations, and common among those in the "other/not MCI" cognitive impairment category. Mean scores for common dementia screening instruments-even among those adjudicated as unimpaired-were relatively low compared to other populations (mean unimpaired 3MSE 92.2, SD 6.4; mean unimpaired MoCA 21.3, SD 3.2), suggesting the need for cultural and environmental adaptation of common screening and evaluation instruments.

Plasma biomarkers of Alzheimer's disease and related dementias in American Indians: The Strong Heart Study.

INTRODUCTION: Identification of Alzheimer's disease (AD) needs inexpensive, noninvasive biomarkers, with validation in all populations. METHODS: We collected plasma markers in older American Indian individuals: phosphorylated-tau181 (pTau181); amyloid-beta (Aß) 40,42; glial fibrillary acidic protein (GFAP); and neurofilament light chain (NfL). Plasma markers were analyzed for discriminant properties with cognitive status and etiology using receiver operating characteristic (ROC) analysis. RESULTS: PTau181, GFAP, NfL plasma values were significantly associated with cognition, but Aß were not. Discriminant performance was moderate for individual markers, with pTau181, GFAP, NfL performing best, but an empirically selected panel of markers (age, sex, education, pTau181, GFAP, NfL, Aß4240 ratio) had excellent discriminant performance (AUC > 0.8). DISCUSSION: In American Indian individuals, pTau181 and Aß values suggested more common pathology than in majority populations. Aß was less informative than in other populations; however, all four markers were needed for a best-performing dementia diagnostic model. These data validate utility of AD plasma markers, while suggesting population-specific diagnostic characteristics.

Telomere Length and Magnetic Resonance Imaging Findings of Vascular Brain Injury and Central Brain Atrophy: The Strong Heart Study.

Telomeres are repeating regions of DNA that cap chromosomes. They shorten over the mammalian life span, especially in the presence of oxidative stress and inflammation. Telomeres may play a direct role in cell senescence, serving as markers of premature vascular aging. Leukocyte telomere length (LTL) may be associated with premature vascular brain injury and cerebral atrophy. However, reports have been inconsistent, especially among minority populations with a heavy burden of illness related to vascular aging. We examined associations between LTL and magnetic resonance imaging in 363 American Indians aged 64-93 years from the Strong Heart Study (1989-1991) and its ancillary study, Cerebrovascular Disease and Its Consequences in American Indians (2010-2013). Our results showed significant associations of LTL with ventricular enlargement and the presence of white matter hyperintensities. Secondary models indicated that renal function may mediate these associations, although small case numbers limited inference. Hypertension and diabetes showed little evidence of effect modification. Results were most extreme among participants who evinced the largest decline in LTL. Although this study was limited to cross-sectional comparisons, it represents (to our knowledge) the first consideration of associations between telomere length and brain aging in American Indians. Findings suggest a relationship between vascular aging by cell senescence and severity of brain disease.

Findings of Vascular Brain Injury and Structural Loss from Cranial Magnetic Resonance Imaging in Elderly American Indians: The Strong Heart Study.

BACKGROUND: The Cerebrovascular Disease and its Consequences in American Indians study conducted cranial MRI examination of surviving participants of the Strong Heart Study, a longitudinal cohort of elderly American Indians. METHODS: Of the 1,033 recruited participants, some were unable to complete the MRI (n = 22), some scans were unusable due to participant motion or technical errors (n = 13), and one community withdrew consent after data collection (n = 209), leaving 789 interpretable MRI scan images. Six image sequences were obtained in contiguous slices on 1.5T scanners. Neuroradiologists graded white matter hyperintensities (WMH), sulci, and ventricles on a 0- to 9-point scale, and recorded the presence of infarcts and hemorrhages. Intracranial, brain, hippocampal, and WMH volumes were estimated by automated image processing. RESULTS: The median scores for graded measures were 2 (WMH) and 3 (sulci, ventricles). About one-third of participants had lacunar (20%) or other infarcts (13%); few had hemorrhages (5.7%). Findings of cortical atrophy were also prevalent. Statistical analyses indicated significant associations between older age and findings of vascular injury and atrophy; male gender was associated with findings of cortical atrophy. CONCLUSIONS: Vascular brain injury is the likely explanation in this elderly American Indian population for brain infarcts, hemorrhages, WMH grade, and WMH volume. Although vascular brain injury may play a role in other findings, independent degenerative other disease processes may underlie abnormal sulcal widening, ventricular enlargement, hippocampal volume, and total brain volume. Further examination of risk factors and outcomes with these findings may expand the understanding of neurological conditions in this understudied population.

Total Brain and Hippocampal Volumes and Cognition in Older American Indians: The Strong Heart Study.

BACKGROUND: Estimates of hippocampal volume by magnetic resonance imaging have clinical and cognitive correlations and can assist in early Alzheimer disease diagnosis. However, little is known about the relationship between global or regional brain volumes and cognitive test performance in American Indians. MATERIALS AND METHODS: American Indian participants (N=698; median age, 72 y) recruited for the Cerebrovascular Disease and its Consequences in American Indians study, an ancillary study of the Strong Heart Study cohort, were enrolled. Linear regression models assessed the relationship between magnetic resonance imaging brain volumes (total brain and hippocampi) and cognitive measures of verbal learning and recall, processing speed, verbal fluency, and global cognition. RESULTS: After controlling for demographic and clinical factors, all volumetric measurements were positively associated with processing speed. Total brain volume was also positively associated with verbal learning, but not with verbal recall. Conversely, left hippocampal volume was associated with both verbal learning and recall. The relationship between hippocampal volume and recall performance was more pronounced among those with lower scores on a global cognitive measure. Controlling for APOE ε4 did not substantively affect the associations. CONCLUSIONS: These results support further investigation into the relationship between structural Alzheimer disease biomarkers, cognition, genetics, and vascular risk factors in aging American Indians.

Tubular Secretion in CKD.

Renal function generally is assessed by measurement of GFR and urinary albumin excretion. Other intrinsic kidney functions, such as proximal tubular secretion, typically are not quantified. Tubular secretion of solutes is more efficient than glomerular filtration and a major mechanism for renal drug elimination, suggesting important clinical consequences of secretion dysfunction. Measuring tubular secretion as an independent marker of kidney function may provide insight into kidney disease etiology and improve prediction of adverse outcomes. We estimated secretion function by measuring secreted solute (hippurate, cinnamoylglycine, p-cresol sulfate, and indoxyl sulfate) clearance using liquid chromatography-tandem mass spectrometric assays of serum and timed urine samples in a prospective cohort study of 298 patients with kidney disease. We estimated GFR by mean clearance of creatinine and urea from the same samples and evaluated associations of renal secretion with participant characteristics, mortality, and CKD progression to dialysis. Tubular secretion rate modestly correlated with eGFR and associated with some participant characteristics, notably fractional excretion of electrolytes. Low clearance of hippurate or p-cresol sulfate associated with greater risk of death independent of eGFR (hazard ratio, 2.3; 95% confidence interval, 1.1 to 4.7; hazard ratio, 2.5; 95% confidence interval, 1.0 to 6.1, respectively). Hazards models also suggested an association between low cinnamoylglycine clearance and risk of dialysis, but statistical analyses did not exclude the null hypothesis. Therefore, estimates of proximal tubular secretion function correlate with glomerular filtration, but substantial variability in net secretion remains. The observed associations of net secretion with mortality and progression of CKD require confirmation.

Cranial Magnetic Resonance Imaging in Elderly American Indians: Design, Methods, and Implementation of the Cerebrovascular Disease and Its Consequences in American Indians Study.

The Cerebrovascular Disease and its Consequences in American Indians (CDCAI) Study recruited surviving members of a 20-year, longitudinal, population-based cohort of American Indians focused on cardiovascular disease, its risk factors, and its consequences. The goal of the CDCAI Study is to characterize the burden, risk factors, and manifestations of vascular brain injury identified on cranial MRI. The CDCAI Study investigators enrolled 1,033 participants aged 60 and older from 11 American Indian communities and tribes in the Northern Plains, Southern Plains, and Southwestern United States. In addition to cranial MRI performed according to standardized protocols, participants underwent extensive medical interview, clinical examination, neurocognitive testing, physical function evaluation, electrocardiogram, and provided blood and urine specimens. Participants also self-administered questionnaires covering demographics, quality of life, and medical history. This report describes the design, implementation, and some of the unique challenges of this study and data collection.

Psychometric Properties of Controlled Oral Word Association (COWA) Test and Associations With Education and Bilingualism in American Indian Adults: The Strong Heart Study.

The Controlled Oral Word Association (COWA) test is used to assess phonemic fluency and executive function. Formal validation of test scores is important for accurate cognitive evaluation. However, there is a dearth of psychometric validation among American Indian adults. Given high burden of dementia risk and key contextual factors associated with cognitive assessments, this represents a critical oversight. In a large, longitudinal population-based cohort study of adult American Indians, we examined several validity inferences for COWA, including scoring, generalization, and extrapolation inferences, by investigation of factor structure, internal consistency, test-retest reliability, and differential test functioning. We found adequate unidimensional model fit, with high factor loadings. Internal consistency reliability and test-retest reliability were 0.88 and 0.77, respectively, for the full group. COWA scores were lowest among the oldest, lowest education, bilingual speakers; group effects for sex and bilingual status were small; age effect was medium; and education effect was largest. However, Wide Range Achievement Test (WRAT) score effect was stronger than education effect, suggesting better contextualization may be needed. These results support interpretation of total COWA score, including across sex, age, or language use strata.

Incidence of Stroke in Indigenous Populations of Countries With a Very High Human Development Index: A Systematic Review.

BACKGROUND AND OBJECTIVES: Cardiovascular disease contributes significantly to disease burden among many Indigenous populations. However, data on stroke incidence in Indigenous populations are sparse. We aimed to investigate what is known of stroke incidence in Indigenous populations of countries with a very high Human Development Index (HDI), locating the research in the broader context of Indigenous health. METHODS: We identified population-based stroke incidence studies published between 1990 and 2022 among Indigenous adult populations of developed countries using PubMed, Embase, and Global Health databases, without language restriction. We excluded non-peer-reviewed sources, studies with fewer than 10 Indigenous people, or not covering a 35- to 64-year minimum age range. Two reviewers independently screened titles, abstracts, and full-text articles and extracted data. We assessed quality using "gold standard" criteria for population-based stroke incidence studies, the Newcastle-Ottawa Scale for risk of bias, and CONSIDER criteria for reporting of Indigenous health research. An Indigenous Advisory Board provided oversight for the study. RESULTS: From 13,041 publications screened, 24 studies (19 full-text articles, 5 abstracts) from 7 countries met the inclusion criteria. Age-standardized stroke incidence rate ratios were greater in Aboriginal and Torres Strait Islander Australians (1.7-3.2), American Indians (1.2), Sámi of Sweden/Norway (1.08-2.14), and Singaporean Malay (1.7-1.9), compared with respective non-Indigenous populations. Studies had substantial heterogeneity in design and risk of bias. Attack rates, male-female rate ratios, and time trends are reported where available. Few investigators reported Indigenous stakeholder involvement, with few studies meeting any of the CONSIDER criteria for research among Indigenous populations. DISCUSSION: In countries with a very high HDI, there are notable, albeit varying, disparities in stroke incidence between Indigenous and non-Indigenous populations, although there are gaps in data availability and quality. A greater understanding of stroke incidence is imperative for informing effective societal responses to socioeconomic and health disparities in these populations. Future studies into stroke incidence in Indigenous populations should be designed and conducted with Indigenous oversight and governance to facilitate improved outcomes and capacity building. REGISTRATION INFORMATION: PROSPERO registration: CRD42021242367.

Educational and Clinical Associations With Longitudinal Cognitive Function and Brain Imaging in American Indians: The Strong Heart Study.

BACKGROUND: Little is known about incidence of vascular and Alzheimer's dementias in American Indians. METHODS We conducted a large, heterogeneous, population-based, longitudinal cohort study of brain aging in community-dwelling American Indians aged 64-95 years from 11 tribes across 3 states, with neurological examinations, 1.5T magnetic resonance imaging (MRI), and extensive cognitive testing. Visit 1 in 2010-2013 (n=817) and Visit 2 in 2017-2019 (n=403) included all willing, surviving participants. Standardized cognitive tests at both visits included Modified Mini Mental Status Examination (3MSE), Wechsler Adult Intelligence Scale digit symbol coding (WAIS), Controlled Oral Word Association fas (COWA), California Verbal Learning Test short form (CVLT). Test materials added at follow-up included Wide Range Achievement (reading) Test (WRAT) and National Alzheimer's Coordinating Center Uniform Data Set cognitive battery (v3 form C2) , including Montreal Cognitive Assessment (MoCA). MRI neuroradiologists coded infarcts, hemorrhages, white matter hyperintensities, sulcal atrophy, and ventricle enlargement. RESULTS Mean time between exams was 6.7 years (SD 1.1, range 3.8-9.1). Years of formal education had modest correlation with WRAT reading score (r=0.45). Prevalence and incidence of infarcts were (respectively) 32% and 12.8/1000 person-years (PY); hemmorhages 6% and 4.4/1000 PY; worsening sulci 74% and 19.0/1000 PY; wosening ventricle 79% and 30.1/1000 PY; worsening leukoaraiosis 44% and 26.1/1000 PY. Linear losses per year in cognitive scores were 0.6% 3MSE, 1.2% WAIS, 0.6% COWA, 2.2% CVLT. Mean MoCA scores were 18.9 (SD 4.3). DISCUSSION These are the first data on longitudinal cognitive and imaging changes in American Indians, as well as first reports of AD related features. Mean scores in MoCA were similar or lower than standard cutoffs used to diagnose dementia in other racial/ethnic groups, suggesting that standardized cognitive tests may not perform well in this population. Test validation, adaptation, and score adjustment are warranted. Years of education was a poor proxy for premorbid function, suggesting novel methods for cognitive score contextualization is also needed in this population. Evaluation of selective survival suggests attrition from death and frailty should be accounted for in causal analyses. Overall, these data represent a unique opportunity to examine neurology topics of critical importance to an understudied population.

Association of stress and resilience with cardiometabolic health among American Indian and Alaska Native adults.

Evidence suggests that perceived stress and psychological resilience are related to the presence and severity of cardiometabolic disease. Despite increased stress and cardiometabolic disease burden among American Indian and Alaska Native (AI/AN) people, the relationships between these factors are not well established in these populations. The objective of this study was to evaluate the relationships of stress with five cardiometabolic health indicators and to assess whether psychological resilience mediates these relationships in AI/AN adults. Four hundred and ninety-six AI/AN attendees were surveyed at three powwows. The questionnaire included sociodemographic items, questions on self-reported obesity, prediabetes, diabetes, high blood pressure, and high cholesterol, the Perceived Stress Scale, and the Brief Resilience Scale. Multivariable logistic regression models were used to measure associations of health indicators with Perceived Stress Scale and Brief Resilience Scale scores while controlling for sociodemographic characteristics. Among respondents, obesity was the most common cardiometabolic health indicator reported (48%), followed by high blood pressure, prediabetes, diabetes, and high cholesterol. Mean Perceived Stress Scale and Brief Resilience Scale scores were 16.1 (6.4 SD) and 3.5 (0.7 SD), respectively. Higher Perceived Stress Scale scores were associated with greater odds of self-reported prediabetes and diabetes. Brief Resilience Scale scores did not serve as a mediator. These results suggest that perceived stress is associated with some self-reported indicators of cardiometabolic health among AI/AN adults, but findings are limited by the convenience sample, reliance on self-report, and cross-sectional design. Future work should capitalize on nationally representative data, longitudinal designs, and objective measures of cardiometabolic health.

Glomerular filtration function decline, mortality, and cardiovascular events: data from the Strong Heart Study.

BACKGROUND: Rapid kidney decline is associated with mortality and cardiovascular disease, even in the absence of chronic kidney disease. American Indians (AI) have particularly high burden of kidney disease, cardiovascular disease, and stroke. This study aims to examine extreme loss in glomerular function in this population in association with clinical outcomes. METHODS: The Strong Heart Study, a large longitudinal cohort of adult AI participants, collected plasma creatinine at 3 examination visits between 1989-1999. Intraindividual regressions of estimated glomerular filtration rate (eGFR) provided linear estimates of change in kidney function over this time period. Surveillance with physician adjudication identified mortality and cardiovascular events between visit 3 through 2017. RESULTS: Mean change in eGFR was loss 6.8 mL/min over the ten year baseline (range: -66.0 to +28.9 mL/min). The top 1 percentile lost approximately 5.7 mL/min/year. Participants with extreme eGFR loss were more likely to have diabetes (95% vs 71%), hypertension (49% vs 33%), or longer smoking history, among smokers (19 pack years vs 17 pack years). CKD (eGFR<60 mL/min) was associated only with mortality, independent of slope: HR 1.1 (95% CI 1.0-1.3). However, extreme loss in eGFR (>20 mL/min over baseline period) was associated with mortality, independent of baseline eGFR: HR 3.5 (95% CI 2.7-4.4), and also independently associated with composite CVD events and CHF: HR 1.4 and 1.7 (95% CI 1.1-1.9 and 1.2-2.6), respectively. CONCLUSION: This is the first examination of decline in eGFR in association with mortality and CVD among AIs. The implications of these findings are broad: clinical evaluation may benefit from evaluating change in eGFR over time in addition to dichotomous eGFR. Also, these findings suggest there may be aspects of renal function that are not well-marked by clinical CKD, but which may have particular relevance to long-term renal and vascular health.

Associations of Binge Drinking With Vascular Brain Injury and Atrophy in Older American Indians: The Strong Heart Study.

Objectives: American Indians (AIs) generally consume less alcohol than the US general population; however, the prevalence of alcohol use disorder is higher. This is the first large cohort study to examine binge drinking as a risk factor for vascular brain injury (VBI). Methods: We used linear and Poisson regression to examine the association of self-reported binge drinking with VBI, measured via magnetic resonance imaging (MRI), in 817 older AIs who participated in the Strong Heart and Cerebrovascular Disease and Its Consequences in American Indians studies. Results: Any binge drinking at multiple time-points was associated with increased sulcal (ß = 0.360, 95% CI [0.079, 0.641]) and ventricle dilatation (ß = 0.512, 95% CI [0.174, 0.850]) compared to no binge drinking. Discussion: These observed associations are consistent with previous findings. Identifying how binge drinking may contribute to VBI in older AIs may suggest modifiable health behaviors for neurological risk reduction and disease prevention.

Tutorial: best practices and considerations for mass-spectrometry-based protein biomarker discovery and validation.

Mass-spectrometry-based proteomic analysis is a powerful approach for discovering new disease biomarkers. However, certain critical steps of study design such as cohort selection, evaluation of statistical power, sample blinding and randomization, and sample/data quality control are often neglected or underappreciated during experimental design and execution. This tutorial discusses important steps for designing and implementing a liquid-chromatography-mass-spectrometry-based biomarker discovery study. We describe the rationale, considerations and possible failures in each step of such studies, including experimental design, sample collection and processing, and data collection. We also provide guidance for major steps of data processing and final statistical analysis for meaningful biological interpretations along with highlights of several successful biomarker studies. The provided guidelines from study design to implementation to data interpretation serve as a reference for improving rigor and reproducibility of biomarker development studies.

The associations among sociocultural factors and neuropsychological functioning in older American Indians: The Strong Heart Study.

OBJECTIVE: Valid neuropsychological assessment is critical to the accurate diagnosis and effective treatment of diverse populations. American Indians and Alaska Natives experience substantial health disparities relative to the general U.S. POPULATION: Given the dearth of studies on neuropsychological health in this population, we aimed to characterize neuropsychological performance among older American Indians with respect to age, sex, education, income, and language use. METHOD: From 2010 to 2014, we recruited 818 American Indians aged 60 and older from the Cerebrovascular Disease and Its Consequences in American Indians Study, who comprised all of the surviving members of a cardiovascular study (Strong Heart Study). This cohort from 11 tribes resided on or near their home reservations in three geographic regions (Northern Plains, Southern Plains, and Southwest). Using a cross-sectional design investigating potential vascular brain injury, we administered a brief, targeted neuropsychological and motor function assessments. RESULTS: Higher scores on neuropsychological tests were associated with younger age, female sex, more education, higher income, and less Native American language use. Similar associations were found for the motor tests, although men had higher scores on both motor function tests. After accounting for other sociocultural and health factors, age, sex, education, income, and Native American language use all had significant associations to the test scores. CONCLUSIONS: Our findings may be used to guide research and inform clinical practice. The development of future normative studies for older American Indians will be more culturally appropriate when sociocultural factors are included. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Left Ventricular Mass, Brain Magnetic Resonance Imaging, and Cognitive Performance: Results From the Strong Heart Study.

Left ventricular mass (LVM) has been shown to serve as a measure of target organ damage resulting from chronic exposure to several risk factors. Data on the association of midlife LVM with later cognitive performance are sparse. We studied 721 adults (mean age 56 years at baseline) enrolled in the Strong Heart Study (SHS, 1993-1995) and the ancillary CDCAI (Cerebrovascular Disease and Its Consequences in American Indians) Study (2010-2013), a study population with high prevalence of cardiovascular disease. LVM was assessed with transthoracic echocardiography at baseline in 1993 to 1995. Cranial magnetic resonance imaging and cognitive testing were undertaken between 2010 and 2013. Generalized estimating equations were used to model associations between LVM and later imaging and cognition outcomes. The mean follow-up period was 17 years. A difference of 25 g in higher LVM was associated with marginally lower hippocampal volume (0.01%; 95% confidence interval, 0.02-0.00; P=0.001) and higher white matter grade (0.10; 95% confidence interval, 0.02-0.18; P=0.014). Functionally, participants with higher LVM tended to have slightly lower scores on the modified mini-mental state examination (0.58; 95% confidence interval, 1.08-0.08; P=0.024). The main results persisted after adjusting for blood pressure levels or vascular disease. The small overall effect sizes are partly explained by survival bias because of the high prevalence of cardiovascular disease in our population. Our findings emphasize the role of cardiovascular health in midlife as a target for the prevention of deleterious cognitive and functional outcomes in later life.

Patient and Provider Factors Associated With American Indian and Alaska Native Adolescent Tobacco Use Screening.

INTRODUCTION: Tobacco use is the leading behavioral cause of death among adults 25 years or older. American Indian (AI) and Alaska Native (AN) communities confront some of the highest rates of tobacco use and of its sequelae. Primary care-based screening of adolescents is an integral step in the reduction of tobacco use, yet remains virtually unstudied. We examined whether delivery of tobacco screening in primary care visits is associated with patient and provider characteristics among AI/AN adolescents. METHODS: We used a cross-sectional analysis to examine tobacco screening among 4757 adolescent AI/AN patients served by 56 primary care providers at a large tribally managed health system between October 1, 2011 and May 31, 2014. Screening prevalence was examined in association with categorical patient characteristics (gender, age, clinic visited, insurance coverage) and provider characteristics (gender, age, tenure) using multilevel logistic regressions with individual provider identity as the nesting variable. RESULTS: Thirty-seven percent of eligible patients were screened. Gender of both providers and patients was associated with screening. Male providers delivered screening more often than female providers (odds ratio [OR] 1.6, 95% confidence interval [CI] 0.7-3.9). Male patients had 20% lower odds of screening receipt (OR 0.8, 95% CI 0.7-0.9) than female patients, independent of patient age and provider characteristics. Individual provider identity significantly contributed to variability in the mixed-effects model (variance component 2.2; 95% CI 1.4-3.4), suggesting individual provider effect. CONCLUSIONS: Low tobacco screening delivery by female providers and the low receipt of screening among younger, male patients may identify targets for screening interventions.

Blood pressure variability and the risk of all-cause mortality, incident myocardial infarction, and incident stroke in the cardiovascular health study.

BACKGROUND: Recent reports have linked variability in visit-to-visit systolic blood pressure (SBP) to risk of mortality and stroke, independent of the effect of mean SBP level. This study aimed to evaluate whether variability in SBP is associated with all-cause mortality, incident myocardial infarction (MI), and incident stroke, independent of mean SBP or trends in SBP levels over time. METHODS: The Cardiovascular Health Study is a longitudinal cohort study of vascular risk factors and disease in the elderly. Participants who attended their first 5 annual clinic visits and experienced no event before the 5th visit were eligible (n = 3,852). Primary analyses were restricted to participants not using antihypertensive medications throughout the first 5 clinic visits (n = 1,642). Intraindividual SBP variables were defined using each participant's 5-visit blood pressure measures. Cox proportional hazards models estimated adjusted hazard ratios (HRs) per SD increase in intraindividual SBP variability, adjusted for intraindividual SBP mean and change over time. RESULTS: Over a mean follow-up of 9.9 years, there were 844 deaths, 203 MIs, and 195 strokes. Intraindividual SBP variability was significantly associated with increased risk of mortality (HR = 1.13; 95% confidence interval (CI) = 1.05-1.21) and of incident MI (HR = 1.20; 95%CI = 1.06-1.36), independent of the effect from adjustment factors. Intraindividual SBP variability was not associated with risk of stroke (HR = 1.03; 95% CI = 0.89-1.21). CONCLUSIONS: Long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and MI but not stroke. More research is needed to determine the relationship of BP variability with cardiovascular risk and the clinical implications.

Hemodynamic fluid shear stress response genes and carotid intima-media thickness: a candidate gene association analysis in the cardiovascular health study.

OBJECTIVE: This study examined whether carotid artery intimal-medial thickness (cIMT) is associated with genetic variations (SNPs) in a hemodynamics-responsive gene pathway. METHODS: Subjects were Cardiovascular Health Study participants free of cardiovascular events at baseline (N=3388). Genotype was measured using Illumina 370CNV HumanHap chip. Carotid IMT was measured using ultrasound. Estimated mean differences in cIMT per additional minor allele for 366 SNPs in MAP2K5, MAPK7, MEF2A/C, and KLF2 were adjusted for sex, age, clinic, and medication use. SNP-SNP interactions were examined using logic regression for 71 tagSNPs. RESULTS: None of the associations was significant after correction for multiple comparisons; smallest P-value=0.065 for MAP2K5 and common cIMT. The best-performing logic regression tree combined two SNPs in MAP2K5-rs745212 and rs12905175- and common cIMT; this association was not significant, corrected P-value=0.062. CONCLUSION: There was not strong evidence of association between genetic variants in a hemodynamics-responsive gene pathway and atherosclerosis among older adults.