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Background and Aims: Despite known Indigenous health and socioeconomic disadvantage in countries with a Very High Human Development Index, data on the incidence of stroke in these populations are sparse. With oversight from an Indigenous Advisory Board, we will undertake a systematic review of the incidence of stroke in Indigenous populations of developed countries or regions, with comparisons between Indigenous and non-Indigenous populations of the same region, though not between different Indigenous populations. Methods: Using PubMed, OVID-EMBASE, and Global Health databases, we will examine population-based incidence studies of stroke in Indigenous adult populations of developed countries published 1990-current, without language restriction. Non-peer-reviewed sources, studies including

Background: Sleep-related disorders have been associated with cognitive decline and neurodegeneration. American Indians are at increased risk for dementia. Here, we aim to characterize, for the first time, the associations between sleep characteristics and subsequent cognitive performance in a sample of aging American Indians. Methods: We performed analyses on data collected in two ancillary studies from the Strong Heart Study, which occurred approximately 10 years apart with an overlapping sample of 160 American Indians (mean age at follow-up 73.1, standard deviation 5.6; 69.3% female and 80% with high school completion). Sleep measures were derived by polysomnography and self-reported questionnaires, including sleep timing and duration, sleep latency, sleep stages, indices of sleep-disordered breathing, and self-report assessments of poor sleep and daytime sleepiness. Cognitive assessment included measures of general cognition, processing speed, episodic verbal learning, short and long-delay recall, recognition, and phonemic fluency. We performed correlation analyses between sleep and cognitive measures. For correlated variables, we conducted separate linear regressions. We analyzed the degree to which cognitive impairment, defined as more than 1.5 standard deviations below the average Modified Mini Mental State Test score, is predicted by sleep characteristics. All regression analyses were adjusted for age, sex, years of education, body mass index, study site, depressive symptoms score, difference in age from baseline to follow-up, alcohol use, and presence of APOE e4 allele. Results: We found that objective sleep characteristics measured by polysomnography, but not subjective sleep characteristics, were associated with cognitive performance approximately 10 years later. Longer sleep latency was associated with worse phonemic fluency (β = -0.069, p = 0.019) and increased likelihood of being classified in the cognitive impairment group later in life (odds ratio 1.037, p = 0.004). Longer duration with oxygen saturation < 90% was associated with better immediate verbal memory, and higher oxygen saturation with worse total learning, short and long-delay recall, and processing speed. Conclusion: In a sample of American Indians, sleep characteristics in midlife were correlated with cognitive performance a decade later. Sleep disorders may be modifiable risk factors for cognitive impairment and dementia later in life, and suitable candidates for interventions aimed at preventing neurodegenerative disease development and progression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Thiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value

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. [ABSTRACT FROM AUTHOR]

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 (Aβ) 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 Aβ 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, Aβ4240 ratio) had excellent discriminant performance (AUC > 0.8). DISCUSSION: In American Indian individuals, pTau181 and Aβ values suggested more common pathology than in majority populations. Aβ 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. [ABSTRACT FROM AUTHOR]

Background: Arsenic and cadmium are known cardiovascular toxicants that pose disproportionate risk to rural communities where environmental exposures are high. American Indians have high vascular risk, which may be attributable in part to these exposures. Objective: We examined urine metal concentrations in association with magnetic resonance imaging findings of vascular brain injury or cerebral atrophy in adult American Indians. Methods: We measured arsenic and cadmium in American Indian participants from the Strong Heart Study (1989-1991) and evaluated these associations with later (2010-2013) measures of infarct, hemorrhage, white matter hyperintensity (WMH) grade, brain and hippocampal volume, and sulcal and ventricle atrophy using nested multivariate regression analyses. Results: Among participants with available data (N = 687), the median urine arsenic:creatinine ratio was 7.54 [micro]g/g [interquartile range (IQR): 4.90-11.93] and the cadmium:creatinine ratio was 0.96 [micro]g/g (IQR: 0.61-1.51). Median time between metal measurement and brain imaging was 21 y (range: 18-25 y). Statistical models detected significant associations between arsenic and higher burden of WMH [grade increase = 0.014 (95% CI: 0.000, 0.028) per 10% increase in arsenic]; and between cadmium and presence of lacunar infarcts [relative risk (RR) = 1.024 (95% CI: 1.004, 1.045) per 10% increase in cadmium]. Discussion: This population-based cohort of American Indian elders had measured values of urine arsenic and cadmium several times higher than previous population- and clinic-based studies in the United States and Mexico, and comparable values with European industrial workers. Our findings of associations for arsenic and cadmium exposures with vascular brain injury are consistent with established literature. Environmental toxicant accumulation is modifiable; public health policy may benefit from focusing on reductions in environmental metals. https://doi.org/10.1289/EHP6930, Introduction Arsenic and cadmium are known environmental toxicants. Geographical regions characterized by subsistence or rural economies may have some of the most heavily arsenic- and cadmium-contaminated soil or groundwater, where [...]

Introduction: Distinguishing Alzheimer's disease (AD) patient subgroups may optimize positive clinical outcomes. Cortical atrophy is correlated with memory deficits, but these associations are understudied in American Indians. Methods: We collected imaging and cognition data in the Strong Heart Study (SHS), a cohort of 11 tribes across three regions. We processed 1.5T MRI using FreeSurfer and iterative principal component analysis. Linear mixed models estimated volumetric associations with diabetes. Results: Over mean 7 years follow‐up (N = 818 age 65–89 years), overall volume loss was 0.5% per year. Significant losses associated with diabetes were especially strong in the right hemisphere. Annualized hippocampal, parahippocampal, entorhinal atrophy were worse for men, older age, diabetes, hypertension, stroke; and associated with both encoding and retrieval memory losses. Discussion: Our findings suggest that diabetes is an important risk factor in American Indians for cortical atrophy and memory loss. Future research should examine opportunities for primary prevention in this underserved population. [ABSTRACT FROM AUTHOR]

Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system (1,2). After initiation of the heartbeat in vertebrates, cells lining the ventral aspect of the dorsal aorta, the placental vessels, and the umbilical and vitelline arteries initiate expression of the transcription factor Runx1 (refs 3-5), a master regulator of haematopoiesis, and give rise to haematopoietic cells (4). It remains unknown whether the biomechanical forces imposed on the vascular wall at this developmental stage act as a determinant of haematopoietic potential (6). Here, using mouse embryonic stem cells differentiated in vitro, we show that fluid shear stress increases the expression of Runx1 in [CD411.sup.+]c-[Kit.sup.+] haematopoietic progenitor cells (7), concomitantly augmenting their haematopoietic colony-forming potential. Moreover, we find that shear stress increases haematopoietic colony-forming potential and expression of haematopoietic markers in the para-aortic splanchnopleura/aorta-gonads-mesonephros of mouse embryos and that abrogation of nitric oxide, a mediator of shear-stress-induced signalling (8), compromises haematopoietic potential in vitro and in vivo. Collectively, these data reveal a critical role for biomechanical forces in haematopoietic development., In the mouse, the first haemogenic areas appear in the yolk sac starting at day 7.5 of development (E7.5) (9). After the establishment of circulation and the onset of vascular [...]

Standardized neuropsychological instruments are used to evaluate cognitive impairment, but few have been psychometrically evaluated in American Indians. We collected Montreal Cognitive Assessment (MoCA) in 403 American Indians 70 to 95 years, as well as age, sex, education, bilingual status, depression symptoms, and other neuropsychological instruments. We evaluated inferences of psychometric validity, including scoring inference using confirmatory factor analysis and structural equation modeling, generalizability inference using reliability coefficient, and extrapolation inference by examining performance across different contexts and substrata. The unidimensional (total score) model had good fit criteria. Internal consistency reliability was high. MoCA scores were positively associated with crystallized cognition (ρ = 0.48, p < .001) and inversely with depression symptoms (ρ = −0.27, p < .001). Significant differences were found by education (d = 0.79, p < .05) depression (d = 0.484, p < .05), and adjudicated cognitive status (p = .0001) strata; however, MoCA was not sensitive or specific in discriminating cognitive impairment from normal cognition (area under the curve <0.5). MoCA scores had psychometric validity in older American Indians, but education and depression are important contextual features for score interpretability. Future research should evaluate cultural or community-specific adaptations, to improve test discriminability in this underserved population. [ABSTRACT FROM AUTHOR]