Malignant Left Ventricular Hypertrophy and Risk of Cognitive Impairment in SPRINT MIND Trial.

BACKGROUND: The association of malignant left ventricular hypertrophy (LVH), a specific subphenotype of LVH characterized by elevated levels of high-sensitivity cardiac troponin (hs-cTnT) or N-terminal pro-B-type natriuretic peptide (NT-proBNP), with cognitive decline remains understudied. METHODS: This post-hoc analysis included a total of 8,027 (67.9±9.3 years) SPRINT MIND trial participants who had with at least one follow-up cognitive assessment. Participants were classified into six groups on the basis of LVH status on electrocardiogram (ECG), and elevations in levels of hs-cTnT ≥14 ng/L or NT-proBNP ≥125 pg/mL at baseline visit. Multivariate Cox proportional hazard models were used to examine the association of LVH/biomarker groups with incident probable dementia, mild cognitive impairment (MCI) and a composite of MCI/probable dementia. RESULTS: Over a median follow-up period of 5 years, there were 306, 597 and 818 incidents of MCI, probable dementia and a composite of MCI/probable dementia, respectively. Compared with participants without LVH and normal biomarker levels, those with concomitant LVH and elevated levels of both biomarkers were associated with a higher risk of probable dementia (HR, 2.50; 95% CI (1.26 - 4.95), MCI (HR, 1.78; 95% CI (0.99 - 3.23) and the composite of MCI/ probable dementia (HR, 1.89; 95% CI, 1.16 - 3.10). CONCLUSIONS: Among SPRINT participants, malignant LVH is associated with incident probable dementia and mild cognitive impairment. These findings underscore the potential utility of measuring hs-cTnT and NT-proBNP levels when LVH is detected on ECG, aiding in the differentiation of individuals with a favorable risk for cognitive impairment from those with a higher risk.

The Association of Mitral Annular Calcification With Cardiovascular and Noncardiovascular Outcomes: The Multi-Ethnic Study of Atherosclerosis.

Mitral annular calcification (MAC) may be a potential marker of biologic aging. However, the association of MAC with noncardiovascular measures, including bone mineral density (BMD), incident renal failure, dementia, and noncardiovascular mortality, is not well-studied in a multiracial cohort. We used data from 6,814 participants (mean age: 62.2 ± 10.2 years, 52.9% women) without cardiovascular disease at baseline in the Multi-Ethnic Study of Atherosclerosis. MAC was assessed with noncontrast cardiac computed tomography at study baseline. Using multivariable-adjusted linear and logistic regression, we assessed the cross-sectional association of MAC with BMD and walking pace. Furthermore, using Cox proportional hazards, we evaluated the association of MAC with incident renal failure, dementia, and all-cause mortality. In addition, we assessed the association of MAC with cardiovascular and noncardiovascular mortality using competing risks regression. The prevalence of MAC was 9.5% and was higher in women (10.7%) than in men (8.0%). MAC was associated with low BMD (coefficient -0.04, 95% confidence interval [CI] -0.06 to -0.02), with significant interaction by gender (p-interaction = 0.035). MAC was, however, not associated with impaired walking pace (odds ratio 1.09, 95% CI 0.89 to 1.33). Compared with participants without MAC, those with MAC had an increased risk of incident renal failure, albeit nonsignificant (hazard ratio [HR] 1.18, 95% CI 0.95 to 1.45), and a significantly higher hazards of dementia (HR 1.36, 95% CI 1.10 to 1.70). In addition, participants with MAC had a substantially higher risk of all-cause (HR 1.47, 95% CI 1.29 to 1.69), cardiovascular (subdistribution HR 1.39, 95% CI 1.04 to 1.87), and noncardiovascular mortality (subdistribution HR 1.35, 95% CI 1.14 to 1.60) than those without MAC. MAC ≥100 versus <100 was significantly associated with reduced BMD, incident renal failure, dementia, all-cause, cardiovascular, and noncardiovascular mortality. In conclusion, MAC was associated with reduced BMD and dementia and all-cause, cardiovascular, and noncardiovascular mortality in this multiracial cohort. Thus, MAC may be a marker not only for atherosclerotic burden but also for other metabolic and inflammatory factors that increase the risk of noncardiovascular outcomes and death from other causes.

Deep phenotyping of dementia in a multi-ethnic cardiovascular cohort: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Our understanding of the specific aspects of vascular contributions to dementia remains unclear. OBJECTIVES: We aim to identify the correlates of incident dementia in a multi-ethnic cardiovascular cohort. METHODS: A total of 6806 participants with follow-up data for incident dementia were included. Probable dementia diagnoses were identified using hospitalization discharge diagnoses according to the International Classification of Diseases Codes (ICD). We used Random Forest analyses to identify the correlates of incident dementia and cognitive function from among 198 variables collected at the baseline MESA exam entailing demographic risk factors, medical history, anthropometry, lab biomarkers, electrocardiograms, cardiovascular magnetic resonance imaging, carotid ultrasonography, coronary artery calcium and liver fat content. Death and stroke were considered competing events. RESULTS: Over 14 years of follow-up, 326 dementia events were identified. Beyond age, the top correlates of dementia included coronary artery calcification, high sensitivity troponin, common carotid artery intima to media thickness, NT-proBNP, physical activity, pulse pressure, tumor necrosis factor-α, history of cancer, and liver to spleen attenuation ratio from computed tomography. Correlates of cognitive function included income and physical activity, body size, serum glucose, glomerular filtration rate, measures of carotid artery stiffness, alcohol use, and inflammation indexed as IL-2 and TNF soluble receptors and plasmin-antiplasmin complex. CONCLUSION: In a deeply phenotyped cardiovascular cohort we identified the key correlates of dementia beyond age as subclinical atherosclerosis and myocyte damage, vascular function, inflammation, physical activity, hepatic steatosis, and history of cancer.

Levels of Soluble Interleukin 6 Receptor and Asp358Ala Are Associated With Cognitive Performance and Alzheimer Disease Biomarkers.

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) is a neurodegenerative disease process manifesting clinically with cognitive impairment and dementia. AD pathology is complex, and in addition to plaques and tangles, neuroinflammation is a consistent feature. Interleukin (IL) 6 is a multifaceted cytokine involved in a plethora of cellular mechanisms including both anti-inflammatory and inflammatory processes. IL6 can signal classically through the membrane-bound receptor or by IL6 trans-signaling forming a complex with the soluble IL6 receptor (sIL6R) and activating membrane-bound glycoprotein 130 on cells not expressing IL6R. IL6 trans-signaling has been demonstrated as the primary mechanism of IL6-mediated events in neurodegenerative processes. In this study, we performed a cross-sectional analysis to investigate whether inheritance of a genetic variation in the IL6R gene and associated elevated sIL6R levels in plasma and CSF were associated with cognitive performance. METHODS: We genotyped the IL6R rs2228145 nonsynonymous variant (Asp358Ala) and assayed IL6 and sIL6R concentrations in paired samples of plasma and CSF obtained from 120 participants with normal cognition, mild cognitive impairment, or probable AD enrolled in the Wake Forest Alzheimer's Disease Research Center's Clinical Core. IL6 rs2228145 genotype and measures of plasma IL6 and sIL6R were assessed for relationships with cognitive status and clinical data, including the Montreal Cognitive Assessment (MoCA), modified Preclinical Alzheimer's Cognitive Composite (mPACC), cognitive domain scores obtained from the Uniform Data Set, and CSF concentrations of phosphoTauT181 (pTau181), ß-amyloid (Aß) Aß40 and Aß42 concentrations. RESULTS: We found that inheritance of the IL6R Ala358 variant and elevated sIL6R levels in plasma and CSF were correlated with lower mPACC, MoCA and memory domain scores, increases in CSF pTau181, and decreases in the CSF Aß42/40 ratio in both unadjusted and covariate-adjusted statistical models. DISCUSSION: These data suggest that IL6 trans-signaling and the inheritance of the IL6R Ala358 variant are related to reduced cognition and greater levels of biomarkers for AD disease pathology. Follow-up prospective studies are necessary, as patients who inherit IL6R Ala358 may be identified as ideally responsive to IL6 receptor-blocking therapies.

The Association of Kidney Function with Plasma Amyloid-ß Levels and Brain Amyloid Deposition.

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-ß and brain amyloid-ß deposition, which could contribute to elevated risk of dementia. OBJECTIVE: To investigate whether kidney impairment is associated with higher levels of circulating amyloid-ß and brain amyloid-ß 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-ß1 - 40 and amyloid-ß1 - 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-ß1 - 40 (standardized difference: 0.12; 95% CI: 0.09,0.14) and higher plasma amyloid-ß1 - 42 (0.08; 95% CI: 0.05,0.10). Lower eGFR was associated with higher plasma amyloid-ß1 - 40 (0.36; 95% CI: 0.33,0.39) and higher amyloid-ß1 - 42 (0.32; 95% CI: 0.29,0.35). CONCLUSION: Low clearance of amyloid-ß 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.

Is an MRI-derived anatomical measure of dementia risk also a measure of brain aging?

Machine learning methods have been applied to estimate measures of brain aging from neuroimages. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI-based measure of dementia risk, the Alzheimer's disease pattern similarity (AD-PS) scores, with measures used to calculate biological age. Participants were those from visit 5 of the Atherosclerosis Risk in Communities Study with cognitive status adjudication, proteomic data, and AD-PS scores available. The AD-PS score estimation is based on previously reported machine learning methods. We evaluated associations of the AD-PS score with all-cause mortality. Sensitivity analyses using only cognitively normal (CN) individuals were performed treating CNS-related causes of death as competing risk. AD-PS score was examined in association with 32 proteins measured, using a Somalogic platform, previously reported to be associated with age. Finally, associations with a deficit accumulation index (DAI) based on a count of 38 health conditions were investigated. All analyses were adjusted for age, race, sex, education, smoking, hypertension, and diabetes. The AD-PS score was significantly associated with all-cause mortality and with levels of 9 of the 32 proteins. Growth/differentiation factor 15 (GDF-15) and pleiotrophin remained significant after accounting for multiple-testing and when restricting the analysis to CN participants. A linear regression model showed a significant association between DAI and AD-PS scores overall. While the AD-PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging.

Potential Protective Mechanisms of S-equol, a Metabolite of Soy Isoflavone by the Gut Microbiome, on Cognitive Decline and Dementia.

S-equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most biologically potent among all soy isoflavones and their metabolites. Soy isoflavones are phytoestrogens and exert their actions through estrogen receptor-ß. Epidemiological studies in East Asia, where soy isoflavones are regularly consumed, show that dietary isoflavone intake is inversely associated with cognitive decline and dementia; however, randomized controlled trials of soy isoflavones in Western countries did not generally show their cognitive benefit. The discrepant results may be attributed to S-equol production capability; after consuming soy isoflavones, 40-70% of East Asians produce S-equol, whereas 20-30% of Westerners do. Recent observational and clinical studies in Japan show that S-equol but not soy isoflavones is inversely associated with multiple vascular pathologies, contributing to cognitive impairment and dementia, including arterial stiffness and white matter lesion volume. S-equol has better permeability to the blood-brain barrier than soy isoflavones, although their affinity to estrogen receptor-ß is similar. S-equol is also the most potent antioxidant among all known soy isoflavones. Although S-equol is available as a dietary supplement, no long-term trials in humans have examined the effect of S-equol supplementation on arterial stiffness, cerebrovascular disease, cognitive decline, or dementia.

Variation in Population Attributable Fraction of Dementia Associated With Potentially Modifiable Risk Factors by Race and Ethnicity in the US.

Importance: 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. Objective: 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. Design, Setting, and Participants: 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. Exposures: Low education, hearing loss, traumatic brain injury, hypertension, excessive alcohol consumption, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and air pollution. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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.

Association of Brain Volumes and White Matter Injury With Race, Ethnicity, and Cardiovascular Risk Factors: The Multi-Ethnic Study of Atherosclerosis.

Background Cardiovascular risk factors are associated with cognitive decline and dementia. Magnetic resonance imaging provides sensitive measurement of brain morphology and vascular brain injury. However, associations of risk factors with brain magnetic resonance imaging findings have largely been studied in White participants. We investigated associations of race, ethnicity, and cardiovascular risk factors with brain morphology and white matter (WM) injury in a diverse population. Methods and Results In the Multi-Ethnic Study of Atherosclerosis, measures were made in 2018 to 2019 of total brain volume, gray matter and WM volume, and WM injury, including WM hyperintensity volume and WM fractional anisotropy. We assessed cross-sectional associations of race and ethnicity and of cardiovascular risk factors with magnetic resonance imaging measures. Magnetic resonance imaging data were complete in 1036 participants; 25% Black, 15% Chinese-American, 19% Hispanic, and 41% White. Mean (SD) age was 72 (8) years and 53% were women. Although WM injury was greater in Black than in White participants in a minimally adjusted model, additional adjustment for cardiovascular risk factors and socioeconomic status each attenuated this association, rendering it nonsignificant. Overall, greater average WM hyperintensity volume was associated with older age and current smoking (69% greater vs never smoking); lower fractional anisotropy was additionally associated with higher diastolic blood pressure, use of antihypertensive medication, and diabetes. Conclusions We found no statistically significant difference in measures of WM injury by race and ethnicity after adjustment for cardiovascular risk factors and socioeconomic status. In all racial and ethnic groups, older age, current smoking, hypertension, and diabetes were strongly associated with WM injury.

Associations of lower-limb atherosclerosis and arteriosclerosis with cardiovascular risk factors and disease in older adults: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND & AIMS: Atherosclerosis and arteriosclerosis contribute to vascular aging and cardiovascular disease (CVD) risk. Both processes can be assessed simply in the lower-limbs and reflect systemic pathology. However, only atherosclerosis is routinely assessed, typically via ankle-brachial index (ABI). Arteriosclerosis can be assessed using femoral-ankle pulse wave velocity (faPWV), but no studies have identified whether ABI and faPWV similarly associate with overt CVD and risk factors, nor whether faPWV confers additional information. The aims of this study were to (i) compare associations of ABI and faPWV with traditional CVD risk factors, including age, sex, systolic blood pressure (SBP), high-density lipoprotein (HDL), total cholesterol (TC), smoking, and diabetes; and (ii) determine the independent and additive associations of ABI and faPWV with a composite measure of prevalent CVD. METHODS: We evaluated ABI and faPWV in 4330 older-aged (75.3 ± 5.0 years) adults using an oscillometric screening device. Associations between ABI and faPWV with CVD risk factors and CVD were determined using mixed-model linear- and logistic-regression. RESULTS: ABI and faPWV were associated with age, HDL, and smoking. ABI was associated with sex, TC, diabetes. faPWV was associated with SBP. Both ABI and faPWV were inversely associated with CVD. Low ABI (≤0.9 vs. >0.9) and low faPWV (≤9.94 vs. >9.94) increased the odds of CVD by 2.41-fold (95% CI:1.85,3.17) and 1.46-fold (95% CI:1.23,1.74), respectively. The inverse association between faPWV and CVD was independent of ABI and CVD risk factors. CONCLUSIONS: ABI and faPWV, measures of lower-limb atherosclerosis and arteriosclerosis, are independently associated with CVD risk factors and prevalent CVD. Assessment of faPWV may confer additional risk information beyond ABI.

Associations between estimated and measured carotid-femoral pulse wave velocity in older Black and White adults: the atherosclerosis risk in communities (ARIC) study.

Introduction: Aortic stiffness offers important insight into vascular aging and cardiovascular disease (CVD) risk. The referent measure of aortic stiffness is carotid-femoral pulse wave velocity (cfPWV). cfPWV can be estimated (ePWV) from age and mean arterial pressure. Few studies have directly compared the association of ePWV to measured cfPWV, particularly in non-White adults. Moreover, whether ePWV and cfPWV correlate similarly with CVD risk remains unexplored. Aim: (1) To estimate the strength of the agreement between ePWV and cfPWV in both Black and White older adults; and (2) to compare the associations of ePWV and cfPWV with CVD risk factors and determine whether these associations were consistent across races. Methods and Results: We evaluated 4478 [75.2 (SD 5.0) years] Black and White older adults in the Atherosclerosis Risk in Communities (ARIC) Study. cfPWV was measured using an automated pulse waveform analyzer. ePWV was derived from an equation based on age and mean arterial pressure. Association and agreement between the two measurements were determined using Pearson's correlation coefficient (r), standard error of estimate (SEE), and Bland-Altman analysis. Associations between traditional risk factors with ePWV and cfPWV were evaluated using linear mixed regression models. We observed weak correlations between ePWV and cfPWV within White adults (r = 0.36) and Black adults (r = 0.31). The mean bias for Bland-Altman analysis was low at -0.17 m/s (95%CI: -0.25 to -0.09). However, the inspection of the Bland-Altman plots indicated systematic bias (P < 0.001), which was consistent across race strata. The SEE, or typical absolute error, was 2.8 m/s suggesting high variability across measures. In models adjusted for sex, prevalent diabetes, the number of prevalent cardiovascular diseases, and medication count, both cfPWV and ePWV were positively associated with heart rate, triglycerides, and fasting glucose, and negatively associated with body mass index (BMI) and smoking status in White adults (P < 0.05). cfPWV and ePWV were not associated with heart rate, triglycerides, and fasting glucose in Black adults, while both measures were negatively associated with BMI in Black adults. Conclusions: Findings suggest a weak association between ePWV and cfPWV in older White and Black adults from ARIC. There were similar weak associations between CVD risk factors with ePWV and cfPWV in White adults with subtle differences in associations in Black adults.

Relationships between cerebral structure and cognitive function in African Americans with type 2 diabetes.

BACKGROUND: Relationships between cognitive function and brain structure remain poorly defined in African Americans with type 2 diabetes. METHODS: Cognitive testing and cerebral magnetic resonance imaging in African Americans from the Diabetes Heart Study Memory IN Diabetes (n = 480) and Action to Control Cardiovascular Risk in Diabetes MIND (n = 104) studies were examined for associations. Cerebral gray matter volume (GMV), white matter volume (WMV) and white matter lesion volume (WMLV) and cognitive performance (Mini-mental State Exam [MMSE and 3MSE], Digit Symbol Coding (DSC), Stroop test, and Rey Auditory Verbal Learning Test) were recorded. Multivariable models adjusted for age, sex, BMI, scanner, intracranial volume, education, diabetes duration, HbA1c, LDL-cholesterol, smoking, hypertension and cardiovascular disease assessed associations between cognitive tests and brain volumes by study and meta-analysis. RESULTS: Mean(SD) participant age was 60.1(7.9) years, diabetes duration 12.1(7.7) years, and HbA1c 8.3(1.7)%. In the fully-adjusted meta-analysis, lower GMV associated with poorer global performance on MMSE/3MSE (ß̂ = 7.1 × 10-3, SE 2.4 × 10-3, p = 3.6 × 10-3), higher WMLV associated with poorer performance on DSC (ß̂ = -3 × 10-2, SE 6.4 × 10-3, p = 5.2 × 10-5) and higher WMV associated with poorer MMSE/3MSE performance (ß̂ = -7.1 × 10-3, SE = 2.4 × 10-3, p = 3.6 × 10-3). CONCLUSIONS: In African Americans with diabetes, smaller GMV and increased WMLV associated with poorer performance on tests of global cognitive and executive function. These data suggest that WML burden and gray matter atrophy associate with cognitive performance independent of diabetes-related factors in this population.

Cerebral Structure and Cognitive Performance in African Americans and European Americans With Type 2 Diabetes.

Background: African Americans typically perform worse than European Americans on cognitive testing. Contributions of cardiovascular disease (CVD) risk factors and educational quality to cognitive performance and brain volumes were compared in European Americans and African Americans with type 2 diabetes. Methods: Association between magnetic resonance imaging-determined cerebral volumes of white matter (WMV), gray matter (GMV), white matter lesions (WMLV), hippocampal GMV, and modified mini-mental state exam (3MSE), digit symbol coding (DSC), Rey Auditory Verbal Learning Test (RAVLT), Stroop, and verbal fluency performance were assessed in Diabetes Heart Study Memory in Diabetes (MIND) participants. Marginal models incorporating generalized estimating equations were employed with serial adjustment for risk factors. Results: The sample included 520 African Americans and 684 European Americans; 56 per cent female with mean ± SD age 62.8 ± 10.3 years and diabetes duration 14.3 ± 7.8 years. Adjusting for age, sex, diabetes duration, BMI, HbA1c, total intracranial volume, scanner, statins, CVD, smoking, and hypertension, WMV (p = .001) was lower and WMLV higher in African Americans than European Americans (p = .001), with similar GMV (p = .30). Adjusting for age, sex, education, HbA1c, diabetes duration, hypertension, BMI, statins, CVD, smoking, and depression, poorer performance on 3MSE, RAVLT, and DSC were seen in African Americans (p = 6 × 10-23-7 × 10-62). Racial differences in cognitive performance were attenuated after additional adjustment for WMLV and nearly fully resolved after adjustment for wide-range achievement test (WRAT) performance (p = .0009-.65). Conclusions: African Americans with type 2 diabetes had higher WMLV and poorer cognitive performance than European Americans. Differences in cognitive performance were attenuated after considering WMLV and apparent poorer educational quality based on WRAT.

Associations of Early Kidney Disease With Brain Magnetic Resonance Imaging and Cognitive Function in African Americans With Type 2 Diabetes Mellitus.

BACKGROUND: Relationships between early kidney disease, neurocognitive function, and brain anatomy are poorly defined in African Americans with type 2 diabetes mellitus (T2DM). STUDY DESIGN: Cross-sectional associations were assessed between cerebral anatomy and cognitive performance with estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) in African Americans with T2DM. SETTING & PARTICIPANTS: African Americans with cognitive testing and cerebral magnetic resonance imaging (MRI) in the African American-Diabetes Heart Study Memory in Diabetes (AA-DHS MIND; n=512; 480 with MRI) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) MIND (n=484; 104 with MRI) studies. PREDICTORS: eGFR (CKD-EPI creatinine equation), spot UACR. MEASUREMENTS: MRI-based cerebral white matter volume (WMV), gray matter volume (GMV), and white matter lesion volume; cognitive performance (Mini-Mental State Examination, Digit Symbol Coding, Stroop Test, and Rey Auditory Verbal Learning Test). Multivariable models adjusted for age, sex, body mass index, scanner, intracranial volume, education, diabetes duration, hemoglobin A1c concentration, low-density lipoprotein cholesterol concentration, smoking, hypertension, and cardiovascular disease were used to test for associations between kidney phenotypes and the brain in each study; a meta-analysis was performed. RESULTS: Mean participant age was 60.1±7.9 (SD) years; diabetes duration, 12.1±7.7 years; hemoglobin A1c concentration, 8.3%±1.7%; eGFR, 88.7±21.6mL/min/1.73m2; and UACR, 119.2±336.4mg/g. In the fully adjusted meta-analysis, higher GMV associated with lower UACR (P<0.05), with a trend toward association with higher eGFR. Higher white matter lesion volume was associated with higher UACR (P<0.05) and lower eGFR (P<0.001). WMV was not associated with either kidney parameter. Higher UACR was associated with lower Digit Symbol Coding performance (P<0.001) and a trend toward association with higher Stroop interference; eGFR was not associated with cognitive tests. LIMITATIONS: Cross-sectional; single UACR measurement. CONCLUSIONS: In African Americans with T2DM, mildly high UACR and mildly low eGFR were associated with smaller GMV and increased white matter lesion volume. UACR was associated with poorer processing speed and working memory.

Frontal gray matter atrophy in middle aged adults with type 1 diabetes is independent of cardiovascular risk factors and diabetes complications.

AIMS: To determine if regional gray matter volume (GMV) differences in middle-aged adults with and without type-1 diabetes (T1D) are localized in areas most vulnerable to aging, e.g. fronto-subcortical networks; and if these differences are explained by cardiovascular risk factors and diabetes complications. METHODS: Regional GMV was computed using 3T MRI of 104 adults with a childhood onset of T1D (mean age: 49±7 and duration: 41±6years) and 151 adults without diabetes (mean age: 40±6). A Bonferroni threshold (n=45, p≤0.001) was applied to account for multiple between-group comparisons and analyses were repeated in an age- and gender-matched subset of participants with T1D and controls (n=44 in each group, mean age [SD] and range: 44.0, [4.3], 17.4 and 44.6 [4.3], 17.0, respectively). RESULTS: Compared to controls, T1D patients had smaller GMV in the frontal lobe (6% to 19% smaller) and adjacent supramarginal and postcentral gyri (8% to 13% smaller). Between-group differences were independent of age, waist circumference, systolic blood pressure, fasting total cholesterol and smoking status and were similar in sensitivity analyses restricted to age- and gender-matched participants. Associations between GMV and diabetes complications were not significant. CONCLUSIONS: These findings extend the notion of accelerated brain aging in T1D to middle-aged adults. The pathophysiology of frontal gray matter atrophy and its impact on future development of disability and dementia need further study, especially as middle-aged T1D patients progress to older age.

Identification and elimination of polysiloxane curing agent interference encountered in the quantification of low-picogram per milliliter methyl tert-butyl ether in blood by solid-phase microextraction headspace analysis.

Widespread use of the gasoline additive methyl tert-butyl ether (MTBE) and the subsequent human exposure that follows have led to the need to quantify MTBE in a variety of complex biological matrixes. In this work, we demonstrate our latest MTBE quantification assay for whole blood and uncover previously unidentified contamination sources that prevented routine quantification in the low picogram per milliliter (parts per trillion, ppt) range despite a sensitive and selective analytical approach. The most significant and unexpected sources of contamination were found in reagents and laboratory materials most relevant to sample preparation and quantification. In particular, significant levels of MTBE were identified in sample vial septa that use poly(dimethylsiloxane) (PDMS)-based polymers synthesized with peroxide curing agents having tert-butyl side groups. We propose that MTBE is one of the byproducts of these curing agents, which cross-link PDMS via the methyl side groups. Residual MTBE levels of approximately 20 microg/septa are seen in septa whose formulations use these curing agents. Fortunately, these levels can be significantly reduced (i.e., <0.2 ng/septa) by additional processing. Performance achieved with this sample preparation approach is demonstrated using a mass spectrometry-based method to quantify blood MTBE levels in the low-ppt range.