Andreea M. Rawlings

Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study.

IMPORTANCE Hypertension is a treatable potential cause of cognitive decline and dementia, but its greatest influence on cognition may occur in middle age. OBJECTIVE To evaluate the association between midlife (48-67 years of age) hypertension and the 20-year change in cognitive performance. DESIGN, SETTING, AND PARTICIPANTS The Atherosclerosis Risk in Communities cohort (1990-1992 through 2011-2013) underwent evaluation at field centers in Washington County, Maryland, Forsyth County, North Carolina, Jackson, Mississippi, and the Minneapolis, Minnesota, suburbs. Of 13 476 African American and white participants with baseline cognitive data, 58.0% of living participants completed the 20-year cognitive follow-up. EXPOSURES Hypertension, prehypertension, or normal blood pressure (BP) at visit 2 (1990-1992) constituted the primary exposure. Systolic BP at visit 2 or 5 (2011-2013) and indication for treatment at visit 2 based on the Eighth Joint National Committee (JNC-8) hypertension guidelines constituted the secondary exposures. MAIN OUTCOMES AND MEASURES Prespecified outcomes included the 20-year change in scores on the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test and in global cognition. RESULTS During 20 years, baseline hypertension was associated with an additional decline of 0.056 global z score points (95% CI, -0.100 to -0.012) and prehypertension was associated nonsignificantly with 0.040 more global z score points of decline (95% CI, -0.085 to 0.005) compared with normal BP. Individuals with hypertension who used antihypertensives had less decline during the 20 years than untreated individuals with hypertension (-0.050 [95% CI, -0.003 to -0.097] vs -0.079 [95% CI, -0.156 to -0.002] global z score points). Having a JNC-8-specified indication for initiating antihypertensive treatment at baseline was associated with a greater 20-year decline (-0.044 [95% CI, -0.085 to -0.003] global z score points) than not having an indication. We observed effect modification by race for the continuous systolic BP analyses (P = .01), with each 20-mm Hg increment at baseline associated with an additional decline of 0.048 (95% CI, -0.074 to -0.022) points in global cognitive z score in whites but not in African Americans (decline, -0.020 [95% CI, -0.026 to 0.066] points). Systolic BP at the end of follow-up was not associated with the preceding 20 years of cognitive change in either group. Methods to account for bias owing to attrition strengthened the magnitude of some associations. CONCLUSIONS AND RELEVANCE Midlife hypertension and elevated midlife but not late-life systolic BP was associated with more cognitive decline during the 20 years of the study. Greater decline is found with higher midlife BP in whites than in African Americans.

Diabetes in Midlife and Cognitive Change Over 20 Years: A Cohort Study

Context Data are limited on the relationship of midlife glycemic control and long-term cognitive impairment. Contribution This prospective longitudinal study involved 13351 adults living in 4 U.S. communities. Diabetes status was defined at baseline, and cognitive function was assessed at baseline and periodically during the 20-year follow-up. Caution The relationship between improvement in glucose control over time and cognitive decline could not be examined. Implication Diabetes and prediabetes in midlife were associated with a greater risk for cognitive decline over 20 years. Longer-duration diabetes had a stronger association with cognitive decline. The Editors The prevalence of diabetes has increased substantially over the past several decades to approximately 10%, and 21 million adults are affected in the United States (1). Type 2 diabetes is an established risk factor for heart disease, stroke, hypertension, blindness, and kidney disease (24). The association of diabetes with dementia risk is well-established (57), but the association of diabetes with cognitive decline is less well-characterized. Because cognitive decline is a precursor to dementia, strong risk factors for decline can help identify persons who may benefit from early intervention. The effects of diabetes and early hyperglycemic states assessed in midlife on long-term cognitive decline are relatively uncharacterized (6). Previous studies have been limited by short follow-up and a lack of rigorous adjustment for potential confounding variables, and most were limited to white persons and were done in elderly populations, where associations tend to be weaker (8, 9). Hemoglobin A1c (HbA1c) level is a measure of the average circulating glucose level in the blood over the preceding 2 to 3 months. It is the standard measure used in the clinical management of diabetes, and its use is now recommended for diagnosis of diabetes and identification of persons at risk for the condition (10). Studies have shown cross-sectional associations between HbA1c level and cognitive scores in persons with diabetes (11, 12). However, there is little evidence prospectively linking better glycemic control to slower cognitive decline, and few studies have examined whether chronic hyperglycemia below the threshold for a diagnosis of diabetes (prediabetes) is associated with long-term cognitive impairment (1315). Our objective was to examine the association of diabetes assessed in middle age with subsequent 20-year cognitive decline in a community-based population of black and white adults. We also examined the associations of prediabetes and glycemic control in the setting of diabetes with 20-year cognitive decline. An inherent challenge to accurately quantifying the long-term risk factor associations in observational studies is that participants who are ill are less likely to return for study visits. In this study, we used methods to account for this attrition, which is important in quantifying the long-term associations of diabetes with cognitive decline. Methods Study Population The ARIC (Atherosclerosis Risk in Communities) study is a community-based, prospective cohort study of 15792 middle-aged adults from 4 U.S. communities: Washington County, Maryland; Forsyth County, North Carolina; and suburbs of Minneapolis, Minnesota, and Jackson, Mississippi. The field centers in all 4 communities selected participants by probability sampling; the Mississippi field center recruited only black persons, the Forsyth County site recruited black and white persons, and the racial distribution in the other locations resulted in a small percentage of nonwhite participants. Participants were seen at 4 visits approximately 3 years apart beginning in 1987 to 1989, and a fifth visit took place in 2011 to 2013. Cognitive function was evaluated at visit 2 (1990 to 1992), at visit 4 (1996 to 1998), and as part of the ARIC-NCS (ARIC Neurocognitive Study) at visit 5 (2011 to 2013). Detailed information about the ARIC study can be found elsewhere (16). Baseline for the present analysis was visit 2, the first visit at which cognitive data were collected. Of the 14348 participants who attended visit 2, we excluded participants who were neither white nor black and the small number of black persons in the Minnesota and Washington County cohorts (n= 91), those missing results from 1 or more cognitive function tests at baseline (n= 217), and those missing variables of interest (n= 689), resulting in a final sample size of 13351 participants at baseline (93% of the visit 2 sample). A flow diagram of the study population and the pattern of visit attendance is provided in Figure 1 . Figure 1. Study flow diagram. Assessment of Cognitive Function We used 3 neuropsychological tests to assess cognitive function: the delayed word recall test (DWRT) (17), the digit symbol substitution test (DSST) of the Wechsler Adult Intelligence Scale-Revised (18), and the word fluency test (WFT) (19). Protocols for the tests were standardized, and trained examiners administered the tests in a fixed order during 1 session in a quiet room. The DWRT is a test of verbal learning and recent memory. Participants were asked to learn 10 common nouns by using each in a sentence. Two exposures to each word were given. After a 5-minute filled delay, participants had 60 seconds to recall the words. The score was equal to the number of words recalled. The DSST is a test of executive function and processing speed. In this 90-second test, participants were asked to use a key to translate numbers to symbols. The score was equal to the count of numbers correctly translated to symbols, with possible scores ranging from 0 to 93. The WFT is a test of executive function and language. Participants were given 60 seconds for each of the letters F, A, and S and were asked to generate as many words as possible beginning with each letter, excluding proper nouns. The score was equal to the total number of words generated for each letter. To facilitate comparison across cognitive tests, Zscores standardized to visit 2 were calculated for each test by subtracting the participants test score at each visit from the mean score at visit 2 and dividing by the SD of the visit 2 scores. A composite global cognitive Zscore was calculated by averaging the Zscores of the 3 tests and was then standardized to visit 2 by using the mean and SD of the global Zscores at visit 2. Thus, a Zscore of 1 would describe cognitive performance that is 1 SD below the mean score at visit 2. Composite global scores derived in this manner have been used in analyses of cognitive change in the ARIC study (20, 21) and elsewhere (2224). Assessment of Diabetes We defined diabetes as self-reported physician diagnosis or diabetes medication use or HbA1c level of 6.5% or greater. HbA1c Measurement We measured HbA1c level in stored whole-blood samples by using high-performance liquid chromatography methods standardized to the Diabetes Control and Complications Trial assay (Tosoh A1c 2.2 Plus and G7 analyzers) (25). For analyses of the association between HbA1c level and cognitive decline, HbA1c level was categorized by using standard clinical cut points (<5.7%, 5.7% to 6.4%, and 6.5% in persons without a history of diabetes and <7.0% and 7.0% in those with a history of diabetes) (10). Covariates All covariates used in the regression models were assessed at visit 2 except education, race, and sex, which were assessed at visit 1. We evaluated the following covariates as confounders: age; age squared; sex; racefield center (white persons from Minnesota, white persons from Washington County, white persons from Forsyth County, black persons from Forsyth County, and black persons from Mississippi); education (less than high school; high school, high school equivalent, or vocational school; or college, graduate, or professional school); cigarette smoking status (current, former, or never); alcohol consumption (current, former, or never); body mass index (kg/m2); hypertension, defined as use of blood pressurelowering medication, systolic blood pressure greater than 140 mm Hg, or diastolic blood pressure greater than 90 mm Hg (yes or no); history of coronary heart disease (yes or no, with persons who were unsure of their history classified as no); history of stroke (yes or no); and apolipoprotein E 4 genotype (0, 1, or 2 alleles). We also included interaction terms between each of these variables and time to allow for different rates of decline by these covariates. In sensitivity analyses, we treated cigarette smoking status, alcohol consumption, body mass index, hypertension, history of coronary heart disease, and history of stroke as time-varying and updated values at each study visit. We also adjusted for total cholesterol level and lipid-lowering medication use. Statistical Analysis We used linear models to estimate associations between diabetes and cognitive decline and fit them with generalized estimating equations to account for the within-person correlations of test scores arising from the repeated measures across time. We used unstructured correlation matrices and robust variance estimates. Time since baseline was modeled by using a linear spline with a knot at 6 years (the mean duration between visits 2 and 4). The spline term allowed for a nonlinear association between time and cognitive decline, more appropriately fit the study design than a quadratic term, and was supported by diagnostic Lowess smoothers. The primary coefficients of interest were the interactions between diabetes and the time spline terms, which address the hypothesis of greater decline among participants with diabetes after adjustment for age and the other covariates. To examine the role of stroke in mediating the association between diabetes and cognitive decline, we censored participant values at the time of stroke, thus excluding any poststroke cognitive information from our analyses. To test the robustness

sRAGE and Risk of Diabetes, Cardiovascular Disease, and Death

Advanced glycation end products (AGEs) and their receptors are strongly implicated in the development of diabetes complications. When stimulated by AGEs, the receptors for AGEs (RAGEs) induce inflammation and are thought to fuel disease progression. Soluble circulating RAGE (sRAGE) may counteract the detrimental effects of RAGE. We measured sRAGE in stored plasma from a random sample of 1,201 participants in the Atherosclerosis Risk in Communities (ARIC) Study who were aged 47–68 years, had normal kidney function, and had no history of cardiovascular disease. In cross-sectional analyses, black race, male sex, higher BMI, and higher C-reactive protein were independently associated with low sRAGE. The racial difference was striking, with blacks approximately three times more likely to have low sRAGE compared with whites even after adjustment. During ~18 years of follow-up, there were 192 incident coronary heart disease events, 53 ischemic strokes, 213 deaths, and 253 cases of diabetes (among the 1,057 persons without diabetes at baseline). In multivariable Cox models comparing risk in the first quartile with that in the fourth quartile of baseline sRAGE, low levels of sRAGE were significantly associated with risk of diabetes (hazard ratio 1.64 [95% CI 1.10–2.44]), coronary heart disease (1.82 [1.17–2.84]), and mortality (1.72 [1.11–2.64]) but not ischemic stroke (0.78 [0.34–1.79]). In conclusion, we found that low levels of sRAGE were a marker of future chronic disease risk and mortality in the community and may represent an inflammatory state. Racial differences in sRAGE deserve further examination.

Fructosamine and glycated albumin for risk stratification and prediction of incident diabetes and microvascular complications: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study

BACKGROUND HbA1c is the standard measure by which to monitor long-term (2-3 months) glucose control in people with diabetes and is now used for diagnosis of diabetes. Fructosamine and glycated albumin are markers of short-term (2-4 weeks) glycaemic control that might add complementary prognostic information to HbA1c. Our aim was to clarify the performance of fructosamine and glycated albumin measurements for identifying people at risk of incident diabetes or diabetic complications. METHODS We measured glycated albumin and fructosamine in blood samples from 11 348 adults without diabetes and 958 adults diagnosed with diabetes mellitus (both type 1 and 2) who attended the second examination of the Atherosclerosis Risk in Communities (ARIC) study in 1990-92 (baseline). We assessed the associations of fructosamine and glycated albumin with risk of incident diabetes, retinopathy, and risk of incident chronic kidney disease (CKD), during two decades of follow-up. We compared these associations with those of HbA1c with incident diabetes, retinopathy, and CKD. For analyses of associations with incident diabetes and CKD, adjusted hazard ratios (HRs) and their corresponding 95% CIs were estimated using Cox proportional hazards models. Model discrimination was assessed using Harrells C statistic. FINDINGS The HRs for incident diabetes were 4·96 (4·36-5·64) for fructosamine above the 95th percentile and 6·17 (5·45-6·99) for glycated albumin above the 95th percentile. Associations were attenuated but persisted after adjustment for HbA1c. Fructosamine and glycated albumin were strongly associated with retinopathy (p<0·0001 for trend). The multivariable-adjusted HRs for CKD for people with fructosamine and glycated albumin above the 95th percentile were 1·50 (95% CI 1·22-1·85) and 1·48 (1·20-1·83), respectively, when compared with people with no diabetes and fructosamine or glycated albumin below the 75th percentile. Prediction of incident CKD by fructosamine (C statistic 0·717) and glycated albumin (0·717) were nearly as strong as by HbA1c (0·726), but HbA1c outperformed fructosamine and glycated albumin for prediction of incident diabetes with C statistics of 0·760, 0·706, and 0·703, respectively. INTERPRETATION Fructosamine and glycated albumin were strongly associated with incident diabetes and its microvascular complications, with prognostic value comparable to HbA1c. FUNDING National Heart, Lung, and Blood Institute.

Impact of Differential Attrition on the Association of Education with Cognitive Change Over 20 Years of Follow-up The ARIC Neurocognitive Study

Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48-67 years (1990-1992) through ages 70-89 years (2011-2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors.

Fructosamine and Glycated Albumin and the Risk of Cardiovascular Outcomes and Death

Background— Hemoglobin A1c (HbA1c) is the standard measure to monitor glucose control in diabetes mellitus and is a marker of future cardiovascular risk. Fructosamine and glycated albumin are markers of short-term glycemic control, but their associations with cardiovascular outcomes are uncharacterized. Methods and Results— We measured glycated albumin and fructosamine in 11 104 participants with and without diabetes in the community-based Atherosclerosis Risk in Communities (ARIC) Study in 1990 to 1992 (baseline). We evaluated associations of fructosamine and glycated albumin with risk of coronary heart disease, ischemic stroke, heart failure, and mortality. We compared associations with those observed for HbA1c. During two decades of follow-up there were 1096 new cases of coronary heart disease, 605 of ischemic stroke, 1432 of heart failure, and 2860 deaths. Elevated baseline concentrations of fructosamine and glycated albumin were significantly associated with each of the outcomes even after adjustment for traditional cardiovascular risk factors, with especially strong associations in persons with diabetes mellitus. Associations were of similar magnitude to those observed for HbA1c and—as has been previously observed for HbA1c—the associations tended to be J-shaped, with an elevation of risk at the lowest levels of each biomarker. Conclusions— The acceptance of new measures of hyperglycemia is partly dependent on establishing their association with long-term outcomes. We found that fructosamine and glycated albumin were associated with vascular outcomes and mortality and that these associations were similar to those observed for HbA1c.

Cardiovascular risk factor burden, treatment, and control among adults with chronic kidney disease in the United States

BACKGROUND Cardiovascular disease is a major concern in persons with chronic kidney disease (CKD). We assessed the current burden of cardiovascular risk factors and differences in risk factor treatment and control in the general US adult population by CKD status. METHODS A cross-sectional study of 10,741 adults aged 20+ years from the 2007-2010 National Health and Nutrition Examination Survey was performed. Persons were categorized into 3 groups: CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m(2)), CKD stages 1 and 2 (urinary albumin-to-creatinine ratio ≥30 mg/g and estimated glomerular filtration rate ≥60 mL/min/1.73 m(2)), and no CKD. RESULTS The majority of adults with CKD stages 3 to 5 (79.8%) and stages 1 and 2 (59.1%) had ≥2 cardiovascular risk factors, substantially higher than adults without CKD (32.7%, P < .001). Diabetes was the most strongly associated risk factor and was highly specific for CKD stages 1 and 2 (prevalence ratio 2.53, 95% CI 2.21-2.89) and, to a lesser extent, CKD stages 3 to 5 (prevalence ratio 1.59, 95% CI 1.38-1.84). Most adults with diagnosed risk factors reported medication use for risk factor control, and pharmacologic treatment was more common among those with than without CKD. However, poor risk factor control was also common among persons treated for risk factors with CKD compared with those without CKD. CONCLUSIONS There continues to be a substantial cardiovascular risk factor burden among adults with CKD stages 3 to 5 and, to a lesser extent, adults with CKD stages 1 and 2 when compared with adults without CKD. Overall, optimal risk factor control is low in adults with CKD, highlighting the need for aggressive cardiovascular risk reduction in adults with CKD.

Association of 1,5-Anhydroglucitol with Diabetes and Microvascular Conditions

BACKGROUND 1,5-Anhydroglucitol (1,5-AG) is inversely related to hyperglycemia and may be a useful indicator of short-term (1-2 weeks) hyperglycemia and glycemic excursions, but its prognostic value is unclear. We sought to evaluate the associations of 1,5-AG with risk of diabetes and microvascular disease. METHODS We measured 1,5-AG in blood samples from over 10 000 participants in the ARIC (Atherosclerosis Risk in Communities) Study (baseline, 1990-1992) and characterized the independent associations with prevalent retinopathy and with incident chronic kidney disease and incident diabetes during approximately 20 years of follow-up. RESULTS We found that 1,5-AG was associated with prevalent retinopathy, driven primarily by the strong association in persons with diagnosed diabetes: adjusted odds ratio (OR) 11.26 (95% CI, 6.17-20.53) for <6 μg/mL compared to 1,5-AG ≥10 μg/mL. This result remained significant after further adjustment for hemoglobin A(1c) (Hb A(1c)) (OR, 4.85; 95% CI, 2.42-9.74). In persons with diagnosed diabetes, low 1,5-AG (<6 μg/mL vs ≥10 μg/mL) was also associated with a >2-fold increased risk of incident chronic kidney disease [adjusted hazard ratio (HR), 2.83; 95% CI, 2.15-3.74] and remained significant after adjustment for Hb A(1c) (HR, 1.43; 95% CI, 1.02-2.00). Nondiabetic participants with high 1,5-AG (≥10 μg/mL) had the lowest prevalence of retinopathy and lowest risk of kidney disease. In persons without diagnosed diabetes at baseline, 1,5-AG <10 μg/mL was also associated with incident diabetes (adjusted HR, 2.29; 95% CI, 2.03-2.58). CONCLUSIONS 1,5-AG was associated with long-term risk of important microvascular outcomes, particularly in persons with diagnosed diabetes and even after adjustment for Hb A(1c). Our results suggest 1,5-AG may capture risk information associated with hyperglycemic excursions.

Association of 1,5-anhydroglucitol with cardiovascular disease and mortality

In diabetes, low concentrations of the biomarker 1,5-anhydroglucitol (1,5-AG) reflect hyperglycemic excursions over the prior 1–2 weeks. To the extent that hyperglycemic excursions are important in atherogenesis, 1,5-AG may provide independent information regarding cardiovascular risk. Nonetheless, few studies have evaluated associations of 1,5-AG with long-term cardiovascular outcomes in a population-based setting. We measured 1,5-AG in 11,106 participants in the Atherosclerosis Risk in Communities (ARIC) study without cardiovascular disease at baseline (1990–1992) and examined prospective associations with coronary heart disease (n = 1,159 events), ischemic stroke (n = 637), heart failure (n = 1,553), and death (n = 3,120) over 20 years of follow-up. Cox proportional hazards models were adjusted for demographic and cardiovascular risk factors. Compared with persons with 1,5-AG ≥6 μg/mL and no history of diabetes, persons with diabetes and 1,5-AG <6.0 μg/mL had an increased risk of coronary heart disease (HR 3.85, 95% CI 3.11–4.78), stroke (HR 3.48, 95% CI 2.66–4.55), heart failure (HR 3.50, 95% CI 2.93–4.17), and death (HR 2.44, 95% CI 2.11–2.83). There was a threshold effect, with little evidence for associations at “nondiabetic” concentrations of 1,5-AG (e.g., >10 μg/mL). Associations remained but were attenuated with additional adjustment for fasting glucose or HbA1c. These data add to the growing evidence for the prognostic value of 1,5-AG for long-term complications in the setting of diabetes.

No Racial Differences in the Association of Glycated Hemoglobin With Kidney Disease and Cardiovascular Outcomes

OBJECTIVE There is debate regarding the clinical significance of well-established racial differences in HbA1c. We compared the associations of diabetes diagnostic categories for HbA1c and fasting glucose with clinical outcomes in black and white persons in the community. RESEARCH DESIGN AND METHODS We conducted a prospective cohort analysis of participants without diabetes or cardiovascular disease from the Atherosclerosis Risk in Communities study. We examined the associations of clinical categories of HbA1c (<5.7%, 5.7–6.4%, ≥6.5%) and fasting glucose (<100, 100–125, ≥126 mg/dL) with outcomes separately among 2,484 black and 8,593 white participants and tested for race interactions. RESULTS Baseline characteristics differed significantly in blacks compared with whites, including HbA1c (5.8 vs. 5.4%; P < 0.001). During 18 years of follow-up, there were trends of increased risk of kidney disease, fatal and nonfatal coronary heart disease, and stroke across categories of HbA1c in both blacks and whites. The adjusted hazard ratios for each outcome across categories of HbA1c were similar in blacks and whites (P for interaction >0.05) except for all-cause mortality. Patterns of association were similar, but weaker, for fasting glucose. HbA1c and fasting glucose both were more strongly associated with all-cause mortality in whites compared with blacks, largely explained by racial differences in the rate of cardiovascular deaths. CONCLUSIONS HbA1c is a risk factor for vascular outcomes and mortality in both black and white adults. Patterns of association for HbA1c were similar to or stronger than those for fasting glucose. With respect to long-term outcomes, our findings support a similar interpretation of HbA1c in blacks and whites for diagnosis and treatment of diabetes mellitus.