Midlife Smaller and Larger Infarctions, White Matter Hyperintensities, and 20-Year Cognitive Decline: A Cohort Study.

Background: Smaller (<3-mm) infarctions are associated with stroke and stroke mortality, but relationships with cognitive decline are unknown. Objective: To characterize the relationships of smaller, larger, and both smaller and larger infarctions in middle age with 20-year cognitive decline. Design: Longitudinal cohort study. Setting: Two ARIC (Atherosclerosis Risk in Communities) study sites with magnetic resonance imaging data (1993 to 1995) and up to 5 cognitive assessments over 20 years. Participants: Stroke-free participants aged 50 years or older. Measurements: Infarctions were categorized as none, smaller only, larger only (3 to 20 mm), or both smaller and larger. Global cognitive Z scores were derived from 3 cognitive tests administered up to 5 times. Mixed-effects models estimated adjusted associations between infarctions and cognitive decline. Results are the average difference in standardized cognitive decline associated with infarctions versus no infarctions. Results: Among 1884 participants (mean age, 62 years; 60% women; 50% black), 1611 (86%) had no infarctions, 50 (3%) had smaller infarctions only, 185 (10%) had larger infarctions only, and 35 (2%) had both. Participants with both smaller and larger infarctions had steeper cognitive decline by more than half an SD (difference, -0.57 SD [95% CI, -0.89 to -0.26 SD]) compared with those who had no infarctions. Amounts of cognitive decline associated with only smaller infarctions and only larger infarctions were similar and were not statistically different from that associated with no infarctions. Limitation: Few participants had only smaller infarctions or both smaller and larger infarctions, and the data lacked counts of smaller infarctions and volumes of white matter hyperintensities. Conclusion: The substantial cognitive decline from middle age associated with having both smaller and larger infarctions, but not larger infarctions alone, suggests that the combination of smaller and larger infarctions may escalate risk for cognitive decline later in life in stroke-free persons. Primary Funding Source: National Institutes of Health.

Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial.

Importance: There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia. Objective: To evaluate the effect of intensive blood pressure control on risk of dementia. Design, Setting, and Participants: Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018. Interventions: Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683). Main Outcomes and Measures: The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. Results: Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97). Conclusions and Relevance: Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Association of Intensive vs Standard Blood Pressure Control With Cerebral White Matter Lesions.

Importance: The effect of intensive blood pressure lowering on brain health remains uncertain. Objective: To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes. Design, Setting, and Participants: A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016. Interventions: Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315). Main Outcomes and Measures: The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome. Results: Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI, -32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, -3.7 cm3 [95% CI, -6.3 to -1.1]). Conclusions and Relevance: Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Midlife vascular risk factors and midlife cognitive status in relation to prevalence of mild cognitive impairment and dementia in later life: The Atherosclerosis Risk in Communities Study.

INTRODUCTION: The interplay between midlife vascular risk factors and midlife cognitive function with later life mild cognitive impairment (MCI) and dementia (DEM) is not well understood. METHODS: In the Atherosclerosis Risk in Communities Study, cardiovascular risk factors and cognition were assessed in midlife, ages 45-64 years. In 2011-2013, 20-25 years later, all consenting Atherosclerosis Risk in Communities participants underwent a cognitive and neurological evaluation and were given adjudicated diagnoses of cognitively normal, MCI, or DEM. RESULTS: In 5995 participants with complete covariate data, midlife diabetes, hypertension, obesity, and hypercholesterolemia were associated with late-life MCI and DEM. Low midlife cognition function was also associated with greater likelihood of late-life MCI or DEM. Both midlife vascular risk factors and midlife cognitive function remained associated with later life MCI or DEM when both were in the model. DISCUSSION: Later life MCI and DEM were independently associated with midlife vascular risk factors and midlife cognition.

Cognitive Function and Kidney Disease: Baseline Data From the Systolic Blood Pressure Intervention Trial (SPRINT).

BACKGROUND: Chronic kidney disease is common and is associated with cardiovascular disease, cerebrovascular disease, and cognitive function, although the nature of this relationship remains uncertain. STUDY DESIGN: Cross-sectional cohort using baseline data from the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING & PARTICIPANTS: Participants in SPRINT, a randomized clinical trial of blood pressure targets in older community-dwelling adults with cardiovascular disease, chronic kidney disease, or high cardiovascular disease risk and without diabetes or known stroke, who underwent detailed neurocognitive testing in the cognition substudy, SPRINT-Memory and Cognition in Decreased Hypertension (SPRINT-MIND). PREDICTORS: Urine albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). OUTCOMES: Cognitive function, a priori defined as 5 cognitive domains based on 11 cognitive tests using z scores, and abnormal white matter volume quantified by brain magnetic resonance imaging. RESULTS: Of 9,361 SPRINT participants, 2,800 participated in SPRINT-MIND and 2,707 had complete data; 637 had brain imaging. Mean age was 68 years, 37% were women, 30% were black, and 20% had known cardiovascular disease. Mean eGFR was 70.8±20.9mL/min/1.73m2 and median urine ACR was 9.7 (IQR, 5.7-22.5) mg/g. In adjusted analyses, higher ACR was associated with worse global cognitive function, executive function, memory, and attention, such that each doubling of urine ACR had the same association with cognitive performance as being 7, 10, 6, and 14 months older, respectively. Lower eGFR was independently associated with worse global cognitive function and memory. In adjusted models, higher ACR, but not eGFR, was associated with larger abnormal white matter volume. LIMITATIONS: Cross-sectional only, no patients with diabetes were included. CONCLUSIONS: In older adults, higher urine ACR and lower eGFR have independent associations with global cognitive performance with different affected domains. Albuminuria concurrently identifies a higher burden of abnormal brain white matter disease, suggesting that vascular disease may mediate these relationships.

Life-course blood pressure in relation to brain volumes.

INTRODUCTION: The impact of blood pressure on brain volumes may be time-dependent or pattern-dependent. METHODS: Of 1678 participants from the Atherosclerosis Risk in Communities Neurocognitive Study, we quantified the association between measures and patterns of blood pressure over three time points (∼24 or ∼15 years prior and concurrent with neuroimaging) with late life brain volumes. RESULTS: Higher diastolic blood pressure ∼24 years prior, higher systolic and pulse pressure ∼15 years prior, and consistently elevated or rising systolic blood pressure from ∼15 years prior to concurrent with neuroimaging, but not blood pressures measured concurrent with neuroimaging, were associated with smaller volumes. The pattern of hypertension ∼15 years prior and hypotension concurrent with neuroimaging was associated with smaller volumes in regions preferentially affected by Alzheimer's disease (e.g., hippocampus: -0.27 standard units, 95% CI: -0.51, -0.03). DISCUSSION: Hypertension 15 to 24 years prior is relevant to current brain volumes. Hypertension followed by hypotension appears particularly detrimental.

Early adult to midlife cardiovascular risk factors and cognitive function.

BACKGROUND: Studies have linked midlife and late-life cardiovascular risk factors (CVRFs) to cognitive function, yet little is known about CVRF exposure in early adulthood and subsequent cognitive function. In addition, most studies rely on single assessments of CVRFs, which may not accurately reflect long-term exposure. We sought to determine the association between cumulative exposure to CVRFs from early to middle adulthood and cognitive function at midlife. METHODS AND RESULTS: In a prospective study of 3381 adults (age, 18-30 years at baseline) with 25 years of follow-up, we assessed cognitive function at year 25 (2010-2011) with the Digit Symbol Substitution Test, Stroop Test, and Rey Auditory Verbal Learning Test analyzed with standardized z scores. The primary predictor was 25-year cumulative exposure estimated by areas under the curve for resting systolic and diastolic blood pressures, fasting blood glucose, and total cholesterol. Higher cumulative systolic and diastolic blood pressures and fasting blood glucose were consistently associated with worse cognition on all 3 tests. These associations were significant primarily for exposures above recommended guidelines; cognitive test z scores were between 0.06 and 0.30 points less, on average, for each 1-SD increase in risk factor area under the curve after adjustment for age, race, sex, and education (P<0.05 for all). Fewer significant associations were observed for cholesterol. CONCLUSIONS: Cumulative exposure to CVRFs from early to middle adulthood, especially above recommended guidelines, was associated with worse cognition in midlife. The meaning of this association and whether it warrants more aggressive treatment of CVRFs earlier in life require further investigation.

Obesity, Insulin Resistance, and Incident Small Vessel Disease on Magnetic Resonance Imaging: Atherosclerosis Risk in Communities Study.

BACKGROUND AND PURPOSE: The term metabolic syndrome describes the clustering of risk factors found in many individuals with obesity. Because of their pathophysiology, we hypothesized that 2 features of metabolic syndrome, central obesity and insulin resistance (IR), would be associated with cerebrovascular changes on magnetic resonance imaging, and specifically with incident lacunar disease and not white matter hyperintensity (WMH) progression. METHODS: Risk factors were defined at study baseline in 934 participants in the Atherosclerosis Risk in Communities (ARIC) study, who completed 2 brain magnetic resonance imagings≈10 years apart. WMH progression and incident lacunes between the 2 magnetic resonance imagings were determined. An IR score for each participant was created using principal component analysis of 11 risk factors, including (among others): insulin, homeostatic model assessment-IR, body mass index, and waist circumference. Metabolic syndrome (presence/absence), using standard clinical definitions, and IR score at the first magnetic resonance imaging, were independent variables, evaluated in multivariate logistic regression to determine odds of WMH progression (Q5 versus Q1-Q4) and incident lacunes. RESULTS: Metabolic syndrome (adjusted odds ratio, 1.98; 95% confidence interval, 1.28-3.05) and IR score (adjusted odds ratio per 1-SD increase, 1.33; 95% confidence interval, 1.05-1.68) were associated with incident lacunes but not with WMH progression. Insulin, homeostatic model assessment-IR, and body mass index were not associated with incident lacunes or WMH progression in separate models. CONCLUSIONS: The IR score and central obesity are associated with incident lacunar disease but not WMH progression in individuals. Central obesity and IR may be important risk factors to target to prevent lacunar disease.

Vascular imaging abnormalities and cognition: mediation by cortical volume in nondemented individuals: atherosclerosis risk in communities-neurocognitive study.

BACKGROUND AND PURPOSE: The relationships between cerebrovascular lesions visible on imaging and cognition are complex. We explored the possibility that the cerebral cortical volume mediated these relationships. METHODS: Total of 1906 nondemented participants (59% women; 25% African-American; mean age, 76.6 years) in the Atherosclerosis Risk in Communities (ARIC) study underwent cognitive assessments, risk factor assessments, and quantitative MRI for white matter hyperintensities (WMH) and infarcts. The Freesurfer imaging analysis pipeline was used to determine regional cerebral volumes. We examined the associations of cognitive domain outcomes with cerebral volumes (hippocampus and separate groups of posterior and frontal cortical regions of interest) and cerebrovascular imaging features (presence of large or small cortical/subcortical infarcts and WMH volume). We performed mediation pathway analyses to assess the hypothesis that hippocampal and cortical volumes mediated the associations between cerebrovascular imaging features and cognition. RESULTS: In unmediated analyses, WMH and infarcts were both associated with worse psychomotor speed/executive function. In mediation analyses, WMH and infarct associations on psychomotor speed/executive function were significantly attenuated, but not abolished, by the inclusion of the posterior cortical regions of interest volume in the models, and the infarcts on psychomotor speed/executive function association were attenuated, but not abolished, by inclusion of the frontal cortical regions of interest volume. CONCLUSIONS: Both WMH and infarcts were associated with cortical volume, and both lesions were also associated with cognitive performance, implying shared pathophysiological mechanisms. Although cross-sectional, our findings suggest that WMH and infarcts could be proxies for clinically covert processes that directly damage cortical regions. Microinfarcts are 1 candidate for such a clinically covert process.

Normative data for 8 neuropsychological tests in older blacks and whites from the atherosclerosis risk in communities (ARIC) study.

Accurate assessment of cognitive impairment requires comparison of cognitive performance in individuals to performance in a comparable healthy normative population. Few prior studies have included a large number of black participants and few have excluded participants from the normative sample with subclinical/latent neurological disease or dementia. This study provides age, race, and education-specific normative data for 8 cognitive tests derived from 320 black and 392 white participants aged 61 to 82 years (mean 71 y) in the Atherosclerosis Risk in Communities (ARIC) study without clinical or subclinical/latent neurological disease. Normative data are provided for the Delayed Word Recall Test, Logical Memory Parts I and II, the Word Fluency Test, Animal Naming, the Trail Making Test Parts A and B and the Digit Symbol Substitution Test. Age, race, and education-specific mean and -1.5 SD scores are given in tabular form and graphically, as well as regression-based equations to derive adjusted score cut-points. These robust normative data should enhance comparison across studies of cognitive aging, where these measures are widely used, and improve interpretation of performance on these tests for the diagnosis of cognitive impairment not only within the ARIC cohort, but also among older blacks and whites with similar demographics.

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.

The metabolic syndrome and cognitive decline in the Atherosclerosis Risk in Communities study (ARIC).

BACKGROUND: Midlife metabolic syndrome (MetS) may impact cognitive health as a construct independently of hypertension, hyperlipidemia and other components. METHODS: 10,866 participants aged 45-64 years at baseline were assessed for MetS and completed cognitive testing at two later time points (3 and 9 years from the baseline visit). RESULTS: MetS is associated with increased odds of low cognitive performance in the domains of executive function and word fluency, but not with 6-year cognitive decline. Individual MetS components explained this association (hypertension, diabetes, low HDL, elevated triglycerides and increased waist circumference). CONCLUSIONS: A focus on the individual risk factors as opposed to MetS during midlife is important to reduce the incidence of cognitive impairment in later life.

Robust demographically-adjusted normative data for the Montreal Cognitive Assessment (MoCA): Results from the systolic blood pressure intervention trial.

To generate robust, demographically-adjusted regression-based norms for the Montreal Cognitive Assessment (MoCA) using a large sample of diverse older US adults.Baseline MoCA scores were examined for participants in the Systolic Blood Pressure Intervention Trial (SPRINT). A robust, cognitively-normal sample was drawn from individuals not subsequently adjudicated with cognitive impairment through 4 years of follow-up. Multivariable Beta-Binomial regression was used to model the association of demographic variables with MoCA performance and to create demographically-stratified normative tables.Participants' (N = 5,338) mean age was 66.9 ± 8.8 years, with 35.7% female, 63.1% White, 27.4% Black, 9.5% Hispanic, and 44.5% with a college or graduate education. A large proportion scored below published MoCA cutoffs: 61.4% scored below 26 and 29.2% scored below 23. A disproportionate number falling below these cutoffs were Black, Hispanic, did not graduate from college, or were ≥75 years of age. Multivariable modeling identified education, race/ethnicity, age, and sex as significant predictors of MoCA scores (p<.001), with the best fitting model explaining 24.4% of the variance. Model-based predictions of median MoCA scores were generally 1 to 2 points lower for Black and Hispanic participants across combinations of age, sex, and education. Demographically-stratified norm-tables based on regression modeling are provided to facilitate clinical use, along with our raw data.By using regression-based strategies that more fully account for demographic variables, we provide robust, demographically-adjusted metrics to improve cognitive screening with the MoCA in diverse older adults.

Retinal microvascular abnormalities and subclinical magnetic resonance imaging brain infarct: a prospective study.

Silent brain infarct and white matter lesions are common radiological findings associated with the risk of clinical stroke and dementia; however, our understanding of their underlying pathophysiology and risk factors remains limited. This study aimed to determine whether assessment of retinal microvascular abnormalities could provide prognostic information regarding the risk of brain infarct and white matter lesions on magnetic resonance imaging. This study is based on a subset of 810 middle-aged persons without clinical stroke or baseline magnetic resonance imaging infarct enrolled in the Atherosclerosis Risk in Communities Brain Magnetic Resonance Imaging Study, a prospective, population-based study. Participants had a baseline magnetic resonance imaging brain examination and retinal photography in 1993-1995, and returned for a repeat magnetic resonance imaging examination in 2004-2006. Magnetic resonance images were graded for presence of any cerebral infarct, infarct with lacunar characteristics and white matter lesions according to standardized protocols. Retinal photographs were graded for presence of retinopathy lesions and retinal arteriolar abnormalities following a standardized protocol. Over a median follow-up of 10.5 years, 164 (20.2%) participants developed cerebral infarct, 131 (16.2%) developed lacunar infarct, 182 (24.2%) developed new white matter lesions and 49 (6.1%) had evidence of white matter lesion progression. After adjusting for age, gender, race, cardiovascular risk factors and carotid intima-media thickness, retinopathy was associated with incident cerebral infarct (odds ratio 2.82; 95% confidence interval 1.42-5.60) and lacunar infarct (odds ratio 3.19; 95% confidence interval: 1.56-6.50). Retinal arteriovenous nicking was associated with incident cerebral infarct (odds ratio 2.82; 95% confidence interval: 1.66-4.76), lacunar infarct (odds ratio 2.48; 95% confidence interval: 1.39-4.40) and white matter lesion incidence (odds ratio 2.12; 95% confidence interval: 1.18-3.81) and progression (odds ratio 2.22; 95% confidence interval: 1.00-5.88). In conclusion, retinal microvascular abnormalities are associated with emergence of subclinical magnetic resonance imaging brain infarcts and white matter lesions, independent of shared risk factors. Retinal vascular imaging may offer a non-invasive tool to investigate the pathogenesis and natural history of cerebral small-vessel disease.

Blood pressure and white-matter disease progression in a biethnic cohort: Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND PURPOSE: Blood pressure (BP) is a predictor of concurrent and subsequently measured white-matter hyperintensity (WMH), but longitudinal studies of WMH changes and data in black participants are lacking. We hypothesized that WMH progression would be (1) strongly related to BP in blacks and whites and (2) predicted more strongly by earlier (midlife) or cumulative BP measurements than by measures at older ages. METHODS: Participants were 983 individuals (49% black) from the Atherosclerosis Risk in Communities (ARIC) Study who underwent cerebral magnetic resonance imaging in 1993-1995 and 2004-2006. Associations between BP (measured at each of 5 visits, in addition to a time-averaged cumulative BP) and progression of WMHs were analyzed and compared. RESULTS: Cumulative systolic BP (SBP) was the strongest BP predictor of WMH progression in adjusted models. Higher cumulative SBP (by 20 mm Hg) was associated with greater progression of WMHs and was similar in blacks (2.5 cm(3), P<0.0001) and whites (2.6 cm(3), P<0.0001). Higher cumulative SBP (per 20 mm Hg) was also associated with being in the top quintile of WMH progression (adjusted odds ratio=2.0; 95% CI, 1.6 to 2.6). Earlier SBP measurements were stronger predictors of WMH progression than were later SBP measurements, but in blacks only. CONCLUSIONS: In this population-based cohort, cumulative SBP was a stronger predictor of WMH progression than SBP from individual visits, in both blacks and whites. Earlier BPs were stronger predictors than BPs measured at later time points in blacks only.

Retinal microvascular signs and 10-year risk of cerebral atrophy: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND PURPOSE: Cerebral atrophy, detected as ventricular enlargement or sulcal widening on MRI, is recognized as a risk factor for vascular dementia or Alzheimer disease. However, its underlying pathophysiology is not known. We examined whether retinal microvascular assessment could provide predictive information on the risk of ventricular enlargement and sulcal widening on MRI. METHODS: A prospective, population-based study was conducted of 810 middle-aged persons without clinical stroke or MRI infarcts. All participants had a first cranial MRI and retinal photography in 1993 to 1995 and returned for a repeated MRI in 2004 to 2006 (median follow-up of 10.5 years). Retinal photographs were graded for presence of retinopathy and retinal microvascular abnormalities, and MRI images were graded for ventricular size and sulcal size according to standardized protocols. Ventricular enlargement and sulcal widening were defined as an increase in ventricular size or sulcal size of >or=3 of 10 grades between baseline and follow-up. RESULTS: After adjusting for age, gender, and cardiovascular risk factors, retinopathy and arteriovenous nicking at baseline were associated with 10-year ventricular enlargement (OR and 95% CI: 2.03, 1.20 to 4.42 for retinopathy and 2.19, 1.23 to 3.90 for arteriovenous nicking). Retinal signs were not associated with 10-year sulcal widening. CONCLUSIONS: Retinopathy and arteriovenous nicking are predictive of long-term risk of ventricular enlargement, but not of sulcal widening, independent of cardiovascular risk factors. These data support a microvascular etiology for subcortical but not cortical cerebral atrophy.

Fourteen-year longitudinal study of vascular risk factors, APOE genotype, and cognition: the ARIC MRI Study.

BACKGROUND: Strokes, vascular risk factors, and apolipoprotein E (APOE) genotype are associated with cognitive decline in the elderly, but definitive evidence that these affect cognition as early as middle age is limited. OBJECTIVE: We describe the relationships of APOE genotype, stroke, and vascular risk factors with cognitive change over a 14-year follow-up in the Atherosclerosis Risk in Communities (ARIC) Study cohort recruited while in middle age. METHODS: Participants included a subset of the ARIC Study who underwent assessments of cognitive function and vascular risk factors. Four cognitive assessments were performed between 1990-1992 and 2004-2006. Cognitive assessments included the Delayed Word Recall (DWR) Test, the Digit Symbol Substitution (DSS) Test, and the Word Fluency (WF) Test. Vascular risk factors were assessed during the baseline visit in 1990-1992. Incident stroke was recorded over the 14 years of follow-up. RESULTS: There were 1130 participants (mean age, 59 +/- 4.3 [SD] years; 62% women; 52% African-American) with longitudinal data. In multivariate, random-effects linear models adjusted for age, education, gender, and race, the risk factors diabetes and APOE epsilon4 genotype were independently associated with a decline in performance on the DSS test (both P < .005), whereas hypertension and stroke were not. For DWR, stroke and APOE epsilon4 genotype were independent predictors of decline (both P < .001). For the WF test, metabolic syndrome, hypertension, and stroke were independently associated with decline (all P < .005). No evidence of differential effects of risk factors on cognitive decline by race, gender, or interactions between risk factors was found. CONCLUSIONS: The vascular risk factors diabetes and hypertension, a history of stroke itself, and APOE epsilon4 genotype independently contribute to cognitive decline in late middle age and early elderly years.

Neuroimaging findings in midlife and risk of late-life dementia over 20 years of follow-up.

OBJECTIVE: To examine the association between neuroimaging features in a predominantly middle-aged cohort and risk of late-life dementia. METHODS: Cerebral MRI was performed on 1,881 individuals with no history of stroke from the Atherosclerosis Risk in Communities Study cohort in 1993 to 1995. White matter hyperintensities (WMH), ventricular size, and sulcal size were graded on a semiquantitative scale, and presence of silent cerebral infarcts was identified. In 2011 to 2013, dementia was determined from neuropsychological testing, informant interview, hospital ICD-9 codes, and death certificate dementia codes. Cox regression was used to evaluate associations between MRI findings and dementia. RESULTS: Over 20 years of follow-up, dementia developed in 279 participants (14.8%). High-grade WMH and high-grade ventricular size were independently associated with increased dementia risk (hazard ratio [HR] for WMH 1.62, 95% confidence interval [CI] 1.14-2.30; HR for ventricular size 1.46, 95% CI 1.06-2.03). There was an increased risk of dementia for diabetic participants with silent infarcts (HR 2.56, 95% CI 1.23-5.31) but not among nondiabetic participants (HR 0.87, 95% CI 0.56-1.37). Each 1-unit increase in the total number of high-grade cerebral abnormalities at baseline (count values range 0-4) showed increased dementia risk, with a considerably higher risk among diabetic participants (HR for diabetes mellitus 1.97, 95% CI 1.44-2.69; HR for no diabetes mellitus 1.20, 95% CI 1.03-1.39). CONCLUSION: In adults without evidence of clinical stroke, MRI-detected WMH and ventricular enlargement in midlife may represent markers of brain injury that increase risk for later-life cognitive impairment. The presence of diabetes mellitus may modify the association between silent infarcts and dementia.

Risk Factor Burden, Heart Failure, and Survival in Women of Different Ethnic Groups: Insights From the Women's Health Initiative.

BACKGROUND: The higher risk of heart failure (HF) in African-American and Hispanic women compared with white women is related to the higher burden of risk factors (RFs) in minorities. However, it is unclear if there are differences in the association between the number of RFs for HF and the risk of development of HF and death within racial/ethnic groups. METHODS AND RESULTS: In the WHI (Women's Health Initiative; 1993-2010), African-American (n=11 996), white (n=18 479), and Hispanic (n=5096) women with 1, 2, or 3+ baseline RFs were compared with women with 0 RF within their respective racial/ethnic groups to assess risk of developing HF or all-cause mortality before and after HF, using survival analyses. After adjusting for age, socioeconomic status, and hormone therapy, the subdistribution hazard ratio (95% confidence interval) of developing HF increased as number of RFs increased (P<0.0001, interaction of race/ethnicity and RF number P=0.18)-African-Americans 1 RF: 1.80 (1.01-3.20), 2 RFs: 3.19 (1.84-5.54), 3+ RFs: 7.31 (4.26-12.56); Whites 1 RF: 1.27 (1.04-1.54), 2 RFs: 1.95 (1.60-2.36), 3+ RFs: 4.07 (3.36-4.93); Hispanics 1 RF: 1.72 (0.68-4.34), 2 RFs: 3.87 (1.60-9.37), 3+ RFs: 8.80 (3.62-21.42). Risk of death before developing HF increased with subsequent RFs (P<0.0001) but differed by racial/ethnic group (interaction P=0.001). The number of RFs was not associated with the risk of death after developing HF in any group (P=0.25; interaction P=0.48). CONCLUSIONS: Among diverse racial/ethnic groups, an increase in the number of baseline RFs was associated with higher risk of HF and death before HF but was not associated with death after HF. Early RF prevention may reduce the burden of HF across multiple racial/ethnic groups.

The Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Study (ACCORD-MIND): rationale, design, and methods.

Type 2 diabetes mellitus and cognitive impairment are 2 of the most common chronic conditions found in persons aged > or = 60 years. Clinical studies have shown a greater prevalence of global cognitive impairment, incidence of cognitive decline, and incidence of Alzheimer disease in patients with type 2 diabetes. To date, there have been no randomized trials of the effects of long-term glycemic control on cognitive function and structural brain changes in patients with type 2 diabetes. The primary aim of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes Study (ACCORD-MIND) is to test whether there is a difference in the rate of cognitive decline and structural brain change in patients with diabetes treated with standard-care guidelines compared with those treated with intensive-care guidelines. This comparison will be made in a subsample of 2,977 patients with diabetes participating in the ongoing ACCORD trial, a clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) with support from the National Institute on Aging (NIA). Data from this ACCORD substudy on the possible beneficial or adverse effects of intensive treatment on cognitive function will be obtained from a 30-minute test battery, administered at baseline and 20-month and 40-month visits. In addition, full-brain magnetic resonance imaging will be performed on 630 participants at baseline and at 40 months to assess the relation between the ACCORD treatments and structural brain changes. The general aim of ACCORD-MIND is to determine whether the intensive treatment of diabetes, a major risk factor for Alzheimer disease and vascular dementia, can reduce the early decline in cognitive function that could later evolve into more cognitively disabling conditions. This report presents the design, rationale, and methods of the ACCORD-MIND substudy.