20-year depressive symptoms, dementia, and structural neuropathology in older women.

INTRODUCTION: The course of depressive symptoms and dementia risk is unclear, as are potential structural neuropathological common causes. METHODS: Utilizing joint latent class mixture models, we identified longitudinal trajectories of annually assessed depressive symptoms and dementia risk over 21 years in 957 older women (baseline age 72.7 years old) from the Women's Health Initiative Memory Study. In a subsample of 569 women who underwent structural magnetic resonance imaging, we examined whether estimates of cerebrovascular disease and Alzheimer's disease (AD)-related neurodegeneration were associated with identified trajectories. RESULTS: Five trajectories of depressive symptoms and dementia risk were identified. Compared to women with minimal symptoms, women who reported mild and stable and emerging depressive symptoms were at the highest risk of developing dementia and had more cerebrovascular disease and AD-related neurodegeneration. DISCUSSION: There are heterogeneous profiles of depressive symptoms and dementia risk. Common neuropathological factors may contribute to both depression and dementia. Highlights The progression of depressive symptoms and concurrent dementia risk is heterogeneous. Emerging depressive symptoms may be a prodromal symptom of dementia. Cerebrovascular disease and AD are potentially shared neuropathological factors.

The relationship between optimism, MCI, and dementia among postmenopausal women.

OBJECTIVES: The relationship between optimism and cognitive functioning is not fully understood. We examined the association of optimism with risk of mild cognitive impairment (MCI) and dementia in the Women's Health Initiative Memory Study (WHIMS). METHODS: Optimism was measured by the Life Orientation Test-Revised (LOT-R) total score, and optimism and pessimism subscales. A panel of experts adjudicated cognitive endpoints based on annual cognitive assessments. We used cox proportional hazard regression models to examine the association of LOT-R total score and optimism and pessimism sub-scores with MCI/dementia. We also examined the relationship between vascular disease, LOT-R total score, optimism and pessimism, and cognition. RESULTS: Mean age was 70.5 (SD = 3.9) years. The sample (N = 7249) was 87% white, and 29.8% of participants had < 12 years of education. Total LOT-R score (HR = 0.96, 95% CI: 0.94, 0.98, p < 0.001) was associated with lower risk of combined MCI or dementia. More pessimism (HR = 1.08, 95% CI: 1.05, 1.11, p < 0.0001) was associated with higher risk of MCI or dementia after adjustment for ethnicity, education, vascular disease, and depression. No significant relationships emerged from the optimism subscale. CONCLUSION: These data suggest that less pessimism, but not more optimism, was associated with a lower risk of MCI and dementia.

Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial.

INTRODUCTION: Dietary supplements are touted for cognitive protection, but supporting evidence is mixed. COSMOS-Mind tested whether daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin-mineral (MVM) versus placebo improved cognition in older women and men. METHODS: COSMOS-Mind, a large randomized two-by-two factorial 3-year trial, assessed cognition by telephone at baseline and annually. The primary outcome was a global cognition composite formed from mean standardized (z) scores (relative to baseline) from individual tests, including the Telephone Interview of Cognitive Status, Word List and Story Recall, Oral Trail-Making, Verbal Fluency, Number Span, and Digit Ordering. Using intention-to-treat, the primary endpoint was change in this composite with 3 years of cocoa extract use. The pre-specified secondary endpoint was change in the composite with 3 years of MVM supplementation. Treatment effects were also examined for executive function and memory composite scores, and in pre-specified subgroups at higher risk for cognitive decline. RESULTS: A total of 2262 participants were enrolled (mean age = 73y; 60% women; 89% non-Hispanic White), and 92% completed the baseline and at least one annual assessment. Cocoa extract had no effect on global cognition (mean z-score = 0.03, 95% CI: -0.02 to 0.08; P = .28). Daily MVM supplementation, relative to placebo, resulted in a statistically significant benefit on global cognition (mean z = 0.07, 95% CI 0.02 to 0.12; P = .007), and this effect was most pronounced in participants with a history of cardiovascular disease (no history: 0.06, 95% CI 0.01 to 0.11; history: 0.14, 95% CI -0.02 to 0.31; interaction, nominal P = .01). Multivitamin-mineral benefits were also observed for memory and executive function. The cocoa extract by MVM group interaction was not significant for any of the cognitive composites. DISCUSSION: Cocoa extract did not benefit cognition. However, COSMOS-Mind provides the first evidence from a large, long-term, pragmatic trial to support the potential efficacy of a MVM to improve cognition in older adults. Additional work is needed to confirm these findings in a more diverse cohort and to identify mechanisms to account for MVM effects. HIGHLIGHTS: COSMOS-Mind was a large simple pragmatic randomized clinical trial in older adults conducted by mail and telephone. The trial used a two-by-two factorial design to assess treatment effects of two different interventions within a single large study. We found no cognitive benefit of daily cocoa extract administration (containing 500 mg flavanols) for 3 years. Daily multivitamin-mineral (MVM) supplementation for 3 years improved global cognition, episodic memory, and executive function in older adults. The MVM benefit appeared to be greater for adults with cardiovascular disease.

Impact of multivitamin-mineral and cocoa extract on incidence of mild cognitive impairment and dementia: Results from the COcoa Supplement and Multivitamin Outcomes Study for the Mind (COSMOS-Mind).

INTRODUCTION: We assessed the effects of multivitamin-mineral and cocoa extract supplementation on incident mild cognitive impairment (MCI) and all-cause probable dementia. METHODS: COSMOS-Mind (N = 2262), a 2 × 2 factorial, randomized-controlled clinical trial administered a telephone-based cognitive battery at baseline and annually for 3 years. Incidence rates of MCI, and separately dementia, were compared among treatment arms with proportional hazards regression. RESULTS: Over 3 years, 110 incident MCI and 14 incident dementia cases were adjudicated. Incidence rates did not vary by assignment to multivitamin-mineral or cocoa extract (all p's ≥ 0.05); however, statistical power was low. When participants assigned to multivitamin-mineral versus placebo converted to MCI, their scores for global cognition (p = 0.03) and executive function (p < 0.001) were higher and had declined less relative to the previous year (p = 0.03 for global cognition; p = 0.004 for executive function). DISCUSSION: Multivitamin-mineral therapy may provide cognitive resilience, countering conversion to MCI, but not significantly reduce its incidence over 3 years. HIGHLIGHTS: Multivitamin-mineral supplementation did not reduce risks for cognitive impairment. Cocoa extract supplementation did not reduce risks for cognitive impairment. Multivitamin-mineral supplementation slowed cognitive declines for incident mild cognitive impairment.

Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure.

RATIONALE & OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in individuals with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial (SPRINT) who underwent brain magnetic resonance imaging studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP <120 mm Hg) versus standard (systolic BP <140 mm Hg) BP lowering. OUTCOMES: The magnetic resonance imaging outcome measures were the 4-year change in global cerebral blood flow (CBF), white matter lesion (WML) volume, and total brain volume (TBV). RESULTS: A total of 716 randomized participants with a mean age of 68 years were enrolled; follow-up imaging occurred after a median 3.9 years. Among participants with eGFR <60 mL/min/1.73 m2 (n = 234), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 3.38 (95% CI, 0.32 to 6.44) mL/100 g/min, -0.06 (95% CI, -0.16 to 0.04) cm3 (inverse hyperbolic sine-transformed), and -3.8 (95% CI, -8.3 to 0.7) cm3, respectively. Among participants with UACR >30 mg/g (n = 151), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 1.91 (95% CI, -3.01 to 6.82) mL/100 g/min, 0.003 (95% CI, -0.13 to 0.13) cm3 (inverse hyperbolic sine-transformed), and -7.0 (95% CI, -13.3 to -0.3) cm3, respectively. The overall treatment effects on CBF and TBV were not modified by baseline eGFR or UACR; however, the effect on WMLs was attenuated in participants with albuminuria (P = 0.04 for interaction). LIMITATIONS: Measurement variability due to multisite design. CONCLUSIONS: Among adults with hypertension who have primarily early kidney disease, intensive versus standard BP treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive BP treatment targets on brain health in persons with early kidney disease. FUNDING: SPRINT was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with study number NCT01206062.

Association of Baseline and Longitudinal Changes in Body Composition Measures With Risk of Heart Failure and Myocardial Infarction in Type 2 Diabetes: Findings From the Look AHEAD Trial.

BACKGROUND: Intentional weight loss is associated with lower risk of heart failure (HF) and atherosclerotic cardiovascular disease among patients with type 2 diabetes. However, the contribution of baseline measures and longitudinal changes in fat mass (FM), lean mass (LM), and waist circumference (WC) to the risk of HF and myocardial infarction (MI) in type 2 diabetes is not well established. METHODS: Adults from the Look AHEAD trial (Action for Health in Diabetes) without prevalent HF were included. FM and LM were predicted using validated equations and compared with dual-energy x-ray absorptiometry measurements in a subgroup. Adjusted Cox models were used to evaluate the associations of baseline and longitudinal changes in FM, LM, and WC over 1- and 4-year follow-up with risk of overall HF, HF with preserved ejection fraction (EF; EF ≥50%), HF with reduced EF (EF <50%), and MI. RESULTS: Among 5103 participants, there were 257 incident HF events over 12.4 years of follow-up. Predicted and measured FM/LM were highly correlated (R2=0.87-0.90; n=1369). FM and LM decreased over 4-year follow-up with greater declines in the intensive lifestyle intervention arm. In adjusted analysis, baseline body composition measures were not significantly associated with HF risk. Decline in FM and WC, but not LM, over 1 year were each significantly associated with lower risk of overall HF (adjusted hazard ratio per 10% decrease in FM, 0.80 [95% CI, 0.68-0.95]; adjusted hazard ratio per 10% decrease in WC, 0.77 [95% CI, 0.62-0.95]). Decline in FM was significantly associated with lower risk of both HF subtypes. In contrast, decline in WC was significantly associated with lower risk of HF with preserved EF but not HF with reduced EF. Similar patterns of association were observed for 4-year changes in body composition and HF risk. Longitudinal changes in body composition were not significantly associated with risk of MI. CONCLUSIONS: In adults with type 2 diabetes, a lifestyle intervention is associated with significant loss of FM and LM. Declines in FM and WC, but not LM, were each significantly associated with lower risk of HF but not MI. Furthermore, decline in WC was significantly associated with lower risk of HF with preserved EF but not HF with reduced EF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00017953.

Association of Intensive Lifestyle Intervention, Fitness, and Body Mass Index With Risk of Heart Failure in Overweight or Obese Adults With Type 2 Diabetes Mellitus: An Analysis From the Look AHEAD Trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with a higher risk for heart failure (HF). The impact of a lifestyle intervention and changes in cardiorespiratory fitness (CRF) and body mass index on risk for HF is not well established. METHODS: Participants from the Look AHEAD trial (Action for Health in Diabetes) without prevalent HF were included. Time-to-event analyses were used to compare the risk of incident HF between the intensive lifestyle intervention and diabetes support and education groups. The associations of baseline measures of CRF estimated from a maximal treadmill test, body mass index, and longitudinal changes in these parameters with risk of HF were evaluated with multivariable adjusted Cox models. RESULTS: Among the 5109 trial participants, there was no significant difference in the risk of incident HF (n=257) between the intensive lifestyle intervention and the diabetes support and education groups (hazard ratio, 0.96 [95% CI, 0.75-1.23]) over a median follow-up of 12.4 years. In the most adjusted Cox models, the risk of HF was 39% and 62% lower among moderate fit (tertile 2: hazard ratio, 0.61 [95% CI, 0.44-0.83]) and high fit (tertile 3: hazard ratio, 0.38 [95% CI, 0.24-0.59]) groups, respectively (referent group: low fit, tertile 1). Among HF subtypes, after adjustment for traditional cardiovascular risk factors and interval incidence of myocardial infarction, baseline CRF was not significantly associated with risk of incident HF with reduced ejection fraction. In contrast, the risk of incident HF with preserved ejection fraction was 40% lower in the moderate fit group and 77% lower in the high fit group. Baseline body mass index also was not associated with risk of incident HF, HF with preserved ejection fraction, or HF with reduced ejection fraction after adjustment for CRF and traditional cardiovascular risk factors. Among participants with repeat CRF assessments (n=3902), improvements in CRF and weight loss over a 4-year follow-up were significantly associated with lower risk of HF (hazard ratio per 10% increase in CRF, 0.90 [95% CI, 0.82-0.99]; per 10% decrease in body mass index, 0.80 [95% CI, 0.69-0.94]). CONCLUSIONS: Among participants with type 2 diabetes mellitus in the Look AHEAD trial, the intensive lifestyle intervention did not appear to modify the risk of HF. Higher baseline CRF and sustained improvements in CRF and weight loss were associated with lower risk of HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00017953.

Particulate matter and episodic memory decline mediated by early neuroanatomic biomarkers of Alzheimer's disease.

Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 µm (PM2.5) may increase the risk for Alzheimer's disease and related dementias. Whether PM2.5 alters brain structure and accelerates the preclinical neuropsychological processes remains unknown. Early decline of episodic memory is detectable in preclinical Alzheimer's disease. Therefore, we conducted a longitudinal study to examine whether PM2.5 affects the episodic memory decline, and also explored the potential mediating role of increased neuroanatomic risk of Alzheimer's disease associated with exposure. Participants included older females (n = 998; aged 73-87) enrolled in both the Women's Health Initiative Study of Cognitive Aging and the Women's Health Initiative Memory Study of Magnetic Resonance Imaging, with annual (1999-2010) episodic memory assessment by the California Verbal Learning Test, including measures of immediate free recall/new learning (List A Trials 1-3; List B) and delayed free recall (short- and long-delay), and up to two brain scans (MRI-1: 2005-06; MRI-2: 2009-10). Subjects were assigned Alzheimer's disease pattern similarity scores (a brain-MRI measured neuroanatomical risk for Alzheimer's disease), developed by supervised machine learning and validated with data from the Alzheimer's Disease Neuroimaging Initiative. Based on residential histories and environmental data on air monitoring and simulated atmospheric chemistry, we used a spatiotemporal model to estimate 3-year average PM2.5 exposure preceding MRI-1. In multilevel structural equation models, PM2.5 was associated with greater declines in immediate recall and new learning, but no association was found with decline in delayed-recall or composite scores. For each interquartile increment (2.81 µg/m3) of PM2.5, the annual decline rate was significantly accelerated by 19.3% [95% confidence interval (CI) = 1.9% to 36.2%] for Trials 1-3 and 14.8% (4.4% to 24.9%) for List B performance, adjusting for multiple potential confounders. Long-term PM2.5 exposure was associated with increased Alzheimer's disease pattern similarity scores, which accounted for 22.6% (95% CI: 1% to 68.9%) and 10.7% (95% CI: 1.0% to 30.3%) of the total adverse PM2.5 effects on Trials 1-3 and List B, respectively. The observed associations remained after excluding incident cases of dementia and stroke during the follow-up, or further adjusting for small-vessel ischaemic disease volumes. Our findings illustrate the continuum of PM2.5 neurotoxicity that contributes to early decline of immediate free recall/new learning at the preclinical stage, which is mediated by progressive atrophy of grey matter indicative of increased Alzheimer's disease risk, independent of cerebrovascular damage.

Kidney Disease, Intensive Hypertension Treatment, and Risk for Dementia and Mild Cognitive Impairment: The Systolic Blood Pressure Intervention Trial.

BACKGROUND: Intensively treating hypertension may benefit cardiovascular disease and cognitive function, but at the short-term expense of reduced kidney function. METHODS: We investigated markers of kidney function and the effect of intensive hypertension treatment on incidence of dementia and mild cognitive impairment (MCI) in 9361 participants in the randomized Systolic Blood Pressure Intervention Trial, which compared intensive versus standard systolic BP lowering (targeting <120 mm Hg versus <140 mm Hg, respectively). We categorized participants according to baseline and longitudinal changes in eGFR and urinary albumin-to-creatinine ratio. Primary outcomes were occurrence of adjudicated probable dementia and MCI. RESULTS: Among 8563 participants who completed at least one cognitive assessment during follow-up (median 5.1 years), probable dementia occurred in 325 (3.8%) and MCI in 640 (7.6%) participants. In multivariable adjusted analyses, there was no significant association between baseline eGFR <60 ml/min per 1.73 m2 and risk for dementia or MCI. In time-varying analyses, eGFR decline ≥30% was associated with a higher risk for probable dementia. Incident eGFR <60 ml/min per 1.73 m2 was associated with a higher risk for MCI and a composite of dementia or MCI. Although these kidney events occurred more frequently in the intensive treatment group, there was no evidence that they modified or attenuated the effect of intensive treatment on dementia and MCI incidence. Baseline and incident urinary ACR ≥30 mg/g were not associated with probable dementia or MCI, nor did the urinary ACR modify the effect of intensive treatment on cognitive outcomes. CONCLUSIONS: Among hypertensive adults, declining kidney function measured by eGFR is associated with increased risk for probable dementia and MCI, independent of the intensity of hypertension treatment.

Dementia outcomes after addition of proxy-based assessments for deceased or proxy-dependent participants.

OBJECTIVES: As people age and the incidence of dementia increases, studies of cognitive function continue to be of importance. Ascertaining cognitive data through different mechanisms is necessary to address missing data concerns. METHODS: The Dementia Questionnaire (DQ), which utilizes proxy-based assessments, is a potential tool to determine cognitive status in participants no longer being followed per traditional study protocol. The DQ is currently being used in the Supplemental Case Ascertainment Protocol (SCAP), which is being conducted in an ongoing study of postmenopausal women as part of the Women's Health Initiative Memory Study (WHIMS). RESULTS: Ninety-four percent of the 1260 SCAP participants were eligible because of being deceased. Those who are SCAP eligible were older, were less likely to be a minority, and were more likely to have hypertension, diabetes, and prior history of cardiovascular disease (CVD) as well as being a past or current smoker. SCAP added 109 cases of probable dementia to WHIMS. Risk factor relationships were modified upon inclusion of the SCAP cases including an attenuation of a hormone therapy effect and discovery of a hypertension effect. CONCLUSIONS: Augmenting clinic-based cases with proxy-based assessments is feasible and leads to increased incident cases of dementia. When planning future clinical trials, it may be of study benefit to include a protocol of proxy-based assessments, develop strong relationships with proxies early on in the study, and attempt to maintain this relationship throughout the lifespan of the trial.

Cognitive resilience among APOE ε4 carriers in the oldest old.

OBJECTIVES: Relatively few APOE ε4+ carriers survive to old age (age 80+) without cognitive impairment (CI); thus, little is known about distinguishing characteristics of resilient APOE ε4+ carriers. Herein, we describe the sociodemographic characteristics of a large sample of resilient APOE ε4+ women from the Women's Health Initiative Memory Study (WHIMS) and compare them to noncarriers and APOE ε4+ women who developed CI before age 80. METHODS: Women were recruited for clinical trials evaluating postmenopausal hormone therapy and incidence of dementia. During posttrial follow-up, cognitive status was adjudicated annually. Among 5716 women, we compared groups by APOE ε4 status using logistic regression, covarying for treatment, demographics, lifestyle, cardiovascular and physical function, well-being, and self-rated general health. RESULTS: Among 557 APOE ε4+ women, those who survived to age 80+ without CI had higher baseline self-rated general health (odds ratio [OR]: 1.02; 95% confidence interval [CI], 1.01-1.04) and cognitive scores (OR: 1.18; 95% CI, 1.12-1.25) than those who did not reach age 80 without CI. Baseline high total cholesterol and low-density lipoprotein (LDL) levels were similar across APOE ε4+ groups but were higher compared with APOE ε4- women. Among women who survived to 80+ without CI, more APOE ε4+ women had a history of high total cholesterol (P = .003) and LDL cholesterol (OR: 1.01; 95% CI, 1.00-1.01). There were no differences in hypertension, diabetes, or other vascular risk factors in APOE ε4+ women compared with noncarriers. CONCLUSIONS: Results highlight the importance of baseline cognitive function and general health for late-life cognition among ε4+ women.

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.

Using high-dimensional machine learning methods to estimate an anatomical risk factor for Alzheimer's disease across imaging databases.

INTRODUCTION: The main goal of this work is to investigate the feasibility of estimating an anatomical index that can be used as an Alzheimer's disease (AD) risk factor in the Women's Health Initiative Magnetic Resonance Imaging Study (WHIMS-MRI) using MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a well-characterized imaging database of AD patients and cognitively normal subjects. We called this index AD Pattern Similarity (AD-PS) scores. To demonstrate the construct validity of the scores, we investigated their associations with several AD risk factors. The ADNI and WHIMS imaging databases were collected with different goals, populations and data acquisition protocols: it is important to demonstrate that the approach to estimating AD-PS scores can bridge these differences. METHODS: MRI data from both studies were processed using high-dimensional warping methods. High-dimensional classifiers were then estimated using the ADNI MRI data. Next, the classifiers were applied to baseline and follow-up WHIMS-MRI GM data to generate the GM AD-PS scores. To study the validity of the scores we investigated associations between GM AD-PS scores at baseline (Scan 1) and their longitudinal changes (Scan 2 -Scan 1) with: 1) age, cognitive scores, white matter small vessel ischemic disease (WM SVID) volume at baseline and 2) age, cognitive scores, WM SVID volume longitudinal changes respectively. In addition, we investigated their associations with time until classification of independently adjudicated status in WHIMS-MRI. RESULTS: Higher GM AD-PS scores from WHIMS-MRI baseline data were associated with older age, lower cognitive scores, and higher WM SVID volume. Longitudinal changes in GM AD-PS scores (Scan 2 - Scan 1) were also associated with age and changes in WM SVID volumes and cognitive test scores. Increases in the GM AD-PS scores predicted decreases in cognitive scores and increases in WM SVID volume. GM AD-PS scores and their longitudinal changes also were associated with time until classification of cognitive impairment. Finally, receiver operating characteristic curves showed that baseline GM AD-PS scores of cognitively normal participants carried information about future cognitive status determined during follow-up. DISCUSSION: We applied a high-dimensional machine learning approach to estimate a novel AD risk factor for WHIMS-MRI study participants using ADNI data. The GM AD-PS scores showed strong associations with incident cognitive impairment and cross-sectional and longitudinal associations with age, cognitive function, cognitive status and WM SVID volume lending support to the ongoing validation of the GM AD-PS score.

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.

Effect of an intensive lifestyle intervention on atrial fibrillation risk in individuals with type 2 diabetes: the Look AHEAD randomized trial.

BACKGROUND: Obesity is associated with higher risk of atrial fibrillation (AF), but the impact of behavioral weight loss interventions on atrial fibrillation (AF) risk in persons with diabetes is unknown. We addressed this question in the Look AHEAD randomized trial. METHODS AND RESULTS: A total of 5,067 overweight or obese individuals 45 to 76 years old with type 2 diabetes without prevalent AF were randomized to either an intensive lifestyle intervention (ILI) designed to achieve and maintain weight loss through caloric reduction and increased physical activity or a diabetes support and education usual care group. Atrial fibrillation was ascertained from electrocardiograms at study examinations and hospitalization discharge summaries. Multivariable Cox models were used to estimate the intention-to-treat effect of the intervention adjusting for baseline covariates. During a mean follow-up of 9.0 years, 294 incident AF cases were identified. Rates of AF were comparable in the ILI and diabetes support and education groups (6.1 and 6.7 cases per 1,000 person-years, respectively, P = .42). The intervention did not affect AF incidence (multivariable hazard ratio [HR] 0.99, 95% CI 0.77-1.28). Similarly, neither weight loss nor improvement in physical fitness during the first year of the intervention was significantly associated with AF incidence: multivariable hazard ratio (95% CI) comparing top versus bottom quartile was 0.70 (0.41-1.18) for weight loss and 0.88 (0.55-1.43) for physical fitness improvement. CONCLUSION: In a large randomized trial of overweight and obese individuals with type 2 diabetes, an ILI that induced modest weight loss did not reduce the risk of developing AF.

Risk factors for endometrial cancer in black and white women: a pooled analysis from the Epidemiology of Endometrial Cancer Consortium (E2C2).

PURPOSE: Endometrial cancer (EC) is the most common gynecologic cancer in the USA. Over the last decade, the incidence rate has been increasing, with a larger increase among blacks. The aim of this study was to compare risk factors for EC in black and white women. METHODS: Data from seven cohort and four case-control studies were pooled. Unconditional logistic regression was used to estimate adjusted odds ratios (OR) and 95 % confidence intervals for each risk factor in blacks and whites separately. RESULTS: Data were pooled for 2,011 black women (516 cases and 1,495 controls) and 19,297 white women (5,693 cases and 13,604 controls). BMI ≥ 30 was associated with an approximate threefold increase in risk of EC in both black and white women (ORblack 2.93, 95 % CI 2.11, 4.07 and ORwhite 2.99, 95 % CI 2.74, 3.26). Diabetes was associated with a 30-40 % increase in risk among both groups. Increasing parity was associated with decreasing risk of EC in blacks and whites (p value = 0.02 and <0.001, respectively). Current and former smoking was associated with decreased risk of EC among all women. Both black and white women who used oral contraceptives for 10 +years were also at reduced risk of EC (OR 0.49, 95 % CI 0.27, 0.88 and OR 0.69, 95 % CI 0.58, 0.83, respectively). Previous history of hypertension was not associated with EC risk in either group. CONCLUSIONS: The major known risk factors for EC exert similar effects on black and white women. Differences in the incidence rates between the two populations may be due to differences in the prevalence of risk factors.

Feasibility of Remote Administration of the Uniform Data Set-Version 3 for Assessment of Older Adults With Mild Cognitive Impairment and Alzheimer's Disease.

OBJECTIVE: Assess the feasibility and concurrent validity of a modified Uniform Data Set version 3 (UDSv3) for remote administration for individuals with normal cognition (NC), mild cognitive impairment (MCI), and early dementia. METHOD: Participants (N = 93) (age: 72.8 [8.9] years; education: 15.6 [2.5] years; 72% female; 84% White) were enrolled from the Wake Forest ADRC. Portions of the UDSv3 cognitive battery, plus the Rey Auditory Verbal Learning Test, were completed by telephone or video within ~6 months of participant's in-person visit. Adaptations for phone administration (e.g., Oral Trails for Trail Making Test [TMT] and Blind Montreal Cognitive Assessment [MoCA] for MoCA) were made. Participants reported on the pleasantness, difficulty, and preference for each modality. Staff provided validity ratings for assessments. Participants' remote data were adjudicated by cognitive experts blinded to the in person-diagnosis (NC [N = 44], MCI [N = 35], Dementia [N = 11], or other [N = 3]). RESULTS: Remote assessments were rated as pleasant as in-person assessments by 74% of participants and equally difficult by 75%. Staff validity rating (video = 92%; phone = 87.5%) was good. Concordance between remote/in-person scores was generally moderate to good (r = .3 -.8; p < .05) except for TMT-A/OTMT-A (r = .3; p > .05). Agreement between remote/in-person adjudicated cognitive status was good (k = .61-.64). CONCLUSIONS: We found preliminary evidence that older adults, including those with cognitive impairment, can be assessed remotely using a modified UDSv3 research battery. Adjudication of cognitive status that relies on remotely collected data is comparable to classifications using in-person assessments.

Examining a Preclinical Alzheimer's Cognitive Composite for Telehealth Administration for Reliability Between In-Person and Remote Cognitive Testing with Neuroimaging Biomarkers.

Background: The preclinical Alzheimer's cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline. At the outset of the COVID-19 pandemic, cognitive testing was increasingly performed remotely by telephone or video administration. It is desirable to have a harmonized composite measurement derived from both in-person and remote assessments for identifying cognitive changes and to examine its relationship with common neuroimaging biomarkers. Objective: We defined a telehealth compatible PACC (tPACC) and examined its relationship with neuroimaging biomarkers related to neurodegeneration, brain function and perfusion, white matter integrity, and amyloid-ß. Methods: We examined 648 participants' neuroimaging and in-person and remote cognitive testing data from the Wake Forest Alzheimer's Disease Research Center's Clinical Core cohort (observational study) to calculate a modified PACC (PACC5-RAVLT) score and tPACC scores (in-person and remote). We performed Spearman/intraclass correlation coefficient (ICC) analyses for reliability of tPACC scores and linear regression models to evaluate associations between tPACC and neuroimaging. Bland-Altman plots for agreement were constructed across cognitively normal and impaired (mild cognitive impairment and dementia) participants. Results: There was a significant positive relationship between tPACCin - person and PACC5-RAVLT (Overall group: r2 = 0.94, N = 648), and tPACCin - person and tPACCremote (validation subgroup: ICC = 0.82, n = 53). Overall, tPACC showed significant associations with brain thickness/volume, gray matter perfusion, white matter free water, and amyloid-ß deposition. Conclusions: There is a good agreement between tPACCand PACC5-RAVLTfor cognitively normal and impaired individuals. The tPACC is associated with common neuroimaging markers of Alzheimer's disease.

Ascertaining dementia-related outcomes for deceased or proxy-dependent participants: an overview of the Women's Health Initiative Memory Study supplemental case ascertainment protocol.

OBJECTIVE: The aim of the study was to compare a two-staged clinic-based standardized protocol with a supplemental proxy-based protocol. METHODS: The Women's Health Initiative Memory Study enrolled 7479 women, aged 65-79 years and free of dementia, in a clinical trial of postmenopausal hormone therapy who were followed for up to 13 years with annual two-staged clinic-based standardized protocols to identify incidence of probable dementia. A supplemental proxy-based protocol, involving telephone administration of the dementia questionnaire, was designed to assess the cognitive status of women who could no longer attend clinic visits because they died (n = 1058) or became dependent (n = 228). Chi-squared tests were used to compare characteristics of women eligible for proxy-based versus clinic-based assessment. Risk factor relationships were described using proportional hazards regression. RESULTS: Women who were eligible for proxy-based assessments tended to have worse cognitive impairment risk factor profiles and had higher rates of probable dementia (15.2% vs 3.5%) than clinic-assessed participants. Augmenting the clinic-based cases with those identified from proxy interviews reduced undercounting and materially altered observed relationships that years since menopause, smoking status, diabetes, and prior use of hormone therapy had with incidence of probable dementia. CONCLUSIONS: Although proxy interviews were successful in reducing biases in estimated incidence rates and risk factor relationships, it is unlikely that they will fully eliminate many biases. Proxy-based assessments are necessary in longer term studies to reduce undercounting of dementia cases and to characterize risk factor relationships.