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Introduction: Weight loss and increased physical activity interventions are commonly recommended for individuals with type 2 diabetes (T2D) and overweight or obesity. We examined the impact of randomization to an intensive lifestyle intervention (ILI) on trajectories of cognitive function over 10 years in a cohort of participants in a randomized clinical trial who had T2D and overweight/obesity at baseline. Methods: Participants aged 45–76 years were enrolled in 2001–2004 and were randomized to the ILI or a diabetes support and education (DSE) condition. Cognitive function was assessed in 3,938 participants at up to 4 time points 8–18 years after randomization. General linear mixed effects models examined cognitive trajectories over time. Subgroup analyses focused on sex, individuals with baseline body mass index >30, those carrying the APOE ε4 allele, and those with a baseline history of cardiovascular disease (CVD). Results: Overall, there were no differences in the rate of cognitive decline by intervention arm. Subgroup analyses showed that participants who had a baseline history of CVD and were randomized to the ILI arm of the study performed significantly worse on the Stroop Color Word Test than those in the DSE arm. Discussion/Conclusions: The ILI did not result in preserved cognitive function or slower rates of cognitive decline in this cohort of individuals who had T2D and were overweight or obese at baseline. [ABSTRACT FROM AUTHOR]

Background: Executive function (EF) is associated with obesity development and self‐management. Individuals who demonstrate or self‐report poorer EF performance tend to have poorer short‐term outcomes in obesity treatment. There may be distinct behavioral self‐management strategies and EF domains related to initial weight loss as compared to weight loss maintenance. Objective: To characterize EF in individuals who achieved clinically significant weight loss via behavioral intervention and examine potential differences in EF between those who maintained versus regained lost weight. Methods: Participants who previously achieved ≥5% weight loss via lifestyle intervention were included (N = 44). "Maintainers" (n = 16) maintained this minimum level of weight loss for ≥1 year. "Regainers" (n = 28) regained some or all initially lost weight. Performance‐based EF, intelligence quotient, health literacy, depression, anxiety, binge eating, demographics, and medical/weight history were assessed using a cross‐sectional design. Descriptive statistics and age‐, gender‐, education‐adjusted reference ranges were used to characterize EF. Analyses of covariance were conducted to examine EF differences between maintainers and regainers. Results: The sample consisted primarily of females with obesity over age 50. Approximately half self‐identified as African–American. Decision‐making performance was better in maintainers than regainers (p = 0.003, partη2 = 0.19). There were no differences between maintainers and regainers in inhibitory control, verbal fluency, planning/organization, cognitive flexibility, or working memory (ps > 0.05, partη2s = 0.003–0.07). At least 75% of the sample demonstrated average‐above average EF test performance, indicated by scaled scores ≥13 or t‐scores > 60. Conclusions: Most individuals with obesity who achieved clinically significant weight loss via behavioral intervention had average to above average EF. Individuals who maintained (vs. regained) their lost weight performed better on tests of decision‐making. [ABSTRACT FROM AUTHOR]

Background: MRI is a widely used modality to evaluate dementia risk. Here, we extend previous work by estimating the Alzheimer's disease pattern similarity (AD‐PS) scores for participants of a community‐dwelling older adult cohort to evaluate neuroanatomic risk of AD using MRI. Method: Baseline MRI data were available from 522 participants from the Wake Forest Alzheimer's Disease Research Center's (ADRC) Clinical Core with mean age 70.2, 81.2% White and 17.6% African American. Of those, 253 were cognitively impaired (dementia and mild cognitive impairment (MCI)) and 138 underwent [11C]PiB PET (MCI = 48 and dementia = 19). Global PiB SUVR was averaged from a cortical region of interest sensitive to early AD. Participants were classified as amyloid positivity using a previously defined threshold (≥1.21 SUVR). AD‐PS scores were estimated based on GM probability maps according to previously reported machine learning methodology[1]. High‐dimensional classifiers were trained using ADNI MRI data. To generate the AD‐PS scores, MRI data from the ADRC cohort was provided as input to the classifiers. We investigated associations that AD‐PS scores [range 0‐1] had with amyloid positivity and cognitive impairment. All analyses were adjusted for age, sex, race and education. AD‐PS scores discrimination of participants with dementia versus normal cognition (CN) was compared to hippocampal volume and cortical thickness in temporal regions based meta‐ROI which are sensitive to AD. Result: AD‐PS scores were strongly associated with cognitive impairment: OR = 4.1, CI: 95% [2.9‐5.9], p<0.0001. In addition, they were associated with amyloid positivity with OR = 2.8,CI: 95% [1.7‐4.7], p<0.001, N = 138. These amyloid positivity results did not hold in analyses limited to CN participants only(N = 71). Performance when discriminating patients with dementia from CN individuals was highest for AD‐PS score (AUC = 92.2, CI: 95% [86.9‐97.5]), followed by hippocampal volume (AUC = 86.5, CI: 95% [81.1‐91.2]) and cortical thickness in temporal regions based meta‐ROI (AUC = 81.5 CI: 95% [74.4‐88.6], See‐Figure). Conclusion: This work highlights further the generalization performance of our machine learning algorithm. AD‐PS scores, a measure of dementia neuroanatomic risk, strongly discriminated individuals with dementia from CN individuals in the Wake Forest ADRC. References [1] Casanova et. al., Alzheimer's & Dementia, 2021, PMID:34310039. [ABSTRACT FROM AUTHOR]

Background: The effect of an intensive lifestyle intervention (ILI) on Alzheimer's disease (AD) blood‐based biomarker levels and cognitive outcomes among individuals with type 2 diabetes (T2D) is unknown. We examined AD biomarkers and cognitive outcomes in the Look AHEAD Study. Method: Participants aged 45‐76 years were randomized at baseline to a 10‐year ILI or a diabetes support and education (DSE) condition. Cognitive assessments at years 8‐18 included measures of attention, executive function, global function, and memory. Mild cognitive impairment (MCI) and probable dementia were adjudicated by an expert panel. Stored baseline and end‐of‐intervention plasma samples were analyzed with the Quanterix Simoa HD‐X Analyzer. Changes in Aβ42/Aβ40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic characteristics, and cognitive outcomes. Cognitive scores and biomarker levels were converted to z‐scores. Cognitive trajectories were evaluated using mixed models to account for repeated measures; logistic regression was used for a composite outcome of MCI/dementia. Models were adjusted for baseline characteristics (age, sex, education, race/ethnicity, body mass index (BMI), CVD history, hypertension, diabetes duration, eGFR), APOE‐ε4, randomization arm, time from randomization, and time between blood draw and cognitive testing. Result: The mean age of 779 participants was 61.4 years; 56% = female, 22.8% = APOE ε4+, mean BMI = 34.8, baseline diabetes duration >5 years = 57%, 16.7% Black, 12.5% Hispanic, 66.2% White, and 4.7% other racial and ethnic groups. There were no associations between the intervention and biomarker levels at baseline or biomarker change over time. Increases in NfL levels significantly predicted lower memory (‐0.04 ±0.01; p = 0.002), global cognition scores (‐0.05 ±0.02; p = 0.011), executive function (‐0.04 ±0.01; p = 0.01), as well as increased risk of MCI/probable dementia (odds ratio [OR] 1.10, 95% CI 1.02‐1.19). Increases in GFAP predicted lower memory (‐0.10 ±0.03; p = 0.0001), global cognition (‐0.09 ±0.03; p = 0.009), executive function scores (‐0.12 ±0.03; p<0.0001), and increased risk of MCI/probable dementia (OR 1.24, 95% CI 1.09‐1.41). Conclusion: There was no association between the intervention and changes in biomarker levels. Increasing levels of NfL and GFAP over the ∼10 year period were associated with reduced cognitive performance and increased risk of MCI/probable dementia. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) is an important modifiable risk factor for cognitive decline, and increasing evidence suggests that worse glucose control, in addition to a diagnosis of T2D, may play a role in cognitive function in later life. Despite this increasing concern, evidence regarding the relative contributions of poor glucose control and higher glucose variability to cognitive dysfunction among individuals with overweight or obesity is limited, mostly due to lack of repeated measures in many studies. Method: Look AHEAD MIND Study participants, aged 45‐76 years at baseline (2001‐04) with T2D and overweight or obesity, were randomized to an intensive lifestyle intervention focused on weight loss or a diabetes support and education condition, which were discontinued after ∼10 years. HbA1c levels were evaluated at years 1‐4, 6, 8, and 10. Cognitive function was evaluated up to four times between years 8‐18 with a cognitive battery that assessed memory, attention, and executive function domains. Cognitive scores were binned into four groups based on relative timing of cognitive assessments (8‐9; 10‐11; 12‐14; and 15‐18 years). We classified HbA1c variability according to: Variability Independent of the Mean (VIM), Average Real Variability (ARV), and data‐driven latent trajectories. Mixed linear regression models for standardized composite cognitive scores were adjusted for: repeated measures, order of cognitive test, years from randomization, randomization arm, age, sex, race/ethnicity, years of education, CVD history, and APOE ε4. Result: Four HbA1c trajectories were identified: increasing, decreasing, stable‐high, and stable‐low. Composite cognitive scores were significantly lower for increasing, decreasing, and stable‐high HbA1c trajectories ‐compared to stable‐low HbA1c (Table). In multivariable analysis, higher baseline HbA1c, ARV, and VIM were associated with lower composite cognitive scores, and differences between groups were similar by years since randomization. Estimates for ARV and VIM were attenuated when adjusted for baseline HbA1c (not shown). Estimates were similar for tests from all cognitive domains, with little heterogeneity by randomization arm. Conclusion: Among individuals with T2D, higher HbA1c at baseline and greater HbA1c variability over 10 years were significantly associated with lower cognitive scores, suggesting that maintaining glucose control may be useful for the prevention of cognitive decline. [ABSTRACT FROM AUTHOR]

Background: A small but growing body of evidence supports a relationship between neighborhood socioeconomic status (NSES) and cognitive decline. Additional work is needed to characterize this relationship controlling for risk factors such as cardiovascular, cerebrovascular, and genetic risk factors. Methods: Cognitive decline was assessed in association with NSES, and cardiovascular and cerebrovascular risk factors (heart disease, diabetes, hypertension, and stroke) in 8,198 individuals from the 1992–2010 waves of the Health and Retirement Study (HRS). Latent class trajectory analysis determined the number of cognitive trajectory classes that best fit the data, and a multinomial logistic regression model in the latent class framework assessed the risk for cognitive classes conferred by NSES index score and heart disease, diabetes, hypertension, and stroke across three trajectory classes of cognitive function. The analyses controlled for genetic risk for cognitive decline (including APOE genotype) and demographic variables, including education. Results: The HRS sample was 57.6% female and 85.5% White, with a mean age of 67.5(3.5) years at baseline. The three-quadratic-class model best fit the data, where higher classes represented better cognitive function. Those with better cognitive function were mainly younger white females. Those in the highest quartile of NSES had 57% higher odds of being in the high cognitive function class. Heart disease, diabetes, hypertension, and stroke each increased the odds having of lower cognitive function. Conclusions: In examining the relationship of cognitive status with various variables, neighborhood socioeconomic status, cardiovascular risk, and cerebrovascular risk persisted across the cognitive trajectory classes. [ABSTRACT FROM AUTHOR]

Delirium is an acute disorder of attention and cognition. It occurs across the life span, yet it is particularly common among older adults, and is closely linked with underlying neurocognitive disorders. Evidence is mounting that intervening on delirium may represent an important opportunity for delaying the onset or progression of dementia. To accelerate the current understanding of delirium, the Network for Investigation of Delirium: Unifying Scientists (NIDUS) held a conference "Advancing Delirium Research: A Scientific Think Tank" in June 2019. This White Paper encompasses the major knowledge and research gaps identified at the conference: advancing delirium definition and measurement, understanding delirium pathophysiology, and prevention and treatment of delirium. A roadmap of research priorities is proposed to advance the field in a systematic, interdisciplinary, and coordinated fashion. A call is made for an international consortium and biobank targeted to delirium, as well as a public health campaign to advance the field. [ABSTRACT FROM AUTHOR]

Objectives Genetic risks for cognitive decline are not modifiable; however their relative importance compared to modifiable factors is unclear. We used machine learning to evaluate modifiable and genetic risk factors for Alzheimer's disease (AD), to predict cognitive decline. Methods Health and Retirement Study participants, aged 65–90 years, with DNA and >2 cognitive evaluations, were included (n = 7,142). Predictors included age, body mass index, gender, education, APOE ε4, cardiovascular, hypertension, diabetes, stroke, neighborhood socioeconomic status (NSES), and AD risk genes. Latent class trajectory analyses of cognitive scores determined the form and number of classes. Random Forests (RF) classification investigated predictors of cognitive trajectories. Performance metrics (accuracy, sensitivity, and specificity) were reported. Results Three classes were identified. Discriminating highest from lowest classes produced the best RF performance: accuracy = 78% (1.0%), sensitivity = 75% (1.0%), and specificity = 81% (1.0%). Top ranked predictors were education, age, gender, stroke, NSES, and diabetes, APOE ε4 carrier status, and body mass index (BMI). When discriminating high from medium classes, top predictors were education, age, gender, stroke, diabetes, NSES, and BMI. When discriminating medium from the low classes, education, NSES, age, diabetes, and stroke were top predictors. Discussion The combination of latent trajectories and RF classification techniques suggested that nongenetic factors contribute more to cognitive decline than genetic factors. Education was the most relevant predictor for discrimination. [ABSTRACT FROM AUTHOR]

Background: Sex may be an important modifier of brain health in response to risk factors. We compared brain structure and function of older overweight and obese women and men with type 2 diabetes mellitus.Methods: Cross-sectional cognitive assessments and magnetic resonance images were obtained in 224 women and 95 men (mean age 69 years) with histories of type 2 diabetes mellitus and overweight or obesity. Prior to magnetic resonance images, participants had completed an average of 10 years of random assignment to either multidomain intervention targeting weight loss or a control condition of diabetes support and education. Total (summed gray and white) matter volumes, white matter hyperintensity volumes, and cerebral blood flow across five brain regions of interest were analyzed using mixed-effects models.Results: After covariate adjustment, women, compared with men, averaged 10.9 [95% confidence interval 3.3, 18.5; ≈1%] cc greater summed region of interest volumes and 1.39 [0.00002, 2.78; ≈54%] cc greater summed white matter hyperintensity volumes. Sex differences could not be attributed to risk factor profiles or intervention response. Their magnitude did not vary significantly with respect to age, body mass index, intervention assignment, or APOE-ε4 genotype. Sex differences in brain magnetic resonance images outcomes did not account for the better levels of cognitive functioning in women than men.Conclusions: In a large cohort of older overweight or obese adults with type 2 diabetes mellitus, differences in brain volumes and white matter disease were apparent between women and men, but these did not account for a lower prevalence of cognitive impairment in women compared with men in this cohort.Trial Registration: NCT00017953. [ABSTRACT FROM AUTHOR]

Summary: Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta‐analysis. Compared with body mass index–defined lower‐normal weight (18.5‐22.4 kg/m2), the risk of all‐cause dementia was higher among underweight individuals but lower among those with upper‐normal (22.5‐24.9 kg/m2) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all‐cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non‐linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative. [ABSTRACT FROM AUTHOR]

BACKGROUND: The prevalence of metabolic syndrome is higher among minority populations, including individuals of Mexican ethnic descent. Whether alignment to healthy dietary patterns is associated with lower risk of metabolic syndrome in this population is largely unknown. OBJECTIVE: To prospectively evaluate the associations between a priori diet quality scores and risk of metabolic syndrome and its components among postmenopausal women of Mexican ethnic descent. METHODS: A total of 334 women of Mexican ethnic descent who participated in the Women's Health Initiative (WHI) observational study without metabolic syndrome or diabetes at baseline (1993–1998) were included. Baseline diets were scored with the Alternate Mediterranean Diet (aMED), the Dietary Approaches to Stop Hypertension (DASH), the Healthy Eating Index (HEI-2010), the Mediterranean Diet Score (MDS), and the traditional Mexican Diet (MexD) score. Multivariable linear and logistic regression models were used to test the associations between baseline diet quality and risk of metabolic syndrome and its individual components at follow-up (2012-2013). RESULTS: Approximately 16% of women met the criteria for metabolic syndrome at follow-up. None of the diet quality indices were associated with risk of metabolic syndrome. However, higher vs lower DASH scores were associated with lower waist circumference (85.2 vs 88.0 cm) and glucose concentrations (90.0 vs 95.1 mg/dL), and higher HDL cholesterol (62.6 vs 59.0 mg/dL), while higher vs lower HEI-2010 scores were associated with lower waist circumference (83.9 vs 88.1 cm), triglycerides (103 vs 117 mg/dL) and glucose concentrations (89.5 vs 94.4 mg/dL), and higher HDL cholesterol levels (63.9 vs 58.5 mg/dL). CONCLUSIONS: Diet quality was not associated with risk of metabolic syndrome in this population. However, the results suggest that alignment to DASH and HEI-2010 recommendations may be beneficial for reducing some individual components of metabolic syndrome among postmenopausal women of Mexican descent. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]