Small vessel cerebrovascular disease is associated with cognition in prospective Alzheimer's clinical trial participants.

BACKGROUND: Secondary prevention clinical trials for Alzheimer's disease (AD) target amyloid accumulation in asymptomatic, amyloid-positive individuals, but it is unclear to what extent other pathophysiological processes, such as small vessel cerebrovascular disease, account for participant performance on the primary cognitive outcomes in those trials. White matter hyperintensities are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) that reflect small vessel cerebrovascular disease. They are associated with cognitive functioning in older adults and with clinical presentation and course of AD, particularly when distributed in posterior brain regions. The purpose of this study was to examine to what degree regional WMH volume is associated with performance on the primary cognitive outcome measure in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, a secondary prevention trial. METHODS: Data from 1791 participants (59.5% women, mean age (SD) 71.6 (4.74)) in the A4 study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) companion study at the screening visit were used to quantify WMH volumes on T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Cognition was assessed with the preclinical Alzheimer cognitive composite (PACC). We tested the association of total and regional WMH volumes with PACC performance, adjusting for age, education, and amyloid positivity status, with general linear models. We also considered interactions between WMH and amyloid positivity status. RESULTS: Increased frontal and parietal lobe WMH volume was associated with poorer performance on the PACC. While amyloid positivity was also associated with lower cognitive test scores, WMH volumes did not interact with amyloid positivity status. CONCLUSION: These results highlight the potential of small vessel cerebrovascular disease to drive AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered when evaluating outcome in trials, both as potential effect modifiers and as a possible target for intervention or prevention.

The effects of insufficient sleep and adequate sleep on cognitive function in healthy adults.

STUDY OBJECTIVES: Although sleep affects a range of waking behaviors, the majority of studies have focused on sleep loss with relatively little attention on sustained periods of adequate sleep. The goal of this study was to use an experimental design to examine the effect of both of these sleep patterns on cognitive performance in healthy adults. METHODS: This study used a randomized crossover design. Participants who regularly slept 7-9 hours/night completed two 6-week intervention conditions, adequate sleep (maintenance of habitual bed/wake times) and insufficient sleep (reduction in sleep of 1.5 hours relative to adequate sleep), separated by a 2-6weeks (median=43days) washout period. Cognitive functioning was evaluated at baseline and endpoint of each intervention using the NIH Toolbox Cognition Battery. General linear models contrasted scores following each condition to the baseline of the first condition; the baseline of the second condition was included to evaluate practice effects. RESULTS: Sixty-five participants (age 35.9 ± 4.9years, 89% women, 52% non-White race/ethnicity) completed study procedures. There was improvement in performance on the List Sorting Working Memory task after the adequate sleep condition that exceeded practice effects. Cognitive performance after insufficient sleep did not reach the level expected with practice and did not differ from baseline. A similar pattern was found on the Flanker Inhibitory Control and Attention task. CONCLUSIONS: These findings contribute to our understanding of the complex interplay between sleep and cognition and demonstrate that consistent, stable sleep of at least 7 hours/night improves working memory and response inhibition in healthy adults. CLINICAL TRIAL REGISTRATION: The manuscript reports on data from two clinical trials: Impact of Sleep Restriction on Performance in Adults (URL: https://clinicaltrials.gov/ct2/show/NCT02960776, ID Number: NCT02960776) and Impact of Sleep Restriction in Women (URL: https://clinicaltrials.gov/ct2/show/NCT02835261, ID Number: NCT02835261).

Multivitamin Supplementation Improves Memory in Older Adults: A Randomized Clinical Trial.

BACKGROUND: Maintenance of cognitive abilities is of critical importance to older adults, yet few effective strategies to slow cognitive decline currently exist. Multivitamin supplementation is used to promote general health; it is unclear whether it favorably affects cognition in older age. OBJECTIVES: To examine the effect of daily multivitamin/multimineral supplementation on memory in older adults. METHODS: The COcoa Supplement and Multivitamin Outcomes Study Web (COSMOS-Web) ancillary study (NCT04582617) included 3562 older adults. Participants were randomly assigned to a daily multivitamin supplement (Centrum Silver) or placebo and evaluated annually with an Internet-based battery of neuropsychological tests for 3 y. The prespecified primary outcome measure was change in episodic memory, operationally defined as immediate recall performance on the ModRey test, after 1 y of intervention. Secondary outcome measures included changes in episodic memory over 3 y of follow-up and changes in performance on neuropsychological tasks of novel object recognition and executive function over 3 y. RESULTS: Compared with placebo, participants randomly assigned to multivitamin supplementation had significantly better ModRey immediate recall at 1 y, the primary endpoint (t(5889) = 2.25, P = 0.025), as well as across the 3 y of follow-up on average (t(5889) = 2.54, P = 0.011). Multivitamin supplementation had no significant effects on secondary outcomes. Based on cross-sectional analysis of the association between age and performance on the ModRey, we estimated that the effect of the multivitamin intervention improved memory performance above placebo by the equivalent of 3.1 y of age-related memory change. CONCLUSIONS: Daily multivitamin supplementation, compared with placebo, improves memory in older adults. Multivitamin supplementation holds promise as a safe and accessible approach to maintaining cognitive health in older age. This trial was registered at clinicaltrials.gov as NCT04582617.

A Pilot Study of Cognition Among Hypoparathyroid Adults.

PURPOSE: Hypoparathyroid patients describe cognitive deficits, yet data regarding objective assessment of cognitive function are limited. We assessed cognition in a pilot study of hypoparathyroid patients using the National Institutes of Health Toolbox® Adult Cognitive Battery (NIHTB-CB). We also sought to determine whether cognition relates to emotion, quality of life, and hypoparathyroidism-related biochemistries. METHODS: Nineteen hypoparathyroid patients were studied. Objective cognition was assessed with NIHTB-CB. Impairment was defined as fully demographically adjusted T-score < 1.5 SD in at least 1 cognitive domain or < 1 SD in 2 or more domains. RESULTS: Of the 19 participants (17 women; median age 49; 18 postsurgical), impaired demographically adjusted NIHTB-CB cognition scores were observed in 13 subjects (68%). Cognition scores correlated with self-reported perception of general health. Processing speed was the most commonly impaired cognitive domain, with T-scores that were ≤2 SD in 6 subjects (32%). Processing speed correlated with serum calcium (r = 0.53, P = 0.023) and inversely with serum phosphate (r = -0.48, P = 0.042) levels. CONCLUSIONS: Impaired cognition using the NIHTB-CB was common in this small pilot cohort of hypoparathyroid patients. Slower processing speed was present and associated with lower serum calcium and higher serum phosphate levels. Larger controlled studies with additional neuropsychological testing are needed to investigate cognitive function in hypoparathyroidism.

Cognitive Functioning and Health in Hispanic/Latina Breast Cancer Survivors.

We examined the effect of waist-to-hip ratio, body mass index (BMI), diet, and physical activity on cognitive functioning among Hispanic/Latina breast cancer survivors in a cross-sectional design study. Participants were 54 Hispanic/Latina breast cancer survivors and completed the NIH Toolbox Cognition Battery. Linear Regression Models tested if statistically significant correlations held with covariates. After controlling for covariates, moderate and hard physical activity were not associated with cognition. However, very hard physical activity was positively associated with faster processing speed (ß = 0.56, p < 0.001) and composite cognition score (ß = 0.36, p < 0.05). Total time (minutes) of moderate to very hard physical activity was positively associated with cognitive flexibility (ß = 0.52, p < 0.001). Total caloric intake was positively associated with episodic memory (ß = 0.35 p < 0.05). BMI and WHR were not associated with cognition. These findings showed positive association with engagement in more MVPA and harder intensity physical activity to better cognitive functioning among Hispanic/Latina breast cancer survivors.ClinicalTrials.gov NCT02780271.

¡Mi Vida Saludable! A randomized, controlled, 2 × 2 factorial trial of a diet and physical activity intervention among Latina breast cancer survivors: Study design and methods.

BACKGROUND: Most Latina breast cancer survivors do not meet diet and physical activity (PA) guidelines for cancer survivors and effective lifestyle interventions to adopt and maintain these recommendations are limited, especially among underserved populations. Here we describe the design, methods and enrollment of a 2 × 2 factorial-designed trial testing the separate effects of the ¡Mi Vida Saludable! (My Healthy Life!) intervention program on changes in diet and PA behaviors among Latina breast cancer survivors. METHODS: Latinas with a history of stage 0-III breast cancer, no evidence of recurrent/metastatic disease, and > 90 days post-treatment were primarily identified via cancer registries and physician referral. Participants were randomized to four arms: 1) 4 weeks of in-person group sessions plus 11 months of eHealth communication, 2) in-person group sessions alone, 3) eHealth alone, or 4) control. All participants received a Fitbit to self-monitor PA. Assessments at baseline, 6 and 12 months include diet, PA, anthropometrics, predictors and mediators of behavior change, psychosocial and quality of life outcomes, and blood draw. RESULTS: Of 884 women screened between January 2016 and September 2018, 27% were eligible. Primary reasons for ineligibility included not being willing/able to participate due to work/life responsibilities, health reasons, or transportation. Of 241 eligible women, 167 completed baseline assessment and enrolled. CONCLUSIONS: We successfully enrolled a diverse group of breast cancer survivors representing more than 15 Latin American nationalities to a diet and physical activity trial. If effective, the ¡Mi Vida Saludable! program can be implemented by community groups and medical centers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02780271, registered May 2016.

Anterolateral entorhinal cortex volume is associated with memory retention in clinically unimpaired older adults.

The entorhinal cortex is subdivided into anterolateral entorhinal cortex (alERC) and posteromedial entorhinal cortex (pmERC) subregions, which are theorized to support distinct cognitive roles. This distinction is particularly important as the alERC is one of the earliest cortical regions affected by Alzheimer's pathology and related neurodegeneration. The relative associations of alERC/pmERC with neuropsychological test performance have not been examined. We examined how alERC/pmERC volumes differentially relate to performance on 1) the Modified Rey Auditory Learning Test (ModRey), a verbal memory test designed to assess normal/preclinical populations, 2) the Montreal Cognitive Assessment (MoCA), and 3) the National Alzheimer's Coordinating Center neuropsychological battery. We also examined whether alERC/pmERC volumes correlate with Alzheimer's disease cerebrospinal fluid (CSF) biomarkers. In 65 cognitively healthy (CDR = 0) older adults, alERC, but not pmERC, volume was associated with ModRey memory retention. Only alERC volume differentiated between participants who scored above and below the MoCA cutoff score for impairment. Evaluating the MoCA subdomains revealed that alERC was particularly associated with verbal recall. On the National Alzheimer's Coordinating Center battery, both alERC and pmERC volumes were associated with Craft story recall and Benson figure copy, but only alERC volume was associated with Craft story retention and semantic fluency. Neither alERC nor pmERC volume correlated with CSF levels of amyloid or tau, and regression analyses showed that alERC volume and CSF amyloid levels were independently associated with ModRey retention performance. Taken together, these results suggest that the alERC is important for memory performance and that alERC volume differences are related to a pattern of neuropsychological test performance (i.e., impairments in episodic memory and semantic fluency) typically seen in clinical Alzheimer's disease.

Tract-defined regional white matter hyperintensities and memory.

White matter hyperintensities (WMH) are common radiological findings among older adults and strong predictors of age-related cognitive decline. Recent work has implicated WMH in the pathogenesis and symptom presentation of Alzheimer's disease (AD), which is characterized clinically primarily by a deficit in memory. The severity of WMH volume is typically quantified globally or by lobe, whereas white matter itself is organized by tracts and fiber classes. We derived WMH volumes within white matter tract classes, including association, projection, and commissural tracts, in 519 older adults and tested whether WMH volume within specific fiber classes is related to memory performance. We found that increased association and projection tract defined WMH volumes were related to worse memory function but not to a global cognition summary score that excluded memory. We conclude that macrostructural damage to association and projection tracts, manifesting as WMH, may result in memory decline among older adults.

Modification of everyday activities and its association with self-awareness in cognitively diverse older adults.

Cognitive impairment (CI) in older adults is frequently accompanied by difficulty performing complex everyday activities (e.g., managing finances). However, it is unclear if and how older adults with CI modify their activities (i.e., Do individuals continue, monitor, seek help with, change their approach to, or stop different activities?). In the current study, we examined if older adults with CI are concerned about their ability to carry out complex activities, if and how they modify activities based on their concern, and the factors associated with activity modification. We hypothesized that older adults with CI will more frequently be concerned about, and modify, everyday activities than cognitively healthy (HE) older adults, and that higher awareness of memory loss in the CI group would relate to more frequent modification. The sample included 81 older adults (51 HEs; mean age 70.02 (7.34) and 30 CI; mean age 75.97 (8.12)). Compared to HEs, the CI group reported having more concern about, F(3,77) = 5.50, p = 0.02, and modifying a greater number of activities, F(3,77) = 5.02, p = 0.03. Medication management (30%) and completing taxes (33.3%) were among the most frequently modified activities for the CI and HE groups, respectively. In the CI group, higher memory awareness was associated with more concern (r = .53, p = .005) and activity modification (r = 0.55, p = .003). Findings provide novel information about how cognitively diverse older adults navigate complex activities in daily life. We propose a preliminary theoretical model by which self-awareness may influence navigation of everyday activities in the context of CI.

Cerebrospinal fluid amyloid levels are associated with delayed memory retention in cognitively normal biomarker-negative older adults.

Alzheimer's disease is defined by abnormal levels of amyloid and tau biomarkers. Even cognitively normal older adults with clinically relevant amyloid and tau levels perform worse on memory tests. However, it is unclear if the relationship between biomarker level and memory extends below clinical thresholds. We hypothesized that even subclinical biomarker levels are associated with memory when measured with neuropsychological tests designed to detect dysfunction in preclinical disease states. In a group of cognitively normal, "biomarker-negative" older men and women, we investigated the relationship between cerebrospinal fluid biomarker levels and memory measured with the ModRey, a list-learning task designed to assess memory in preclinical and cognitively normal adults. Cerebrospinal amyloid levels were associated with ModRey memory retention, the proportion of information retained after a delay period. When older adults with mild impairment were included, cerebrospinal fluid tau levels were also associated with ModRey retention. The association of amyloid and tau levels with memory was independent of each other. These results suggest cognitive changes associated with Alzheimer's disease pathology might occur earlier than currently thought.

Neuropsychological Function Response to Nocturnal Blue Light Blockage in Individuals With Symptoms of Insomnia: A Pilot Randomized Controlled Study.

OBJECTIVES: Insomnia is associated with neuropsychological dysfunction. Evidence points to the role of nocturnal light exposure in disrupted sleep patterns, particularly blue light emitted through smartphones and computers used before bedtime. This study aimed to test whether blocking nocturnal blue light improves neuropsychological function in individuals with insomnia symptoms. METHODS: This study used a randomized, placebo-controlled crossover design. Participants were randomly assigned to a 1-week intervention with amber lenses worn in wrap-around frames (to block blue light) or a 1-week intervention with clear lenses (control) and switched conditions after a 4-week washout period. Neuropsychological function was evaluated with tests from the NIH Toolbox Cognition Battery at three time points: (1) baseline (BL), (2) following the amber lenses intervention, and (3) following the clear lenses intervention. Within-subjects general linear models contrasted neuropsychological test performance following the amber lenses and clear lenses conditions with BL performance. RESULTS: Fourteen participants (mean(standard deviation, SD): age = 46.5(11.4)) with symptoms of insomnia completed the protocol. Compared with BL, individuals performed better on the List Sorting Working Memory task after the amber lenses intervention, but similarly after the clear lenses intervention (F = 5.16; p = .014; η2 = 0.301). A similar pattern emerged on the Pattern Comparison Processing Speed test (F = 7.65; p = 0.002; η2 = 0.370). Consideration of intellectual ability indicated that treatment with amber lenses "normalized" performance on each test from approximately 1 SD below expected performance to expected performance. CONCLUSIONS: Using a randomized, placebo-controlled crossover design, we demonstrated improvement in processing speed and working memory with a nocturnal blue light blocking intervention among individuals with insomnia symptoms. (JINS, 2019, 25, 668-677).

The ModRey: An Episodic Memory Test for Nonclinical and Preclinical Populations.

List learning tests are used in practice for diagnosis and in research to characterize episodic memory, but often suffer from ceiling effects in unimpaired individuals. We developed the Modified Rey Auditory Verbal Learning Test, or ModRey, an episodic memory test for use in normal and preclinical populations. We administered the ModRey to 230 healthy adults and to 86 of the same individuals 102 days later and examined psychometric properties and effects of demographic factors. Primary measures were normally distributed without evidence of ceiling effect. Differences between alternate forms were of very small magnitude and not significant. Test-retest reliability was good. Higher participant age and lower participant education was associated with poorer performance across most outcome measures. We conclude that the ModRey is appropriate for episodic memory characterization in normal populations and could be used as an outcome measure in studies involving preclinical populations.

Expression of positive emotions differs in illness and recovery in anorexia nervosa.

People with Anorexia Nervosa (AN) display reduced facial expression of emotions. This study investigated the expression of positive affect in response to a film, examining Duchenne and non-Duchenne smiles in 20 women who have recovered from AN (REC), 20 with acute AN and 20 healthy controls (HC). The results indicated that the REC group exhibited Duchenne and non-Duchenne smiles with higher duration and intensity than the AN group, comparable to the HC group. The findings warrant longitudinal studies to confirm that reduced expressivity is linked to acute AN, ameliorating after recovery.

Facial expression of positive emotions in individuals with eating disorders.

A large body of research has associated Eating Disorders with difficulties in socio-emotional functioning and it has been argued that they may serve to maintain the illness. This study aimed to explore facial expressions of positive emotions in individuals with Anorexia Nervosa (AN) and Bulimia Nervosa (BN) compared to healthy controls (HC), through an examination of the Duchenne smile (DS), which has been associated with feelings of enjoyment, amusement and happiness (Ekman et al., 1990). Sixty participants (AN=20; BN=20; HC=20) were videotaped while watching a humorous film clip. The duration and intensity of DS were subsequently analyzed using the facial action coding system (FACS) (Ekman and Friesen, 2003). Participants with AN displayed DS for shorter durations than BN and HC participants, and their DS had lower intensity. In the clinical groups, lower duration and intensity of DS were associated with lower BMI, and use of psychotropic medication. The study is the first to explore DS in people with eating disorders, providing further evidence of difficulties in the socio-emotional domain in people with AN.