Capturing Cognitive Aging in Vivo: Application of a Neuropsychological Framework for Emerging Digital Tools.

As the global burden of dementia continues to plague our healthcare systems, efficient, objective, and sensitive tools to detect neurodegenerative disease and capture meaningful changes in everyday cognition are increasingly needed. Emerging digital tools present a promising option to address many drawbacks of current approaches, with contexts of use that include early detection, risk stratification, prognosis, and outcome measurement. However, conceptual models to guide hypotheses and interpretation of results from digital tools are lacking and are needed to sort and organize the large amount of continuous data from a variety of sensors. In this viewpoint, we propose a neuropsychological framework for use alongside a key emerging approach-digital phenotyping. The Variability in Everyday Behavior (VIBE) model is rooted in established trends from the neuropsychology, neurology, rehabilitation psychology, cognitive neuroscience, and computer science literature and links patterns of intraindividual variability, cognitive abilities, and everyday functioning across clinical stages from healthy to dementia. Based on the VIBE model, we present testable hypotheses to guide the design and interpretation of digital phenotyping studies that capture everyday cognition in vivo. We conclude with methodological considerations and future directions regarding the application of the digital phenotyping approach to improve the efficiency, accessibility, accuracy, and ecological validity of cognitive assessment in older adults.

Age-related differences in ventral striatal and default mode network function during reciprocated trust.

Social relationships change across the lifespan as social networks narrow and motivational priorities shift to the present. Interestingly, aging is also associated with changes in executive function, including decision-making abilities, but it remains unclear how age-related changes in both domains interact to impact financial decisions involving other people. To study this problem, we recruited 50 human participants (Nyounger = 26, ages 18-34; Nolder = 24, ages 63-80) to play an economic trust game as the investor with three partners (friend, stranger, and computer) who played the role of investee. Investors underwent functional magnetic resonance imaging (fMRI) during the trust game while investees were seated outside of the scanner. Building on our previous work with younger adults showing both enhanced striatal responses and altered default-mode network (DMN) connectivity as a function of social closeness during reciprocated trust, we predicted that these relations would exhibit age-related differences. We found that striatal responses to reciprocated trust from friends relative to strangers and computers were blunted in older adults relative to younger adults, thus supporting our primary pre-registered hypothesis regarding social closeness. We also found that older adults exhibited enhanced DMN connectivity with the temporoparietal junction (TPJ) during reciprocated trust from friends compared to computers while younger adults exhibited the opposite pattern. Taken together, these results advance our understanding of age-related differences in sensitivity to social closeness in the context of trusting others.

A person-centered framework for designing music-based therapeutic studies in dementia: current barriers and a path forward.

Objectives: Music-based interventions have received growing attention to improve quality of life for people diagnosed with dementia. Results of randomized controlled trials and meta-analytic reviews to date, however, reveal a lack of conclusive evidence for or against the effectiveness of such interventions. Herein, we critically review the basic assumptions and methodological issues ingrained in the cultures of research and care as they relate to evaluating music-based treatments for people with dementia, and propose a shift in the methodology by which music interventions are empirically evaluated.Method: We begin by reviewing existing barriers to achieving clarity on the effectiveness of music interventions, and we highlight methodological and sociocultural constraints that have limited our ability to reach concrete conclusions in research studies to-date. We then consider several key factors that have demonstrated relevance in matching people to specific music-based interventions. Based on these key factors, we developed a person-centered framework integrating elements from precision-medicine methodology to guide intervention studies.Results: Our organizing framework systematically integrates the following factors to inform the design of intervention studies: 1) person-centered goals and desired outcomes; 2) differences among individuals in clinical, cognitive, and historical attributes; and 3) the context of intervention and access to resources.Conclusion: Integration of the proposed framework into empirical investigations of music interventions for people living with dementia will inform precise and tailored interventions that will bring clarity to this growing body of research. Another aim of this framework is to foster a more humane, person-centered approach to our culture of care.

Remind Me To Remember: A pilot study of a novel smartphone reminder application for older adults with dementia and mild cognitive impairment.

The SmartPrompt is a smartphone-based reminder application informed by a neuropsychological model of functional disability. This laboratory-based pilot study examined the SmartPrompt feasibility, efficacy, and subjective usability using a within-participant, counterbalanced, cross-over design. Ten participants (M age = 80.3 + 8.2; M education = 15.7 + 2.5; 60% female) with mild cognitive impairment or mild dementia completed the Remember to Drink Test, which required preparing a glass of water at four predetermined times, in a SmartPrompt (SP) and Unprompted condition (UP). Written cues and a clock were available in both conditions; however, in the SP, the smartphone presented auditory alarms and visual reminders to obtain the water at specified times and required photo logging. In a separate session, caregivers were trained and tested on configuring the SmartPrompt. Overall, caregivers and participants learned to effectively use the SmartPrompt. Caregivers achieved near-perfect scores on the configuration quiz and responded well to training. Participants completed significantly more Remember to Drink tasks in the SP (93%) than UP (56%); checking the cues/clock decreased by 87% in the SP. Usability ratings were excellent among caregivers and fair among participants. Results indicate that the SmartPrompt holds promise for reducing functional disability in older adults with cognitive difficulties in at-home contexts.

The goal-control model: An integrated neuropsychological framework to explain impaired performance of everyday activities.

OBJECTIVE: This review describes the relatively small body of neuropsychological and cognitive research conducted over the past 100 years focused on theoretical models explaining the neurocognitive processes that support everyday functioning and the breakdown of functional abilities in the face of neurological damage or disease. METHOD: The historical roots of the theories of everyday activities based on direct observation of behavior in neurology and diary reports of everyday errors in cognitive psychology are presented, followed by a review of the empirical findings and resulting theoretical conceptualizations from case studies and group studies of various clinical populations in neuropsychology. RESULTS: We conclude with a new framework (the goal-control model) that integrates the most recent empirical findings in neuropsychology with mechanisms proposed by cognitive models. CONCLUSIONS: The goal-control model offers empirically supported solutions to understanding and predicting functioning in the real world. This new model generates testable predictions for future research and provides guidance for clinical assessment and interventions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

When and how did you go wrong? Characterizing mild functional difficulties in older adults during an everyday task.

Mild functional difficulties associated with cognitive aging may be reliably measured by coding "micro-errors" during everyday tasks, like meal preparation. Micro-errors made by 25 older adult and 48 younger adults were coded on four dimensions to evaluate the influence of: 1) poor error monitoring; 2) goal decay; 3) competition for response selection when switching to a new subtask; and 4) interference from distractor objects. Micro-errors made by young adults under a dual task load also were analyzed to determine the influence of overall performance level. Older adults' micro-errors were observed when switching to a new subtask and to unrelated distractors. Slowed error monitoring and goal decay also influenced micro-errors in older adults, but not significantly more so than younger adults under the dual task. Interventions to reduce interference from distractors and to increase attention at critical choice points during tasks may optimize everyday functioning and preclude decline in older adults.

Effectiveness of online education for recruitment to an Alzheimer's disease prevention clinical trial.

INTRODUCTION: Low awareness of Alzheimer's disease (AD) clinical trials is a recruitment barrier. To assess whether online education may affect screening rates for AD prevention clinical trials, we conducted an initial prospective cohort study (n = 10,450) and subsequent randomized study (n = 351) using an online digital tool: AlzU.org. METHODS: A total of 10,450 participants were enrolled in an initial cohort study and asked to complete a six-lesson course on AlzU.org, as well as a baseline and 6-month follow-up questionnaire. Participants were stratified into three groups based on lesson completion at 6 months: group 1 (zero to one lesson completed), group 2 (two to four lessons), and group 3 (five or more lessons). For the subsequent randomized-controlled trial (RCT), 351 new participants were enrolled in a six-lesson course (n = 180) versus a time-neutral control (n = 171). Screening and enrollment in the Anti-Amyloid Treatment in Asymptomatic AD (A4) clinical trial were reported via the 6-month questionnaire and are the primary outcomes. RESULTS: Cohort: 3.9% of group 1, 5% of group 2, and 8.4% of group 3 screened for the A4 trial. Significant differences were found among the groups (P < 0.001). Post hoc analyses showed differences in A4 screening rates between groups 1 and 3 (P < 0.001) and groups 2 and 3 (P = 0.0194). There were no differences in enrollment among the three groups. RCT: 2.78% of the intervention group screened for A4 compared to 0% of controls (P = 0.0611). DISCUSSION: Online education via the AlzU.org digital tool may serve as an effective strategy to supplement clinical trial recruitment.

Informant Reporting in Mild Cognitive Impairment: Sources of Discrepancy on the Functional Activities Questionnaire.

OBJECTIVE: Relative to dementia, little is known about informant bias in mild cognitive impairment (MCI). We investigated the influence of informant demographic and relational characteristics on reports of everyday functioning using the Functional Activities Questionnaire (FAQ). METHOD: Four thousand two hundred eighty-four MCI participants and their informants from the National Alzheimer's Coordinating Center Uniform Data Set were included. Informants were stratified according to cohabitation, relationship, visit frequency, race/ethnicity, education, and sex. Informant-rated Mean FAQ score was compared across these groups using univariate general linear model analyses and post hoc tests. Interactions were tested between informant variables. The predictive contribution of informant variables to FAQ score was explored using hierarchical linear regression. Analyses covaried for participant cognition using a cognitive composite score, and for participant age, sex, and depression. RESULTS: After controlling for participant cognition, depression, age, and sex, informant-rated FAQ scores varied significantly across all informant variables (p's < .005, ηp2's ≤ .033) except sex and visit frequency. FAQ scores were higher (more impaired) among informants who cohabitate with the participant, among paid caregivers, spouses, and adult children, and among informants with higher levels of education. Scores were lowest (less impaired) among Black/African American informants as compared to all other racial/ethnic groups. CONCLUSIONS: Demographic and relational characteristics of informants influence the perception and reporting of instrumental activities of daily living in adults with MCI. As everyday functioning is crucial for differential diagnosis and treatment outcome measurement, it is important to be aware of sources of informant report discrepancies.

Individualized clinical management of patients at risk for Alzheimer's dementia.

INTRODUCTION: Multidomain intervention for Alzheimer's disease (AD) risk reduction is an emerging therapeutic paradigm. METHODS: Patients were prescribed individually tailored interventions (education/pharmacologic/nonpharmacologic) and rated on compliance. Normal cognition/subjective cognitive decline/preclinical AD was classified as Prevention. Mild cognitive impairment due to AD/mild-AD was classified as Early Treatment. Change from baseline to 18 months on the modified Alzheimer's Prevention Cognitive Composite (primary outcome) was compared against matched historical control cohorts. Cognitive aging composite (CogAging), AD/cardiovascular risk scales, and serum biomarkers were secondary outcomes. RESULTS: One hundred seventy-four were assigned interventions (age 25-86). Higher-compliance Prevention improved more than both historical cohorts (P = .0012, P < .0001). Lower-compliance Prevention also improved more than both historical cohorts (P = .0088, P < .0055). Higher-compliance Early Treatment improved more than lower compliance (P = .0007). Higher-compliance Early Treatment improved more than historical cohorts (P < .0001, P = .0428). Lower-compliance Early Treatment did not differ (P = .9820, P = .1115). Similar effects occurred for CogAging. AD/cardiovascular risk scales and serum biomarkers improved. DISCUSSION: Individualized multidomain interventions may improve cognition and reduce AD/cardiovascular risk scores in patients at-risk for AD dementia.

The Virtual Kitchen Challenge: preliminary data from a novel virtual reality test of mild difficulties in everyday functioning.

Background: Efficient, objective measures of mild functional difficulties are lacking. Preliminary data from a novel, non-immersive virtual reality, performance-based task (Virtual Kitchen Challenge; VKC) were obtained to address this gap. Methods: 14 older and 21 younger adults completed cognitive tests and two everyday tasks (breakfast, lunch) in the VKC with virtual objects and a touch-screen and in the Real Kitchen with real objects (order counterbalanced). Automated performance measures were obtained from the VKC program and human coders scored VKC and Real Kitchen videos for errors. Results: Older adults made more errors than younger adults on the VKC and Real Kitchen, with similar error patterns across measures. VKC automated measures were significantly related to measures from human coders, performance on the Real Kitchen, and cognitive test scores. Conclusion: The VKC is a valid and highly efficient performance-based measure of subtle functional difficulties with great potential for future clinical and research applications.

Utility of the NIH Toolbox for assessment of prodromal Alzheimer's disease and dementia.

INTRODUCTION: The NIH Toolbox Cognition Battery (NIHTB-CB) is a computer-based protocol not yet validated for clinical assessment. METHODS: We administered the NIHTB-CB and traditional neuropsychological tests to 247 Memory Disorders and Alzheimer's Prevention Clinic patients with subjective cognitive decline, mild cognitive impairment, mild dementia due to Alzheimer's disease, and normal cognition. Principal component analysis, partial correlations, and univariate general linear model tests were performed to assess construct validity. Discriminant function analyses compared classification accuracy. RESULTS: Principal component analysis identified three conceptually coherent factors: memory (MEMNIH), executive function (EFNIH), and crystallized intelligence (CINIH). These factors were strongly associated with corresponding traditional tests and differed across diagnostic groups as expected. Both NIHTB and traditional batteries yielded strong overall discriminative ability (>80%). DISCUSSION: The NIHTB-CB is a valid method to assess neurocognitive domains pertinent to aging and dementia and has utility for applications in a memory clinic setting.

The clinical practice of risk reduction for Alzheimer's disease: A precision medicine approach.

Like virtually all age-related chronic diseases, late-onset Alzheimer's disease (AD) develops over an extended preclinical period and is associated with modifiable lifestyle and environmental factors. We hypothesize that multimodal interventions that address many risk factors simultaneously and are individually tailored to patients may help reduce AD risk. We describe a novel clinical methodology used to evaluate and treat patients at two Alzheimer's Prevention Clinics. The framework applies evidence-based principles of clinical precision medicine to tailor individualized recommendations, follow patients longitudinally to continually refine the interventions, and evaluate N-of-1 effectiveness (trial registered at ClinicalTrials.gov NCT03687710). Prior preliminary results suggest that the clinical practice of AD risk reduction is feasible, with measurable improvements in cognition and biomarkers of AD risk. We propose using these early findings as a foundation to evaluate the comparative effectiveness of personalized risk management within an international network of clinician researchers in a cohort study possibly leading to a randomized controlled trial.

Detection of neurodevelopmental diversity in memory clinics-Validation of a self-report measure.

BACKGROUND: Neurodevelopmental learning and attentional disorders (NLAD) such as dyslexia, dyscalculia and attention deficit hyperactivity disorder (ADHD) affect at least 6% of the adult population or more. They are associated with atypical cognitive patterns in early and adult life. The cognitive patterns of affected individuals in late life have never been described. One main challenge is detecting individuals in clinical settings during which mild cognitive changes could be confounding the clinical presentation. This is a critical research gap because these conditions interact, across the life course, with an individual's risk for dementia. Also, learning disabilities which present in childhood pose persistent cognitive differences in areas involving executive function, reading and math. Clinicians lack tools to detect undiagnosed neurodevelopmental in adults with memory disorders. The majority of patients presenting at memory clinics today come from a generation during which NLAD were not yet clinically recognized. In this study, we hypothesized that a self-report scale can detect NLAD in a memory clinic population. METHODS: We developed a self-report, retrospective childhood cognitive questionnaire including key attributes adapted from prior validated measures. 233 participants were included in the primary analysis. RESULTS: Confirmatory Factor Analysis resulted in a best-fit model with six labelled factors (Math, Language, Attention, Working Memory, Sequential Processing, and Executive Function) and 15 total question items. The model demonstrated unidimensionality, reliability, convergent validity, discriminant validity, and predictive validity. Using 1.5 standard deviations as the cut-off, subjects were categorized into: Normal (n = 169), Language (n = 10), Math (n = 12), Attention (n = 10) or Other/Mixed (n = 32). CONCLUSION: A self-report measure can be a useful tool to elicit childhood cognitive susceptibilities in various domains that could represent NLAD among patients in a memory clinic setting, even in the presence of mild cognitive impairment.

Using social media to disseminate education about Alzheimer's prevention & treatment: a pilot study on Alzheimer's universe (www.AlzU.org).

BACKGROUND: The use of social media may be a valuable tool for dissemination of patient education interventions. However, in Alzheimer's disease (AD), little data exists about the effectiveness, associated cost, or conditions for utilization. METHODS: Alzheimer's Universe (www.AlzU.org) is an online educational portal that provides evidence-based educational content for the public and a variety of activities related to optimizing AD management. The primary goal of our study was to assess the effectiveness of using the social media platform Facebook.com as a tool to recruit subjects to visit AlzU.org via targeted advertising and evaluate the associated costs. Secondary outcomes included AlzU.org join rates, lesson and activity completion rates, user demographics and attitudes about the education research platform. RESULTS: A total of $706 generated 4268 visits to AlzU.org via a series of page posts promoted with targeted advertising to individuals with previously expressed interest in 'Alzheimer's disease,' to those who had 'liked' the Alzheimer's Association page, and followers of www.facebook.com/AlzheimersDisease. Advertising used different promotional taglines in the Facebook Advertising manager tool using 'Cost Per Click' and the 'Optimized for Engagement' settings. Across all strategies combined, 503 visitors joined AlzU.org (11.8% join rate), 412 engaged with at least one lesson/activity (82%), and 100 completed all available lessons and activities (19.8%). Users were primarily women (79.8%) and the most common age group was 50's (43.3%, range 22-92). The majority joined AlzU.org to learn more about AD prevention or treatment (66.3% and 65.3%, respectively). Over 90% were satisfied with their experience. DISCUSSION: Subjects were quickly and cost-effectively recruited to AlzU.org. Completion rates of education content and activities were adequate, and subjects were highly satisfied with their experiences. Overall, targeted advertising on Facebook.com was an effective means of disseminating AD education online.

Nutritional interventions for Alzheimer's prevention: a clinical precision medicine approach.

Alzheimer's disease (AD) is a major source of morbidity and mortality, with the disease burden expected to rise as the population ages. No disease-modifying agent is currently available, but recent research suggests that nutritional and lifestyle modifications can delay or prevent the onset of AD. However, preventive nutritional interventions are not universally applicable and depend on the clinical profile of the individual patient. This article reviews existing nutritional modalities for AD prevention that act through improvement of insulin resistance, correction of dyslipidemia, and reduction of oxidative stress, and discusses how they may be modified on the basis of individual biomarkers, genetics, and behavior. In addition, we report preliminary results of clinical application of these personalized interventions at the first AD prevention clinic in the United States. The use of these personalized interventions represents an important application of precision medicine techniques for the prevention of AD that can be adopted by clinicians across disciplines.

Giant coronary artery aneurysm in a patient with Behçet's disease.

Behçet's disease is a rare autoimmune vasculitis that may cause coronary artery aneurysms. We discuss the evaluation and management decisions for a 19-year-old female with a giant rapidly expanding aneurysm of the proximal left anterior descending coronary artery and Behçet's disease.