Jason Hassenstab, Ph.D. - US grants

DESCRIPTION (provided by applicant): This is an application for a Mentored Patient-Oriented Career Development Award (K23). This award will provide the Applicant with advanced skills needed to establish an independent program of research in obesity and metabolic dysfunction using neuroimaging and neuropsychological methodologies. The proposed study will use fMRI, biomarkers of metabolic functioning, and neuropsychological tests to examine changes in cognition and brain response in obese and sedentary middle aged adults undergoing treatment for insulin resistance. We will enroll 75 obese participants who are participating in an existing study of weight reduction at the Nutrition and Obesity Research Center at Washington University Medical School. The participants will be randomly assigned to one of three conditions: 1) Six months of treatment with an oral thiazolidinedione medication (pioglitazone) to increase insulin sensitivity (n=25); 2) Six months of a standardized weight reduction intervention to achieve an 8-10% weight reduction and increased insulin sensitivity (n=25); or 3) A wait-list control group following 6 months of usual diet and weight maintenance (n=25). At baseline and follow- up, all participants will complete glucose clamp testing, body composition assessment, blood tests, blood pressure checks, comprehensive psychometric assessment, brief psychiatric assessment, physical activity questionnaires, and structural and functional MRI. The aims of the study are: 1) To determine if neuropsychological performance will improve as a function of increased insulin sensitivity and 2) To determine whether improved sensitivity to insulin will result in increased neural efficiency as measured by fMRI brain response. The Applicant proposes a comprehensive training plan, combining didactic instruction with established researchers; formal coursework including completion of a Master's Degree in Clinical Investigation; participation in several advanced workshops; participation in ongoing seminars at Washington University Medical School including the Nutrition and Obesity Research Seminar, the Knight Alzheimer's Disease Research Center; and applied training experiences with individual mentors. Specific training goals include advanced knowledge and skill acquisition in neuroimaging methodologies, including task-based fMRI, longitudinal approaches in fMRI, and structural MRI cortical reconstruction techniques. Training in advanced statistical modeling methodologies will also be provided by coursework and workshop participation. Additional coursework will be completed in nutrition, metabolism, endocrinology, multimodal neuroimaging, and the responsible conduct of research. The overall research goal of this proposal is to test the hypothesis that improved insulin sensitivity achieved through weight reduction or thiazolidinedione treatment is accompanied by beneficial changes in cognitive performance and fMRI brain response.

The Ambulatory Research in Cognition (ARC) study will leverage the increasing popularity of smartphones to improve upon standard in-clinic cognitive testing, providing a robust characterization of cognition in participants enrolled in the Dominantly-Inherited Alzheimer Network (DIAN) study. One of the most important and face-valid indicators of Alzheimer?s disease (AD) is a change in cognition, but assessing cognition in-clinic has several drawbacks. First, performance is influenced by day to day fluctuations in stress, fatigue, sleep patterns, and mood. Second, the testing takes place in environments that are fundamentally different from where cognitively demanding tasks are performed in daily life. Finally, by design, cognition is typically assessed very infrequently, usually once per year or every two years (as is the case in DIAN). One solution would be to increase the frequency of in-clinic testing, but this is impractical and burdensome, especially for DIAN participants. DIAN participants come from families that have a ~50% chance of inheriting an extremely rare autosomal dominant causal mutation for AD. Carriers of these mutations become symptomatic between 30 and 50 years of age, decades earlier than the more common sporadic form of AD. Most are still working and many are primary caretakers for their young children and often for affected family members, therefore traveling to sites more frequently for assessments is extraordinarily burdensome. The ARC study will provide a solution to these difficulties by assessing cognition with an iOS and Android app installed on ~248 DIAN participants? personal smartphones. Every three months, participants will complete extremely brief (<3 minutes each) testing sessions 4x/day over the course of one week. Tests are averaged across the week to provide a score that captures and normalizes natural variability and dramatically increases reliability. Pilot studies show that ARC assessments demonstrate extraordinary reliability, ranging from 0.86 to 0.98. Another advantage is the ability to measure variability within a day, across a week, and across the 3- month intervals of assessments. We hypothesize that ARC assessments will be more sensitive than in-clinic assessments to disease stage and AD biomarkers and that mutation carriers in DIAN will show more variability in cognitive performance than non-carriers, even in the preclinical stages of disease. If successful, the increases in sensitivity and reliability of ARC assessments will provide extraordinary statistical power to characterize cognitive decline in observational studies of AD. In addition, ARC assessments could benefit clinical trials by shortening trial duration and requiring fewer participants.

Core H: Cognition SUMMARY The Cognition Core of the Dominantly Inherited Alzheimer Network (DIAN) is a newly formed core that will serve the overall grant by overseeing rater training and maintaining rigorous quality control (QC) and documentation standards that ensure the fidelity of longitudinal cognitive assessments. A primary goal of the core is to revise the cognitive assessment battery to align with scientific aims and minimize participant burden. We will remove burdensome and insensitive measures and incorporate novel measures and novel assessment methodologies that are more sensitive to early cognitive changes. These methodologies will improve reliability in measurement of the key features of autosomal dominant Alzheimer disease (ADAD). The assessment of cognition is central for achieving the scientific aims of all DIAN Projects and Cores. The Cognition Core will work with the Project and Core leaders to ensure that fully validated cognitive data is available for DIAN data freezes and provide guidance on appropriate cognitive measures and data analyses to support project and core aims. Due to the unique value of the ADAD population, there is great enthusiasm from DIAN investigators and external investigators to add novel cognitive measures to DIAN. However, any revisions or additions to the battery can be extraordinarily complicated in a global study like DIAN. The Cognition Core has formed an advisory board including leaders in clinical neuropsychology and cognitive psychology from academic institutions and industry who have specific expertise in global AD studies, clinical trials, computerized assessment, and remote technologies. In consultation with the advisory board, the Cognition Core has developed a formalized process for evaluating, piloting, and integrating new cognitive measures. This process involves scrutiny of preliminary data, test characteristics, availability of translations and suitability for remote test administration. A goal of the DIAN renewal is to harmonize DIAN across all affiliated studies to maximize the power of this remarkable dataset for insights into the essential characteristics of ADAD and to support more effective clinical trials. A dedicated Cognition Core serves this mission directly by creating multiple efficiencies across DIAN, the DIAN-Trials Unit (DIAN-TU) and the DIAN Expanded Registry (DIAN EXR). Core measures of the cognitive assessment battery in DIAN formed the basis for the DIAN-TU battery, but there remain crucial differences in the assessments collected, differences in rater training and certification, differences in QC processes, and DIAN only recently has implemented a rigorous system of documentation. A dedicated core will align these procedures, improve QC processes, and facilitate communications between sites and the DIAN Coordinating Center, thus achieving a critical aim of the core: to improve the rigor and reproducibility of cognitive data collected across all DIAN studies.

Project 4 Project Summary Project 4 will leverage the increasing popularity of smartphones to improve upon standard in-clinic cognitive testing, providing a robust characterization of cognition in participants enrolled in the Healthy Aging and Senile Dementia PPG. One of the most important and face-valid indicators of Alzheimer disease (AD) is a change in cognition, but assessing cognition in-clinic has several drawbacks. First, performance is influenced by day-to- day fluctuations in stress, fatigue, sleep patterns, and mood. Second, the testing takes place in environments that are fundamentally different from where cognitively demanding tasks are performed in daily life. Finally, by design, cognition is typically assessed very infrequently, usually once per year (as currently is the case in HASD). One solution would be to increase the frequency of in-clinic testing or to complete assessments in the natural environments in which participants use cognition such as their homes, workplaces, while traveling, etc., but this is impractical and burdensome, especially for older adults. Project 4 will provide a solution to these difficulties by taking advantage of the increasing popularity of smartphones. Smartphone usage is climbing in every age category, and even in older adults, 50% have and regularly use internet-enabled smartphones. In Project 4, we have designed an iOS and Android app called the Ambulatory Research in Cognition (ARC) app that will be installed on HASD participants' personal smartphones. If participants do not own a smartphone or have an antiquated model, we will provide a study phone for use while enrolled. Every six months, participants will complete extremely brief (<3 minutes each) testing sessions 4x/day over the course of one week. Tests are averaged across the week to provide a score that captures and normalizes natural variability and dramatically increases reliability. Pilot studies show that ARC assessments demonstrate extraordinary reliability, ranging from 0.92 to 0.99. Another advantage is the ability to measure variability within a day, across a week, and across the 6-month intervals of assessments. We hypothesize that ARC assessments will be more sensitive than in-clinic assessments to disease stage and AD biomarkers and that amyloid-positive HASD participants will show more variability in cognitive performance than amyloid-negative participants, even in the preclinical stages of disease. If successful, the increases in sensitivity and reliability of ARC assessments will provide extraordinary statistical power to characterize cognitive decline in observational studies of AD. In addition, ARC assessments could benefit clinical trials by shortening trial duration and requiring fewer participants.

Project Summary The Ambulatory Research in Cognition (ARC) study will leverage the increasing popularity of smartphones to improve upon standard in-clinic cognitive testing, providing a robust characterization of cognition in participants enrolled in the Dominantly-Inherited Alzheimer Network (DIAN) study. One of the most important and face-valid indicators of Alzheimer?s disease (AD) is a change in cognition, but assessing cognition in-clinic has several drawbacks. First, performance is influenced by day to day fluctuations in stress, fatigue, sleep patterns, and mood. Second, the testing takes place in environments that are fundamentally different from where cognitively demanding tasks are performed in daily life. Finally, by design, cognition is typically assessed very infrequently, usually once per year or every two years (as is the case in DIAN). One solution would be to increase the frequency of in-clinic testing, but this is impractical and burdensome, especially for DIAN participants. DIAN participants come from families that have a ~50% chance of inheriting an extremely rare autosomal dominant causal mutation for AD. Carriers of these mutations become symptomatic between 30 and 50 years of age, decades earlier than the more common sporadic form of AD. Most are still working and many are primary caretakers for their young children and often for affected family members, therefore traveling to sites more frequently for assessments is extraordinarily burdensome. The ARC study will provide a solution to these difficulties by assessing cognition with an iOS and Android app installed on ~248 DIAN participants? personal smartphones. Every three months, participants will complete extremely brief (<3 minutes each) testing sessions 4x/day over the course of one week. Tests are averaged across the week to provide a score that captures and normalizes natural variability and dramatically increases reliability. Pilot studies show that ARC assessments demonstrate extraordinary reliability, ranging from 0.86 to 0.98. Another advantage is the ability to measure variability within a day, across a week, and across the 3- month intervals of assessments. We hypothesize that ARC assessments will be more sensitive than in-clinic assessments to disease stage and AD biomarkers and that mutation carriers in DIAN will show more variability in cognitive performance than non-carriers, even in the preclinical stages of disease. If successful, the increases in sensitivity and reliability of ARC assessments will provide extraordinary statistical power to characterize cognitive decline in observational studies of AD. In addition, ARC assessments could benefit clinical trials by shortening trial duration and requiring fewer participants.