Kevin Duff, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Mild Cognitive Impairment (MCI) has been proposed as a middle ground between normal aging and dementia, and this concept holds promise for the early identification and treatment of individuals likely to develop Alzheimer's disease (AD). 1 limitation of the predictive value of this concept is that only a fraction of individuals with MCI go on to develop AD each year (approximately 12%). If the individuals who convert from MCI to AD were more easily identified, then clinical trials could be more efficiently conducted. Since no specific biomedical/psychometric marker is available that identifies these potential converters, the present study seeks to utilize a novel paradigm to identify these individuals who are at greater risk to convert to AD. 1 goal of this project is to determine the relative magnitude of practice effects (i.e., increased cognitive test performance due to repeated exposure to test materials) among elderly individuals with no cognitive impairments (NCI) or MCI. Recently, practice effects have been shown to be useful in detecting MCI, and a logical extension of these findings is to evaluate their ability to predict decline in MCI. Therefore, a second goal is to determine the relative value of practice effects in predicting future cognitive functioning. Specifically, we propose a longitudinal observational study in elderly subjects with NCI or MCI. All participants will receive a baseline assessment of cognitive functioning, which will be immediately repeated to assess practice effects. It is expected that participants with NCI will demonstrate larger practice effects than participants with MCI. It is also expected that within the MCI group, some individuals will display relatively larger practice effects and some will display smaller practice effects. Follow-up cognitive evaluations will be conducted on all participants at 6- and 12-months. It is hypothesized that the amount of practice demonstrated during the baseline phase will be inversely related to the amount of cognitive decline on follow-up, which could lead to earlier identification of cognitive decline.

DESCRIPTION (provided by applicant): This revised Mentored Patient-Oriented Research Career Development Award ,(K23) application is a request to support the training and research activities necessary for Kevin Duff, Ph.D. to further develop a novel cognitive index (i.e., practice effects), which could assist in the prediction of outcomes in Mild Cognitive Impairment (MCI). Although the concept of MCI has'advanced our understanding of the transition between normal aging and dementia, it remains an imperfect heuristic for identifying which patients will progress to dementia, and which will not.The current research proposal will examine if there is an inverse relationship between practice effects and cognitive outcome, so that an absence of practice effects increases the risk for conversion to dementia in amnestic MCI across 2 years;and, conversely, robust practice effects are associated with a decreased risk for dementia. Specifically, this research plan will address the following research aims: 1) determine if practice effects predict conversion to dementia in MCI, and 2) examine a variety of moderators of practice effects, and see how they affect conversion rates. The training plan detailed in this application offers a multidisciplinary program capitalizing on the diverse resources available at the University of Iowa and on the expertise of national researchers in memory disorders. As a neuropsychologist, Dr. Duff has set the following training goals: 1) develop skills necessary to further develop practice effects as a predictor of cognitive decline, 2) gain additional expertise in tracking cognitive decline in MCI and diagnosing dementia, 3) gain knowledge in identifying moderators of MCI to dementia conversion, and 4) expand knowledge of statistical techniques necessary for answering these questions. Additionally, training will be provided in conducting ethical research and grant writing. The training and proposed project will lay the foundation for Dr. Duffs long-term scientific goal of creating an independent and externally-funded program of research on examining markers of disease progression in normal aging, MCI, and dementia. Identifying early markers of progression from normal aging to MCI to dementia clearly fits with the mission of the National Institute on Aging, in that, it provides greater knowledge about aging and aging- related diseases. Additionally, identification of early cognitive disorders can have profound public health significance with inaccurate or delayed identification of these disorders leading to missed opportunities for treatment and medical, legal, and family planning. Finally, the availability of a brief, non-invasive, and cost effective marker of disease progression would allow for more efficient and better powered clinical trials.

DESCRIPTION (provided by applicant): The overall aim of this submission is to examine if cognitive functioning in MCI can be improved with training exercises. These findings could further our understanding about the mechanisms of MCI, inform our attempts to intervene in this disease, and influence the design and methodology of future clinical trials. We propose a randomized, placebo-controlled, clinical trial using [230] older adults with MCI. Following pre-testing with a cognitive battery, participants will be randomly assigned to either the experimental group or an active control group. Those in the experimental group will complete 40 1-hour sessions of online, computerized exercises designed to improve processing speed and auditory memory (Brain Plasticity, Inc.). Those in the control group will complete 40 1-hour sessions of online, computerized activities that are not specifically designed to improve cognition (e.g., crossword puzzles). Post-testing will follow completion of training in both groups. We will also examine effects of the training program after 12 months. By achieving these aims, we expect to advance our understanding of the mechanisms and treatment of MCI, which will have effects for clinical care and research. For example, if these individuals do benefit from cognitive training, then this may reduce the disability associated with this disease. This project is consistent with the mission of the National Institute on Aging. Relevance. Minimizing the deleterious effects of MCI is critical for providing clinical care and advancing research with this disease. For example, if cognitive deficits can be minimized, then individuals may retain functional independence for longer periods of time. Similarly, awareness of factors that moderate the effects of intervention will allow us to target individuals for future clinical trials in MCI.

The main objective of this new application is to demonstrate that individuals with low practice effects on repeated cognitive testing across one week are likely to be identified as ?positive? on amyloid imaging and other biomarkers associated with Alzheimer's disease. This project would also examine if short-term practice effects and amyloid deposition differ across the disease spectrum in late adulthood by comparing older individuals who are cognitively intact to those with Mild Cognitive Impairment and Alzheimer's disease. These findings would add to the supporting evidence of practice effects as a marker of diagnosis, prognosis, and treatment response in normal aging, Mild Cognitive Impairment, and dementing illnesses. By realizing the aims of this pragmatic project, we would be able to offer more efficient screening of potential participants for clinical trials, which would reduce participant burden and financial costs associated with these trials. Practice effects could also be used to enrich trials with those more likely to progress and to monitor treatment benefit as a proximal outcome measure. Practice effects also have considerable clinical benefits for diagnosis and prognosis of cognitive disorders in late life. This project is consistent with the mission of the National Institute on Aging. Relevance. Many current clinical trials in Mild Cognitive Impairment and Alzheimer's disease are using biomarkers (e.g., ?positive? on amyloid imaging, atrophic hippocampi, APOE e4) as part of the inclusion criteria. Similarly, biomarkers are becoming increasingly important in the diagnosis of Alzheimer's disease and other types of dementia. However, many of these biomarkers are costly, invasive, provide little clinical information, and may be only completed at sites with unique resources. There is a need for more practical markers of disease and its progression, which could be used to enrich clinical trials. Practice effects, collected on cognitive testing across one week, may fill this important gap. In the current pragmatic project, we expect to provide clinicians and researchers with a new tool (i.e., practice effects) for predicting current amyloid positivity in seniors with and without cognitive impairments. We will also examine the relationship between short-term practice effects and other biomarkers associated with Alzheimer's disease (e.g., atrophic hippocampi, APOE e4, functional connectivity of brain networks). We expect to provide supporting evidence to include practice effects in future clinical trials in normal aging, Mild Cognitive Impairment, and Alzheimer's disease.

Project Summary The main objective of this new application is to demonstrate that individuals with low practice effects on measures of daily functioning repeated across one week are more likely to cognitively progress over the following year. This project would also examine if practice effects on these performance-based functional scales differ across the disease spectrum in late adulthood by comparing older individuals who are cognitively intact to those with Mild Cognitive Impairment and Alzheimer's disease. In an exploratory aim, the relationship between practice effects on these functional scales and various biomarkers of Alzheimer's disease (e.g., hippocampal volumes via MRI, amyloid deposition via PET, APOE e4) will be studied. These findings would add to the supporting evidence of practice effects as a marker of diagnosis, prognosis, and treatment response in normal aging, Mild Cognitive Impairment, and dementing illnesses. However, it will extend our prior work by focusing on practice effects on functional measures (whereas our prior work looked at practice effects on cognitive tests). By realizing the aims of this pragmatic project, we would be able to offer more efficient screening of potential participants for clinical trials, which would reduce participant burden and financial costs associated with these trials. Practice effects could also be used to enrich trials with those more likely to progress and to monitor treatment benefit as a proximal outcome measure. Practice effects also have considerable clinical benefits for diagnosis and prognosis of cognitive disorders in late life. This project is consistent with the mission of the National Institute on Aging. Relevance. Current clinical trials in Mild Cognitive Impairment and Alzheimer's disease require participants to progress/decline across the trial to accurately evaluate the experimental intervention. Although existing biomarkers (e.g., tau and amyloid imaging) are being used to identify those most likely to progress, these biomarkers are expensive and invasive. Cheaper, less invasive, and more sensitive biomarkers are clearly needed to make these trials more efficient. We propose that practice effects on performance-based functional measures might fill this important gap in the literature. In the current pragmatic project, we expect to provide clinicians and researchers with a new tool (i.e., practice effects on functional scales) for predicting cognitive decline in seniors with and without cognitive impairments. We expect to provide supporting evidence to include practice effects in future clinical trials in normal aging, Mild Cognitive Impairment, and Alzheimer's disease.