Frederick Schmitt - US grants

DESCRIPTION (Provided by Applicant): Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300,000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) in their 40th year. However, dementia may not develop until up to a decade later, and some people remain cognitively intact. Thus, the investigators seek to follow a group of adults ranging in age from 20-40 years over a five year period of time to identify age and dementia-associated changes in cognition, and in particular focus on frontal lobe function. The aims are four-fold. Aim 1 will cognitively characterize a cohort of adults with DS and follow individuals for a period of five years. Aim 2 will use magnetic resonance imaging to measure white matter integrity on an annual basis in longitudinally followed people. Aim 3 will assay plasma drawn annually from the cohort and measure signaling protein changes to identify biomarkers of AD development and that are also correlated with cognition. Aim 4 will study archived and new autopsy brain samples from DS adults to identify molecular pathways that change prior and during AD development. The outcomes of the proposed studies will contribute to the development of noninvasive biomarkers that will assist in early AD diagnosis in DS and monitor disease progression. Further, novel biomarkers that are mechanistically related to aging, AD neuropathology as well as dementia will also provide outcomes for the design of future therapeutic clinical trials to treat or prevent dementia in DS. PROJECT NARRATIVE: The proposed study will identify new ways in which to detect Alzheimer's disease (AD) in adults with Down syndrome (DS) by monitoring changes in cognitive function, measuring brain changes by magnetic resonance imaging, and profiling patterns of proteins in the plasma. In parallel, autopsy studies of brain samples will help us to understand how noninvasive cognitive, imaging, and blood measures reflect the development of AD in DS. Treatments for AD in DS will be more effective if the disease is detected early, and identifying biomarkers will greatly facilitate the development of therapeutics.

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD), the most common late-onset dementing disorder, affects approximately four million individuals in the USA and is projected to affect 14 to 16 million individuals by the year 2050. Prevention may be the key to eliminate AD. It is clear that oxidative damage plays a role in the pathogenesis of AD, and our studies show that it is present in mild cognitive impairment (MCI), the earliest phase of AD, and thus, preventive measures should be initiated in the presymptomatic stages. This research project is an add-on study to the Selenium (Se) and Vitamin E Prostate Cancer Prevention Trial (SELECT). The SELECT study is funded by the NCI to assess the effect of Se and vitamin E, alone and in combination, on the reduction of incidence of prostate cancer in 35,534 healthy men age 55 or older (50 or older if African American). The Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADVISE) evaluates the effectiveness of these supplements on reducing incident AD and other dementias in a group of more than 6,100 men (17% of whom are minorities, recruited from the SELECT Study). The study duration is 12 years. While SELECT has reached its recruitment goal, PREADVISE has permission to continue recruiting to exceed 6,500 participants. This is the first randomized controlled trial to evaluate the effect of antioxidants (vitamin E and Se) on preventing dementia in the elderly. The specific aims are:1) To define the effect of Se and vitamin E, in combination and alone, in the reduction of the incidence of AD, as determined by the clinical evaluation, in a population of men age 62 or older (60 if minority) participating in SELECT;2) To assess the effect of Se and vitamin E on the reduction of other neurodegenerative dementing diseases while also ascertaining the effect of the supplements on transition from normal to MCI and from MCI to AD and dementia;. 3) To validate the two-stage screening methodology with in-depth longitudinal cognitive assessments in a subset of 500 subjects who "pass" their initial screen;4) To increase the number of subjects in PREADVISE to 6,504 or more;and 5) To emphasize retention of subjects in PREADVISE and SELECT.

DESCRIPTION (provided by applicant): Population demographics suggest that with the expected dramatic increase in age-associated dementias a public health crisis is looming. Current emphasis is on disease prevention with a focus on elderly individuals who express some cognitive impairment. We propose to identify authoritatively the risk and protective factors for cognitive decline in older persons. We have shown how to define these impaired states retrospectively, how to account for reverse transitions, how to distinguish prevalence from incidence, and how to account for competing risks by using a unique statistical (Markov) model. But sufficient longitudinal and neuropathological data is currently not available to distinguish among different types of dementia. No single Alzheimer's Disease Center (ADC) or cooperative study has an adequate sample size to reliably track transitions to dementia and differentiate Alzheimer's disease (AD) from other prevalent brain diseases that include vascular dementia (VaD) and Lewy body disease (LBD). This project will pool data from six well established longitudinal cohorts to identify risk factors for (1) preservation of intact cognition in those meeting neuropathological criteria for varying types of dementia and MCI and (2) specific forms of dementia (clinical and neuropathological). This will improve our understanding of intervening impaired states and factors that promote resistance to clinical symptoms despite the presence of neuropathology. These considerations lead to the specific aims below. Specific Aim 1: To merge databases from six large projects that follow cohorts of cognitively intact subjects to dementia, for the purpose of rigorous, statistical, biologically-informed analyses that accentuate longitudinal follow-up: BRAiNS (University of Kentucky), Nun Study (University of Minnesota), Memory and Aging Project (Washington U), Kuakini Honolulu-Asia Aging Study, Religious Orders Study (ROS, Rush Medical University), and the OHSC ADC (Oregon Health &Science University). The database would be made publicly accessible. Specific Aim 2: To identify appropriate intervening states between intact cognition and dementia based on periodic assessments of cognition and functional skills from data collected at these centers. Specific Aim 3: To study transitions and associated risk factors (e.g., genetic, medical, time in an impaired state) using novel statistical methods. Specific Aim 4: To standardize the neuropathological findings across databases (including quantitative neuropathological assessments) to enable the analysis of novel pathogenetic determinants of outcomes. This aim allows us to evaluate how actual brain pathology (e.g., microinfarcts, Lewy bodies, hippocampal sclerosis, and mixed pathologies) relates to antemortem states in the subset of participants coming to autopsy. This aim could support proposed revisions of current neuropathological and clinical research diagnostic criteria in dementia and preclinical dementia conditions. PUBLIC HEALTH RELEVANCE: With the graying of America the cost of caring for demented elderly will rise substantially in the next few decades. Current emphasis is on preventing this disease. This project will identify risk factors for various forms of dementia as well as impaired states that precede this disease.

DESCRIPTION (provided by applicant): Population demographics suggest that with the expected dramatic increase in age-associated dementias a public health crisis is looming. Current emphasis is on disease prevention with a focus on elderly individuals who express some cognitive impairment. We propose to identify authoritatively the risk and protective factors for cognitive decline in older persons. We have shown how to define these impaired states retrospectively, how to account for reverse transitions, how to distinguish prevalence from incidence, and how to account for competing risks by using a unique statistical (Markov) model. But sufficient longitudinal and neuropathological data is currently not available to distinguish among different types of dementia. No single Alzheimer's Disease Center (ADC) or cooperative study has an adequate sample size to reliably track transitions to dementia and differentiate Alzheimer's disease (AD) from other prevalent brain diseases that include vascular dementia (VaD) and Lewy body disease (LBD). This project will pool data from six well established longitudinal cohorts to identify risk factors for (1) preservation of intact cognition in those meeting neuropathological criteria for varying types of dementia and MCI and (2) specific forms of dementia (clinical and neuropathological). This will improve our understanding of intervening impaired states and factors that promote resistance to clinical symptoms despite the presence of neuropathology. These considerations lead to the specific aims below. Specific Aim 1: To merge databases from six large projects that follow cohorts of cognitively intact subjects to dementia, for the purpose of rigorous, statistical, biologically-informed analyses that accentuate longitudinal follow-up: BRAiNS (University of Kentucky), Nun Study (University of Minnesota), Memory and Aging Project (Washington U), Kuakini Honolulu-Asia Aging Study, Religious Orders Study (ROS, Rush Medical University), and the OHSC ADC (Oregon Health & Science University). The database would be made publicly accessible. Specific Aim 2: To identify appropriate intervening states between intact cognition and dementia based on periodic assessments of cognition and functional skills from data collected at these centers. Specific Aim 3: To study transitions and associated risk factors (e.g., genetic, medical, time in an impaired state) using novel statistical methods. Specific Aim 4: To standardize the neuropathological findings across databases (including quantitative neuropathological assessments) to enable the analysis of novel pathogenetic determinants of outcomes. This aim allows us to evaluate how actual brain pathology (e.g., microinfarcts, Lewy bodies, hippocampal sclerosis, and mixed pathologies) relates to antemortem states in the subset of participants coming to autopsy. This aim could support proposed revisions of current neuropathological and clinical research diagnostic criteria in dementia and preclinical dementia conditions.

? DESCRIPTION (provided by applicant): Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300,000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of AD in their 40th year. However, dementia may not develop until up to a decade later and some people remain cognitively intact. In this competitive renewal we propose to continue following (and expand) our cohort of aging adults with DS as well as recruit younger individuals to establish the role of white matter (WM) integrity losses, cerebrovascular dysfunction (CVF) and neuroinflammation on cognitive decline. Aim 1 will continue to cognitively characterize a cohort of adults with DS and follow individuals for a period of 5 years as well as recruit a younger cohort that is pre-AD pathology. Magnetic resonance imaging (MRI) using diffuse tensor imaging will be used to track losses in WM integrity. Aim 2 will use MRI methods to detect cerebrovascular dysfunction by susceptibility weighted imaging, fluid attenuated inversion recovery and arterial spin labeling. Aim 3 will use magnetic resonance spectroscopy and blood biomarkers to detect neuroinflammation as a function of age, AD neuropathology and declines in cognition. Aim 4 will measure proteins and RNA to reflect protein and RNA changes to determine the neurobiological mechanisms underlying losses in WM integrity, CVF and shifts in neuroinflammation in the brains of autopsy cases with DS. We will be able to identify targets for intervention studies (Aim 4) that could be implemented to promote healthy brain aging and would result in cognitive (Aim 1), WM structural integrity (Aim 1), and CVF improvements (Aim 2), and reduced neuroinflammation (Aim 3) in future clinical trials. Identifying the earliest signs of dementia and indicators of individual variation in cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration.

Project Summary/Abstract: Outreach and Recruitment Core The Outreach and Recruitment (OR) Core functions as a key link between the UK-ADC and the local and state communities. OR Core programs and activities have created and will maintain an educated local community eager to receive updated information on AD and to participate in our Center?s research. Through OR Core efforts, the UK-ADC will continue to work with both the Commonwealth of Kentucky and UK partners in directing state and institutional responses to meeting dementia health care needs and increasing health literacy in the elderly. Over the past five years, the OR Core has taken the lead in developing innovative partnerships and products to support research participation by African Americans, the largest minority group in Kentucky. We will continue to emphasize recruitment and retention of research participants at the earliest stages of the cognitive continuum (Cognitively Normal and MCI). These efforts involve engaging these participants in the ADC longitudinal cohort, as well as agreement to brain donation in support of the Neuropathology Core, willingness to engage in clinical studies and therapeutic trials that support the Clinical Core, and donation of antemortem biospecimens (plasma, DNA, CSF, and neuroimaging) that support all Cores. In the next cycle, we will maintain and further build on these efforts and partnerships through the following specific aims: Aim 1. Recruit and retain individuals into our longitudinal cohort, ADC-affiliated research studies, and national initiatives, with a special focus on recruitment and retention of African Americans. Aim 2. Increase community awareness of AD and related disorders through the promotion of health literacy that further enhances recruitment and retention of minority participants in research. Aim 3. Evaluate the effectiveness of our outreach, recruitment, and educational activities with both qualitative and quantitative metrics of success. Aim 4. Support and collaborate with the other Cores to reach UK-ADC goals. The OR Core plays a critical role in the UK-ADC and works closely with the other Cores to support recruitment and retention activities for research protocols, clinical trials, and national initiatives; increase community awareness of AD and maintain a strong presence in the African-American community; support educational initiatives for the lay community in collaboration with key partners. These functions are vital to the UK-ADC mission to catalyze outstanding and innovative research, outreach, education, and clinical programs.

Project Summary/Abstract: Outreach, Recruitment and Engagement Core The Outreach, Recruitment and Engagement (ORE) Core plays a central role in achieving UK-ADRC goals by functioning as a key link between the Center and the local and state communities. ORE Core programs and activities have created and will maintain an educated local community eager to receive updated information on AD and to participate in our Center?s research. Through ORE Core efforts, the UK-ADRC will continue to work with both the Commonwealth of Kentucky and UK partners in directing state and institutional responses to meeting dementia health care needs and increasing health literacy in the elderly. ORE Core activities include recruitment and retention of diverse participants into a longitudinal cohort with annual clinical examinations and brain donation upon death. Other activities involve the development and testing of innovative outreach and engagement activities in the community to increase awareness of AD/ADRD plus the importance of research and research participation. Over the past five years, the ORE Core has taken the lead in developing innovative partnerships and products to support research participation by African Americans, the largest minority group in Kentucky. We will continue to emphasize recruitment and retention of research participants at the earliest stages of the cognitive continuum (Cognitively Normal and MCI). These efforts involve engaging these participants in the ADRC longitudinal cohort, as well as activities to enhance agreement to brain donation, willingness to engage in affiliated clinical studies and therapeutic trials, and donation of antemortem biospecimens. In the next cycle, we will maintain and further build on these efforts and partnerships through the following specific aims: Aim 1. Recruit and retain participants into our longitudinal cohort, affiliated research, and NIA initiatives, focusing on improving recruitment and retention of African Americans and other URGs. Aim 2. Increase community awareness of AD and ADRD through the promotion of health literacy that further enhances recruitment and retention of minority participants in research. Aim 3. Evaluate the effectiveness of our activities with both qualitative and quantitative metrics. Aim 4. Support the UK-ADRC Cores to maximize national and international collaborations. The ORE Core plays a critical role in the UK-ADRC and works closely with the other Cores to support recruitment and retention activities for research protocols, clinical trials, and national initiatives; increase community awareness of AD and maintain a strong presence in the African-American community; and support outreach initiatives for the lay community in collaboration with key partners. These functions are vital to the UK- ADRC mission to catalyze outstanding and innovative research, outreach, education, and clinical programs.