Meredith N. Braskie - US grants

DESCRIPTION (provided by applicant): The goal of this proposal is to explore the relationship between neurofibrillary tangles and amyloid plaques, the hallmarks of Alzheimer's disease (AD) and the hippocampal response during a memory-taxing task in young (aged 45 to 60) participants who have a genetic risk for, but not yet any symptoms of AD. It is also to attempt to identify the earliest signs of the disease, and predictive factors for developing the disease. Volunteers, who have the APOE-4 allele, a known risk factor for AD, and their age-matched counterparts without APOE-4, will undergo functional magnetic resonance imaging while learning new associations, a task that previously has been shown to activate the hippocampus. These same subjects will undergo PET scans using FDDNP, a probe that attaches preferentially to amyloid plaques and neurofibrillary tangles and allows them to be imaged. The images will be "unfolded", or portrayed in a two-dimensional field, using a computer application designed for that purpose. This will allow specific activation within the hippocampus to be identified and localized. The PET images and fMRI images will then be superimposed in such a way that it will be possible to determine whether localization of amyloid plaques and neurofibrillary tangles correspond to increases in signal intensity during memory tasks as seen in AD patients.

ABSTRACT PROJECT 2: METABOLIC FACTORS AND ALZHEIMER DISEASE Type 2 diabetes mellitus (T2DM) increases Alzheimer's disease (AD) risk by ~1.5 times, but the mechanisms are unclear. We focus on two metabolic risk-related mechanisms that may link early T2DM to AD: insulin & insulin-like growth factor 1 (IGF1) and cholesterol transport. In non-demented adults, we relate these metabolic factors to 1) cerebrospinal fluid (CSF) markers of AD pathology, 2) structural and functional brain connectivity and hippocampal subregion thickness in regions selectively vulnerable to AD, and 3) changes over 2 years in brain connectivity and memory. Our multimodal longitudinal project includes multi-shell diffusion tensor imaging analyzed with a novel fiber orientation distribution tool. These innovations improve our ability to measure brain connectivity even in the presence of crossed fibers and white matter lesions. We also will use resting state functional magnetic resonance imaging (rs-fMRI) to assess functional connectivity, and will evaluate entorhinal cortex and hippocampal CA1 thickness. We will examine 180 adults with no or mild cognitive impairment; aged 70-90 yrs. We will recruit subjects with low vascular risk, with hypertension, and those with elevated glycated hemoglobin and low HDL-C. Using continuous measures of insulin, IGF1, IGF binding proteins, and cholesterol efflux capacity derived from blood and CSF, we will evaluate: 1) How IGF1 and IGFBPs relate to neurodegeneration, mediated by CSF ptau181 levels and measured as atrophy in the entorhinal cortex and CA1 of the hippocampus and loss of functional and structural connectivity in AD-relevant regions; 2) How insulin and cholesterol efflux capacity relate to demyelination and functional connectivity deficits in AD-relevant regions, mediated by A¿42 levels; and 3) How insulin signaling peptides and cholesterol efflux capacity are related to 2-year changes in cognition, and brain structure and function. We anticipate improved understanding of how T2DM and metabolic risk contribute to preclinical AD brain changes. This is crucial to enabling tailored treatment and prevention efforts to persons at specific risk.

PROJECT SUMMARY/ABSTRACT To prepare ourselves for the aging of our increasingly diverse population, we must increase minority representation in the sciences, and train young researchers to understand neurocognitive aging and Alzheimer's disease and related dementias (ADRD), and associated health disparities. CSUF and USC propose an innovative and transformative program entitled, ?Neurocognitive Aging & Analytics Research Education (NAARE)? that builds upon our current biomedical research education program on data science and brain health. In the coming decades, the United States and the world will face a rapidly growing aging population, with an insufficient number of experts trained in ADRD research to accommodate this increase. Even though ethnic and racial minorities, including African Americans, Latinos and Native Americans/Alaskans comprise over a third of the U.S. population, they are under-represented in aging studies, leaving us with insufficient knowledge of the genetic and environmental risk factors that contribute to cognitive decline in these populations. The representation of minorities in science and biomedical fields also remains comparatively low. Increasing the number of trained researchers from these underrepresented groups may provide insights into social contextual issues and other factors related to underrepresentation, which may subsequently promote access to these important populations in order to subsequently improve health disparities related to neurocognitive aging in these vulnerable populations. Therefore increasing the number of underrepresented aging researchers continues to be a high national priority. The NAARE program addresses this gap as follows: Aim 1: Provide NAARE scholars hands-on research experiences: Engage three consecutive cohorts (n = 10 per year) of predominantly underrepresented minority undergraduates (50% female) in a 1.5 - year faculty mentored, student-driven research focusing on neurocognitive aging, ADRD, and related health disparities and modifiable risk factors. Aim 2: Develop educational curricula: Traditional and multimedia curricula will be developed for NAARE scholars and also targeted towards a larger diverse student audience (n = 4,500) on the following: basic science behind normal brain aging and ADRD; health disparities, modifiable risk factors and neurocognitive aging; neuroimaging and analytics; and research methods in neurocognitive aging. Aim 3: NAARE Scholar Graduate/Career Preparation: To ensure sustainability and student success, NAARE students will engage in ongoing faculty advising, receive exhaustive graduate school application support via hands-on guidance, and explore first-hand, research intensive universities. In-depth mentored, yet student- owned research experiences that integrate intensive neurocognitive aging and ADRD training, and belonging in the broader scientific community will result in successful future scientists. This program will lead to a greater number of students from underrepresented backgrounds choosing careers in neurocognitive aging and succeeding at them. Our students will become diverse role models for future students for generations to come.