Thalamic Contributions to Functional Network Abnormalities in Alzheimer's Disease

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Project Summary / Abstract This is an application for a K23 Mentored Patient-Oriented Research Career Development Award for Dr. Carolyn A. Fredericks. A Clinical Assistant Professor at the Stanford Center for Memory Disorders, Dr. Fredericks is an early-career clinical researcher whose long-term goal is to establish a multimodal neuroimaging research program investigating the role of subcortical nuclei in amnestic and atypical Alzheimer's disease. To accomplish this long-term goal and transition to independence as an investigator, Dr. Fredericks seeks to meet the following goals during the period of the K award: (1) learning cutting-edge methods in structural and functional MRI study design and analysis; (2) gaining expertise in the project management of large clinical studies; (3) deepening her knowledge of the cognitive psychology and neuroanatomy of memory; (4) improving her knowledge of biostatistics; and (5) building leadership skills and adding to her understanding of research ethics. To achieve these goals, Dr. Fredericks has the support of a mentoring team including primary mentor Dr. Anthony Wagner, a psychologist with expertise in the neuroscience of memory and high-resolution task-based fMRI; co-mentor Dr. Michael Greicius, a behavioral neurologist with expertise in the neuroimaging of intrinsic connectivity networks in Alzheimer's disease; consultant Dr. Brian Rutt, a radiologist specializing in high-field (7T) structural MRI; consultants Drs. Vinod Menon and Manish Saggar, experts in advanced imaging analysis techniques in neuroimaging; and consultant Dr. Lu Tian, a biostatistician with expertise in longitudinal data analysis. The proposed research uses a multimodal imaging approach to understand the role of specific thalamic nuclei in intrinsic connectivity networks in healthy aging, and to characterize structural and functional abnormalities in these nuclei and networks in Alzheimer's disease. Aim 1 evaluates the relationship between anterior thalamic volume and specific aspects of memory task performance, both in healthy older individuals and those with preclinical Alzheimer's disease, and aims to show that lower volumes over time predict worse memory performance. Aim 2 uses high-resolution task-based MRI to examine how connectivity between anterior thalamus and other key structures affected in Alzheimer's disease relates to memory task performance in healthy aging and preclinical Alzheimer's disease. In Aim 3, patients with mild cognitive impairment and two variants of Alzheimer's disease undergo fMRI scans at rest, and graph theoretic and seed-based analyses are used to understand the role of thalamic nuclei within functional networks that are abnormal in Alzheimer's disease. Successful completion of this work could result in the earlier detection and more accurate classification of people at risk for Alzheimer's disease and in the identification of new promising targets for treatments.