PROJECT SUMMARY/ABSTRACT This is a K23 career development award application for Dr. David Soleimani-Meigooni, a behavioral neurologist and Clinical Instructor who is establishing himself as a junior investigator at the University of California, San Francisco (UCSF) Memory and Aging Center (MAC). His long-term goal is to become a clinician-scientist who will lead an independent research program to advance the pre-clinical development/translation of novel PET tracers for diagnosis and monitoring of neurodegenerative diseases associated with frontotemporal lobar degeneration (FTLD) pathology. Through the K23 and the optimal training environment and resources of the MAC, Dr. Soleimani-Meigooni aims to achieve these training goals: 1. To become proficient in pharmacokinetic radiotracer modeling and optimization of PET image acquisition. 2. To become proficient in quantitative PET analyses. 3. To learn quantitative neuropathology techniques. 4. To gain advanced skills in study design and biostatistics. 5. To gain skills in clinical research operations, research ethics, and grantsmanship. 6. To implement his K23 training and findings into an R01 that will allow him to become an independent investigator involved in pre-clinical development/translation of novel PET tracers for FTLD. To achieve these training goals, Dr. Soleimani-Meigooni has assembled a world-class mentorship team including primary mentor, Dr. Gil Rabinovici, a behavioral neurologist and leader in PET neuroimaging of neurodegenerative diseases; co-mentor, Dr. William Jagust, a behavioral neurologist and expert in technical aspects of PET imaging, including radiotracer development and pharmacokinetic modeling; co-mentor, Dr. Lea Grinberg, a neuropathologist, co-leader of the UCSF Neurodegenerative Disease Brain Bank, and expert on FTLD and quantitative neuropathological measures; collaborator, Dr. Suzanne Baker, a scientist with technical expertise in PET imaging; and, collaborator, Dr. Isabel Elaine Allen, an expert biostatistician. This project will evaluate/validate new PET tracers to aid in diagnosis and monitoring of FTLD. Candidate PET tracers include a novel ligand that binds to non-Alzheimer tau proteins, [18F]PI-2620, and another ligand that binds to synapses, [18F]SynVesT-1. Further evaluation is needed to determine if [18F]PI-2620 can distinguish FTLD with tau pathology (FTLD-tau) from FTLD with TDP-43 pathology (FTLD-TDP), and if [18F]SynVesT-1 is a sensitive marker of synapse loss and disease state in FTLD. In this project, both tracers will be evaluated/validated by comparing patterns of tracer retention in patients with FTLD-tau to FTLD-TDP and other neurodegenerative diseases (Aim 1); correlating regional tracer retention to clinical measures and structural brain MRI changes (loss of cortical thickness or subcortical volume) (Aim 2); and performing quantitative PET-to-pathology correlations (Aim 3). This project provides critical data that could support the translation of these radiotracers for clinical use and application as clinical trial biomarkers.

PROJECT NARRATIVE Frontotemporal dementia (FTD) is a leading cause of dementia and one of the most common causes of early- onset dementia. Diverse molecular pathologies cause FTD (collectively known as frontotemporal lobar degeneration [FTLD] pathology), which has complicated the development of positron emission tomography (PET) tracers for these diseases. This project will evaluate and validate new PET tracers, which could improve FTD/FTLD diagnosis and differential diagnosis and facilitate drug development for these diseases.