This is an application for a K23 award for Dr. Suzee Lee, a behavioral neurologist at the University of California, San Francisco (UCSF). Dr. Lee is establishing herself as a young investigator in patient-oriented clinical research of neurodegenerative disorders. This K23 award will provide Dr. Lee with the support necessary to accomplish the following goals: (1) to become an expert at patient-oriented clinical research in frontotemporal dementia (FTD);(2) to conduct clinical investigations of presymptomatic carriers of genes implicated in FTD;(3) to implement novel and advanced neuroimaging techniques in clinical studies;and (4) to develop an independent clinical research career. To achieve these goals, Dr. Lee has assembled a mentoring team comprised of two co-primary mentors. Dr. Bruce Miller, clinical director of the UCSF Memory and Aging Center (MAC), directs a program project grant on FTD (FTD-PPG) and a Hillblom Aging Network grant to study normal aging. Dr. William Seeley, director the UCSF MAC Autopsy Program and the Neuropathology Core, conducts neuroimaging studies on selective vulnerability in neurodegenerative diseases to explore early-stage disease pathogenesis. The mentoring team also includes two collaborators: Dr. Maria-Luisa Gorno-Tempini, a neurologist who focuses on neuroimaging in primary progressive aphasia and Dr. John Neuhaus, a statistician, who is an expert in study design and biostatistical analysis. Early diagnosis of front temporal dementia is notoriously challenging. Dr. Lee's research will focus on detecting vulnerable brain networks in presymptomatic carriers of FTD gene mutations (Aims 1 and 2). Dr. Lee will use the existing infrastructure and subject cohorts of the FTD-PPG and Hillblom Aging Network to study 50 unaffected family members of probands with FTD to determine the effect of FTD-related genes on alterations in large-scale structural and functional connectivity neural networks. This research will be the first step in a series of investigations that will aid the longitudinal characterization of the natural history of FTD from its earliest stages, paving the way for the field to establish disease monitoring strategies and time points for future treatments in gene mutation carriers.
Improved understanding of when and where in the brain neurodegeneration begins in presymptomatic carriers of front temporal dementia genes are critical to early diagnosis and disease-monitoring. Characterizing the history of front temporal dementia in this way will be crucial for the successful implementation of future treatments of this disease.
|Krabbe, Grietje; Minami, S Sakura; Etchegaray, Jon I et al. (2017) Microglial NF?B-TNF? hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia. Proc Natl Acad Sci U S A 114:5029-5034|
|Lee, Suzee E; Sias, Ana C; Mandelli, Maria Luisa et al. (2017) Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers. Neuroimage Clin 14:286-297|
|Ranasinghe, Kamalini G; Rankin, Katherine P; Pressman, Peter S et al. (2016) Distinct Subtypes of Behavioral Variant Frontotemporal Dementia Based on Patterns of Network Degeneration. JAMA Neurol 73:1078-88|
|Ranasinghe, Kamalini G; Rankin, Katherine P; Lobach, Iryna V et al. (2016) Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage. Neurology 86:600-10|
|Sha, Sharon J; Khazenzon, Anna M; Ghosh, Pia M et al. (2016) Early-onset Alzheimer's disease versus frontotemporal dementia: resolution with genetic diagnoses? Neurocase 22:161-7|
|Naasan, Georges; Rabinovici, Gil D; Ghosh, Pia et al. (2016) Amyloid in dementia associated with familial FTLD: not an innocent bystander. Neurocase 22:76-83|
|Ng, Adeline S L; Sias, Ana C; Pressman, Peter S et al. (2015) Young-onset frontotemporal dementia in a homozygous tau R406W mutation carrier. Ann Clin Transl Neurol 2:1124-8|
|Sha, Sharon J; Ghosh, Pia M; Lee, Suzee E et al. (2015) Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. Alzheimers Res Ther 7:8|
|Lee, Suzee E; Khazenzon, Anna M; Trujillo, Andrew J et al. (2014) Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 137:3047-60|
|Vossel, Keith A; Beagle, Alexander J; Rabinovici, Gil D et al. (2013) Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol 70:1158-66|
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