Recent major discoveries in the genetics of frontotemporal lobar degeneration (FTLD) have accelerated the understanding of the pathogenetic mechanisms underlying FTLD and related disorders. These include the discovery of mutations in progranulin (GRN) as an important cause of FTLD and the finding of TAR DNA binding protein 43 (TDP43/TARDBP) as a major component of the intraneuronal inclusions in FTLD. Over the past years, the Genetics Core has 1) screened a significant number of PPG patients for mutations in known genes causing dementia (including MAPT), identifying known and novel mutations and a novel risk factor for neurodegeneration;2) characterized the genotype for most of the known risk factors for dementia, including APOE and MAPT haplotypes;and 3) started a productive collaboration with the laboratory of Rosa Rademakers at Mayo Clinic Jacksonville, a leading group in the study of FTD genetics. We will continue to collect DNA and RNA from peripheral blood from patients and controls with FTD-spectrum disorders evaluated through the PPG, and to screen select cases for mutation in all the dementia-causing genes. Indepth analysis of peripheral progranulin level will be performed in collaboration with the Rademakers lab.Cell lines will be created and stored in the NIH-funded AD National Cell Repository. We will also assess a panel of common polymorphisms in several genes that have been reported to modulate the dementia risk, memory performance, or social behavior, RNA from peripheral blood will be collected and used for gene expression studies. Finally, we propose to identify new loci associated with FTD and AD using novel mapping methods. These genetic data will be integrated with clinical, pathological and imaging data to achieve the core aims of the PPG projects, which are advancing our understanding of the diagnosis, characterization, and genetic architecture of neurodegenerative dementia and, in conjunction with the other sections of the current Program Project, building an extremely well characterized series of patients with neurodegenerative dementia and controls, a potentially invaluable resource for the field.

Public Health Relevance

This core will accelerate research into the genetics of FTLD by identifying known and novel mutations in patients with dementia, characterizing in depth progranulin mutation carriers, and possibly identifying novel causative genes and risk factors. Extensively phenotyped and followed longitudinally, the PPG patient cohort is one of the best characterized dementia patient series in the world, and storing DNA samples in a central repository will provide an invaluable resource for the field.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
San Francisco
United States
Zip Code
Taylor, Alexander N W; Kambeitz-Ilankovic, Lana; Gesierich, Benno et al. (2017) Tract-specific white matter hyperintensities disrupt neural network function in Alzheimer's disease. Alzheimers Dement 13:225-235
Riancho, Javier; Pozueta, Ana; Santos, Miguel et al. (2017) Logopenic Aphasia due to a Strategic Stroke: New Evidence from a Single Case. J Alzheimers Dis 57:717-721
Olney, Nicholas T; Spina, Salvatore; Miller, Bruce L (2017) Frontotemporal Dementia. Neurol Clin 35:339-374
Hagedorn, Christina; Proctor, Michael; Goldstein, Louis et al. (2017) Characterizing Articulation in Apraxic Speech Using Real-Time Magnetic Resonance Imaging. J Speech Lang Hear Res 60:877-891
Gola, Kelly A; Shany-Ur, Tal; Pressman, Peter et al. (2017) A neural network underlying intentional emotional facial expression in neurodegenerative disease. Neuroimage Clin 14:672-678
Watson, Christa L; Possin, Katherine; Allen, I Elaine et al. (2017) Visuospatial Functioning in the Primary Progressive Aphasias. J Int Neuropsychol Soc :1-10
Lwi, Sandy J; Ford, Brett Q; Casey, James J et al. (2017) Poor caregiver mental health predicts mortality of patients with neurodegenerative disease. Proc Natl Acad Sci U S A 114:7319-7324
Spina, Salvatore; Schonhaut, Daniel R; Boeve, Bradley F et al. (2017) Frontotemporal dementia with the V337M MAPT mutation: Tau-PET and pathology correlations. Neurology 88:758-766
Elahi, Fanny M; Miller, Bruce L (2017) A clinicopathological approach to the diagnosis of dementia. Nat Rev Neurol 13:457-476
Spinelli, Edoardo G; Mandelli, Maria Luisa; Miller, Zachary A et al. (2017) Typical and atypical pathology in primary progressive aphasia variants. Ann Neurol 81:430-443

Showing the most recent 10 out of 563 publications