Frontotemporal Lobar degenerafion (FTLD) manifests clinically with progressive behavioral and/or language deficits. Subtypes of FTLD are classified neuropathologically by the protein composition of cellular inclusion bodies. The most common neuropathological correlates of FTLD have TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP) or tau inclusions (FTLD-tau). FTLD is frequenfiy familial and can occur as an autosomal dominantly inherited disorder. Genes with mutations causing FTLD include /W/APT (encodes tau) and GRN (encodes progranulin) among others, each of which is associated with a specific FTLD pathological subtype: GRN mutations with FTLD-TDP and MAPT mutafions with FTLD-tau. Studying the genetics of FTLD can help elucidate its etiology and pathophysiology and provide targets for therapy as well as identify risk factors that modify disease risk or phenotype. To enable genefic studies of FTLD the Genetics Core, as an integral part of this Program Project Grant, will collect and bank DNA from Clinical Core B subjects with FTLD and autopsy brains characterized in the Neuropathology Core as well as control samples. For participafing individuals, a study coordinator trained as a certified genetic counselor will provide genetic educafion to foster a better understanding of the research and to obtain informed consent. Banked DNA will be used for genetic analysis by the Core itself, as well as by Project 1, and other collaborators within and outside of UPenn. Genetic analysis of FTLD associated genes willbe performed by the Core and in collaboration with Project 1. Genotype data will enable clinical, pathologic and genetic correlafions with data from Projects 1 and 3 and the Clinical and Neuropathology Cores with stafisfical analysis by the Biostatistics and Data Management Core. Projects 2 and 4 will use genotype data for case selection for analysis. Finally, the Genefics Core will coordinate with the Hosp. of the Univ. of Penn Molecular Pathology Lab to make CLIA-certified genetic testing available. To this end, the Core will identify new genetic tests which are ready for translafion into clinical tests and assist with validation by providing primer sequences, protocols, and samples.

Public Health Relevance

The Studies proposed in this Core taken together with the complementary activities in the other Cores and Projects in this PPG will lead to improved understanding of the genetics of FTLD and related neurodegenerative disorders and will contrilDute samples to collaborafive projects advancing the field as a whole.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017586-14
Application #
8645557
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2014
Total Cost
$177,365
Indirect Cost
$66,512
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Makani, Vishruti; Zhang, Bin; Han, Heeoon et al. (2016) Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy. Acta Neuropathol Commun 4:106
Price, Amy Rose; Peelle, Jonathan E; Bonner, Michael F et al. (2016) Causal Evidence for a Mechanism of Semantic Integration in the Angular Gyrus as Revealed by High-Definition Transcranial Direct Current Stimulation. J Neurosci 36:3829-38
Santos-Santos, Miguel A; Mandelli, Maria Luisa; Binney, Richard J et al. (2016) Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration. JAMA Neurol 73:733-42
Ash, Sharon; Ternes, Kylie; Bisbing, Teagan et al. (2016) Dissociation of quantifiers and object nouns in speech in focal neurodegenerative disease. Neuropsychologia 89:141-52
Kovalevich, Jane; Cornec, Anne-Sophie; Yao, Yuemang et al. (2016) Characterization of Brain-Penetrant Pyrimidine-Containing Molecules with Differential Microtubule-Stabilizing Activities Developed as Potential Therapeutic Agents for Alzheimer's Disease and Related Tauopathies. J Pharmacol Exp Ther 357:432-50
Cousins, Katheryn A Q; Ash, Sharon; Irwin, David J et al. (2016) Dissociable substrates underlie the production of abstract and concrete nouns. Brain Lang 165:45-54
Shinagawa, Shunichiro; Catindig, Joseree Ann; Block, Nikolas R et al. (2016) When a Little Knowledge Can Be Dangerous: False-Positive Diagnosis of Behavioral Variant Frontotemporal Dementia among Community Clinicians. Dement Geriatr Cogn Disord 41:99-108
Vu, An T; Phillips, Jeffrey S; Kay, Kendrick et al. (2016) Using precise word timing information improves decoding accuracy in a multiband-accelerated multimodal reading experiment. Cogn Neuropsychol 33:265-75
McMillan, Corey T; Irwin, David J; Nasrallah, Ilya et al. (2016) Multimodal evaluation demonstrates in vivo (18)F-AV-1451 uptake in autopsy-confirmed corticobasal degeneration. Acta Neuropathol 132:935-937
Spiller, Krista J; Restrepo, Clark R; Khan, Tahiyana et al. (2016) Progression of motor neuron disease is accelerated and the ability to recover is compromised with advanced age in rNLS8 mice. Acta Neuropathol Commun 4:105

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