Our prior work demonstrated hypothesis-driven characterizations of the phenotypes associated with frontotemporal lobar degeneration (FTLD), including progressive non-fluent aphasia (PNFA), semantic dementia (SD), and behavioral variant patients with a social and executive disorder (bvFTD). We also began to relate these syndromes to the major pathologies underlying FTLD. However, little work has determined the value of clinical features for predicting pathology. We propose novel studies that optimize features we can use to characterize PNFA, SD and bvFTD. We will obtain converging evidence for these observations from novel MRI techniques integrating grey matter (GM) atrophy and white matter (WM) tract defects, and from functional MRI (fMRI) studies of healthy adults using the same materials. Finally, we will relate FTLD phenotypes to pathology, and determine how these associations are modulated by genetic factors.
Aim 1 addresses the basis for non-fluent speech in PNFA. We propose studies of conversational discourse in PNFA to highlight the combined role of grammatical and executive deficits in their language disorder. Integrated GM-WM imaging will relate this to left frontal disease, and converging evidence for an fMRI study of healthy adults will confirm this.
Aim 2 will examine the role of degraded perceptual feature knowledge in the semantic deficit of SD patients. Imaging studies will, relate poor knowledge of visual object features to visual association cortex in the ventral temporal lobe and poor auditory feature knowledge to dorsal temporal regions. An fMRI study in healthy adults will provide converging evidence for the anatomic relationships of visual and auditory feature knowledge of object concepts.
Aim 3 will demonstrate the role executive limitations in the most devastating social disorders of bvFTD patients. We will identify two forms of apathy - a vegetative form manifested as poor motivation, and an executive form that relates apathy to difficulty with multi-step tasks. Using integrated GM-WM imaging, we expect these two forms of apathy to be associated with disease in different frontal regions. Different forms of disinhibition also will be identified. One form will be related in part to impoverished social knowledge and right temporal disease, and a second form related to executive dysfunction (e.g. mental switching difficulty) involving right ventral prefrontal disease.
Aim 4 will test the hypothesis that non-fluent speech due to grammatical difficulty in PNFA is associated with FTLD-Tau, and this association will be strengthened by tau haplotype. Degraded feature knowledge for object concepts in SD will be associated with FTLD-TDP, and this will be strengthened by TMEM106B. We will also test the hypothesis that the vegetative form of apathy in bvFTD is related to FTLD-Tau, while disinhibition due to impaired social knowledge is related to FTLD-TDP. This work will advance cognitive neuroscience in the areas of language processing, semantic memory, and social cognition. These findings will contribute crucially to diagnostic accuracy, clarify specific clinical features that are most likely to refiect underlying pathology, and provide meaningful endpoints for treatment trials.

Public Health Relevance

Frontotemporal lobar degeneration is as common as Alzheimer's disease in the segment of the population that is under 65 years of age. Taken together with other tauopathies such as corticobasal degeneration and progressive supranuclear palsy, this represents an important segment of the population that must be identified for treatment. Clinical Core B, working together with the other Cores and Projects of this PPG, will contribute directly to this effort through the development of multimodal diagnostic strategies. These efforts will improve the care of patients as well as advance our scientific understanding of this disease.

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 Pennsylvania
United States
Zip Code
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
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
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
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
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
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
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
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
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
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

Showing the most recent 10 out of 487 publications