The overall purpose of Clinical Core B is to recruit and characterize patients with frontotemporal lobar degeneration (FTLD) to support the Cores and Projects of this Program Project Grant (PPG). Clinical Core B will obtain multimodal data during life that will be analyzed with Biostatistics Core E. We will develop a comprehensive diagnostic picture of clinical FTLD that corresponds to FTLD spectrum pathology, together with Pathology Core D. Genetic studies suggest that up to 40% of patients have a strong family history of FTLD Spectrum disease, and specific genetic mutations identified in 15% of FTLD patients lead to particular patterns of pathology. With Genetics Core C, we will recruit and study patients with familial FTLD. One major clinical phenotype is Primary Progressive Aphasia (PPA). This includes a subgroup with effortful speech known as progressive non-fluent aphasia (PNFA), a subgroup with degraded word and object meaning known as semantic dementia (SD), and logopenic progressive aphasia (LPA) that presents with impaired word-finding and repetition. The second major clinical phenotype is behavioral-variant FTD (bvFTD). This presents as a disorder of social comportment, personality and executive functioning, including apathy, disinhibition and obsessive rigidity. The spectrum of pathology most commonly causing FTLD includes FTLD-Tau and forms of FTLD related to ubiquitin pathology such as FTLD-TDP. However, about 30% of cases with a clinical diagnosis of FTLD have atypical presentations of Alzheimer's disease (AD) at autopsy. Because of these diagnostic ambiguities. Core B will collect extensive biomarker data to improve diagnostic accuracy.
Aim 1 will recruit patients with FTLD for clinical and autopsy studies for the Cores and Projects of this PPG, characterize these patients clinically, and follow them longitudinally, in collaboration with Core E.
Aim 2 will collect structural MRI, diffusion tensor imaging (DTI), arterial spin labeling (ASL), cerebrospinal fluid (CSF), blood, and plasma in FTLD.
Aim 3 will recruit patients and families at high risk for familial FTLD, together with Core C, and assess affected as well as clinically asymptomatic family members. We will advise Core C and Project 1 about clinical features of patients with genetic mutations, and collect novel biomarkers with Core C.
Aim 4 will support comparative studies of FTLD with other neurodegenerative conditions such as AD, amyotrophic lateral sclerosis (ALS), and synucleinopathies such as dementia with Lewy bodies (DLB) and other movement disorders. We will also continue to collaborate with investigators at other institutions on multi-center studies of FTLD. This work will support the other Projects and Cores of this PPG and advance our knowledge of FTLD from a multidimensional perspective.

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)
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Special Emphasis Panel (ZAG1-ZIJ-4)
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University of Pennsylvania
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Zhang, Bin; Yao, Yuemang; Cornec, Anne-Sophie et al. (2018) A brain-penetrant triazolopyrimidine enhances microtubule-stability, reduces axonal dysfunction and decreases tau pathology in a mouse tauopathy model. Mol Neurodegener 13:59
Porta, Sílvia; Xu, Yan; Restrepo, Clark R et al. (2018) Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat Commun 9:4220
Sanchez-Contreras, Monica Y; Kouri, Naomi; Cook, Casey N et al. (2018) Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol Neurodegener 13:37
Robinson, John L; Corrada, Maria M; Kovacs, Gabor G et al. (2018) Non-Alzheimer's contributions to dementia and cognitive resilience in The 90+ Study. Acta Neuropathol :
Brettschneider, Johannes; Suh, EunRan; Robinson, John L et al. (2018) Converging Patterns of ?-Synuclein Pathology in Multiple System Atrophy. J Neuropathol Exp Neurol 77:1005-1016
Suh, EunRan; Grando, Kaitlyn; Van Deerlin, Vivianna M (2018) Validation of a Long-Read PCR Assay for Sensitive Detection and Sizing of C9orf72 Hexanucleotide Repeat Expansions. J Mol Diagn 20:871-882
Zee, Jarcy; Xie, Sharon X (2018) The Kaplan-Meier Method for Estimating and Comparing Proportions in a Randomized Controlled Trial with Dropouts. Biostat Epidemiol 2:23-33
Oukoloff, Killian; Kovalevich, Jane; Cornec, Anne-Sophie et al. (2018) Design, synthesis and evaluation of photoactivatable derivatives of microtubule (MT)-active [1,2,4]triazolo[1,5-a]pyrimidines. Bioorg Med Chem Lett 28:2180-2183
Phillips, Jeffrey S; Das, Sandhitsu R; McMillan, Corey T et al. (2018) Tau PET imaging predicts cognition in atypical variants of Alzheimer's disease. Hum Brain Mapp 39:691-708
Smith, Kara M; Ash, Sharon; Xie, Sharon X et al. (2018) Evaluation of Linguistic Markers of Word-Finding Difficulty and Cognition in Parkinson's Disease. J Speech Lang Hear Res 61:1691-1699

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