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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017586-13
Application #
8444442
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
13
Fiscal Year
2013
Total Cost
$236,166
Indirect Cost
$88,564
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Irwin, David J; Xie, Sharon X; Coughlin, David et al. (2018) CSF tau and ?-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders. Neurology 90:e1038-e1046
Ferraro, Pilar M; Jester, Charles; Olm, Christopher A et al. (2018) Perfusion alterations converge with patterns of pathological spread in transactive response DNA-binding protein 43 proteinopathies. Neurobiol Aging 68:85-92
Massimo, Lauren; Xie, Sharon X; Rennert, Lior et al. (2018) Occupational attainment influences longitudinal decline in behavioral variant frontotemporal degeneration. Brain Imaging Behav :
Spiller, Krista J; Restrepo, Clark R; Khan, Tahiyana et al. (2018) Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat Neurosci 21:329-340
Rey, Nolwen L; George, Sonia; Steiner, Jennifer A et al. (2018) Spread of aggregates after olfactory bulb injection of ?-synuclein fibrils is associated with early neuronal loss and is reduced long term. Acta Neuropathol 135:65-83
Irwin, David J; McMillan, Corey T; Xie, Sharon X et al. (2018) Asymmetry of post-mortem neuropathology in behavioural-variant frontotemporal dementia. Brain 141:288-301
Lewczuk, Piotr; Riederer, Peter; O'Bryant, Sid E et al. (2018) Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry. World J Biol Psychiatry 19:244-328
Phillips, Jeffrey S; Da Re, Fulvio; Dratch, Laynie et al. (2018) Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease. Neurobiol Aging 63:75-87
Kassubek, Jan; Müller, Hans-Peter; Del Tredici, Kelly et al. (2018) Longitudinal Diffusion Tensor Imaging Resembles Patterns of Pathology Progression in Behavioral Variant Frontotemporal Dementia (bvFTD). Front Aging Neurosci 10:47
Cousins, Katheryn A Q; Ash, Sharon; Grossman, Murray (2018) Production of verbs related to body movement in amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD). Cortex 100:127-139

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