# Frontotemporal Dementias: Genotypes and Phenotypes

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $711,440

## Abstract

OVERALL: Program Project Summary/Abstract
The major goals of this competing renewal of this Program Project Grant (PPG) are to advance
understanding of the etiology and pathogenesis of frontotemporal lobar degeneration (FTLD) spectrum
disorders with a specific emphasis on patients with aggregated tau pathology (FTLD-Tau), so as to improve
the diagnosis and treatment of patients with FTLD-Tau disorders and related diseases. FTLD, referred to
clinically as frontotemporal degeneration (FTD), manifests with progressive behavioral and/or language
deficits but neuropathologically, FTLD is heterogeneous, with ~50% of cases characterized by TDP-43 (i.e.
FTLD-TDP subtype) or tau (FTLD-Tau) pathology, while rare cases are due to FUS pathology (i.e. FTLD-
FUS). Since clinical diagnoses do not precisely predict the underlying neuropathology of different FLTD
variants, and since potential treatments for these different subtypes of FTLD (e.g. targeting the removal of
tau versus TDP-43 pathology) are likely different, it is imperative that we develop a better understanding of
the clinical, genetic, biochemical, biomarker and neuropathological phenotypes as well as the molecular
abnormalities in patients with the spectrum of FTLD diseases. The focus of this PPG is on FTLD-Tau
diseases that progressively accumulate distinct pathological tau species that we refer to here as “strains” in
different tauopathy variants including corticobasal degeneration (CBD), progressive supranuclear palsy
(PSP) and Pick's disease (PiD) in a distinct and stereotypical manner. The pathological tau strains
propagate through the neuroanatomical connectome and glial cells producing patterns of tau pathology
mediated neurodegeneration that reflect the clinical and pathological diversity of these tauopathies. Thus,
the overarching objectives of the overall PPG which is comprised of 5 Cores and 4 Projects, are to test the
“transmission” hypothesis and the “strain” hypothesis of pathological tau spread in patients and in model
systems by: 1) characterizing the spectrum of the clinical phenotypes seen in FTD patients; 2) identifying
new genetic mutations in FTLD-Tau kindreds as well as novel genetic modifiers of tau pathogenicity through
human postmortem brain expression analyses; 3) developing novel neuronal culture and animal models of
FTLD-Tau disorders using FTLD brain-derived tau strains; 4) elucidating the molecular basis of cell-to-cell
spread involving uptake, release and intracellular trafficking of pathological tau; 5) transmission of tau
pathology in brains of transgenic mouse models injected with tau strains purified from human PSP, CBD
and PiD brains. By addressing these and other closely related questions defined in each of the Projects with
the innovative approaches described here, this PPG will advance understanding of the onset and
progression of FTLD-Tau disorders, especially PSP, CBD and PiD, as well as open up new directions for
the accurate and early diagnosis of these t...

## Key facts

- **NIH application ID:** 10392563
- **Project number:** 3P01AG017586-20S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** VIRGINIA M LEE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $711,440
- **Award type:** 3
- **Project period:** 2000-03-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10392563

## Citation

> US National Institutes of Health, RePORTER application 10392563, Frontotemporal Dementias: Genotypes and Phenotypes (3P01AG017586-20S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10392563. Licensed CC0.

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