This project will investigate selective vulnerability in frontotemporal dementia (FTD) and Alzheimer's disease (AD). Whereas AD begins with memory impairment, early FTD leads to social-emotional processing deficits. Some patients with FTD develop motor neuron disease (MND), which shortens the disease course and provides a window into early FTD anatomical deficits. In the behavioral variant of FTD (bvFTD), early atrophy and metabolic dysfunction focally affects the anterior cingulate (ACC) and frontoinsular (FI) cortices, especially in the right hemisphere. Recent work suggests selective vulnerability of a unique class of large projection neurons, von Economo neurons (VENs), found only in ACC and FI and restricted, among primates, to humans and great apes. The proposed studies will further examine the hypothesis that VENs are a central feature of the early bvFTD anatomic injury pattern.
Our aims are to (1) Determine whether FI VENs are selectively vulnerable in bvFTD vs. AD and non-neurological controls (NNC) and explore laterality effects, (2) Examine histopathological correlates and antecedents of VEN cell death, and (3) explore the hypothesis that VEN vulnerability in bvFTD relates to specific neurodevelopmental signaling proteins alterations. We will study brain autopsy materials from 15 NNC, 15 AD, 20 bvFTD-MND, and 30 bvFTD subjects using quantitative neuroanatomical and immunohistochemical methods to assess neuron number and morphology, disease protein inclusion formation, synapse loss, astrogliosis, and neurodevelopmental/plasticity signals. The knowledge gained could help create a more comprehensive bvFTD pathogenesis model by determining the specific anatomical substrates of early disease and pathophysiological events that surround this targeted injury.

Public Health Relevance

This project will investigate the specific brain regions and neurons that degenerate in frontemporal dementia, a neurological disease that causes changes in personality and behavior. The goal of the research is to clarify where in the brain the disease strikes and what biological properties render specific brain cells vulnerable. This information may provide clues regarding new potential treatments for the disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033017-02
Application #
7778861
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Refolo, Lorenzo
Project Start
2009-03-15
Project End
2014-02-28
Budget Start
2010-03-15
Budget End
2011-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$514,376
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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