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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Petanceska, Suzana
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Nana, Alissa L; Sidhu, Manu; Gaus, Stephanie E et al. (2018) Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology. Acta Neuropathol :
Cobos, Inma; Seeley, William W (2015) Human von Economo neurons express transcription factors associated with Layer V subcerebral projection neurons. Cereb Cortex 25:213-20
Henry, Maya L; Wilson, Stephen M; Ogar, Jennifer M et al. (2014) Neuropsychological, behavioral, and anatomical evolution in right temporal variant frontotemporal dementia: a longitudinal and post-mortem single case analysis. Neurocase 20:100-9
Kauppinen, Tiina M; Gan, Li; Swanson, Raymond A (2013) Poly(ADP-ribose) polymerase-1-induced NAD(+) depletion promotes nuclear factor-?B transcriptional activity by preventing p65 de-acetylation. Biochim Biophys Acta 1833:1985-91
Grinberg, Lea Tenenholz; Wang, Xuehua; Wang, Chao et al. (2013) Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol 125:581-93
Seeley, William W; Zhou, Juan; Kim, Eun-Joo (2012) Frontotemporal dementia: what can the behavioral variant teach us about human brain organization? Neuroscientist 18:373-85
Kim, Eun-Joo; Sidhu, Manu; Gaus, Stephanie E et al. (2012) Selective frontoinsular von Economo neuron and fork cell loss in early behavioral variant frontotemporal dementia. Cereb Cortex 22:251-9
Pievani, Michela; de Haan, Willem; Wu, Tao et al. (2011) Functional network disruption in the degenerative dementias. Lancet Neurol 10:829-43
Rohrer, J D; Geser, F; Zhou, J et al. (2010) TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia. Neurology 75:2204-11
Seeley, William W (2010) Anterior insula degeneration in frontotemporal dementia. Brain Struct Funct 214:465-75