Primary progressive aphasia (PPA) is one of the clinical presentations of the frontotemporal dementia- spectrum disorders. It occurs when neurodegeneration selectively targets the language networks of the brain. Discoveries from previous cycles of this PPG were fundamental in characterizing PPA and its main clinic- anatomical presentations: the nonfluent/agrammatic (nfvPPA), semantic (svPPA) and logopenic (lvPPA) variants. These three syndromes are associated with specific patterns of language and anatomical damage, and are each thought to have different probable underlying molecular causes. Despite these significant advances in PPA characterization, many questions regarding clinical heterogeneity, prognosis and biological basis remain unanswered. In this project, we will take advantage of the wealth of multidisciplinary expertise and data available through this PPG to investigate differential diagnosis, clinical and neuroimaging progression and in-vivo pathological prediction in PPA. We propose a five-year cross-sectional and longitudinal study of the cognitive, anatomical and biological features of more than 100 newly recruited individuals with PPA. We will use the most modern techniques, from computerized, tablet-based cognitive tests to molecular neuroimaging and gene expression, to develop principles and diagnostic concepts that can also be applied in less specialized settings. In particular, in Aim 1 we will use validated and tablet-based tests of visuo-spatial, executive and socio-emotional functions to study non-language features in the PPA variants. We hypothesize that specific patterns of cognitive dysfunction will be found in each PPA variant at presentation and at 1-year follow-up, depending on the anatomical network involved.
In Aim 2, we will use the human healthy connectome architecture to predict longitudinal neuroimaging changes in PPA. Based on the transynaptic-spread theory of neurodegeneration, we hypothesize that regions strongly connected to syndrome-specific epicenters will show atrophy and molecular PET changes at one-year follow-up. Finally, in Aim 3, we will combine clinical, neuroimaging, genetic and pathological data in the largest and most comprehensive PPA dataset ever examined, in a multivariate analyze that will determine whether molecular diagnosis can be predicted in-vivo. This project will provide crucial data for the diagnosis of neurodegenerative diseases in their early stages, when treatment can be most effective.

Public Health Relevance

The research focuses on Primary Progressive Aphasia (PPA), a fatal neurodegenerative disorder that manifests with speech and language symptoms. In this project, we will combine cognitive, neuroimaging and biological data from a large PPA cohort with the goal of improving differential diagnosis, prognosis and ultimately treatment of this devastating disorder.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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University of California San Francisco
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Seo, Sang Won; Thibodeau, Marie-Pierre; Perry, David C et al. (2018) Early vs late age at onset frontotemporal dementia and frontotemporal lobar degeneration. Neurology 90:e1047-e1056
Santos-Santos, Miguel A; Rabinovici, Gil D; Iaccarino, Leonardo et al. (2018) Rates of Amyloid Imaging Positivity in Patients With Primary Progressive Aphasia. JAMA Neurol 75:342-352
Bergeron, David; Gorno-Tempini, Maria L; Rabinovici, Gil D et al. (2018) Prevalence of amyloid-? pathology in distinct variants of primary progressive aphasia. Ann Neurol 84:729-740
Björkhem, Ingemar; Patra, Kalicharan; Boxer, Adam L et al. (2018) 24S-Hydroxycholesterol Correlates With Tau and Is Increased in Cerebrospinal Fluid in Parkinson's Disease and Corticobasal Syndrome. Front Neurol 9:756
Pottier, Cyril; Zhou, Xiaolai; Perkerson 3rd, Ralph B et al. (2018) Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol 17:548-558
Theofilas, Panos; Ehrenberg, Alexander J; Nguy, Austin et al. (2018) Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans. Neurobiol Aging 61:1-12
Eser, Rana A; Ehrenberg, Alexander J; Petersen, Cathrine et al. (2018) Selective Vulnerability of Brainstem Nuclei in Distinct Tauopathies: A Postmortem Study. J Neuropathol Exp Neurol 77:149-161
Burette, Alain C; Judson, Matthew C; Li, Alissa N et al. (2018) Subcellular organization of UBE3A in human cerebral cortex. Mol Autism 9:54
Deleon, Jessica; Miller, Bruce L (2018) Frontotemporal dementia. Handb Clin Neurol 148:409-430
Zakrzewski, Jessica J; Datta, Samir; Scherling, Carole et al. (2018) Deficits in physiological and self-conscious emotional response to errors in hoarding disorder. Psychiatry Res 268:157-164

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