Primary progressive aphasia (PPA) is a clinical syndrome characterized by isolated, progressive loss of speech and language abilities. PPA occurs when neurodegeneration selectively targets the language networks in the brain. It is most often caused by molecular and pathological changes typical of Frontotemporal lobar degeneration (FTLD) or Alzheimer?s disease (AD). Over the past 12 years of this project, we have studied a cohort of 300 well-characterized PPA patients, and have obtained an unprecedented number of post-mortem samples. We have published more than 130 papers, and have made discoveries that were essential in characterizing the PPA clinical variants and in defining the main clinico-anatomical presentations: the nonfluent/agrammatic (nfvPPA), semantic (svPPA) and logopenic (lvPPA) variants, each associated with a different probability of underlying molecular causes. Despite this significant progress, many questions regarding cognitive presentation, clinical course and biological basis remain unanswered. In this project, we will apply novel neuroimaging and cognitive neuroscience techniques to study clinical symptoms, in-vivo tau deposition, longitudinal progression, and prediction of pathological and molecular changes in PPA. We propose a five-year cross-sectional and longitudinal study of the cognitive, anatomical and biological features of more than 200 newly recruited individuals with PPA. In particular, in Aim 1, we will study the differential contribution of white matter, gray matter, and functional changes in the brain to the development of PPA symptoms, and use new tasks to investigate semantic, grammatical, and orthographic functions.
In Aim 2, we will apply the novel positron emission tomography [18F]AV1451 tau ligand to study how in-vivo molecular brain changes relate to clinical and cognitive factors in lvPPA and nfvPPA. Finally, in Aim 3, we will study PPA progression, and the validity of the network-spread theory of neurodegeneration, by relating longitudinal neuroimaging changes in patients to the healthy connective architecture. Furthermore, we will perform multivariate analyses on the combined clinical, neuroimaging, genetic, and pathological data, in the largest and most comprehensive PPA dataset ever examined to determine whether molecular diagnosis can be predicted in-vivo. This project will provide novel evidence on the neural basis of language, and provide crucial data for the diagnosis of neurodegenerative diseases in their early stages, when treatment can be most effective.

Public Health Relevance

This research program focuses on Primary Progressive Aphasia (PPA), a debilitating and 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 and ultimately treatment of this devastating disorder. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Language and Communication Study Section (LCOM)
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Babcock, Debra J
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Mandelli, Maria Luisa; Welch, Ariane E; Vilaplana, Eduard et al. (2018) Altered topology of the functional speech production network in non-fluent/agrammatic variant of PPA. Cortex 108:252-264
Pressman, Peter S; Shdo, Suzanne; Simpson, Michaela et al. (2018) Neuroanatomy of Shared Conversational Laughter in Neurodegenerative Disease. Front Neurol 9:464
Caverzasi, Eduardo; Mandelli, Maria Luisa; Hoeft, Fumiko et al. (2018) Abnormal age-related cortical folding and neurite morphology in children with developmental dyslexia. Neuroimage Clin 18:814-821
Watson, Christa L; Possin, Katherine; Allen, I Elaine et al. (2018) Visuospatial Functioning in the Primary Progressive Aphasias. J Int Neuropsychol Soc 24:259-268
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
Miller, Zachary A; Rosenberg, Lynne; Santos-Santos, Miguel A et al. (2018) Prevalence of Mathematical and Visuospatial Learning Disabilities in Patients With Posterior Cortical Atrophy. JAMA Neurol 75:728-737
Montembeault, Maxime; Brambati, Simona M; Gorno-Tempini, Maria Luisa et al. (2018) Clinical, Anatomical, and Pathological Features in the Three Variants of Primary Progressive Aphasia: A Review. Front Neurol 9:692
Iaccarino, Leonardo; Tammewar, Gautam; Ayakta, Nagehan et al. (2018) Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease. Neuroimage Clin 17:452-464

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