PROJECT 2 - ABSTRACT Primary progressive aphasia (PPA) is a collection of clinical syndromes characterized by gradual, selective decline in speech and language functions. It is caused by neurodegeneration in the brain regions that sustain language. PPA is a devastating disease affecting adults in the prime of their life, depriving them of the ability to communicate and function in society. In the last decade, the cognitive and neural bases of PPA have been studied thoroughly, and three clinic-anatomical variants of the disease have been described. Importantly, each variant is characterized by a different probability of underlying frontotemporal lobar degeneration (FTLD) or Alzheimer's disease (AD) pathology. Recent preliminary data suggest that different neurodevelopmental and biological factors are associated with each of the main PPA variants. In this project, we will further develop this line of research and investigate developmental, genetic and molecular factors that might determine susceptibility of the language network to each PPA subtype. We will recruit 125 new PPA patients and combine data with that of our large existing cohort to realize the following main goals: (1) Identify the presence of language-based learning disabilities, such as dyslexia, and determine their effect on cognitive and anatomical phenotypes. We hypothesize that language-based learning disabilities will be present most often in the logopenic variant PPA and will predict earlier age at onset and greater phonological impairment. (2) Measure hemispheric lateralization of language function an asses brain symmetry using magnetoencephalography and structural MRI. We predict that svPPA patients will show anomalous lateralization of language activation and decreased asymmetry of specific perisylvian language regions. (3) evaluate APOE allele status, inflammatory gene expression patterns and plasma cytokines levels. We expect to find a lower incidence of the APOE4 allele among logopenic patients with learning disabilities than those without, and to find biomarkers indicative of an altered immunological response in svPPA. This research will increase our knowledge about the pathogenesis of PPA and the neurobiology of language. Moreover, the results might serve as the foundation to develop early intervention strategies and personalized risk assessment for the prediction of neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
2P50AG023501-11
Application #
8677150
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (J1))
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
11
Fiscal Year
2014
Total Cost
$122,543
Indirect Cost
$44,861
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Vatsavayai, Sarat C; Nana, Alissa L; Yokoyama, Jennifer S et al. (2018) C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies. Acta Neuropathol :
Barnes, Josephine; Bartlett, Jonathan W; Wolk, David A et al. (2018) Disease Course Varies According to Age and Symptom Length in Alzheimer's Disease. J Alzheimers Dis 64:631-642
Brent, Robert J (2018) Estimating the monetary benefits of medicare eligibility for reducing the symptoms of dementia. Appl Econ 50:6327-6340
Hua, Alice Y; Sible, Isabel J; Perry, David C et al. (2018) Enhanced Positive Emotional Reactivity Undermines Empathy in Behavioral Variant Frontotemporal Dementia. Front Neurol 9:402
Ossenkoppele, Rik; Rabinovici, Gil D; Smith, Ruben et al. (2018) Discriminative Accuracy of [18F]flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA 320:1151-1162
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
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
Rojas, Julio C; Stephens, Melanie L; Rabinovici, Gil D et al. (2018) Multiproteinopathy, neurodegeneration and old age: a case study. Neurocase 24:1-6
Zylstra, Bradley; Netscher, George; Jacquemot, Julien et al. (2018) Extended, continuous measures of functional status in community dwelling persons with Alzheimer's and related dementia: Infrastructure, performance, tradeoffs, preliminary data, and promise. J Neurosci Methods 300:59-67
Pressman, Peter S; Shdo, Suzanne; Simpson, Michaela et al. (2018) Neuroanatomy of Shared Conversational Laughter in Neurodegenerative Disease. Front Neurol 9:464

Showing the most recent 10 out of 590 publications