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
Kirson, Noam Y; Scott Andrews, J; Desai, Urvi et al. (2018) Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. J Alzheimers Dis 61:295-307
Crum, Jana; Wilson, Jeffrey; Sabbagh, Marwan (2018) Does taking statins affect the pathological burden in autopsy-confirmed Alzheimer's dementia? Alzheimers Res Ther 10:104
Nguyen, Andrew D; Nguyen, Thi A; Zhang, Jiasheng et al. (2018) Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay. Proc Natl Acad Sci U S A 115:E2849-E2858
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
Arnemann, Katelyn L; Stöber, Franziska; Narayan, Sharada et al. (2018) Metabolic brain networks in aging and preclinical Alzheimer's disease. Neuroimage Clin 17:987-999
McKeever, Paul M; Schneider, Raphael; Taghdiri, Foad et al. (2018) MicroRNA Expression Levels Are Altered in the Cerebrospinal Fluid of Patients with Young-Onset Alzheimer's Disease. Mol Neurobiol 55:8826-8841
Burke, Shanna L; Cadet, Tamara; Maddux, Marlaina (2018) Chronic Health Illnesses as Predictors of Mild Cognitive Impairment Among African American Older Adults. J Natl Med Assoc 110:314-325
Burke, Shanna L; Hu, Tianyan; Fava, Nicole M et al. (2018) Sex differences in the development of mild cognitive impairment and probable Alzheimer's disease as predicted by hippocampal volume or white matter hyperintensities. J Women Aging :1-25
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

Showing the most recent 10 out of 590 publications