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
Bernier, Patrick J; Gourdeau, Christian; Carmichael, Pierre-Hugues et al. (2017) Validation and diagnostic accuracy of predictive curves for age-associated longitudinal cognitive decline in older adults. CMAJ 189:E1472-E1480
Ranasinghe, Kamalini G; Hinkley, Leighton B; Beagle, Alexander J et al. (2017) Distinct spatiotemporal patterns of neuronal functional connectivity in primary progressive aphasia variants. Brain 140:2737-2751
Sposato, Luciano A; Ruíz Vargas, Estefanía; Riccio, Patricia M et al. (2017) Milder Alzheimer's disease pathology in heart failure and atrial fibrillation. Alzheimers Dement 13:770-777
Moga, Daniela C; Abner, Erin L; Wu, Qishan et al. (2017) Bladder antimuscarinics and cognitive decline in elderly patients. Alzheimers Dement (N Y) 3:139-148
Scherling, Carole S; Zakrzewski, Jessica; Datta, Samir et al. (2017) Mistakes, Too Few to Mention? Impaired Self-conscious Emotional Processing of Errors in the Behavioral Variant of Frontotemporal Dementia. Front Behav Neurosci 11:189
Sturm, Virginia E; Perry, David C; Wood, Kristie et al. (2017) Prosocial deficits in behavioral variant frontotemporal dementia relate to reward network atrophy. Brain Behav 7:e00807
Fernández-Fournier, Mireya; Perry, David C; Tartaglia, Maria Carmela et al. (2017) Precipitous Deterioration of Motor Function, Cognition, and Behavior. JAMA Neurol 74:591-596
Sennik, Simrin; Schweizer, Tom A; Fischer, Corinne E et al. (2017) Risk Factors and Pathological Substrates Associated with Agitation/Aggression in Alzheimer's Disease: A Preliminary Study using NACC Data. J Alzheimers Dis 55:1519-1528
Burke, Shanna L; O'Driscoll, Janice; Alcide, Amary et al. (2017) Moderating risk of Alzheimer's disease through the use of anxiolytic agents. Int J Geriatr Psychiatry 32:1312-1321
Neu, Scott C; Pa, Judy; Kukull, Walter et al. (2017) Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol 74:1178-1189

Showing the most recent 10 out of 501 publications