Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive impairment of behavior, language and motor functions caused by neurodegeneration within temporal and frontal brain networks. It is the most frequent cause of dementia under the age of 60. Project 4 of this PPG focuses on differential diagnosis of FTD, which, until recently, was thought to be undistinguishable form Alzheimer's disease (AD) during life. In the previous cycle we have concentrated on identifying distinctive features between FTD and AD and have incorporated our findings into novel research criteria for the behavioral variant (bvFTD), the language variants (primary progressive aphasia-PPA) and the mixed cognitive/behavioral and motor presentation (corticobasal syndromes or CBS) of the disease.
The first aim of this application will focus on establishing sensitivity and specificity of these novel classification systems, combined with established PSP-S and amytrophic lateral sclerosis criteria, in predicting in vivo FTLD versus AD pathology. For this purpose we will consider pathology as the gold standard and we will have a large cohort of pathology-confirmed cases that have undergone our extensive clinical and cognitive evaluations. Project 4, and this PPG in general, have also contributed to the recent, discovery that FTD is associated with not only tau aggregates, but also with TDP-43 and FUS. Recognition that the clinical FTD syndrome is associated with a spectrum of diseases at the pathological level (called frontotemporal lobar degeneration-FTLD) poses a new challenge for differential diagnosis that will be tackled by this new project. The second and third aims of Project 4 apply all of the data acquired from the Cores, and some projects, into a multidimensional dataset comprised of clinical, neuroimaging and genetic data that will be analyzed with modern multivariate statistical methods in order to predict in vivo which pathological subtype patients will have, tau, TDP or FUS. By the year 2017 we predict we will have pathological and clinical data on about 250 FTLD cases, creating the largest FTD cohort in the world and allowing us to be at the forefront of diagnosing, and eventually treating, this devastating disease.

Public Health Relevance

Project 4 will develop enhanced clinical tests to improve the ability to detect and diagnosis frontotemporal dementias. The project aims to discover and identify new risk factors. This work will lead to improved diagnostic services and disease specific treatment to individuals with neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG019724-12
Application #
8531792
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
12
Fiscal Year
2013
Total Cost
$210,120
Indirect Cost
$56,553
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Barton, Cynthia; Ketelle, Robin; Merrilees, Jennifer et al. (2016) Non-pharmacological Management of Behavioral Symptoms in Frontotemporal and Other Dementias. Curr Neurol Neurosci Rep 16:14
Naasan, Georges; Rabinovici, Gil D; Ghosh, Pia et al. (2016) Amyloid in dementia associated with familial FTLD: not an innocent bystander. Neurocase 22:76-83
Yokoyama, Jennifer S; Marx, Gabe; Brown, Jesse A et al. (2016) Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging. Brain Imaging Behav :
Ranasinghe, Kamalini G; Rankin, Katherine P; Pressman, Peter S et al. (2016) Distinct Subtypes of Behavioral Variant Frontotemporal Dementia Based on Patterns of Network Degeneration. JAMA Neurol 73:1078-88
Schott, Jonathan M; Crutch, Sebastian J; Carrasquillo, Minerva M et al. (2016) Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease. Alzheimers Dement 12:862-71
Vatsavayai, Sarat C; Yoon, Soo Jin; Gardner, Raquel C et al. (2016) Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain 139:3202-3216
Mair, Waltraud; Muntel, Jan; Tepper, Katharina et al. (2016) FLEXITau: Quantifying Post-translational Modifications of Tau Protein in Vitro and in Human Disease. Anal Chem 88:3704-14
Chételat, Gaël; Ossenkoppele, Rik; Villemagne, Victor L et al. (2016) Atrophy, hypometabolism and clinical trajectories in patients with amyloid-negative Alzheimer's disease. Brain 139:2528-39
Nascimento, Camila; Suemoto, Claudia K; Rodriguez, Roberta D et al. (2016) Higher Prevalence of TDP-43 Proteinopathy in Cognitively Normal Asians: A Clinicopathological Study on a Multiethnic Sample. Brain Pathol 26:177-85
Silva, M Catarina; Cheng, Chialin; Mair, Waltraud et al. (2016) Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability. Stem Cell Reports 7:325-40

Showing the most recent 10 out of 497 publications