Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that cause dementia and hence are a major health concern. Both diseases affect the elderly and are increasing in prevalence as the aging population increases. These diseases are both associated with pathological changes in the brain including the deposition of abnormal proteins. Alzheimer's disease is associated with deposition of the proteins beta-amyloid and tau, whereas recently FTLD has been shown to be associated with the transactive response DNA binding protein 43 (TDP-43). We recently demonstrated that almost 50% of patients with AD also have deposition of the protein TDP-43 in their brain cells. This finding may be an important clue to understanding the underlying disease mechanisms causing FTLD and AD. However, it is currently unknown whether the role of TDP-43 in AD differs from its role in FTLD and whether TDP-43 deposition in AD has any clinical significance. The main objective of this R01 is to better understand the role, and hence significance, of TDP-43 in FTLD and AD. To accomplish this goal we will study a large cohort of autopsy confirmed cases of AD and FTLD that were ascertained through our NIH funded Alzheimer's Disease Research Center. We will assess and compare pathological characteristics of TDP-43 in FTLD and AD including its distribution, intracellular appearance, association with tau, and protein fragmentation. Associations between pathological characteristics and clinical and imaging characteristics will then be determined. Imaging-pathological associations will be investigated using state of the art automated imaging techniques, including voxel-based morphometry and atlas-based parcellation. The methods will be performed by a team of world renowned scientists including a dementia and movement disorder specialist, a neuropathologist, radiology researchers, and biostatisticians. The long term goal of our research is to aid in the development of treatments for AD and FTLD that will likely target underlying proteins.

Public Health Relevance

This study will improve our understanding of the role of the transactive DNA binding protein 43 (TDP-43) in Alzheimer's disease and frontototemporal lobar degeneration. A better understanding of the role of TDP-43 is important to the development of targeted treatments for both diseases. Alzheimer's disease and frontototemporal lobar degeneration affect over 5 million Americans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG037491-02
Application #
8101180
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Refolo, Lorenzo
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2011-07-15
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$308,926
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Josephs, Keith A (2017) Current Understanding of Neurodegenerative Diseases Associated With the Protein Tau. Mayo Clin Proc 92:1291-1303
Josephs, Keith A; Dickson, Dennis W; Tosakulwong, Nirubol et al. (2017) Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer's disease: a longitudinal retrospective study. Lancet Neurol 16:917-924
Whitwell, Jennifer L; Höglinger, Günter U; Antonini, Angelo et al. (2017) Radiological biomarkers for diagnosis in PSP: Where are we and where do we need to be? Mov Disord 32:955-971
Josephs, Keith A; Tosakulwong, Nirubol; Weigand, Stephen D et al. (2017) Brain tau deposition linked to systemic causes of death in normal elderly. Neurobiol Aging 50:163-166
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Flanagan, Eoin P; Duffy, Joseph R; Whitwell, Jennifer L et al. (2016) Mixed tau and TDP-43 pathology in a patient with unclassifiable primary progressive aphasia. Neurocase 22:55-9
Koga, Shunsuke; Josephs, Keith A; Ogaki, Kotaro et al. (2016) Cerebellar ataxia in progressive supranuclear palsy: An autopsy study of PSP-C. Mov Disord 31:653-62
Josephs, Keith A; Murray, Melissa E; Whitwell, Jennifer L et al. (2016) Updated TDP-43 in Alzheimer's disease staging scheme. Acta Neuropathol 131:571-85
Pottier, Cyril; Bieniek, Kevin F; Finch, NiCole et al. (2015) Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol 130:77-92

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