Alzheimer disease (AD) is a devastating neurodegenerative diseases with a variety of distinct clinical phenotypes, including typical amnesic dementia as well as atypical language, visual and behavioral/dysexecutive presentations. Our ability to be confident in a diagnosis of atypical AD has been greatly improved by technology to image brain beta-amyloid (A?) in living patients using PET scans. We have known for years that the other major protein involved in AD- paired helical filament (PHF) tau- appears more closely correlated with brain atrophy and neurodegeneration, the lesions most closely associated with symptoms and clinical phenotype. In the past this has only been possible to measure in post-mortem brain tissue after death. In this proposal, we aim to perform an investigation of a new PET imaging ligand that binds to brain PHF tau in order to try to measure this protein in living individuals with typical AD and PCA-AD. We will scan individuals who have one of two major clinical phenotypes (typical amnestic AD, and posterior cortical atrophy and a known biomarker of AD pathobiology (CSF tau/ A? or amyloid PET imaging). We will compare 18F-T807 tau and 11C-PiB amyloid PET images within and between the clinical phenotypes, and examine them in relation to regional brain atrophy. We will focus particular attention to the posterior cingulate/precuneus as a region of potential overlap between typical AD and PCA-AD to determine whether topographical differences in the underlying molecular pathologies and/or neurodegeneration in this region correlate with differences in clinical phenotype. The ultimate goal of this research is to begin to determine whether 18F-T807 PET will be a useful tool for the design of clinical trials aiming to treat both typical and atypical clinical forms of AD.

Public Health Relevance

The ability to detect brain beta-amyloid (A?) in living patients with Alzheimer disease (AD) has revolutionized the field, and has confirmed that many patients with brain A? and presumed underlying AD have atypical symptoms. This project aims to test the utility of a new imaging measure of brain paired helical filament tau in patients with typical AD and posterior cortical atrophy due to AD to improve early diagnosis and monitoring and to further understanding of the similarities and differences between these conditions in terms of topography of underlying molecular pathologies and neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG051987-02
Application #
9329355
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Hsiao, John
Project Start
2016-08-15
Project End
2018-05-31
Budget Start
2017-07-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Racine, Annie M; Brickhouse, Michael; Wolk, David A et al. (2018) The personalized Alzheimer's disease cortical thickness index predicts likely pathology and clinical progression in mild cognitive impairment. Alzheimers Dement (Amst) 10:301-310
Putcha, Deepti; McGinnis, Scott M; Brickhouse, Michael et al. (2018) Executive dysfunction contributes to verbal encoding and retrieval deficits in posterior cortical atrophy. Cortex 106:36-46
Makaretz, Sara J; Quimby, Megan; Collins, Jessica et al. (2018) Flortaucipir tau PET imaging in semantic variant primary progressive aphasia. J Neurol Neurosurg Psychiatry 89:1024-1031
Das, Sandhitsu R; Xie, Long; Wisse, Laura E M et al. (2018) Longitudinal and cross-sectional structural magnetic resonance imaging correlates of AV-1451 uptake. Neurobiol Aging 66:49-58
Dickerson, Bradford C; Brickhouse, Michael; McGinnis, Scott et al. (2017) Alzheimer's disease: The influence of age on clinical heterogeneity through the human brain connectome. Alzheimers Dement (Amst) 6:122-135
Xia, Chenjie; Makaretz, Sara J; Caso, Christina et al. (2017) Association of In Vivo [18F]AV-1451 Tau PET Imaging Results With Cortical Atrophy and Symptoms in Typical and Atypical Alzheimer Disease. JAMA Neurol 74:427-436
Dickerson, Bradford C; McGinnis, Scott M; Xia, Chenjie et al. (2017) Approach to atypical Alzheimer's disease and case studies of the major subtypes. CNS Spectr 22:439-449
Xia, Chenjie; Dickerson, Bradford C (2016) Tau PET: the next frontier in molecular imaging of dementia. Int Psychogeriatr 28:1403-6