Dementia represents a major public health problem which will grow significantly with the aging of our society. Recently, multiple pieces of converging clinical and neuropathological data indicate that dementia is typically a multi-factorial process. This evolution in thinking about the biology of dementia comes at a time when the most significant recent development in dementia imaging has been the introduction of amyloid plaque labeling compounds;the most widely studied at this point is Pittsburgh Compound - B (PiB). A central principle underlying this renewal is this. Amyloid imaging is unquestionably a major advance. However, since the biology of dementia is more complex than brain amyloidosis alone, imaging of dementia is more complex than brain amyloid imaging alone. Our primary goal in this renewal is to use various imaging modalities to identify different mechanisms underlying dementia. This is the first resubmission of a competitive renewal of AG11378. We have revised the grant in accordance with each point raised in the critique and we believe this has resulted in a much stronger application. Each of the five aims is cast to answer variations on the questions: What is the contribution of specific imaging-based proxies of pathology to clinical/cognitive decline? When in the course of the disease do these relationships hold true? For whom is this true? Where in the brain are the relevant pathologies expressed? Principle outcome measures will be clinical and psychometric decline over time which we will use as indicators of disease progression. Our predictor variables will include various imaging modalities which will serve as proxies for specific pathologic mechanisms underlying dementia. PiB will serve as a measure of plaque burden and we will use various Magnetic Resonance Imaging (MRI) modalities to assess cerebro- vascular disease, tissue loss, tissue perfusion, diffusion, neuronal integrity, and inflammation. Features that distinguish this renewal from past cycles of AG11378 include a mechanistic focus, multi- modality imaging including multiple MRI modalities as well as PET amyloid imaging, MR imaging now at 3T, inclusion of both amnestic and non-amnestic MCI, and voxel-based analytic methods including an exciting new computational approach which employs a support vector machine algorithm to provide diagnosis in individual subjects. In addition, subjects will now be recruited from a new population-based study of aging and dementia, which differentiates this renewal from past cycles as well as from most dementia imaging studies which recruit from referral practices and thus risk sampling bias. Previous cycles of this grant have contributed significantly to recognition of the utility of imaging in dementia. An active debate is currently underway about revising clinical criteria for AD, specifically whether imaging and fluid biomarker information should be included among the criteria. Results from this renewal grant will inform this debate about multiple time dependent mechanisms leading to dementia that are accessible in living subjects through imaging.

Public Health Relevance

Identifying Mechanisms of Dementia: Role for MRI in the Era of Molecular Imaging (AG11378) Dementia is a leading public health problem now and will have an increasingly serious impact on public health as the number of elderly individuals increase. Dementia has many possible underlying causes and several different causes are at work in most elderly demented subjects. In this grant, we will use modern brain imaging to identify specific mechanisms underlying progression to dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG011378-20
Application #
8292033
Study Section
Special Emphasis Panel (ZRG1-CND-E (90))
Program Officer
Hsiao, John
Project Start
1993-06-01
Project End
2013-06-30
Budget Start
2012-08-01
Budget End
2013-06-30
Support Year
20
Fiscal Year
2012
Total Cost
$934,653
Indirect Cost
$253,406
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Graff-Radford, Jonathan; Madhavan, Malini; Vemuri, Prashanthi et al. (2016) Atrial fibrillation, cognitive impairment, and neuroimaging. Alzheimers Dement 12:391-8
Petersen, Ronald C; Wiste, Heather J; Weigand, Stephen D et al. (2016) Association of Elevated Amyloid Levels With Cognition and Biomarkers in Cognitively Normal People From the Community. JAMA Neurol 73:85-92
Staubo, Sara C; Aakre, Jeremiah A; Vemuri, Prashanthi et al. (2016) Mediterranean diet, micronutrients and macronutrients, and MRI measures of cortical thickness. Alzheimers Dement :
Cummings, Jeffrey; Aisen, Paul S; DuBois, Bruno et al. (2016) Drug development in Alzheimer's disease: the path to 2025. Alzheimers Res Ther 8:39
Risacher, Shannon L; McDonald, Brenna C; Tallman, Eileen F et al. (2016) Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults. JAMA Neurol 73:721-32
Jack Jr, Clifford R; Wiste, Heather J; Weigand, Stephen D et al. (2016) Defining imaging biomarker cut points for brain aging and Alzheimer's disease. Alzheimers Dement :
Wennberg, Alexandra M V; Savica, Rodolfo; Hagen, Clinton E et al. (2016) Cerebral Amyloid Deposition Is Associated with Gait Parameters in the Mayo Clinic Study of Aging. J Am Geriatr Soc :
Tobin, W O; Popescu, B F; Lowe, V et al. (2016) Multiple sclerosis masquerading as Alzheimer-type dementia: Clinical, radiological and pathological findings. Mult Scler 22:698-704
Raman, Mekala R; Schwarz, Christopher G; Murray, Melissa E et al. (2016) An MRI-Based Atlas for Correlation of Imaging and Pathologic Findings in Alzheimer's Disease. J Neuroimaging 26:264-8
Wennberg, Alexandra M V; Gustafson, Deborah; Hagen, Clinton E et al. (2016) Serum Adiponectin Levels, Neuroimaging, and Cognition in the Mayo Clinic Study of Aging. J Alzheimers Dis 53:573-81

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