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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CND-E (90))
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Hsiao, John
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Mayo Clinic, Rochester
United States
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Jack Jr, Clifford R; Wiste, Heather J; Weigand, Stephen D et al. (2014) Age-specific population frequencies of cerebral ?-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: a cross-sectional study. Lancet Neurol 13:997-1005
Knopman, David S; Jack Jr, Clifford R; Wiste, Heather J et al. (2014) 18F-fluorodeoxyglucose positron emission tomography, aging, and apolipoprotein E genotype in cognitively normal persons. Neurobiol Aging 35:2096-106
Broski, Stephen M; Hunt, Christopher H; Johnson, Geoffrey B et al. (2014) Structural and functional imaging in parkinsonian syndromes. Radiographics 34:1273-92
Adeli, Anahita; Savica, Rodolfo; Lowe, Val J et al. (2014) The GGGGCC repeat expansion in C9ORF72 in a case with discordant clinical and FDG-PET findings: PET trumps syndrome. Neurocase 20:110-20
Raman, Mekala R; Preboske, Gregory M; Przybelski, Scott A et al. (2014) Antemortem MRI findings associated with microinfarcts at autopsy. Neurology 82:1951-8
Thomas, Jewell B; Brier, Matthew R; Bateman, Randall J et al. (2014) Functional connectivity in autosomal dominant and late-onset Alzheimer disease. JAMA Neurol 71:1111-22
Josephs, Keith A; Murray, Melissa E; Whitwell, Jennifer L et al. (2014) Staging TDP-43 pathology in Alzheimer's disease. Acta Neuropathol 127:441-50
Raman, Mekala R; Wiste, Heather J; Senjem, Matthew L et al. (2014) Spontaneous amyloid-related imaging abnormalities in a cognitively normal adult. Neurology 83:1771-2
Jack Jr, Clifford R; Wiste, Heather J; Knopman, David S et al. (2014) Rates of ?-amyloid accumulation are independent of hippocampal neurodegeneration. Neurology 82:1605-12
Roberts, Rosebud O; Knopman, David S; Cha, Ruth H et al. (2014) Diabetes and elevated hemoglobin A1c levels are associated with brain hypometabolism but not amyloid accumulation. J Nucl Med 55:759-64

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