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)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CND-E (90))
Program Officer
Hsiao, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Weiner, Michael W; Harvey, Danielle; Hayes, Jacqueline et al. (2017) Effects of traumatic brain injury and posttraumatic stress disorder on development of Alzheimer's disease in Vietnam Veterans using the Alzheimer's Disease Neuroimaging Initiative: Preliminary Report. Alzheimers Dement (N Y) 3:177-188
Pichler, Michael; Vemuri, Prashanthi; Rabinstein, Alejandro A et al. (2017) Prevalence and Natural History of Superficial Siderosis: A Population-Based Study. Stroke 48:3210-3214
Raman, Mekala R; Tosakulwong, Nirubol; Zuk, Samantha M et al. (2017) Influence of preeclampsia and late-life hypertension on MRI measures of cortical atrophy. J Hypertens 35:2479-2485
Wiepert, Daniela A; Lowe, Val J; Knopman, David S et al. (2017) A robust biomarker of large-scale network failure in Alzheimer's disease. Alzheimers Dement (Amst) 6:152-161
Zeydan, Burcu; Lowe, Val J; Schwarz, Christopher G et al. (2017) Pittsburgh compound-B PET white matter imaging and cognitive function in late multiple sclerosis. Mult Scler :1352458517707346
Zeydan, Burcu; Deelchand, Dinesh K; Tosakulwong, Nirubol et al. (2017) Decreased Glutamate Levels in Patients with Amnestic Mild Cognitive Impairment: An sLASER Proton MR Spectroscopy and PiB-PET Study. J Neuroimaging 27:630-636
Kantarci, Kejal; Murray, Melissa E; Schwarz, Christopher G et al. (2017) White-matter integrity on DTI and the pathologic staging of Alzheimer's disease. Neurobiol Aging 56:172-179
Jones, David T; Graff-Radford, Jonathan; Lowe, Val J et al. (2017) Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum. Cortex 97:143-159
Kantarci, Kejal; Lowe, Val J; Boeve, Bradley F et al. (2017) AV-1451 tau and ?-amyloid positron emission tomography imaging in dementia with Lewy bodies. Ann Neurol 81:58-67
Vemuri, Prashanthi; Lesnick, Timothy G; Przybelski, Scott A et al. (2017) Age, vascular health, and Alzheimer disease biomarkers in an elderly sample. Ann Neurol 82:706-718

Showing the most recent 10 out of 282 publications