Postmortem studies previously suggested, and in vivo amyloid imaging studies have now unambiguously confirmed that individuals with a similar burden of amyloid-beta (A|3) in their brains can be cognitively normal, have Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD). Thus, it seems highly likely that there are modulators that can accelerate or retard the effects of AB on the brain. Postmortem studies also have suggested that the presence and amount of vascular pathology in the brain is a likely modulator. The overall concept is that the presence of vascular pathology in the brain establishes a vulnerable state in which the deposition of AB much more quickly leads to the onset and progression of cognitive impairment and the clinical syndromes of MCI and AD. The modulators of the transition from normal cognition to MCI will be explored in Project 4. In this project (Project 5) we will explore the modulators of the transition from MCI to clinical AD. The fundamental hypothesis is that the brain, like the rest of the body, tries to maintain homeostasis in the face of injury (induced, in this case, by AP). We propose that one of the most important mechanisms for successful homeostasis and compensation is modulation of cerebral blood flow and even subclinical cerebrovascular disease can significantly accelerate the adverse effects of AB deposition. We propose to test this hypothesis by using PiB PET to measure the effect of AB deposition (the toxin) on three main outcomes: 1) cerebral metabolism (FDG PET);2) brain volume (structural MRI);and 3) cognition (neuropsychological testing). We also will measure potential AB modulators such as cerebral and systemic subclinical vascular disease and cerebral blood flow (perfusion MRI). We further propose that cognitive vulnerability accumulates along with markers of vascular disease with aging and in very elderly individuals, the relative importance of vascular and AB burden may be different than in younger persons. Thus, we will make use of a younger group of MCI subjects that have been studied for 24 months or more in the previous project period of this Program Project and an existing older group (>83 years) who have participated in a seven-year study of gingko biloba in aging and who have also been studied once with PiB prior to this study.

Public Health Relevance

It is clear that levels of fibrillar AB deposition alone cannot fully account for the variability in cognitive status across the normal aging-MCI-AD spectrum. While efforts at reducing AP accumulation are essential, understanding the modulators of the effect of AB may be equally important and lead to a further appreciation of the importance of cerebrovascular and cardiovascular health with aging. Identifying individuals particularly prone to damaging the effects of AB should help select the best candidates for future anti-amyloid therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG025204-09
Application #
8572489
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$267,813
Indirect Cost
$46,135
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Mizukami, Katsuyoshi; Akatsu, Hiroyasu; Abrahamson, Eric E et al. (2016) Immunohistochemical analysis of hippocampal butyrylcholinesterase: Implications for regional vulnerability in Alzheimer's disease. Neuropathology 36:135-45
Ikonomovic, Milos D; Abrahamson, Eric E; Price, Julie C et al. (2016) [F-18]AV-1451 positron emission tomography retention in choroid plexus: More than "off-target" binding. Ann Neurol 80:307-8
Perez, Sylvia E; He, Bin; Nadeem, Muhammad et al. (2015) Resilience of precuneus neurotrophic signaling pathways despite amyloid pathology in prodromal Alzheimer's disease. Biol Psychiatry 77:693-703
Klunk, William E; Koeppe, Robert A; Price, Julie C et al. (2015) The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimers Dement 11:1-15.e1-4
Marquié, Marta; Normandin, Marc D; Vanderburg, Charles R et al. (2015) Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol 78:787-800
Nichols, Noah; Bras, Jose M; Hernandez, Dena G et al. (2015) EIF4G1 mutations do not cause Parkinson's disease. Neurobiol Aging 36:2444.e1-4
Goodheart, A E; Tamburo, E; Minhas, D et al. (2015) Reduced binding of Pittsburgh Compound-B in areas of white matter hyperintensities. Neuroimage Clin 9:479-83
Yau, Wai-Ying Wendy; Tudorascu, Dana L; McDade, Eric M et al. (2015) Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study. Lancet Neurol 14:804-13
Chen, Yin J; Rosario, Bedda L; Mowrey, Wenzhu et al. (2015) Relative 11C-PiB Delivery as a Proxy of Relative CBF: Quantitative Evaluation Using Single-Session 15O-Water and 11C-PiB PET. J Nucl Med 56:1199-205
Mountz, James M; Laymon, Charles M; Cohen, Ann D et al. (2015) Comparison of qualitative and quantitative imaging characteristics of [11C]PiB and [18F]flutemetamol in normal control and Alzheimer's subjects. Neuroimage Clin 9:592-8

Showing the most recent 10 out of 88 publications