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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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University of Pittsburgh
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Marquié, Marta; Normandin, Marc D; Meltzer, Avery C et al. (2017) Pathological correlations of [F-18]-AV-1451 imaging in non-alzheimer tauopathies. Ann Neurol 81:117-128
Edelman, Kathryn; Tudorascu, Dana; Agudelo, Christian et al. (2017) Amyloid-Beta Deposition is Associated with Increased Medial Temporal Lobe Activation during Memory Encoding in the Cognitively Normal Elderly. Am J Geriatr Psychiatry 25:551-560
Nadkarni, Neelesh K; Perera, Subashan; Snitz, Beth E et al. (2017) Association of Brain Amyloid-? With Slow Gait in Elderly Individuals Without Dementia: Influence of Cognition and Apolipoprotein E ?4 Genotype. JAMA Neurol 74:82-90
Mathis, Chester A; Lopresti, Brian J; Ikonomovic, Milos D et al. (2017) Small-molecule PET Tracers for Imaging Proteinopathies. Semin Nucl Med 47:553-575
Nadkarni, Neelesh K; Lopez, Oscar L; Perera, Subashan et al. (2017) Cerebral Amyloid Deposition and Dual-Tasking in Cognitively Normal, Mobility Unimpaired Older Adults. J Gerontol A Biol Sci Med Sci 72:431-437
Counts, Scott E; Ikonomovic, Milos D; Mercado, Natosha et al. (2017) Biomarkers for the Early Detection and Progression of Alzheimer's Disease. Neurotherapeutics 14:35-53
Mi, Zhiping; Abrahamson, Eric E; Ryu, Angela Y et al. (2017) Loss of precuneus dendritic spines immunopositive for spinophilin is related to cognitive impairment in early Alzheimer's disease. Neurobiol Aging 55:159-166
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
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

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