Cardiovascular risk factors (hypertension, hyperlipidemia, diabetes, apolipoprotein e4 genotype) and cerebrovascular dysfunction are associated with an enhanced risk for the development of Alzheimer's Disease (AD). Therefore, assessments of developing Alzheimer's pathology should ideally address both cerebrovascular function as well as amyloid pathology. Positron emission tomography (PET) is capable of quantifying both attributes through cerebral blood flow and amyloid imaging using the gold-standard tracers [15O]water and [11C]PIB, respectively. Previous studies have explored the potential of [11C]PIB as both a functional and pathological biomarker, with early phases of the uptake reflecting blood flow and later retention reflecting amyloid burden. However, the reported studies have a number of shortcomings. Recently, in a small sample of subjects (N = 5 male subjects, 5 x 63 regions), we have found early phase PIB-based measures that were significantly related to global and regional CBF determined by quantitative [15O]water imaging. In this proposal, we plan to compare uptake measures derived from early phase, dynamic [11C]PIB imaging to global and regional cerebral blood flow (CBF) determined at rest with quantitative [15O]water in older participants (N = 24), representative of the population at-risk fo the development of AD (i.e., male and female subjects, 55 - 90 years old). To this end, we propose the following specific aim and hypothesis:
Specific Aim : Determine the early phase global and regional [11C]PIB uptake and using this information in conjunction with relevant demographic information characterize the relationship between these measures and global and regional cerebral blood flow (CBF) as determined by quantitative [15O]water PET imaging. Hypothesis: Early phase [11C]PIB uptake, globally and regionally, is significantly related to global and regional measures of CBF, respectively. If a clinically-accessible metric, significantly related to CBF, can be established for [11C]PIB, then the stage is set for extension of this methodology to alternative amyloid agents with widespread clinical use potential, i.e., F-18 labeled radiotracers, and PIB-like kinetic behavior (e.g., [18F]NAV4694). If that goal is realized, a single agent in a single scan session could be used to define both the functional (CBF) and pathological (amyloid burden) status of a patient at-risk for vascular and/or Alzheimer's dementia.
Assessments of developing Alzheimer's pathology should ideally address both cerebrovascular function as well as amyloid pathology. This proposal will explore the utility of early phase [11C]PIB, an amyloid imaging agent, as a surrogate for cerebral blood flow measures as determined by the gold standard, [15O]water. If a clinically- accessible metric, significantly related to CBF, can be established for [11C]PIB, then the stage is set for extension of this methodology to alternative amyloid agents with widespread clinical use potential. If that goal is realized, a single agent in a single scan session could be used to define both the functional (CBF) and pathological (amyloid burden) status of a patient at-risk for vascular and/or Alzheimer's dementia.
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