We propose to develop a novel PET biomarker, [1-11C]Arachidonic Acid (AA) for the regional estimation of brain inflammation. Inflammation a well known feature of Alzheimer's disease (AD), is associated with amyloid plaques, neurofibrillary pathology, and neuronal damage, but there is no accepted in vivo imaging modality for brain inflammation. There is clear evidence that [11C]PIB-PET signal is predominantly from amyloid beta (A2) containing structures. However, uncertainty remains as to the relative contributions of diffuse vs compact/classical A2 plaques to the PIB-PET signal. Without a brain inflammation marker to identify regions with both PIB uptake and with inflammation (presumably classical plaque regions), our understanding of the relationships between PIB uptake and the risk for brain pathology as assessed by either FDG-PET or MRI is limited. Currently, one considers the glucose metabolic rate (MRglc) an index for tissue integrity, with reductions interpreted as evidence for tissue damage. However, recent reports show that brain inflammation can be associated with increased MRglc thus potentially masking pathology. Our studies in non-demented subjects demonstrate elevated MRglc in the presence of PIB. On the other hand, our studies in AD show both reduced and elevated MRglc in regions associated with PIB uptake. The major focus of this project is to evaluate whether a brain inflammation marker will improve the clinical assessment of AD and secondarily, if inflammation imaging when combined with PIB imaging will facilitate recognition of brain tissue at risk. This project has two major goals: 1) to synthesize [11C]AA) and using PET, test the diagnostic value of [11C]AA in a cross-sectional study involving 120 subjects (40/group) characterized as AD, mild cognitive impairment (MCI) and normal elderly (NL);and 2) to examine the relationships between the combined regional uptake of [11C]AA and of brain A2 pathology (PIB-PET uptake) on brain integrity using FDG-PET, and MRI. We propose to synthesize all the radiotracers at the Cornell imaging center, a site with extensive radiotracer experience. The subject recruitment, clinical studies and image analysis protocols will be conducted at NYU. We will test the following hypotheses: 1) [11C]AA levels are superior (increment) PIB and FDG-PET in differentiating both MCI and AD from NL controls;2) inflammation when co-localized with A2 deposits ([11C]PIB levels) increases the risk for brain atrophy as assessed by decreased MRI gray matter density and volume;3) inflammation in regions with preserved gray matter volume and density is associated with elevated glucose metabolism (18FDG levels);and 4) Brain [11C]AA levels are associated with CSF IsoP and plasma TNF-1 levels. This project has the potential for improving the early diagnosis for AD and for increasing our understanding the effects of inflammation and amyloid pathology on the risk for brain damage. Our study protocols and materials will be freely available and are expected to generate many new research projects.
Inflammation in the brain is a well known feature of Alzheimer's disease (AD). At this time positron emission tomography (PET) scans are available to study brain glucose metabolism and amyloid protein deposition. This research proposal is designed to validate a new inflammation imaging agent known as [11C]Arachidonic acid (AA) in normal subjects and subjects with cognitive dysfunction. The data will be compared to other PET and MR scans and also with blood markers of inflammation.
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