IMAGING NEUROINFLAMMATION IN ALZHEIMER DISEASE? Postmortem studies demonstrate neuroinflammatory markers in Alzheimer disease, but our ability to image neuroinflammation in humans in vivo is limited. Based on studies in a rat model of neuroinflammation, we predicted that brain uptake of intravenously injected radiolabeled arachidonic acid (AA) would be elevated in patients with Alzheimer disease. We confirmed this prediction using positron emission tomography (PET) in 8 mildly-severely demented Alzheimer disease patients compared with 8 aged-matched controls. AA incorporation was elevated in neocortical brain regions known to have high densities of senile neuritic plaques and activated microglia. Cerebral blood flow was reduced by comparison in these regions. Our PET method, after confirmation, might be used to examine progression of neuroinflammation in Alzheimer and other diseases in which it plays a role, and disease response to medication (Esposito et al. 2008).? ? CHOLINERGIC MODULATION OF SYNAPTIC FUNCTION IN HEALTHY VOLUNTEERS? Frontal cortex blood flow, measured using positron emission tomography (PET) and 15O-water, was elevated in relation to working memory-task difficulty in young healthy volunteers, in relation to prolongation of reaction time. Administration of the anticholinesterase, physostigmine, prevented these changes. Thus, cholinergic modulation of synaptic transmission enhanced memory performance and reduced effortful synaptic recruitment in the frontal cortex. These changes may be related to the usefulness of anticholinesterase treatment in patients with Alzheimer disease (Furey et al. 2008).? ? IMAGING HUMAN BRAIN SIGNALING INVOLVING DOPAMINE? We initiated a PET protocol with the NIMH to image brain signal transduction via arachidonic acid, related to dopaminergic transmission, in adults with Attention Deficit Hyperactivity Disorder (ADHD) and age-matched controls. Apomorphine, a dopamine D2/D3 receptor agonist, is administered to activate arachidonic acid signaling via D2 receptors, as proven in preclinical studies. We hypothesize that this signaling will be disturbed in ADHD patients, based on genetic evidence of their altered dopamine receptor and transporter alleles. We have completed scans on 6 normal volunteers and are evaluating the results.? ? REGIONAL DOCOSAHEXAENOIC ACID IMAGING IN THE HUMAN BRAIN? Docosahexaenoic acid (DHA) is a nutritionally essential polyunsaturated fatty acid in brain cell membranes and participates in many brain metabolic processes. Being able to image its consumption in human health and disease would be useful. We are conducting a PET protocol together with NIAAA investigator to quantify brain DHA signaling and consumption in healthy volunteers, based on our preclinical studies. For the entire brain, the mean rate of DHA incorporation from plasma equaled 3.8 mg/day. We are preparing a manuscript on this research.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000148-08
Application #
7732146
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2008
Total Cost
$159,786
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Pichika, Rama; Taha, Ameer Y; Gao, Fei et al. (2012) The synthesis and in vivo pharmacokinetics of fluorinated arachidonic acid: implications for imaging neuroinflammation. J Nucl Med 53:1383-91
Igarashi, Miki; Ma, Kaizong; Gao, Fei et al. (2011) Disturbed choline plasmalogen and phospholipid fatty acid concentrations in Alzheimer's disease prefrontal cortex. J Alzheimers Dis 24:507-17
Cunnane, Stephen; Nugent, Scott; Roy, Maggie et al. (2011) Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition 27:3-20
Rapoport, Stanley I; Ramadan, Epolia; Basselin, Mireille (2011) Docosahexaenoic acid (DHA) incorporation into the brain from plasma, as an in vivo biomarker of brain DHA metabolism and neurotransmission. Prostaglandins Other Lipid Mediat 96:109-13
Umhau, John C; Zhou, Weiyin; Carson, Richard E et al. (2009) Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography. J Lipid Res 50:1259-68
Esposito, Giuseppe; Giovacchini, Giampiero; Der, Margaret et al. (2007) Imaging signal transduction via arachidonic acid in the human brain during visual stimulation, by means of positron emission tomography. Neuroimage 34:1342-51
Alexander, Gene E; Chen, Kewei; Merkley, Tricia L et al. (2006) Regional network of magnetic resonance imaging gray matter volume in healthy aging. Neuroreport 17:951-6
Rapoport, Stanley I (2005) [In vivo imaging for evaluating synaptic integrity in Alzheimer disease] Psychol Neuropsychiatr Vieil 3:97-106
Rapoport, Stanley I (2005) In vivo approaches and rationale for quantifying kinetics and imaging brain lipid metabolic pathways. Prostaglandins Other Lipid Mediat 77:185-96
Ibanez, Vicente; Pietrini, Pietro; Furey, Maura L et al. (2004) Resting state brain glucose metabolism is not reduced in normotensive healthy men during aging, after correction for brain atrophy. Brain Res Bull 63:147-54

Showing the most recent 10 out of 24 publications