DOPAMINE SIGNALING IMAGING HUMAN BRAIN SIGNALING INVOLVING DOPAMINE Dopaminergic dysfunction has been reported in Alzheimer disease and human aging. To address this issue, we developed a novel method to image dopaminergic neurotransmission in the human brain using positron emission tomography (PET) and 1-11Carachidonic acid (1-11CAA), as well as regional cerebral blood flow (rCBF) with 15Owater. We measured regional incorporation coefficients K* for AA, and rCBF, in healthy men given the dopaminergic D1/D2 receptor agonist (10 or 20 mg/kg s.c.) apomorphine or saline, after pretreatment with trimethobenzamide to prevent nausea. We demonstrated a robust central dopaminergic response to apomorphine by observing significant increases in serum growth hormone, and significant increases and decreases in AA incorporation plus increments in rCBF with PET. The AA incorporation changes reflected neuronal signaling associated with activation of D2-like receptors coupled to phospholipase A2. The rCBF changes represented general functional effects of D1/D2 receptor activation. The 1-11CAA PET method should be useful for studying disturbed dopaminergic neurotransmission in Parkinson disease, Alzheimer disease and other disorders.(3) NEUROINFLAMMATION IMAGING NEUROINFLAMMATION IN ALZHEIMER DISEASE WITH RADIOLABELED ARACHIDONIC ACID: We reported that brain uptake of radiolabeled arachidonic acid (1-14CAA) could be used to assess neuroinflammation in different animal models, and confirmed using PET and the positron-emitting isotope 1-11CAA the presence of neuroinflammation in the brain of Alzheimer disease (AD) patients (Esposito et al., J Nucl Medicine. 2008 49:1414-21). Based on this work, in collaboration with researchers at the Departments of Psychiatry at NYU School of Medicine and of Radiochemistry at Weill Cornell Medical College, we are conducting a protocol to extend this observation and to neuroimage neuroinflammation with 1-11CAA and brain glucose metabolism using PET in a larger cohort of AD patients in relation to dementia severity and brain amyloid distribution (Imaging Neuroinflammation in Alzheimer's Disease with 11CArachidonic Acid and PET, OHSR Exemption #5877). IMAGING NEUROINFLAMMATION IN HIV-1 INFECTED SUBJECTS Thirty million people worldwide are infected with Human Immunodeficiency Virus (HIV)-1;some 30-50% develop HIV-1 associated neurocognitive disorder (HAND) while on antiretroviral therapy, and the prevalence of HAND increases with age and causes interaction with Alzheimer disease. Thus, HIV-1 infection is of major concern to the NIA. We hypothesized that cognitive dysfunction in HIV-1 patients is exacerbated by concurrent neuroinflammation. To test this hypothesis, we first confirmed neuroinflammation as upregulated brain arachidonic acid metabolism in a noninfectious transgenic HIV-1 rat model, using our in vivo fatty acid imaging method (Basselin et al. Imaging upregulated brain arachidonic acid metabolism in HIV-1 transgenic rats. J Cereb Blood Flow Metab Jul 28 2010). On this basis, we now are writing a collaborative clinical protocol with the NIAID to quantify brain arachidonic acid metabolism and blood flow using PET in HIV-1 infected patients for the first time, in relation to severity of neurocognitive dysfunction. This study should identify neuroinflammation in the course of HIV-1 infection, and to establish a surrogate biomarker for efficacy of therapy against HAND. SYNTHESIS AND IN VIVO PHARMACOKINETICS OF FLUORINATED ARACHIDONIC ACID: IMPLICATIONS FOR IMAGING NEUROINFLAMMATION IN HUMANS. Arachidonic acid (AA) is released from membrane phospholipid during neuroinflammation, and we have reported upregulated brain AA metabolism as a biomarker of neuroinflammation in Alzheimer disease (AD) patients using 1-11CAA and PET. However, the radioactive half-life of 11C is short (20 minutes), limiting its use to research centers having a cyclotron oon site that can synthesize 1-11CAA. As a first step to develop a clinically useful (18)F-fluoroarachidonic acid ((18)F-FAA) with a long radioactive half-life of 109.8 min, which could be synthesized at multiple sites or delivered from a commercial source, we developed a high-yield stereoselective synthetic method for nonradioactive 20-(19)F-FAA. After intravenous injection in unanesthetized mice, its brain uptake, distribution and kinetics were identical to uptake of the natural AA (as measured with 1-14CAA). These results suggest that it would be feasible to translate our stereoselective synthetic method for (19)F-FAA to synthesize positron-emitting (18)F-FAA to image brain AA metabolism in AD and other neuroinflammatory disorders, and that imaging could be conducted routinely in multiple clinical centers with high resolution than 11C-AA (2). DOCOSAHEXAENOIC ACID METABOLISM INCORPORATION OF DOCOSAHEXAENOIC ACID (DHA) INTO HUMAN BRAIN AS BIOMARKER OF DISTURBED BRAIN LIPID METABOLISM AND NEUROTRANSMISSION. Docosahexaenoic acid (DHA, 22:6n-3) is critical for maintaining normal brain structure and function, and is considered neuroprotective. Dietary DHA supplementation has been tested in patients with Alzheimer disease, and its plasma concentration is reported reduced in such patients. Its brain concentration depends on dietary DHA content and hepatic conversion from its dietary derived n-3 precursor, alpha-linolenic acid. We developed an in vivo method in rats using quantitative autoradiography and intravenously injected radiolabeled DHA to measure DHA incorporation into brain, and showed that the incorporation rate equals the rate of brain metabolic DHA consumption. We then extended the method for use in humans with positron emission tomography (PET) (Umhau et al., Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography J. Lipid Res, 50, 1259, 2009). We are now using PET to quantify brain DHA incorporation in patients with chronic alcoholism and different brain diseases. GLUCOSE METABOLISM ROLE OF REDUCED GLUCOSE METABOLISM IN SUBJECTS AT RISK FOR ALZHEIMER DISEASE. In a critical review, we pointed out that lower brain glucose metabolism may be present before the onset of measurable cognitive decline in people at risk for Alzheimer disease (AD). Cerebral hypometabolism likely precedes and contributes to the neuropathological cascade leading to cognitive decline. The neurodegenerative processes in AD further decreases brain glucose metabolism because of reduced synaptic functionality and hence reduced energy needs, thereby completing a vicious cycle. Strategies to reduce risk of AD by breaking this cycle should aim to (1) improve insulin sensitivity by improving systemic glucose utilization, or (2) bypass deteriorating brain glucose metabolism using approaches that safely induce mild, sustainable ketonemia (1).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000148-12
Application #
8552321
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2012
Total Cost
$74,864
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Thambisetty, Madhav; Gallardo, Kathy A; Liow, Jeih-San et al. (2012) The utility of (11)C-arachidonate PET to study in vivo dopaminergic neurotransmission in humans. J Cereb Blood Flow Metab 32:676-84
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
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Rapoport, Stanley I; Nelson, Peter T (2011) Biomarkers and evolution in Alzheimer disease. Prog Neurobiol 95:510-3
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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

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