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 upregulated AA incorporation as a marker of neuroinflammation in 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 NIH-grant supported 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 accumulation (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 prolonged 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 (AA) 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). In collaboration with scientists at NIAID, we are submitting a collaborative clinical protocol to the NIAID IRB to quantify brain AA metabolism and blood flow using PET in HIV-1 infected patients, in relation to severity of neurocognitive dysfunction (M. DeMascio PI. Protocol: Imaging Neuroinflammation in HIV infection with Radiolabeled Arachidonic Acid and PET). This study should identify neuroinflammation in the course of HIV-1 infection, and to establish a surrogate biomarker for efficacy of therapy against HAND. BRAIN IMAGING IN BIPOLAR DISORDER PATIENTS. We reported that the postmortem brain from bipolar disorder (BD) demonstrated increased markers of neuroinflammation, in association with increased markers of upregulated arachidonic acid (AA) metabolism. Taken in the context of our findings that mood stabilizers used in BD downregulate rat brain AA metabolism, Dr. Elizabeth Sublette at New York Psychiatric Institute has initiated a NIH Grant-supported collaborative clinical protocol to image brain AA metabolism, using our PET method in depressed patients with BD, compared to healthy controls (Pilot PET study characterizing 1-11C AA in bipolar disorder). PET ARACHIDONIC ACID IN TRAUMATIC BRAIN INJURY. In collaboration with colleagues at the NINDS and USUHS, we are preparing a protocol for submission to conduct an open-label, proof of principle, pilot study to assess the safety and feasibility of treating patients with acute traumatic brain injury (TBI) with supplemental docosahexaenoic acid (DHA, 22:6n-3). The goal is to image the brain of human TBI subjects with PET following administration of radiolabeled arachidonic acid (AA, 20:4 n-6), 1-11CAA-PET, before and after treatment with DHA, to demonstrate changes in the incorporation of AA in brain tissue. We hypothesize that incorporation of circulating, unesterified AA will be increased in wide areas of the brain in TBI subjects with diffuse MRI abnormalities as well as regionally increased in the vicinity of focal MRI abnormalities due to neuroinflammation and brain damage. These changes can be quantified as an increase in the incorporation coefficient, K*, and the incorporation rate, Jin (K* x plasma unesterified AA concentration), by means of a validated PET method. Treatment with supplemental DHA could reduce AA incorporation thereby providing key evidence for its biological response in human brain after TBI. A grant supporting this research has been awarded from the Center for Neuroscience and Regenerative Medicine (CNRM). NEW PET LIGAND SYNTHESIS AND PHARMACOKINETICS OF FLUORINATED ARACHIDONIC ACID FOR IMAGING NEUROINFLAMMATION. 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 on 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 (1). DOCOSAHEXAENOIC ACID METABOLISM IS INCREASED IN CHRONIC ALCOHOLICS ATROPHY CORRECTED BRAIN DOCOSAHEXAENOIC ACID INCORPORATION AND BLOOD FLOW ARE INCREASED IN CHRONIC ALCOHOLICS In animal models, excessive alcohol consumption is reported to reduce brain docosahexaenoic acid (DHA) concentration, suggesting disturbed brain DHA metabolism. We hypothesized that brain DHA metabolism and regional cerebral blood flow (rCBF) also are abnormal in chronic alcoholics. We compared 15 non-smoking chronic alcoholics, studied within 7 days of their last drink, with 22 non-smoking healthy controls. Using our published neuroimaging methods with PET, we measured regional coefficients (K*) and rates (Jin) of DHA incorporation from plasma into the brain of each group using 1-11CDHA, and regional cerebral blood flow (rCBF) using 15Owater. Data were partial volume error corrected for brain atrophy. Plasma unesterified DHA concentration was quantified. Mean K* for DHA was significantly and widely elevated by 10-20%, and rCBF was elevated by 7%-34%, in alcoholics compared with controls. Unesterified plasma DHA did not differ significantly between groups nor did whole brain Jin, the product of K* and unesterified plasma DHA concentration. Significantly higher values of K* in alcoholics indicate increased brain avidity for DHA, thus a brain DHA metabolic deficit vis--vis plasma DHA availability. Higher rCBF in alcoholics suggests increased energy consumption. These changes may reflect a hypermetabolic state related to early alcohol withdrawal, or a general brain metabolic change in chronic alcoholics. (2)

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000148-13
Application #
8736483
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2013
Total Cost
$395,231
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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
Ricciardi, Emiliano; Pietrini, Pietro; Schapiro, Mark B et al. (2009) Cholinergic modulation of visual working memory during aging: a parametric PET study. Brain Res Bull 79:322-32
Esposito, Giuseppe; Giovacchini, Giampiero; Liow, Jeih-San et al. (2008) Imaging neuroinflammation in Alzheimer's disease with radiolabeled arachidonic acid and PET. J Nucl Med 49:1414-21
Furey, Maura L; Ricciardi, Emiliano; Schapiro, Mark B et al. (2008) Cholinergic enhancement eliminates modulation of neural activity by task difficulty in the prefrontal cortex during working memory. J Cogn Neurosci 20:1342-53