Brain Imaging In Human Aging, Alzheimer Disease And Other Disorders

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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 (Ref. 1). CHOLINERGIC MODULATION OF SYNAPTIC FUNCTION IN HEALTHY VOLUNTEERS Frontal cortex blood flow, measured using 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 (Ref. 2 and 3). IMAGING HUMAN BRAIN SIGNALING INVOLVING DOPAMINE We are conducting a PET protocol with the NIMH to image brain signal transduction via AA, 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 AA 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 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 equals 3.8 mg/day (Ref. 4). 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.