BRAIN VOLUME NETWORK CHANGES WITH AGING Healthy aging is associated with volume reductions in the frontal cortex and other brain regions. We developed a Scaled Subprofile Model (SSM) to identify brain network changes in relation to age in healthy adults, using volume measured obtained with magnetic resonance imaging (MRI). The SSM analysis identified a regional pattern of gray matter atrophy associated with healthy aging that included reductions in bilateral dorsolateral and medial frontal, anterior cingulate, insula/perisylvian, precuneus, parietotemporal, and caudate regions with areas of relative preservation in bilateral cerebellum, thalamus, putamen, mid cingulate, and temporal pole regions. Network analysis with SSM can help detect reproducible age-related MRI patterns, assisting efforts in the study of healthy and pathological aging (Bergfield et al., 2010) CHOLINERGIC ENHANCEMENT OF SYNAPTIC FUNCTION IN HEALTHY VOLUNTEERS A method to examine the effect of cholinergic enhancement on synaptic function in vivo could be used to examine this function in health and disease. We developed such a method by giving subjects a working memory task and measuring frontal cortex blood flow with PET and 15O-water. Flow was elevated in relation to working memory-task difficulty in young healthy volunteers, and 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 clarify the usefulness of anticholinesterase treatment in patients with Alzheimer disease (Ricciardi et al., 2009). IMAGING HUMAN BRAIN SIGNALING INVOLVING DOPAMINE Dysfunctional dopaminergic neurotransmission occurs in a number of human brain diseases, including Parkinson and Alzheimer disease, bipolar disorder and schizophrenia. However, no method has been published to examine signal transduction related to this dysfunction in the human brain in vivo. Based on our preclinical studies in which we developed such a method, we are conducting a clinical protocol to image brain arachidonic acid (AA) signaling involving dopamine in healthy volunteers using positron emission tomography (PET). Apomorphine, a dopamine D2/D3 receptor agonist, is administered to activate AA signaling via D2 receptors that are coupled to cytoplasmic phospholipase A2 (cPLA2) activation. In the same PET session, regional cerebral blood flow is measured following injection of 15Owater. We have completed scan sessions on 12 healthy volunteers and are evaluating the results for publication. REGIONAL DOCOSAHEXAENOIC ACID IMAGING IN THE HUMAN BRAIN Docosahexaenoic acid (DHA, 22:6n-3) is a nutritionally essential polyunsaturated fatty acid found in high concentrations in brain cell membranes and participates in critical brain metabolic processes. Being able to image its regional brain consumption rates in and relating this rate to diet would better help to understand its function in health and disease. We published results of a positron emission tomography (PET) protocol that provide for the first time regional rates of DHA consumption by the brain in health volunteers. For the entire brain, the mean rate of incorporation (consumption) equaled 3.8 mg/day (Umhau et al. 2009). IMAGING NEUROINFLAMMATION IN ALZHEIMER DISEASE An in vivo imaging method to evaluate neuroinflammation in Alzheimer disease patients could help in the early identification of neuroinflammation, in understanding its contribution to dementia status, and in evaluating efficacy of antiinflammatory and other agents. We used our in vivo imaging method to identify increased uptake of intravenously infused radiolabeled arachidonic acid into the brain as a marker of inflammation in a rat model. Based on this evidence, we then used positron emission tomography (PET) to demonstrate increased brain arachidonic uptake as a marker of neuroinflammation in patients with Alzheimer disease (Esposito et al., J Nuclear Medicine. 2008 49:1414-21). Recently, researchers at the Departments of Psychiatry at NYU School of Medicine, and Department of Radiochemistry at Weill Cornell Medical College, applied for and received an NIH grant to image neuroinflammation in collaboration with members of the BPMS, in a large cohort of Alzheimer disease patients in relation to dementia severity and brain uptake of a beta-amyloid marker. Studies have been initiated. IMAGING NEUROINFLAMMATION IN HIV-1 DEMENTIA Thirty million people worldwide are infected with the Human Immunodeficiency Virus (HIV)-1;some develop dementia despite antiretroviral therapy, whereas up to 50% develop depression and some cognitive dysfunction. We hypothesized that cognitive dysfunction in HIV-1 patients is exacerbated by concurrent neuroinflammation, and that drugs designed to treat the neuroinflammation would reduce the dysfunction. To test this hypothesis, we first identified 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 are preparing a collaborative clinical protocol supported by the NIAID to quantify brain arachidonic acid metabolism with positron emission tomography (PET) in HIV-1 infected patients in relation to dementia severity and cerebrospinal fluid viral and cytokine load. This study should help to identify neuroinflammation in the course of HIV-1 infection, and to establish a surrogate marker for efficacy of anti-inflammatory therapy.
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