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Brain Imaging In Human Aging, Alzheimer Disease And Other Disorders
NATIONAL INSTITUTE ON AGING
Total Funding: $ 487,078
BRAIN VOLUME NETWORK CHANGES WITH HEALTHY 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). IMAGING HUMAN BRAIN SIGNALING INVOLVING DOPAMINE. We have 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 confirmed a robust central dopaminergic response to apomorphine by observing significant increases in serum concentration of growth hormone. We observed significant increases as well as decreases in K* and increments in rCBF in response to apomorphine. The changes in AA incorporation likely reflect neuronal signaling events downstream of activated D2-like receptors coupled to phospholipase A2 within the striatum. The changes in rCBF are consistent demonstrate net functional effects of D1/D2 receptor activation. Based on these data, the 1-11CAA PET method should be useful for studying disturbances of dopaminergic neurotransmission in conditions such as Parkinson disease and schizophrenia. Results of this work have been submitted for publication. 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 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, under an NIH grant we are imaging neuroinflammation and brain glucose metabolism with PET in Alzheimer disease patients in relation to dementia severity and amyloid distribution. IMAGING NEUROINFLAMMATION IN HIV-1 INFECTED SUBJECTS 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 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 preparing a collaborative clinical protocol supported by the NIAID to quantify brain arachidonic acid metabolism and regional cerebral blood flow 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. DOCOSAHEXAENOIC ACID (DHA) INCORPORATION AS BIOMARKER OF BRAIN DHA METABOLISM AND NEUROTRANSMISSION. Docosahexaenoic acid (DHA) is critical for maintaining normal brain structure and function, and is considered neuroprotective. 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 incorporation into brain of unesterified plasma DHA, and showed that the incorporation rate equals the rate of brain metabolic DHA consumption. We extended the method for use in humans with positron emission tomography (PET). BIOMARKERS AND EVOLUTION IN ALZHEIMER DISEASE. Brain regions and their highly neuroplastic long axonal connections, which expanded rapidly during hominid evolution, are preferentially affected by Alzheimer disease (AD), and there is no natural animal model with full disease pathology (neurofibrillary tangles and neuritic amyloid plaques). Thus, it is possible that AD is uniquely human disease that was introduced during hominid evolution. This introduction may be related to increased neuroplasticity of vulnerable regions. Measuring biomarkers such as reduced glucose metabolism in association neocortex and changes in arachidonic acid metabolism with PET, defects in long white matter tracts, RNA neurochemical changes, and high CSF levels of total and phosphorylated tau protein, may be useful to identify MCI and presymptomatic patients. These same biomarkers may help explain why humans appear to be uniquely vulnerable to this disease (Rapoport and Nelson, 2011). BRAIN FUEL METABOLISM, AGING, AND ALZHEIMER DISEASE. Lower brain glucose metabolism is present before the onset of measurable cognitive decline in people at risk for Alzheimer disease--carriers of apolipoprotein E4, and those with maternal family history of AD. These reports suggest that hypometabolism precedes and contribute to the neuropathological cascade leading to cognitive decline in AD. Reasons may include defects in brain glucose transport, disrupted glycolysis, or impaired mitochondrial function. A contributing role of deteriorating glucose availability to or metabolism by the brain in AD does not exclude the opposite effect, i.e., that neurodegenerative processes in AD further decrease brain glucose metabolism because of reduced synaptic functionality and hence reduced energy needs, thereby completing a vicious cycle. Strategies to reduce the 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 (Cunnane et al., 2011).
8 Resulting Publications
Rama Pichika; Ameer Y Taha; Fei Gao; Kishore Kotta; Yewon Cheon; Lisa Chang; Dale Kiesewetter; Stanley I Rapoport; William C EckelmanJournal of nuclear medicine : official publication, Society of Nuclear Medicine 2012;53(9):1383-91.
Mireille Basselin; Epolia Ramadan; Stanley I RapoportBrain research bulletin 2012;87(2-3):154-71.
Stanley I Rapoport; Epolia Ramadan; Mireille BasselinProstaglandins & other lipid mediators 2011;96(1-4):109-13.
Stephen Cunnane; Scott Nugent; Maggie Roy; Alexandre Courchesne-Loyer; Etienne Croteau; Sébastien Tremblay; Alex Castellano; Fabien Pifferi; Christian Bocti; Nancy Paquet; et al.Nutrition (Burbank, Los Angeles County, Calif.) 2011;27(1):3-20.
Miki Igarashi; Kaizong Ma; Fei Gao; Hyung-Wook Kim; Stanley I Rapoport; Jagadeesh S RaoJournal of Alzheimer's disease : JAD 2011;24(3):507-17.
Miki Igarashi; Kaizong Ma; Fei Gao; Hyung-Wook Kim; Deanna Greenstein; Stanley I Rapoport; Jagadeesh S RaoJournal of psychiatric research 2010;44(3):177-82.
Giuseppe Esposito; Giampiero Giovacchini; Jeih-San Liow; Abesh K Bhattacharjee; Dede Greenstein; Mark Schapiro; Mark Hallett; Peter Herscovitch; William C Eckelman; Richard E Carson; et al.Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2008;49(9):1414-21.
Maura L Furey; Emiliano Ricciardi; Mark B Schapiro; Stanley I Rapoport; Pietro PietriniJournal of cognitive neuroscience 2008;20(7):1342-53.
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