Difference between revisions of "Bioimaging Sciences"
(Created page with ' September 7, Tuesday (4:15 pm) at Hope 110 (310 Cedar Street)* "Psychiatric diseases: A core pathology of synapse regression" Max Bennett (Brain and Mind Research Institute, Un…') |
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| − | + | ='''September 7, Tuesday (4:15 pm) at Hope 110 (310 Cedar Street)*'''= | |
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| − | September 7, Tuesday (4:15 pm) at Hope 110 (310 Cedar Street)* | ||
"Psychiatric diseases: A core pathology of synapse regression" | "Psychiatric diseases: A core pathology of synapse regression" | ||
| − | Max Bennett (Brain and Mind Research Institute, University of Sydney) | + | '''Max Bennett''' (Brain and Mind Research Institute, University of Sydney) |
At the beginning of the last century Cajal identified glial cells, neurons and their interconnections at synapses as the major constituents of grey matter. At this time the patients in the great asylums of Europe and the UK, such as Bethlem, were beginning to be differentiated as suffering different syndromes on the basis of distinctive symptoms. One of these, dementia, when subjected to the new clinicopathological approach, was in many cases found by Alzheimer to possess the core pathology of neuron degeneration. This resulted in an entirely different view of dementia, removing stigma and focusing research on the prevention of the pathology. At this time Kraepelin also identified the distinctive syndromes of schizophrenia (then dementia praecox) and manic depression (now major depressive disorder and bipolar disorder) but with the techniques available no pathology was identified. So these conditions languished in stigma during the 20th century as they had since time immemorial. It will be argued that we now have a pathology for these diseases, which consists of characteristic patterns of grey matter loss, determined with MRI, consequent on the degeneration of synapses and their dendrites. Furthermore, there are indications as to how the extraordinary plasticity of these structures can be marshaled to reconstitute synapses, dendrites, and so grey matter, thereby helping to ameliorate these diseases. | At the beginning of the last century Cajal identified glial cells, neurons and their interconnections at synapses as the major constituents of grey matter. At this time the patients in the great asylums of Europe and the UK, such as Bethlem, were beginning to be differentiated as suffering different syndromes on the basis of distinctive symptoms. One of these, dementia, when subjected to the new clinicopathological approach, was in many cases found by Alzheimer to possess the core pathology of neuron degeneration. This resulted in an entirely different view of dementia, removing stigma and focusing research on the prevention of the pathology. At this time Kraepelin also identified the distinctive syndromes of schizophrenia (then dementia praecox) and manic depression (now major depressive disorder and bipolar disorder) but with the techniques available no pathology was identified. So these conditions languished in stigma during the 20th century as they had since time immemorial. It will be argued that we now have a pathology for these diseases, which consists of characteristic patterns of grey matter loss, determined with MRI, consequent on the degeneration of synapses and their dendrites. Furthermore, there are indications as to how the extraordinary plasticity of these structures can be marshaled to reconstitute synapses, dendrites, and so grey matter, thereby helping to ameliorate these diseases. | ||
| − | September 14, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street) | + | ='''September 14, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)'''= |
"Image Segmentation of Multiple Objects with Topology Control" | "Image Segmentation of Multiple Objects with Topology Control" | ||
| − | Jerry Prince (Johns Hopkins University) | + | '''Jerry Prince ('''Johns Hopkins University) |
In medical imaging and other applications, it is often desirable to simultaneously segment multiple objects and to impose topological conditions and neighborhood relationships on the objects that are sought. Finding specific compartments that subdivide or parcellate objects according to known anatomy or geometry is an | In medical imaging and other applications, it is often desirable to simultaneously segment multiple objects and to impose topological conditions and neighborhood relationships on the objects that are sought. Finding specific compartments that subdivide or parcellate objects according to known anatomy or geometry is an | ||
example of this task. This talk presents a level set segmentation algorithm for multiple objects or compartments. In contrast to other techniques, the method can handle large numbers of objects and relationships without a large additional computational burden. Background on level set segmentation and digital topology will be briefly provided and results on both illustrative examples and thalamus and whole brain parcellation will be shown. | example of this task. This talk presents a level set segmentation algorithm for multiple objects or compartments. In contrast to other techniques, the method can handle large numbers of objects and relationships without a large additional computational burden. Background on level set segmentation and digital topology will be briefly provided and results on both illustrative examples and thalamus and whole brain parcellation will be shown. | ||
| − | September 28, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street) | + | ='''September 28, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)'''= |
"Identifying PET Tracer Candidates Using Non-radioactive Compounds and LC/MS: Discovery of Novel Kappa Selective Opioid Receptor Antagonists" | "Identifying PET Tracer Candidates Using Non-radioactive Compounds and LC/MS: Discovery of Novel Kappa Selective Opioid Receptor Antagonists" | ||
| − | Charlie Mitch (Eli Lilly) | + | '''Charlie Mitch''' (Eli Lilly) |
Currently, PET/SPECT imaging is limited by the number of tracers for novel targets. The application of LC/MS/MS technology to tracer discovery enables high-throughput in vivo analyses of non-radiolabeled compounds as potential tracers, through terminal rodent experiments. Such experiments provide data to determine if a potential structure is worth labeling and scanning in nonhuman primate (both costly processes). Properties including binding potential, standardized uptake value (SUV), tissue kinetics, and specific binding to the target of interest can be determined in a matter of days. Here we exemplify the application of this technology to drive structure-activity relationship (SAR) search for a kappa antagonist PET tracer. For purposes of benchmarking, our LC/MS/MS methodology in the rat was also used to evaluate kappa opioid receptor tracers previously reported by other workers. By our method, the kappa agonist, GR103545, was found to have appropriate differential distribution and brain uptake (BP = 1.6 and SUV = 50%, respectively, at 30 min post dose) (Need et al, 2007). The recently reported Kappa antagonist, N-Me-JDTic, showed minimal differential distribution (BP = 0.4 at 20 min post dose) and poor brain uptake (SUV= 23% at 30 min post dose). The novel antagonist, LY2795050, compares favorably to the benchmark kappa tracers in terms of both differential distribution and brain uptake. LY2795050 also was found to have high affinity and selectivity for kappa opioid receptors in vitro (Ki = 1.37, 87.3, and 475 nM, respectively, for kappa, mu, and delta receptors). Potential feasibiity for C-11 label incorporation was also demonstrated by the preparation of LY2795050 via palladium mediated cyanide displacement of a corresponding aryl iodide precursor followed by rapid hydrolysis to the desired carboxamide product. The favorable in vitro binding and in vivo rat LC/MS/MS evaluation provides compelling data to warrant further investigation of LY2795050 as a potential PET receptor occupancy trace. Application of LC/MS/MS receptor occupancy methodology in drug discovery will also be exemplified by the discovery of new, kappa selective opioid receptor antagonists with activity in preclinical models of anxiety, depression and alcohol dependence. | Currently, PET/SPECT imaging is limited by the number of tracers for novel targets. The application of LC/MS/MS technology to tracer discovery enables high-throughput in vivo analyses of non-radiolabeled compounds as potential tracers, through terminal rodent experiments. Such experiments provide data to determine if a potential structure is worth labeling and scanning in nonhuman primate (both costly processes). Properties including binding potential, standardized uptake value (SUV), tissue kinetics, and specific binding to the target of interest can be determined in a matter of days. Here we exemplify the application of this technology to drive structure-activity relationship (SAR) search for a kappa antagonist PET tracer. For purposes of benchmarking, our LC/MS/MS methodology in the rat was also used to evaluate kappa opioid receptor tracers previously reported by other workers. By our method, the kappa agonist, GR103545, was found to have appropriate differential distribution and brain uptake (BP = 1.6 and SUV = 50%, respectively, at 30 min post dose) (Need et al, 2007). The recently reported Kappa antagonist, N-Me-JDTic, showed minimal differential distribution (BP = 0.4 at 20 min post dose) and poor brain uptake (SUV= 23% at 30 min post dose). The novel antagonist, LY2795050, compares favorably to the benchmark kappa tracers in terms of both differential distribution and brain uptake. LY2795050 also was found to have high affinity and selectivity for kappa opioid receptors in vitro (Ki = 1.37, 87.3, and 475 nM, respectively, for kappa, mu, and delta receptors). Potential feasibiity for C-11 label incorporation was also demonstrated by the preparation of LY2795050 via palladium mediated cyanide displacement of a corresponding aryl iodide precursor followed by rapid hydrolysis to the desired carboxamide product. The favorable in vitro binding and in vivo rat LC/MS/MS evaluation provides compelling data to warrant further investigation of LY2795050 as a potential PET receptor occupancy trace. Application of LC/MS/MS receptor occupancy methodology in drug discovery will also be exemplified by the discovery of new, kappa selective opioid receptor antagonists with activity in preclinical models of anxiety, depression and alcohol dependence. | ||
| − | October 5, Tuesday (4:15 pm) at Becton Faculty Lounge (10 Hillhouse Ave, Dunham lab) | + | ='''October 5, Tuesday (4:15 pm) at Becton Faculty Lounge (10 Hillhouse Ave, Dunham lab) '''= |
"Machine learning problems in medical imaging and crime analysis" | "Machine learning problems in medical imaging and crime analysis" | ||
| − | Miles Wernick (Illinois Institute of Technology) | + | '''Miles Wernick''' (Illinois Institute of Technology) |
Machine learning refers to the development of algorithms that quantify relationships within data for purposes of drawing inferences or making predictions. Machine learning has seen explosive growth in fields such as banking and e-commerce, and is receiving rapidly increasing attention in two important fields: medical imaging and law enforcement. In medical imaging, machine learning can be used to make diagnostic decisions, to form functional images, to drive search tools, and to predict diagnostic performance. This talk will also introduce the speaker’s recent partnership with the Chicago Police Department, which is part of a government initiative to demonstrate the potential of predictive policing. | Machine learning refers to the development of algorithms that quantify relationships within data for purposes of drawing inferences or making predictions. Machine learning has seen explosive growth in fields such as banking and e-commerce, and is receiving rapidly increasing attention in two important fields: medical imaging and law enforcement. In medical imaging, machine learning can be used to make diagnostic decisions, to form functional images, to drive search tools, and to predict diagnostic performance. This talk will also introduce the speaker’s recent partnership with the Chicago Police Department, which is part of a government initiative to demonstrate the potential of predictive policing. | ||
| − | October 19, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)* | + | ='''October 19, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)*'''= |
"Why do astrocytes need metabolic energy and how do they get it?" | "Why do astrocytes need metabolic energy and how do they get it?" | ||
| − | + | L'''eif Hertz''' (University of Saskatchewan) | |
Studies using 13C-based MRS during the last decade have convincingly shown that astrocytes contribute 20-30 percent of total oxidative metabolism in cerebral cortex and that between one third and one half of their glucose metabolism occurs by pyruvate carboxylation, with the remainder by conventional pyruvate dehydrogenation to acetyl coenzyme A (acetylCoA). Their total contribution to oxidative metabolism at least matches their total contribution to cerebral cortical volume. This high rate of oxidative metabolism per cell volume has profoundly changed concepts regarding metabolism of astrocytes in vivo and is raising questions of the type(s) of energy-requiring processes undertaken by them, which must far exceed their role in glutamate uptake, on which the energy budgets by Attwell have been based. The high rate of pyruvate carboxylation serves to produce transmitter glutamate and GABA for neurons, which are unable to synthesize these amino acids themselves, due to their lack of pyruvate carboxylase activity, demonstrated by studies in cultured cells and confirmed histochemically. The high rate of pyruvate carboxylation, combined with an at least equally active rate of acetyl CoA formation, produces a ‘new’ molecule of citrate, which is circled in the TCA cycle to -ketoglutarate and transaminated to glutamate, which is then transported to neurons in the glutamate-glutamine cycle. This cycle also serves to return previously released transmitter glutamate – and to a lesser extent GABA – to neurons after an initial uptake in astrocytes. The pyruvate carboxylase-mediated pathway accounts for about one third of glutamine carried in the glutamate-glutamine cycle. It is stimulated during functional activity, which leads to a rapid, millimolar, increase in cellular glutamate. Subsequently the glutamate content returns to resting levels, accomplished by complete oxidative metabolism of glutamate, mainly in astrocytes, after formation of -ketoglutarate, circling to malate, exit of malate from the TCA cycle and its decarboxylation to pyruvate. Synthesis and subsequent oxidative degradation of glutamate produces only slightly less energy (ATP) than oxidative degradation of glucose exclusively by pyruvate dehydrogenation. Glutamate uptake by astrocytes accounts only for a few percent of oxidative metabolism in brain, but uptake of potassium ions, increasing extracellularly to higher levels, is likely to require several times more energy, and the energy associated with active transport of calcium ions at low concentrations, but changing at high frequencies, is unknown. | Studies using 13C-based MRS during the last decade have convincingly shown that astrocytes contribute 20-30 percent of total oxidative metabolism in cerebral cortex and that between one third and one half of their glucose metabolism occurs by pyruvate carboxylation, with the remainder by conventional pyruvate dehydrogenation to acetyl coenzyme A (acetylCoA). Their total contribution to oxidative metabolism at least matches their total contribution to cerebral cortical volume. This high rate of oxidative metabolism per cell volume has profoundly changed concepts regarding metabolism of astrocytes in vivo and is raising questions of the type(s) of energy-requiring processes undertaken by them, which must far exceed their role in glutamate uptake, on which the energy budgets by Attwell have been based. The high rate of pyruvate carboxylation serves to produce transmitter glutamate and GABA for neurons, which are unable to synthesize these amino acids themselves, due to their lack of pyruvate carboxylase activity, demonstrated by studies in cultured cells and confirmed histochemically. The high rate of pyruvate carboxylation, combined with an at least equally active rate of acetyl CoA formation, produces a ‘new’ molecule of citrate, which is circled in the TCA cycle to -ketoglutarate and transaminated to glutamate, which is then transported to neurons in the glutamate-glutamine cycle. This cycle also serves to return previously released transmitter glutamate – and to a lesser extent GABA – to neurons after an initial uptake in astrocytes. The pyruvate carboxylase-mediated pathway accounts for about one third of glutamine carried in the glutamate-glutamine cycle. It is stimulated during functional activity, which leads to a rapid, millimolar, increase in cellular glutamate. Subsequently the glutamate content returns to resting levels, accomplished by complete oxidative metabolism of glutamate, mainly in astrocytes, after formation of -ketoglutarate, circling to malate, exit of malate from the TCA cycle and its decarboxylation to pyruvate. Synthesis and subsequent oxidative degradation of glutamate produces only slightly less energy (ATP) than oxidative degradation of glucose exclusively by pyruvate dehydrogenation. Glutamate uptake by astrocytes accounts only for a few percent of oxidative metabolism in brain, but uptake of potassium ions, increasing extracellularly to higher levels, is likely to require several times more energy, and the energy associated with active transport of calcium ions at low concentrations, but changing at high frequencies, is unknown. | ||
| − | November 2, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street) | + | ='''November 2, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)'''= |
"Spatiotemporal Evolution of the fMRI Response to Ultrashort Stimuli" | "Spatiotemporal Evolution of the fMRI Response to Ultrashort Stimuli" | ||
| − | Afonso Silva (NINDS, NIH) | + | '''Afonso Silva''' (NINDS, NIH) |
The specificity of the hemodynamic response function (HRF) is determined spatially by the vascular architecture and temporally by the evolution of hemodynamic changes. The stimulus duration has additional influence on the spatiotemporal evolution of the HRF, as brief stimuli elicit responses that engage only the local vasculature, while long stimuli lead to the involvement of remote vascular supply and drainage. We have been investigating the spatiotemporal evolution of the blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF) and cerebral blood volume (CBV) HRF to ultrashort forelimb stimulation in anesthetized rats and in awake non-human primates. The HRFs to a single 333us-long stimulus consist of a rapid response in both CBF and CBV, with an onset time (OT) of 350ms and a full-width-at-half-maximum of 1s. Longer stimuli elicit dispersive transit of oxygenated blood across the cortical microvasculature that significantly prolongs the evolution of the CBV HRF, but not the CBF. The CBF and CBV OTs suggest that vasoactive messengers are synthesized, released and effective within 350ms. In addition, the difference between the BOLD and CBV OT (~100ms) is significantly smaller than the arteriolar-venular transit time (~500ms), indicating an arterial contribution to the BOLD HRF. Finally, the rapid rate of growth of the active region with stimulus elongation suggests that functional hyperemia is an integrative process that involves the entire functional cortical column. These findings offer a new view into the spatiotemporal dynamics of functional hemodynamic regulation in the brain. | The specificity of the hemodynamic response function (HRF) is determined spatially by the vascular architecture and temporally by the evolution of hemodynamic changes. The stimulus duration has additional influence on the spatiotemporal evolution of the HRF, as brief stimuli elicit responses that engage only the local vasculature, while long stimuli lead to the involvement of remote vascular supply and drainage. We have been investigating the spatiotemporal evolution of the blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF) and cerebral blood volume (CBV) HRF to ultrashort forelimb stimulation in anesthetized rats and in awake non-human primates. The HRFs to a single 333us-long stimulus consist of a rapid response in both CBF and CBV, with an onset time (OT) of 350ms and a full-width-at-half-maximum of 1s. Longer stimuli elicit dispersive transit of oxygenated blood across the cortical microvasculature that significantly prolongs the evolution of the CBV HRF, but not the CBF. The CBF and CBV OTs suggest that vasoactive messengers are synthesized, released and effective within 350ms. In addition, the difference between the BOLD and CBV OT (~100ms) is significantly smaller than the arteriolar-venular transit time (~500ms), indicating an arterial contribution to the BOLD HRF. Finally, the rapid rate of growth of the active region with stimulus elongation suggests that functional hyperemia is an integrative process that involves the entire functional cortical column. These findings offer a new view into the spatiotemporal dynamics of functional hemodynamic regulation in the brain. | ||
| − | November 9, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street) | + | ='''November 9, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)'''= |
"Active Mean Fields: Evolving Curves via an Explicit Probabilistic Representation" | "Active Mean Fields: Evolving Curves via an Explicit Probabilistic Representation" | ||
| − | Kilian Pohl (University of Pennsylvania) | + | '''Kilian Pohl''' (University of Pennsylvania) |
In this talk we develop a new curve evolution formulation for estimating the posterior distribution of objects in images. Similar to level sets, we describe the segmentation of images via a conventional likelihood model combined with a curve prior on boundaries. Unlike level sets, the curves are encoded via the logarithm-of-odds representing the posterior distribution on labels in an unconstrained vector space. The posterior distributions are sought via the Mean Field approach. By choosing a different representation and optimization, our framework sidesteps many of the issues traditionally associated with level set implementations. For example, applications with more than two labels are easily accommodated, as the label assignment is accomplished by the Maximum A Posteriori rule, so there are no problems of overlap or vacuum between level set functions. We demonstrate the effectiveness of this technology on a synthetic noisy image and real 3D medical scans. | In this talk we develop a new curve evolution formulation for estimating the posterior distribution of objects in images. Similar to level sets, we describe the segmentation of images via a conventional likelihood model combined with a curve prior on boundaries. Unlike level sets, the curves are encoded via the logarithm-of-odds representing the posterior distribution on labels in an unconstrained vector space. The posterior distributions are sought via the Mean Field approach. By choosing a different representation and optimization, our framework sidesteps many of the issues traditionally associated with level set implementations. For example, applications with more than two labels are easily accommodated, as the label assignment is accomplished by the Maximum A Posteriori rule, so there are no problems of overlap or vacuum between level set functions. We demonstrate the effectiveness of this technology on a synthetic noisy image and real 3D medical scans. | ||
| − | December 14, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street) | + | ='''December 14, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)'''= |
"Mechanisms of altered mGluR5 function in Fragile X Syndrome" | "Mechanisms of altered mGluR5 function in Fragile X Syndrome" | ||
| − | Kimberly Huber (University of Texas, Southwestern) | + | '''Kimberly Huber''' (University of Texas, Southwestern) |
Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and a leading genetic cause of autism. In the mouse model of Fragile X Syndrome, Fmr1 knockout (KO) mice, there is evidence for enhanced function of the metabotropic glutamate receptor 5 (mGluR5). Remarkably, many phenotype of Fragile X Syndrome in animal models are reversed by pharmacological antagonism or genetic reduction of mGluR5. The molecular basis of mGluR5 dysfunction in Fragile X is unknown. New data indicating that altered mGluR5 function stems from two distinct molecular mechanisms in Fragile X will be presented. | Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and a leading genetic cause of autism. In the mouse model of Fragile X Syndrome, Fmr1 knockout (KO) mice, there is evidence for enhanced function of the metabotropic glutamate receptor 5 (mGluR5). Remarkably, many phenotype of Fragile X Syndrome in animal models are reversed by pharmacological antagonism or genetic reduction of mGluR5. The molecular basis of mGluR5 dysfunction in Fragile X is unknown. New data indicating that altered mGluR5 function stems from two distinct molecular mechanisms in Fragile X will be presented. | ||
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*co-sponsored by the Neuroimaging Sciences Training Program | *co-sponsored by the Neuroimaging Sciences Training Program | ||
Latest revision as of 23:55, 6 October 2010
September 7, Tuesday (4:15 pm) at Hope 110 (310 Cedar Street)*
"Psychiatric diseases: A core pathology of synapse regression" Max Bennett (Brain and Mind Research Institute, University of Sydney) At the beginning of the last century Cajal identified glial cells, neurons and their interconnections at synapses as the major constituents of grey matter. At this time the patients in the great asylums of Europe and the UK, such as Bethlem, were beginning to be differentiated as suffering different syndromes on the basis of distinctive symptoms. One of these, dementia, when subjected to the new clinicopathological approach, was in many cases found by Alzheimer to possess the core pathology of neuron degeneration. This resulted in an entirely different view of dementia, removing stigma and focusing research on the prevention of the pathology. At this time Kraepelin also identified the distinctive syndromes of schizophrenia (then dementia praecox) and manic depression (now major depressive disorder and bipolar disorder) but with the techniques available no pathology was identified. So these conditions languished in stigma during the 20th century as they had since time immemorial. It will be argued that we now have a pathology for these diseases, which consists of characteristic patterns of grey matter loss, determined with MRI, consequent on the degeneration of synapses and their dendrites. Furthermore, there are indications as to how the extraordinary plasticity of these structures can be marshaled to reconstitute synapses, dendrites, and so grey matter, thereby helping to ameliorate these diseases.
September 14, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)
"Image Segmentation of Multiple Objects with Topology Control" Jerry Prince (Johns Hopkins University) In medical imaging and other applications, it is often desirable to simultaneously segment multiple objects and to impose topological conditions and neighborhood relationships on the objects that are sought. Finding specific compartments that subdivide or parcellate objects according to known anatomy or geometry is an example of this task. This talk presents a level set segmentation algorithm for multiple objects or compartments. In contrast to other techniques, the method can handle large numbers of objects and relationships without a large additional computational burden. Background on level set segmentation and digital topology will be briefly provided and results on both illustrative examples and thalamus and whole brain parcellation will be shown.
September 28, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)
"Identifying PET Tracer Candidates Using Non-radioactive Compounds and LC/MS: Discovery of Novel Kappa Selective Opioid Receptor Antagonists" Charlie Mitch (Eli Lilly) Currently, PET/SPECT imaging is limited by the number of tracers for novel targets. The application of LC/MS/MS technology to tracer discovery enables high-throughput in vivo analyses of non-radiolabeled compounds as potential tracers, through terminal rodent experiments. Such experiments provide data to determine if a potential structure is worth labeling and scanning in nonhuman primate (both costly processes). Properties including binding potential, standardized uptake value (SUV), tissue kinetics, and specific binding to the target of interest can be determined in a matter of days. Here we exemplify the application of this technology to drive structure-activity relationship (SAR) search for a kappa antagonist PET tracer. For purposes of benchmarking, our LC/MS/MS methodology in the rat was also used to evaluate kappa opioid receptor tracers previously reported by other workers. By our method, the kappa agonist, GR103545, was found to have appropriate differential distribution and brain uptake (BP = 1.6 and SUV = 50%, respectively, at 30 min post dose) (Need et al, 2007). The recently reported Kappa antagonist, N-Me-JDTic, showed minimal differential distribution (BP = 0.4 at 20 min post dose) and poor brain uptake (SUV= 23% at 30 min post dose). The novel antagonist, LY2795050, compares favorably to the benchmark kappa tracers in terms of both differential distribution and brain uptake. LY2795050 also was found to have high affinity and selectivity for kappa opioid receptors in vitro (Ki = 1.37, 87.3, and 475 nM, respectively, for kappa, mu, and delta receptors). Potential feasibiity for C-11 label incorporation was also demonstrated by the preparation of LY2795050 via palladium mediated cyanide displacement of a corresponding aryl iodide precursor followed by rapid hydrolysis to the desired carboxamide product. The favorable in vitro binding and in vivo rat LC/MS/MS evaluation provides compelling data to warrant further investigation of LY2795050 as a potential PET receptor occupancy trace. Application of LC/MS/MS receptor occupancy methodology in drug discovery will also be exemplified by the discovery of new, kappa selective opioid receptor antagonists with activity in preclinical models of anxiety, depression and alcohol dependence.
October 5, Tuesday (4:15 pm) at Becton Faculty Lounge (10 Hillhouse Ave, Dunham lab)
"Machine learning problems in medical imaging and crime analysis" Miles Wernick (Illinois Institute of Technology) Machine learning refers to the development of algorithms that quantify relationships within data for purposes of drawing inferences or making predictions. Machine learning has seen explosive growth in fields such as banking and e-commerce, and is receiving rapidly increasing attention in two important fields: medical imaging and law enforcement. In medical imaging, machine learning can be used to make diagnostic decisions, to form functional images, to drive search tools, and to predict diagnostic performance. This talk will also introduce the speaker’s recent partnership with the Chicago Police Department, which is part of a government initiative to demonstrate the potential of predictive policing.
October 19, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)*
"Why do astrocytes need metabolic energy and how do they get it?" Leif Hertz (University of Saskatchewan) Studies using 13C-based MRS during the last decade have convincingly shown that astrocytes contribute 20-30 percent of total oxidative metabolism in cerebral cortex and that between one third and one half of their glucose metabolism occurs by pyruvate carboxylation, with the remainder by conventional pyruvate dehydrogenation to acetyl coenzyme A (acetylCoA). Their total contribution to oxidative metabolism at least matches their total contribution to cerebral cortical volume. This high rate of oxidative metabolism per cell volume has profoundly changed concepts regarding metabolism of astrocytes in vivo and is raising questions of the type(s) of energy-requiring processes undertaken by them, which must far exceed their role in glutamate uptake, on which the energy budgets by Attwell have been based. The high rate of pyruvate carboxylation serves to produce transmitter glutamate and GABA for neurons, which are unable to synthesize these amino acids themselves, due to their lack of pyruvate carboxylase activity, demonstrated by studies in cultured cells and confirmed histochemically. The high rate of pyruvate carboxylation, combined with an at least equally active rate of acetyl CoA formation, produces a ‘new’ molecule of citrate, which is circled in the TCA cycle to -ketoglutarate and transaminated to glutamate, which is then transported to neurons in the glutamate-glutamine cycle. This cycle also serves to return previously released transmitter glutamate – and to a lesser extent GABA – to neurons after an initial uptake in astrocytes. The pyruvate carboxylase-mediated pathway accounts for about one third of glutamine carried in the glutamate-glutamine cycle. It is stimulated during functional activity, which leads to a rapid, millimolar, increase in cellular glutamate. Subsequently the glutamate content returns to resting levels, accomplished by complete oxidative metabolism of glutamate, mainly in astrocytes, after formation of -ketoglutarate, circling to malate, exit of malate from the TCA cycle and its decarboxylation to pyruvate. Synthesis and subsequent oxidative degradation of glutamate produces only slightly less energy (ATP) than oxidative degradation of glucose exclusively by pyruvate dehydrogenation. Glutamate uptake by astrocytes accounts only for a few percent of oxidative metabolism in brain, but uptake of potassium ions, increasing extracellularly to higher levels, is likely to require several times more energy, and the energy associated with active transport of calcium ions at low concentrations, but changing at high frequencies, is unknown.
November 2, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)
"Spatiotemporal Evolution of the fMRI Response to Ultrashort Stimuli" Afonso Silva (NINDS, NIH) The specificity of the hemodynamic response function (HRF) is determined spatially by the vascular architecture and temporally by the evolution of hemodynamic changes. The stimulus duration has additional influence on the spatiotemporal evolution of the HRF, as brief stimuli elicit responses that engage only the local vasculature, while long stimuli lead to the involvement of remote vascular supply and drainage. We have been investigating the spatiotemporal evolution of the blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF) and cerebral blood volume (CBV) HRF to ultrashort forelimb stimulation in anesthetized rats and in awake non-human primates. The HRFs to a single 333us-long stimulus consist of a rapid response in both CBF and CBV, with an onset time (OT) of 350ms and a full-width-at-half-maximum of 1s. Longer stimuli elicit dispersive transit of oxygenated blood across the cortical microvasculature that significantly prolongs the evolution of the CBV HRF, but not the CBF. The CBF and CBV OTs suggest that vasoactive messengers are synthesized, released and effective within 350ms. In addition, the difference between the BOLD and CBV OT (~100ms) is significantly smaller than the arteriolar-venular transit time (~500ms), indicating an arterial contribution to the BOLD HRF. Finally, the rapid rate of growth of the active region with stimulus elongation suggests that functional hyperemia is an integrative process that involves the entire functional cortical column. These findings offer a new view into the spatiotemporal dynamics of functional hemodynamic regulation in the brain.
November 9, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)
"Active Mean Fields: Evolving Curves via an Explicit Probabilistic Representation" Kilian Pohl (University of Pennsylvania) In this talk we develop a new curve evolution formulation for estimating the posterior distribution of objects in images. Similar to level sets, we describe the segmentation of images via a conventional likelihood model combined with a curve prior on boundaries. Unlike level sets, the curves are encoded via the logarithm-of-odds representing the posterior distribution on labels in an unconstrained vector space. The posterior distributions are sought via the Mean Field approach. By choosing a different representation and optimization, our framework sidesteps many of the issues traditionally associated with level set implementations. For example, applications with more than two labels are easily accommodated, as the label assignment is accomplished by the Maximum A Posteriori rule, so there are no problems of overlap or vacuum between level set functions. We demonstrate the effectiveness of this technology on a synthetic noisy image and real 3D medical scans.
December 14, Tuesday (4:15 pm) at N135 TAC (300 Cedar Street)
"Mechanisms of altered mGluR5 function in Fragile X Syndrome" Kimberly Huber (University of Texas, Southwestern) Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and a leading genetic cause of autism. In the mouse model of Fragile X Syndrome, Fmr1 knockout (KO) mice, there is evidence for enhanced function of the metabotropic glutamate receptor 5 (mGluR5). Remarkably, many phenotype of Fragile X Syndrome in animal models are reversed by pharmacological antagonism or genetic reduction of mGluR5. The molecular basis of mGluR5 dysfunction in Fragile X is unknown. New data indicating that altered mGluR5 function stems from two distinct molecular mechanisms in Fragile X will be presented.
- co-sponsored by the Neuroimaging Sciences Training Program
Refreshments served 15 minutes prior to start of seminar.
Please call 5-6199 / 5-6622 for directions.
