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Alan P. Koretsky - US grants
Affiliations: | National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States |
Area:
MRI methodsWebsite:
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High-probability grants
According to our matching algorithm, Alan P. Koretsky is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1989 — 1993 | Koretsky, Alan P. | R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Mechanism of Respiratory Control in Heart @ Carnegie-Mellon University oxygen consumption; pulmonary respiration; mitochondria; heart metabolism; nicotinamide adenine dinucleotide; phosphates; oxidation reduction reaction; heart contraction; glucose metabolism; calcium; adrenergic agents; muscle stimulant; muscle relaxants; cytochromes; perfusion; nuclear magnetic resonance spectroscopy; laboratory rat; fluorescence spectrometry; |
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1993 — 1997 | Koretsky, Alan P. | K04Activity Code Description: Undocumented code - click on the grant title for more information. |
Mitochondrial Respiratory Control @ Carnegie-Mellon University The long term goals of this research are to understand the control of mitochondrial ATP production in heart during changes in cardiac work in normal and pathological states. A number of heart diseases such as ischemia and hypertrophy are associated with defects in energy metabolism. This work relies on the application of NMR, to monitor levels of key metabolites, and molecular genetic techniques, to produce transgenic mice with alterations in energy metabolism. The immediate aims of the proposed research are to use a transgenic mouse model expressing creatine kinase in liver to determine the relation between extra mitochondrial ADP, mitochondrial NADH, and oxygen consumption in vivo. These data will be used to test the hypothesis that hormone stimulation of oxidative ATP production occurs due to increases in mitochondrial NADH. In addition, experiments will be performed to understand the role of creatine kinase, an abundant cardiac enzyme, in cellular energetics. A transgenic mouse expressing mitochondrial creatine kinase in liver will be produced. The effects of mitochondrial creatine kinase on the control of oxidative ATP production will be assessed. Finally, a set of transgenic mice with an altered creatine kinase isoenzyme distribution will be studied to see if alteration of creatine kinase affects muscle energy metabolism. |
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1994 — 1998 | Koretsky, Alan P. | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanism of Mitochondrial Respiratory Control @ Carnegie-Mellon University The long term goal of this research is to understand the control of mitochondrial ATP production during changes in cellular work both in normal and pathological states. A number of clinical disorders, such as those due to cardiac ischemia and hypertrophy are associated with defects in energy metabolism. The proposed studies rely on the application of NMR, to monitor levels of key metabolites in the intact organ, and molecular genetic techniques, to produce transgenic mice with altered enzyme content and distribution. The immediate aims of the proposed research are to use a transgenic mouse model expressing creatine kinase in liver to determine the relation between cellular ADP levels, mitochondrial NADH levels, and oxygen consumption in vivo. The transgenic liver expressing creatine kinase offers unique opportunities to study mitochondrial respiratory control. This mouse model allows quantitation of both mitochondrial NADH redox state and ADP concentrations in the same tissue. Data relating ADP, mitochondrial NADH and oxygen consumption will be obtained and then used to test the hypothesis that hormone stimulation of oxidative ATP production occurs due to increases in mitochondrial NADH To set the stage for studies using transgenic mouse hearts, we propose to establish a working mouse heart perfusion model and investigate the relation between work, oxygen consumption and high energy phosphates. Finally, experiments will be performed to understand the role of mitochondrial creatine kinase, an abundant cardiac enzyme central to energy metabolism. A transgenic mouse expressing mitochondrial creatine kinase in liver will be produced. The effects of mitochondrial creatine kinase on the control of oxidative ATP production will be assessed in order to test the hypothesis that mitochondrial creatine kinase alters the response of mitochondria to changes in ADP concentrations. The proposed work will lead to a greater understanding of mitochondrial respiratory control in normal tissues. This is one of the first attempts to combine NMR and molecular genetics to dissect out the quantitative control of a metabolic pathway. The lessons learned should, in the future, be applicable to help plan, monitor, and interpret human gene therapy protocols |
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2000 — 2008 | Koretsky, Alan P. | Z01Activity Code Description: Undocumented code - click on the grant title for more information. |
Functional Imaging of the Brain and Heart @ Neurological Disorders and Stroke The overall goal of this work is to develop anatomical, functional, and molecular magnetic resonance imaging (MRI) techniques that allow non-invasive assessment of brain function and apply these tools to study plasticity and learning in the rodent brain. MRI techniques are having a broad impact on understanding brain. Anatomical based MRI has been very useful for separating gray and white matter and detecting numerous brain disorders. Functional MRI techniques enable detection of regions of the brain that are active during a task. Molecular MRI is an emerging area, whose major goal is to image a large variety of processes in tissues. The goal of this project is to translate MRI developments in all these areas to study system level changes that occur in the rodent brain during plasticity and learning. [unreadable] [unreadable] Aim 1: Over the past few years, we have completed studies in the rodent brain that acquired very high temporal and spatial resolution functional MRI (fMRI) to monitor changes in hemodynamics as a surrogate marker of electrical activity during forepaw stimulation. Work over the past year has been completed that has acquired very high signal to noise fMRI maps to determine if the borders of activated areas can be well defined. fMRI results can be compared to anatomical borders to get precise localization of functional and anatomical boundaries. Results indicate that when very high signal to noise fMRI maps are obtained that the border of the fMRI map becomes well defined. There are two spatial components of the fMRI signal in somatosensory cortex when either forepaw or hindpaw are stimulated. The major component corresponds to the normal representation expected based on anatomy. Interestingly the minor component extends well into the neighboring region and may represent known projections that send sub-threshold information into neighboring regions. To test this idea plasticity was induced in the forepaw representation by severing the nerves in the hindpaw on the same side of the body as fMRI maps of the forepaw are made. Interestingly after a few weeks there is a change in the fMRI map such that only a single major component exists that now extends into the hindpaw representation and ends in a region similar to the minor component of the normal fMRI response. This lends support to the notion that the minor component is delineating a neuronal response that is relevant to communication between regions. Future work will use electrophysiological measurements to probe the underlying neural activity responsible for these interesting fMRI results. Finally, attempts were made to map single digits of the rat forepaw and to test if fMRI could detect well known changes that occur after amputation of a digit early in life. If a differential imaging paradigm is used, single digits can be detected with fMRI and changes in representation due to loss of a digit can be detected. These are the first results that indicate well known changes in neural representations can be detected in the rodent brain and suggest fMRI strategies that enable quantitative delineation of the precise location of these changes.[unreadable] [unreadable] Aim 2: Over the past several years we have demonstrated that manganese chloride enables MRI contrast that defines neural architecture, can monitor activity, and can be used to trace neural connections. Over the last couple of years we have completed the assignment of cortical layers detected using manganese enhanced MRI by comparison to histology and have demonstrated that functional anatomy of several cortical regions of the rodent brain can be defined in individual animals. In particular, clear cytoarchitectural boundaries can be detected between numerous brain areas enabling, for the first time, cytoarchitectural changes to be followed in individual brains over time. We have also demonstrated that activity in the olfactory bulb can be imaged to the level of single glomeruli using manganese enhanced MRI and we hypothesize and have obtained evidence that indicates the flow of neural information from the glomerular to mitral layer can be imaged. Finally, we have developed sensitive MRI techniques to monitor manganese levels and can now track neural connections from the olfactory bulb to the amygdala in individual animals and laminar specific connections from thalamus to cortex and laminar specific cortical-cortical connections. Indeed, neural track tracing with manganese enables delineation of columns and dysgranular regions between major representations in the cortex. Future studies will verify these exciting initial observations that contrast to the anatomy of columns in the brain can be obtained by MRI. [unreadable] [unreadable] Aim 3: Functional MRI studies were performed to measure changes in brain activation that occur after denervation of peripheral nerves. After severing the saphanous and sciatic nerve of one hindpaw, the good hindpaw is now able to cause activation of about 50% of the damaged hindpaw's cortical representation even though it is in the opposite brain hemisphere. Lesion experiments support the model that cortical-cortical communication via the corpus collosum is responsible for this plasticity. Similar results were obtained after severing the nerves that innervate the forepaw and looking at fMRI activation of the good forepaw. High resolution fMRI indicates that the activation in the damaged cortex is about 30% of the normal amplitude and occupies about 50% of the representation. Additionally the good cortex activation increases by a factor of about two. to understand the neural basis of these changes electrophysiology was performed. Consistent with the increased fMRI in the good cortex there was an increase in local field potentials and an increase in the number of single units that responded to stimulation from about 30% of cells to 60% of cells. Interestingly in the cortex ipsalateral to the good paw, no significant local field potential could be detected even though signifcant fMRI was detected. To the best of our knowledge this is the first time fMRI and local field potentials do not coreelate without using pharmacological manipulation. Single unit recordings found a number of cells that responded to stimulation on the ipsalateral side. The majority of cells had short action potential duration and juxtapositional labeling indicates that these cells are interneurons. Thus, the fMRI activation is attributed to increased interneuron activity without significant pyramidal cell activiation in this model of injury induced plasticity. This represents the first time in the intact brain where fMRI has been caused by interneuron acitivity. This has far reaching implications for the analysis of fMRI data. Furthermore, the fact that the ipsalateral cortex is in an increased state of inhibition has behavioral consequences which will be explored in the coming year. Finally, we have begun to use manganese enhanced MRI based neuronal track tracing to determine which connections are most likely to have changed in this model of plasticity.[unreadable] [unreadable] Aim 4: We have begun to explore the use of advanced MRI tools for studying simple learning paradigms in the rodent. We have begun by examining changes in neural connectivity induced by simple fear conditioning. After pairing a specific odor with a shock, manganese enhanced MRI is used to trace connections from the olfactory bulb into the brain. Preliminary results indicate that the non-invasive, functional tracing afforded by manganese enhanced MRI enables changes in connectivity to the amygdala, cortex, and putamen to be detected after fear conditioning. Over the coming year, we will need to reproduce these results. Furthermore we will use fMRI techniques to determine if fear conditioning leads to changes in odor maps in the bulb. |
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2007 — 2018 | Koretsky, Alan | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Mri Contrast For Molecular and Cellular Imaging of the Brain @ Neurological Disorders and Stroke There is rapidly increasing interest in developing molecular imaging approaches that enable traditional radiological imaging techniques to obtain a wide range of information about molecular and cellular processes that occur in normal and diseased tissue. A range of information is considered important such as the ability to monitor cell migration, the development of reporters that enable imaging of gene expression, the development of robust strategies to image receptors, and the development of environmentally sensitive agents that can be used to detect the presence of specific enzymes or monitor changes in ion status. The long term goals of this work are to develop strategies that enable MRI contrast that is sensitive to a wide range of molecular and cellular processes. This work builds on over 15 years of work where we have demonstrated the first MRI strategy for detecting gene expression, the first MRI approach for monitoring a surrogate of calcium influx, the first MRI approach for performing neuronal track tracing, and the first MRI approach for monitoring the migration of single cells in vivo. These all represented initial reports by any radiological imaging technique which enabled these processes to be measured. These techniques are finding widespread application to imaging pre-clinical models of a broad range of diseases. Over the past year we have made progress in all of the specific aims. Aim 1: Develop iron oxide based contrast for labeling and imaging the migration of endogenous neural stem cells. Over the past few years we have demonstrated the unique advantages of micron sized iron oxide particles for MRI of specific cells. Single cells can be detected and indeed, single particles within single cells can be detected. The main paradigm for MRI of cell migration is to label cells ex vivo and monitor migration after transplantation into an animal. These studies have traditionally required very efficient labeling using nano sized particles. The ability to detect a single particle enables inefficient labeling strategies. In particular we have demonstrated that injection of particles into the ventricles of the rat brain enables particles to be taken up by neural precursors in the subventricular zone and MRI can monitor the migration of cells to the oflactory bulb. Over the past year we have used the ability of MRI to count new cells in the bulb to address the issue of whether odor exposure alters migratory patterns of these cells. PReviosu work by a number of groups has led to conflicting results, potentially due to bias analysis of histological data. Rats were expsoed to specific odors for two weeks and cells counted throughout the bulb. No changes in cell counts were detected in any region of the bulb except in the mitral cell layer where the number of new cells doubled. This increase occurred primarily in regions known to be activated by the odor. These cells have been shown to be interneurons. The role of these cells in olfactory processing and whether other odor specific behaviors effect cell number in this region of the brain will be assessed. Aim 2: Apply microfabrication techniques to manufacture unique metal structures that may be valuable for MRI contrast. Iron oxide particles commonly used for MRI are very potent contrast agents enabling detection of single mciron sized particles. However, due to bulk phase manufacture of particles they are not very uniform and they do not contain very high content of metal. A solution to this problem is to use modern microfabrication techniques to manufacture metal based, micron sized contrast agents. To begin this work we have explored a variety of approachs to microfabrication of MRI contrast agents. We have demonstrated that precise definition of shapes and spacing of microfabricatedstructures leads to novel MRI agents. As expected micron sized microfabricated nickel structures are very potent MRI contrast agents. Microfabrication gives us a great deal of flexibility to make structures that may have novel uses. For example, particles spaced at distances much smaller than an MRI voxel can be distinguished and water associated with properly designed structures can be distinguished. Over the past year we have demonstrated that micron sized cylinders are very useful for distinguishing structures. Furthermore, we have made simple gold coated iron discs that are about 10 times better than traditional micron sized iron oxide particles. Over the next year we plan to begin to label cells and transplant into animal sto show the in vivo efficacy of these microfabricated structures. Aim 3: Develop novel delivery mechanisms to extend the applicability of manganese enhanced MRI. Over the past ten years we have demonstrated the remarkable utility of the manganese ion for MRI contrast. Manganese ion enters cells on ligand or voltage gated calcium channels and so can be used as an MRI agent to monitor calcium influx. Once inside of neurons, manganese will move in an anterograde direction and cross functional synapses enabling neuronal networks to be imaged with MRI. Finally, manganese given systemically gives cytoarchitectural information about the rodent brain. These successed have us interested in broadening the ways in which manganese ion can be delivered to cells. Over the past couple of years we have made transferrin-manganese complexes. When bound to transferrin manganese is a poor MRI contrast agent. However, when transferrin is taken up by cells it can release manganese which is then trapped intracellularly. Thus, transferrin manganese is an agent that monitors the successful endocytosis of the transferrin by its receptor. Experiments in hepatocytes and in brain demonstrate that this strategy is succesful and gives efficient contrast. We have managed to get similar effects with MnOxide based nanoparticles. At pH 7 MnO is insoluble and a very weak contrast agent. At low pH, as found in endosomes/lysosomes these particles dissolve greatly increasing MRI relaxation effects. Over hte apst year we have demonstrated that a silica coat on these particles delays dissolution for up to four hours both in vitro and in vivo. Particles injected into the brain had slower rates of contrast development and neuronal tracing then did injection of MnCl2. This opens the possibility of making coatings that can be enzymatically degraded enabling specific in vivo assay of these enzymes. This strategy is limited to endosomal/lysomal enzymes but hold promise for increasing the specificity imaging agents. Aim 4: Develop strategies that enable cellular processes to alter the relaxivity of MRI contrast agents. In specific aim 3 we demonstrated a way in which a normal biological process (endocytosis of transferrin-Mn) can alter the effectiveness of an MRI contrast agent. It would be very exciting to find ways in which this can occur which are sensitive to other biological processes. To this end we have begun to explore ways in which the microfabricated particles produced under Aim 2 can be modulated. It is clear that modulating water exchange alters contrast properties and practical approaches to achieving this aim will be explored over the coming year. |
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2009 — 2018 | Koretsky, Alan | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Functional Imaging of the Brain @ Neurological Disorders and Stroke The overall goal of this work is to develop anatomical, functional, and molecular magnetic resonance imaging (MRI) techniques that allow non-invasive assessment of brain function and apply these tools to study plasticity and learning in the rodent brain. MRI techniques are having a broad impact on understanding brain. Anatomical based MRI has been very useful for separating gray and white matter and detecting numerous brain disorders. Functional MRI techniques enable detection of regions of the brain that are active during a task. Molecular MRI is an emerging area, whose major goal is to image a large variety of processes in tissues. The goal of this project is to translate MRI developments in all these areas to study system level changes that occur in the rodent brain during plasticity and learning. Aim 1: Over the past few years, we have completed studies in the rodent brain that acquired very high temporal and spatial resolution functional MRI (fMRI) to monitor changes in hemodynamics as a surrogate marker of electrical activity during forepaw stimulation. Over the past year we have demonstrated that fMRI from single arterioles from deep cortex can be effectively imaged using blood volume based MRI techniques. fMRI has long been able to detect individual draining vessels but now we have demonstrated the ability to detect individual vessels in deep tissue. The ability to detect single arterioles complements our previous work detecting single venuoles. In the coming year we will do a detailed analysis of time courses in the different vessel compartments. In addition, a one dimensional imaging technique has been developed that enables us to achieve 50 micron spatial resolution through the cortex and 50 msec temporal resolution. In somatosensory cortex, fMRI signals start in layer 4 at about 600-800 msec consistent with our previous work. In motor cortex fMRI onset corresponds to the neural input in mid-cortical areas. In a model where neural input into somatosensory cortex switches to beginning in layer 2/3 and or layer 5 rather than layer 4, the fMRI onset also switches to layer 2/3 and layer 5. This work is consistent with the hypothesis that the onset of fMRI enables extracting information about the onset of neural activity in a brain region. In the coming year we will verify this idea as well as consider beginning studies on the human brain to look at onset dynamics at high spatial temporal resolution. Aim 2: Over the past several years we have demonstrated that manganese chloride enables MRI contrast that defines neural architecture, can monitor activity, and can be used to trace neural connections. Over the last couple of years we have completed the assignment of cortical layers detected using manganese enhanced MRI by comparison to histology and have demonstrated that functional anatomy of several cortical regions of the rodent brain can be defined in individual animals. The ability to detect layers has been applied to a mouse model of neurodegeneration in the olfactory bulb demonstrating the MRI at his level of resolution can detect layer specific degeneration. In addition, we have completed studies that trace the laminar inputs of the olfactory pathway from the olfactory bulb to rodent frontal cortex using manganese enhanced MRI. In a simple fear conditioning experiment (odor with foot shock)a small increase in manganese influx from olfactory cortex to orbital frontal cortex was the only significant change detected. Analysing this change at higher spatial resolution indicated that tracing of manganese was increased by 50% into layer 1 of orbital frontal cortex. This predicts a strengthening of this synapse. There were increases into sub-regions of amygdala as well. In the next year we will verify the synaptic strength increase using optogenetics with MRI and work towards performing slice physiology experiments to verify the manganese work. Aim 3: Over the past few years we established a rodent model that uses peripheral denervation to study brain plasticity in response to the injury. Over the past couple of years we have shown that denervation of the infraorbital nerve leads to large increases in barrel cortex responses along the spared whisker pathway as well as large ipslateral cortical activity consistent with our previouus work in the forepaw and hindpaw. fMRI and manganese enhanced MRI predicted a strengthening of thalamo-cortical input along the spared pathway which was verified in slice electrophysiology studies in collaboration with John Isaac's laboratory. Prior to this it was widely believed that the thalamo-cortical input was not capable of strengthening after the critical period. The mechanisms of this strengthening are under study. Interestingly, the denervation is causing a re-activation of the ability of this synapse to demonstrate long term potentiation which is usually lost after the critical period during the first week of life. This LTP is NMDA dependent but not dependent on the NR2B subunit of the NMDA receptor. Experiments to test whether activation of silent synpases explains the LTP detected and the relation between the potentiaition and LTP are being explored. Over the past year we have implemented optogenetics techniques into our fMRI studies to asses plasticity on the ipsilateral side. Furthermore evidence from manganese based track tracing shows a strengthening of input into layer 2/3 and 5. Over the next year we will use slice electrophysiology to verify this strengthening in analogy to the work done on the thalamo-cortical synapse. Aim 4: We have begun to explore the use of advanced MRI tools for studying simple learning paradigms in the rodent. In order to accomplish this we have been developing techniques that will enable routine fMRI in awake rodents. While fMRI is widely performed in humans and awake primates there have only been a few scattered studies on awake rodents. Training regimens and techniques to hold the head have been developed over the past two years. Interestingly, we have large differences in brain fMRI activation due to somatosensory stimulation or visual stimulation in the awake animal vs anesthetized animal that are stimulation dependent. Somatosensory stimulation gives a strong fMRI response in anesthetized but not awake rodents and visual stimulation give a strong response in awake but not anesthetized animals. Electrophysiology from these areas verifires this result. This is important to lay the ground work for the best types of stimuli that give good fMRI responses in the awake rodent to better design behavioral pardigms that are consistent with fMRI. In the coming year we will begin to see if fMRI can detect changes in circuit level activity during fear conditioning. |
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2010 — 2016 | Koretsky, Alan | ZICActivity Code Description: Undocumented code - click on the grant title for more information. |
Maintenance and Improvement of Ninds Infrastructure @ Neurological Disorders and Stroke NATIONAL INSTITUTES OF HEALTH NINDS Facilities Planning / Equipment Bldg 35, GF352-4 The following laboratories and research support areas underwent renovations during FY 2013: 1. Renovate Electrophysiology and imaging/ microscopy for Dr Kevin Briggman, Chief, Circuit Dynamics and Connectivity unit. Location, NIH Campus, Bldg 35. 2. Renovate animal imaging and physiology laboratory space for Dr Alfonso Silva, Chief, Cerebral Microcirculation Unit. Location, NIH Bethesda Campus, Bldg 35. 3. Renovate microscopy and basic laboratory for Dr Russ Lonser, Chief, Surgical Neurology Branch, Location, NIH Bethesda Campus, Building 10. 4. Relocation and activation activities for the Porter Neuroscience Research Center Phase 2, Mixed institute laboratory building, with NINDS as the lead institute. Location, NIH Bethesda Campus, Bldg 36. 5. Renovate the office of Dr Harish Pant, Chief, Neuronal Cytoskeletal Protein Regulation Section. Location, NIH Campus, Bldg 49. 6. Relocate and renovate an Animal Procedure Room Associated with the Surgical Neurology Branch in conjunction with the NINDS Veterinary Staff. Location, NIH Bethesda Campus, Bldg 49. 7. Perform Hood upgrade and associated laboratory renovation for Dr Kevin Briggman, Chief, Circuit Dynamics and Connectivity unit. Location, NIH Campus, Bldg 37. 8. Perform a lab renovation and fit-out for Dr Quan Yuan, Chief, Dendrite Morphogenesis and Plasticity Unit. Location, NIH Bethesda Campus, Bldg 35. 9. Renovate Scope Room for Dr Kenton Swartz, Chief, Molecular Physiology & Biophysics Section. Location, NIH Bethesda Campus, Bldg 35. 10. Renovate offices for the NINDS/ NIMH Section on Instrumentation for George Dold, Chief, Section on Instrumentation (NIMH). Location, NIH Bethesda Campus, Bldg 13. 11. Renovate and Relocate the Office for Dr Abhik Ray-Chaudhury. Location, NIH Bethesda Campus, Bldg 10. 12. Renovate the Clinical Center On-Call Room for Dr Avi Nath, Director, Office of the Clinical Director. Location, NIH Bethesda Campus, Bldg 10. 13. Relocation and activation activities for the F-Wing project, Mixed institute laboratory wing. Laboratory construction includes work for laboratories and offices for three PIs, Dr Dragan Maric Chief, FACS Facility, Dr Gene Major, Chief, Molecular Medicine & Virology Section, and Dr Dorian McGavern, Chief, Viral Immunology and Intravital Imaging Section. Location, NIH Bethesda Campus, Bldg 10. The following pieces of major shared equipment were purchased to support a large number of PIs: 1. Upgrade existing Thermo Orbitrap Velos mass spectrometer to Thermo Orbitrap Elite equivalent for the Clinical Proteomics Unit 2. Shimadzu Perfinity Workstation for the Clinical Proteomics Unit 3. Microlab Liquid Handler for the Protein/Peptide Sequencing Facility 4. Automated TALEN for a collaborative project between the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and National Institute of Neurological Disorders and Stroke (NINDS) 5. 11.7T Superconducting Magnet system for MRI of animals for the Laboratory of Functional and Molecular Imaging 6. 3T MRI System for human brain imaging as part of a shared initiative between the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute of Child Health and Human Development (NICHD), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and National Institute of Neurological Disorders and Stroke (NINDS) 7. Animal imaging gradient with integrated shims for ultra-high animal MRI for the Laboratory of Functional and Molecular Imaging |
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2011 | Koretsky, Alan | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Cognitive Neuroplasticity and Recovery of Function Following Brain Damage @ Neurological Disorders and Stroke We examined the relationship of preinjury intelligence, brain tissue volume loss, lesion location, demographic variables and a number of genetic markers to long-term cognitive decline in a group of Vietnam veterans with predominantly penetrating head injury (PHI) suffered more than thirty years ago. Using linear and stepwise regression procedures, we found that those with PHI demonstrated a greater degree of cognitive decline overall during the years following injury compared to a control group of uninjured Vietnam veterans. This became increasingly significant later in life. We also found that preinjury intelligence was the most consistent predictor of cognitive outcome across all phases of potential recovery and decline after such injuries. Laterality of lesion was not a factor. Finally, we found evidence for an association between level of cognitive decline following penetrating head injury and the possession of certain genetic markers that have been linked with brain injury and neurodegeneration. Thus exacerbated decline does occur in Vietnam veterans with PHI, is apparently unrelated to dementia and is determined by multiple factors (most notably preinjury intelligence). Post-traumatic stress disorder (PTSD) is an often debilitating mental illness that is characterized by recurrent distressing memories of traumatic events. PTSD is associated with hypoactivity in the ventromedial prefrontal cortex (vmPFC), hyperactivity in the amygdala and reduced volume in the hippocampus, but it is unknown whether these neuroimaging findings reflect the underlying cause or a secondary effect of the disorder. To investigate the causal contribution of specific brain areas to PTSD symptoms, we studied a unique sample of Vietnam War veterans who suffered brain injury and emotionally traumatic events. We found a substantially reduced occurrence of PTSD among those individuals with damage to one of two regions of the brain: the vmPFC and an anterior temporal area that included the amygdala. These results suggest that the vmPFC and amygdala are critically involved in the pathogenesis of PTSD. |
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2011 | Koretsky, Alan | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Cognitive Neuroscience Investigations of Human Frontal Lobes @ Neurological Disorders and Stroke The Section focuses its research on the functions of the human prefrontal cortex and cognitive neuroplasticity. We continue to refine a model developed in the Section that specifies some of the characteristics of the prefrontal cortex's underlying cognitive architecture and representational knowledge. We have determined that ease of access to knowledge stored in the prefrontal cortex is determined by the category and familiarity of that knowledge. In addition, failure to selectively retrieve such knowledge leads to impaired plan development and/or execution. Activating knowledge stored in prefrontal cortex allows that knowledge to manage information that has to be kept temporarily active. Social and non-social knowledge may be distinctively stored in the prefrontal cortex. Access to such knowledge helps modulate more primitive behaviors such as aggression. In an effort to better understand some aspects of cognitive neuroplasticity, we have examined the learning rate of patients recovering from brain damage and with deficits on the task of interest and compared their performance to matched controls. There is some indication that patients can show new learning in deficit areas but it is not clear that if new learning is without a cost to preserved cognitive functions. The section also utilizes positron emission tomography (PET), functional magnetic resonance imaging (fMRI), Direct Current Polarization (DCp) and transcranial magnetic stimulation (rTMS) to map planning processes, representational knowledge, reasoning processes, social cognition, reward systems, number processing and calculation to brain. For example, we have determined with fMRI the importance of the anterior prefrontal cortex for multitasking, task-switching, and adaptive behavior. We have used rTMS to facilitate the speed of analogical reasoning in healthy normal control subjects possibly providing a framework to use rTMS to aid rehabilitation of brain-injured patients. The Section utilizes data from normal control studies, patient studies, functional neuroimaging, and rTMS to provide convergent evidence about the functions of the human prefrontal cortex and cognitive neuroplasticity. |
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2011 | Koretsky, Alan | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
@ Neurological Disorders and Stroke Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined. We examined 84 FTD patients from families not known previously to have illness linked to chromosome 17 for identified PGRN and MAPT mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the prevalence, clinical characteristics, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography results, and neuropsychological testing of patients with the PGRN R493X mutation with those patients without identified PGRN mutations. We discovered a new PGRN mutation (R493X) resulting in a stop codon in two patients. This was the only PGRN mutation identified in our sample. The patients with the PGRN R493X mutation had a rapid illness course and had predominant right-sided atrophy and hypometabolism on magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography. The affected father of one of the patients with the PGRN R493X mutation showed frontal and temporal atrophy without neurofibrillary tangles on neuropathological examination. Our judgment that this mutation results in a heterogeneous clinical presentation has been confirmed in an international in press study of a much large sampling of patients. Many patients with FTD come to our evaluations still driving. To evaluate driving competency and the relationship between neuropsychiatric symptoms and driving behavior in frontotemporal dementia (FTD) patients, we studied 15 patients with a diagnosis of FTD and 15 healthy controls using a driving simulation task. The FTD patients received more speeding tickets, ran more stop signs and were involved in more off-road crashes and collisions than the controls. The patients'overall average speed was significantly higher. Driving performance was correlated with agitated behavior. Based on this finding that behavioral changes characteristic of FTD patients have an impact on their driving skills leading to inappropriate driving behavior, we now caution that all patients with a diagnosis of FTD should cease driving. Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the Microtubule-Associated Protein Tau(MAPT) gene or the Progranulin(PGRN) gene. MAPT mutations lead to widespread deposition of hyperphosphorylated tau protein (FTDP-17T). PGRN mutations are associated with ubiquitin- and TDP-43-positive inclusions in the frontotemporal cortex, striatum and hippocampus (FTDP-17U). Despite the differences, FTDP-17T and FTDP-17U share a largely overlapping clinical phenotype. We attempted to determine whether neuroimaging studies may allow an in vivo early differentiation between FTDP-17T and FTDP-17U. We studied 25 individuals affected with FTDP-17T associated with either the exon 10+3 (24 subjects) or the G335S (1 subject) MAPT mutation, as well as 3 FTDP-17U individuals, who were carriers of the A9D, IVS6-2A>G or R493X PGRN mutation. Neuroimaging studies, obtained along the course of the disease, were compared to the neuropathologic findings. FTDP-17T cases were associated with symmetric frontotemporal atrophy. Behavioral changes constituted the predominant clinical presentation. Conversely, an asymmetric degenerative process was seen in all 3 PGRN cases, who presented with either corticobasal syndrome (A9D) or frontotemporal dementia and language deterioration (IVS6-2A>G and R493X). We conclude that neuroimaging data, in the early disease stage of FTDP-17, may offer the possibility of an early differentiation of FTDP-17T and FTDP-17U phenotypes, independent of the genetic analysis. |
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