Abstracts of Funded National Institutes of Health Grants

Research Corner

Abstracts of Funded NationalInstitutes of Health Grants

The following abstracts of diagnostic radiology research and training grants funded by the National Institutes of Health(NIH) were awarded to principal investigators (PIs) whose primary appointments are in medical school departments ofradiology. These abstracts are listed on the NIH Web page (http://www-commons.cit.nih.gov/crisp/) and are printed hereverbatim.

The grant identification number (eg, 1R01AI12345-01) contains a three-digit activity code (in the previous example, R01)that identifies a specific category of extramural activity. All current NIH activity code titles and definitions can beobtained at the NIH Web page http://silk.nih.gov/silk/brownbooks/actcod.

IRG (Internal Review Group) refers to the study section that reviewed the application. ICD (Institute, Center, Division)refers to the NIH funding source.

The abstracts of the funded grants are printed alphabetically by author according to the funding institute or center.

National Institute on Aging

FUNCTIONAL IMAGING OF AGING ANDALZHEIMER’S DISEASE

Grant Number: 5R01AG020302-02PI Name: Aine, Cheryl J.

Abstract: Description (provided by applicant): The goals ofthis project are: 1) to characterize the functional networks ofhealthy aged brains while engaged in sensory, declarativememory and working memory tasks and to contrast thesephysiological patterns with age-matched patients diagnosedas having mild Alzheimer’s Disease (AD) or minimal cogni-tive impairment (MCI); 2) to follow longitudinally patientsdiagnosed as AD or MCI and the healthy elderly, via repeattesting across a 5-year period in order to document func-tional changes in patients where the memory deficits arelikely to become progressively worse. A long-term goal is touse these results to develop new protocols that will enable usto diagnose AD earlier than current capabilities permit (i.e.,preclinically) and to develop a better understanding of theneural mechanisms mediating AD so that appropriate inter-vention strategies can be developed. Neuropathology studiesreveal deficits in the medial temporal lobes (i.e., presence ofsenile plaques and neurofibrillary tangles) of mild AD pa-tients. In contrast, recent studies in the elderly (nonhumanprimates and humans) suggest alterations in the microstruc-ture of neurons or glial cells (e.g., alterations in myelin
sheaths) accompany normal aging that have a more general-
ized effect, often referred to as sensory and cognitive slow-ing. We hypothesize that mild AD patients will show impair-ment on a delayed verbal recognition memory task, a taskthat normally evokes activity in medial temporal lobe struc-tures, as well as orbitofrontal regions. If normal aging resultsfrom a slow degenerative process, then effects should beevident across sensory and cognitive tasks. As ADprogresses, there will be more overlap in the affected corticalstructures. A functional brain imaging technique, magnetoen-cephalography (MEG), that has good spatial and temporalresolution, will be used in conjunction with anatomical mag-netic resonance imaging (MRI) to characterize the functionalnetworks associated with various sensory and cognitivetasks. Automated source localization and cross-covarianceprocedures will be used for identifying the active corticalnetworks affected by MCI and AD. Ten mild AD/MCI pa-tients will be tested the first year and compared with 20healthy age-matched controls. All 30 patients/subjects willhave repeat exams (MEG, MRI, neuropsychological exams,etc) for each of the remaining 4 years. We anticipate somesubject mortality in the healthy elderly group which will al-low us to add more patients to the MCI and mild AD groupacross time. This longitudinal information will help elucidatethe neural mechanisms affected by MCI and AD.

Thesaurus Terms: Alzheimer’s disease, brain disorder diag-nosis, brain imaging /visualization /scanning, cognition disor-der, diagnosis design /evaluation, neural degeneration, patho-logic process frontal lobe /cortex, longitudinal human study,neuritic plaque, neurofibrillary tangle, speech recognition,temporal lobe /cortex clinical research, human old age
(65�), human subject, magnetic resonance imaging, magne-
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http://www-commons.cit.nih.gov/crisp/

http://silk.nih.gov/silk/brownbooks/actcod

NIA Academic Radiology, Vol 14, No 7, July 2007

toencephalography, neuropsychological test, patient orientedresearch

Institution: University Of New MexicoAlbuquerque

Health Sciences Ctr, Financial Srvs Div.Albuquerque, NM 87131

Fiscal Year: 2005Department: RadiologyProject Start: 01-Jun-2004Project End: 31-May-2009ICD: National Institute On AgingIRG: BDCN

COMPUTATIONAL NEUROANATOMY OFAGING USING SHAPE ANALYSIS

Grant Number: 2R01AG014971-06A2PI Name: Davatzikos, Christos

Abstract: Description (provided by applicant): The goal ofthis project is to continue and significantly expand our workon image analysis methods for brain magnetic resonance im-ages, with emphasis on deformable registration and its appli-cation to morphometric analysis and spatial normalization ofbrain images in a longitudinal study of aging, and the use ofthese methods to develop an image-based early diagnostictool for mild cognitive impairment and Alzheimer’s Disease.Quantification of individual morphometric characteristics isachieved via a shape transformation, i.e. a spatial transforma-tion that adapts a template of anatomy to the morphology ofthe individual under study. The shape transformation is avery detailed mathematical representation of anatomy, and isused for inter-individual comparisons and spatial normaliza-tion of structural and functional images. The overall goal ofthis project is to address three limitations of current technol-ogy, which are treated in the respective specific aims. Spe-cifically we propose to 1) develop and validate a methodol-ogy for obtaining a rich image representation from MR im-ages, which will allow for different brain regions to havedistinctive morphological signatures, thereby facilitating au-tomated algorithms for determining anatomically accurateshape transformations, 2) develop and validate a methodol-ogy for finding 4-dimensional shape transformations fromlongitudinal image data, with the fourth dimension represent-ing time; this methodology will significantly reduce measure-ment error by incorporating temporal smoothness constrainsinto the estimation of the shape transformation at differenttime-points, 3) develop and validate a morphological repre-sentation based on the shape transformation of Aim 2, whichwill represent an individual’s anatomy in terms of a shapetransformation of an anatomical template, and a residual im-age that captures information that is not captured by the
shape transformation, and 4) to apply these methods to the
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Baltimore Longitudinal Study of Aging, in order to test ourhypothesis that sensitivity and specificity of early detectionof cognitive decline using MR images will be significantlyimproved by the new technology, because of improved accu-racy in morphologic measurements, and to develop a high-dimensionality image-based pattern classification method forearly diagnosis of Alzheimer’s Disease.

Thesaurus Terms: aging, brain imaging /visualization /scan-ning, brain mapping, brain morphology, computational neu-roscience, image enhancement, magnetic resonance imaging,technology /technique development Alzheimer’s disease, bi-omarker, diagnosis design /evaluation, early diagnosis, imageprocessing, mathematical model, model design /developmentbioimaging /biomedical imaging, clinical research, humandata, human old age (65�)

Institution: University Of Pennsylvania3451 Walnut StreetPhiladelphia, PA 19104

Fiscal Year: 2005Department: RadiologyProject Start: 01-Aug-1998Project End: 31-Mar-2009ICD: National Institute On AgingIRG: BMIT

FMRI ANALYSIS OF AGING ANDAWARENESS IN CONDITIONING

Grant Number: 5R01AG021501-02PI Name: Desmond, John E.

Abstract: Description (provided by applicant): The overallgoal of this research is to elucidate, using functional mag-netic resonance imaging (fMRI), how aging in humans af-fects neural systems critical for eyeblink conditioning, in-cluding the cerebellum and the medial temporal lobe (MTL).While the cerebellum is essential for conditioned eyeblinkresponses, the MTL is also necessary for a specific type oflearning referred to as “trace” conditioning, in which there isa gap in time between the offset of the conditioned stimulus(CS) and the onset of the unconditioned stimulus (US).Trace conditioning is also impaired in older subjects, and inboth older and younger subjects who do not acquire aware-ness of the stimulus contingencies during the conditioningtraining. Our hypothesis is that in trace conditioning differ-ences in MTL activation, along with differences in patternsof functional connectivity among neocortical and subcorticalstructures, will account for differences in trace conditioningbehavioral performance in both older and unaware subjects.We predict that when the gap in time is absent (i.e., “delay”conditioning), awareness will have less effect on either per-
formance or cerebellar activations, age group differences in

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cerebellar activation will account for more of the age differ-ences in conditioned eyeblink performance than will MTLactivation differences, and age group differences in patternsof functional connectivity will differ from those observed intrace conditioning. We plan to first characterize age-relatedchanges in CS and US pathways using unpaired CS and USpresentations, and hypothesize that any age differences willbe observed in the cerebellum for short CSs and in the MTLduring the trace period. We will investigate age-relatedchanges in brain activation during delay and trace condition-ing protocols, and hypothesize differential importance of cer-ebellar and MTL activations, respectively, for age-relatedchanges in performance of delay and trace conditioning. Fi-nally, we will investigate the role of awareness in age-relatedchanges in brain activation underlying eyeblink conditioningby (a) disrupting the acquisition of awareness and observingits effect on conditioning and brain activation and (b) mea-suring the concurrent development of awareness, eyeblinkconditioning, and brain activation. We predict that in traceconditioning, subjects that acquire awareness will conditionbetter and exhibit greater MTL activation than unaware sub-jects, age differences in conditioning and MTL activationwill be reduced or eliminated after equating for awareness,age-related changes in functional connectivity will differ be-tween delay and trace conditioning, patterns of functionalconnectivity will change as a function of awareness for traceconditioning, and left prefrontal cortex will be a critical nodein awareness-related functional circuits. Finally, we will ex-amine the link between age-related differences in trace con-ditioning and other types of age-related cognitive decline,and we will test a model of MTL/neocortical involvement intrace conditioning and awareness using transcranial magneticstimulation.

Thesaurus Terms: aging, association learning, awareness,cerebellum, conditioning, neuroimaging, neurophysiology,neuropsychology, reflex, temporal lobe /cortex age differ-ence, neocortex, performance, prefrontal lobe /cortex, shortterm memory behavioral /social science research tag, bioim-aging /biomedical imaging, clinical research, functional mag-netic resonance imaging, human old age (65�), human sub-ject, transcranial magnetic stimulation, young adult human(21-34)

Institution: Stanford University1215 Welch Road, Mod BStanford, CA 943055402

Fiscal Year: 2005Department: RadiologyProject Start: 15-Jun-2004Project End: 31-May-2006ICD: National Institute On Aging
IRG: ZRG1
PET DETECTION OF THE EFFECTS OFAGING ON THE HUMAN HEART

Grant Number: 5R01AG015466-08PI Name: Gropler, Robert J.

Abstract: Description (provided by applicant): Cardiovascu-lar disease is the leading cause of death and disability inolder Americans. Results of studies in experimental animalshave shown that with senescence there is a decline in myo-cardial fatty acid utilization (MFAU) and oxidation (MFAO)and a relative increase in glucose utilization (MGU). Thesemetabolic changes are paralleled by a decline in mechanicalfunction. During the current grant interval, we have con-firmed these observations in humans. The goal of this re-newal application is to identify potential mechanisms respon-sible for the age-related shift in myocardial substrate metab-olism and relate them to changes in left ventricular (LV)function. The nitric oxide (NO) system and the peroxisomeproliferator activated receptor alpha (PPAR alpha) are prom-ising candidates that will be investigated. Our first hypothe-sis is that changes in substrate utilization in the aging heartare mediated, at least in part, by a decline NO productionand that these changes are paralleled by a decline in LVfunction. We will prove or disprove this hypothesis by per-forming a series of fairly-complex experiments that utilizePET quantification of myocardial substrate metabolism andechocardiographic measurements of LV systolic and diastolicfunction under conditions designed to reduce NO productionin younger subjects (using L-NMMA) and increase NO pro-duction in older subjects (using L-arginine). Our second hy-pothesis is that changes in myocardial substrate metabolismand LV function in the aging heart may be mediated, at leastin part, via a decline in PPAR alpha-mediated responses.Thus, administration of a PPAR alpha agonist to older hu-mans will result in an increase in MFAO and MFAU and adecline in MGU and that this metabolic shift will be paral-leled by an improvement in LV function. Using the sameimaging techniques we will measure myocardial substratemetabolism and function before and after the administrationof the PPAR alpha partial agonist, gemfibrozil to healthyolder subjects to prove or disprove this hypothesis. The re-sults of these studies should further our understanding of therole of NO and PPAR alpha in modulating this age-depen-dent myocardial metabolic shift and its impact on LV func-tion. As a result, potentially new targets could be identifiedfor novel therapeutics designed to treat various cardiac disor-ders that increase with age and potentially slow the impactof aging on the human heart.

Thesaurus Terms: age difference, fatty acid metabolism,heart imaging /visualization /scanning, heart metabolism,human old age (65�), positron emission tomography, youngadult human (21-34) arginine, gemfibrozil, heart function,
heart pharmacology, muscle metabolism, myocardium, nitric
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oxide, peroxisome proliferator activated receptor bioimaging/biomedical imaging, clinical research, echocardiography,human subject

Institution: Washington University1 Brookings Dr, Campus Box 1054Saint Louis, MO 631304899

Fiscal Year: 2005Department: RadiologyProject Start: 01-May-1998Project End: 30-Jun-2008ICD: National Institute On AgingIRG: RNM

SPATIALLY ORIENTED DATABASE FORDIGITAL BRAIN IMAGES

Grant Number: 5R01AG013743-10PI Name: Herskovits, Edward H.

Abstract: Description (provided by applicant): The overallgoal of this project is the integration of advanced image-processing, data-analysis, and data management techniquesinto a brain-image database (BRAID), for the support of im-age-based clinical trials. The integration of these componentshas greatly aided our collaborators’ management and analy-sis of image-based clinical trials (IBCTs) for the elucidationof structure-function associations for the human brain. In theprevious cycle, we added segmentation capabilities, imple-mented Bayesian methods for lesion-deficit analysis, andbegan construction of a functional white-matter atlas basedon lesion-deficit data. These methods, in conjunction withBRAID’s visualization and other statistical tools, have re-sulted in contributions to the peer-reviewed clinical and en-gineering literature. However, our experience also demon-strates the need for extensions to BRAID. First, our segmen-tation algorithm is limited by its foundation on a statisticalsignal-intensity model of T 1-weighted spoiled gradient-re-called echo images. Second, given improvements in our reg-istration techniques, we now have high-quality morphologi-cal data from our collaborators’ IBCTs, but lack sophisti-cated methods for morphology-function analysis. Third,given the brain’s plasticity, construction of an advancedfunctional atlas requires access to acute lesion-deficit data;our current collaborators are collecting subacute or chroniclesion-deficit data. Finally, we could facilitate the inter-change of data, software, and analytic results with our col-laborators and other colleagues by implementing BRAIDbased on open-source software. Towards these ends, we pro-pose four specific aims to further extend BRAID’s function-ality: extension of our segmentation algorithm to incorporatemore complex spatial and signal-intensity information; devel-opment of Bayesian methods for morphological analysis, to
complement our Bayesian methods for lesion-deficit analysis;
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extension of BRAID to accommodate acute-stroke data, in-cluding magnetic-resonance (MR) perfusion and diffusionsequences; and reimplementation of BRAID using open-source components. We will test these image analysis, seg-mentation, and acutestroke extensions to BRAID using datafrom three IBCTs.

Thesaurus Terms: brain imaging /visualization /scanning,brain morphology, computational neuroscience, computerdata analysis, computer program /software, computer sys-tem design /evaluation, digital imaging, image processing,information system aging, brain injury, information sys-tem analysis, longitudinal human study, neuroanatomy,statistics /biometry, stroke bioimaging /biomedical imag-ing, human data, magnetic resonance imaging, positronemission tomography


Fiscal Year: 2005Department: RadiologyProject Start: 30-Sep-1995Project End: 31-Jul-2008ICD: NATIONAL INSTITUTE ON AGINGIRG: ZRG1

SPECT IMAGING OF ABETA PLAQUES INBRAIN

Grant Number: 5R21AG021868-04PI Name: Kung, Mei-Ping

Abstract: Description (provided by applicant): Alzheimer’sdisease (AD) is a neurodegenerative disease of the braincharacterized by dementia, cognitive impairment and mem-ory loss. Formation and accumulation of aggregates of&-amyloid (AB) peptides in the brain are critical factorscontributing to the development and progression of AD. Cur-rently, early appraisal of clinical symptoms for diagnosis ofAD is often difficult and unreliable. Therefore, there is anurgent need for in vivo imaging agents, which can specifi-cally demonstrate the location and density of amyloidplaques in the brain. The objective of this project is to de-velop potential 1-123 labeled diagnostic imaging agents spe-cific for detection of AB plaques. Recent advances in devel-oping tracers for binding A13 plaques suggest that there arespecific and saturable binding sites on the aggregates of At3that can be selectively labeled and imaged in vivo. The pro-posed agents are derivatives of stilbenes containing ap-MezN-, -SH, -SMe, -0Me or -OH group on one of thebenzene rings, while radioactive iodine can be attached tothe other benzene ring without affecting the binding affinity.
They are simple, relatively small, neutral and lipophilic. On


the basis of their exquisitely high binding affinity to At3140aggregates (Ki at the range of 0.1-40 nM), they are suitablecandidates as A&-plaque-selective imaging agents. They alsoshowed ability to penetrate the intact blood-brain barrier, anessential pre-requisite for a useful plaque-imaging agent. Theproposed synthesis and methodology provide a framework totest the hypothesis that small probes can be used to detectAt3 plaques in vivo. The proposed compounds are innova-tive and carefully crafted to meet the stringent requirementsfor t3-amyloid imaging agents. Together with the compellingpreliminary data presented in this project we believe that At3plaque-selective imaging agents can be successfully devel-oped. The At3-plaque-specific imaging agents will be usefulfor early detection or monitoring the progression and effec-tiveness of treatment of AD.

Thesaurus Terms: Alzheimer’s disease, amyloid protein,biomaterial development /preparation, brain disorder diagno-sis, brain imaging /visualization /scanning, iodination, ligand,neuritic plaque, radionuclide, reagent /indicator, stilbene bio-material evaluation, chemical binding, chemical synthesis,contrast media, early diagnosis, radiation dosage, radiogra-phy, single photon emission computed tomography, toxicol-ogy autoradiography, bioimaging /biomedical imaging, ge-netically modified animal, histopathology, laboratory mouse


Fiscal Year: 2005Department: RadiologyProject Start: 15-Sep-2002Project End: 31-Aug-2007ICD: National Institute On AgingIRG: ZRG1

HUMAN WHITE MATTER TRACTMAPPING BY DIFFUSION MRI

Grant Number: 5R01AG020012-05PI Name: Mori, Susumu

Abstract: Description (provided by applicant): The overall aimof this study is to demonstrate the feasibility to generate com-puterized human white matter tract maps based on a newly de-veloped magnetic resonance imaging (MRI) technique, calleddiffusion tensor imaging (DTI). Knowledge of neuronal connec-tions by the white matter tracts is of critical importance for theunderstanding of normal brain functions and abnormalities offunction. However, to date most approaches have relied on in-vasive in vivo techniques and, necessarily, human data havebeen severely limited. In the DTI technique, the directionality(anisotropy) of water diffusion in the brain is measured. This
technique provides two types of data that have previously been
inaccessible. First, as we have demonstrated recently, it enablesus to reconstruct the 3-dimensional (3D) structure of white mat-ter tracts. Second, it provides a unique contrast called anisot-ropy map that indicates how anisotropic the water diffusion isand is believed to reflect the degree of fiber density and myeli-nation. In this proposal, DTI measurements will be performedon postmortem tissues, which allow the acquisition of ultrahigh-resolution 3D DTI data. The long-term goals of thisproject are two-fold. First, these unique capabilities of the DTItechnique provide novel opportunities to study neuroanatomy ofhuman whiter matter and its variations due to individual, gen-der, normal and abnormal development/aging processes andother diseases. Second, the study will provide vital informationfor the future application of this novel technology to clinicalstudies, such as the range of normal deviation and nature andextent of expected white matter abnormalities in terms of DTIfindings in each disease. Use of postmortem tissues also allowshistology studies to explore the precise meanings of the DTIfindings. To achieve these goals and as a Phase I feasibilitystudy for Human Brain Project, this project is designed to buildsystems for data acquisition, fiber reconstruction, statistical anal-ysis, and visualization. Toward this end, we propose four princi-pal aims. 1) to acquire ultra high-resolution 3D DTI data ofnormal brains, 2) to develop fiber reconstruction technology, 3)to develop statistical tools to study individual variations inwhite matter structures, and 4) to develop tools to visualize 3Dwhite matter architectures/creation of electric white matter atlas.

Thesaurus Terms: brain mapping, central neural pathway/tract, information system diffusion human data, magneticresonance imaging, postmortem

Institution: Johns Hopkins UniversityW400 Wyman Park BuildingBaltimore, MD 212182680

Fiscal Year: 2005Department: Radiology And Radiological SciencesProject Start: 01-Jun-2001Project End: 31-May-2007ICD: National Institute On AgingIRG: ZRG1

FMRI STUDIES IN EARLY ALZHEIMER’SDISEASE

Grant Number: 5R01AG019728-05PI Name: Petrella, Jeffrey R.

Abstract: The broad, long-term goal of this research is todevelop antemortem markers that are sensitive to the de-tection of the earliest neuronal changes in Alzheimer’sdisease (AD). Such markers may be useful to characterizesubjects at risk, to differentiate normal age-related mem-
ory changes from prodromal dementia, and to monitor the
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effects of therapy as adjuncts to neuropsychological andclinical assessments. The short term goals of this proposalare to further elucidate the specific neural substrates andpotential compensatory mechanisms underlying the mem-ory deficits in early AD. AD is a progressive neurodegen-erative dementia associated with disruption of neuronalfunction. Accumulating evidence suggests that histologicalchanges in specific temporal and frontal lobe structuresmay begin years prior to the development of clinicalsymptoms. Further, the diagnosis of probable AD is oftenpreceded by a prodromal phase in which specific memorydeficits may precede other cognitive or functional impair-ments. In longitudinal studies, approximately 10-15 per-cent of such “prodromal AD” patients progress to diag-nosable probable AD annually. Functional magnetic reso-nance imaging (fMRI) offers great promise to studyneuronal activation patterns in specific brain regions dur-ing the performance of memory tasks in early AD. Clini-cally, such studies may offer diagnostic or prognostic po-tential by revealing subtle neural deficits not obvious onresting scans or clinical assessments alone. We have vali-dated a novel event- related working memory fMRI para-digm that can study activation during component pro-cesses of memory as well as how such patterns are af-fected by increasing memory load. We propose to use thisparadigm to study three carefully characterized groups ofelderly subjects: mild AD, prodromal AD, and matchedcontrols. Our primary aim is to study the neural correlates ofmemory impairment in memory specific brain regions of thefrontal and medial temporal lobes in early or questionableAD. We will also examine whether there is recruitment of“new” brain regions in patients with prodromal AD com-pared to normals as well as the differential effects of increas-ing memory load on the “reserve” capacity to activate thesesame brain regions. As a secondary aim, we will test thesensitivity of fMRI activation patterns to separate mild ADcases from controls as well as the prognostic utility of abaseline fMRI, as an adjunct to genetic and neuropsychologi-cal tests, in predicting cognitive decline over a 3-5 year fol-low-up period in prodromal AD.

Thesaurus Terms: Alzheimer’s disease, brain imaging/visualization /scanning, diagnosis design /evaluation,mental disorder diagnosis, nervous system disorder diag-nosis polipoprotein, apolipoprotein E, memory disorder,neural information processing, neuritic plaque, prefrontallobe /cortex, temporal lobe /cortex clinical research, func-tional magnetic resonance imaging, human subject, neuro-psychological test

Institution: Duke University2424 Erwin Rd.Durham, NC 27705

Fiscal Year: 2005
Department: Radiology
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Project Start: 01-Sep-2001Project End: 31-Jul-2007ICD: National Institute On AgingIRG: ZRG1

VASCULAR AND METABOLICMECHANISMS IN ALZHEIMER’S DISEASE

Grant Number: 1R01AG025826-01PI Name: Powers, William J.

Abstract: Description (provided by applicant): Alzheimer’sDisease (AD) is the most common cause of dementia in theelderly. While acknowledging the important role of abnormalprotein deposition in the pathogenesis of AD, there exists aconsiderable body of evidence indicating that both cerebralvascular and cerebral metabolic mechanisms play a role inthe development of pathological AD and in the developmentof dementia in subjects with pathological AD. This projectwill address 3 specific aspects of these mechanisms in AD.Specific Aim 1 will test the hypothesis that patients withclinically diagnosed AD have impaired autoregulation of ce-rebral blood flow to reductions in systemic mean arterialpressure. Specific Aim 2 will test the hypothesis that patientswith clinically diagnosed AD have an abnormality in cere-bral oxidative energy metabolism. In Specific Aim 3 we willdevelop and optimize a method to label the synthetic amy-loid peptide A-beta (1-40) with C-11 and perform animalstudies to prepare for eventual studies in human subjects.The hypotheses that we will test are soundly based on mech-anisms described in animal models and in vitro studies ofhuman tissue. To bridge the gap between the laboratorybench and the patient, we will rigorously test these hypothe-ses in human AD in vivo by well-designed studies. Thistranslational approach will allow us to determine the impor-tance of these mechanisms in the human disease and poten-tially provide the information necessary for designing futuretreatment strategies. We will employ precise, accurate andwell-validated techniques to measure cerebral blood flow andmetabolism as well as innovative new neuroimaging tech-niques to evaluate brain amyloid deposition and BBB trans-port of amyloid. This proposal brings together accomplishedinvestigators from the Alzheimer’s Disease Research Centerand the Division of Radiological Sciences with complemen-tary expertise. Through the use of the unique resources andpersonnel at Washington University Medical Center, we havethe opportunity to provide answers to important clinical andmechanistic questions in AD.

Thesaurus Terms: Alzheimer’s disease, bioenergetics, bloodvessel disorder, brain circulation, brain metabolism, cerebralcortex, pathologic process amyloid protein, autonomic nervoussystem, blood brain barrier, dementia, oxidative stress, proteintransport clinical research, magnetic resonance imaging, neuro-
imaging, positron emission tomography, psychometrics



Fiscal Year: 2005Department: RadiologyProject Start: 15-Jun-2005Project End: 31-May-2010ICD: national institute on agingIRG: CND

3D SONOELASTOGRAPHY IMAGING FORPROSTATE CANCER

Grant Number: 5R01AG016317-06PI Name: Rubens, Deborah J.

Abstract: Description (provided by applicant): Prostate Can-cer, the most prevalent male cancer and second leadingcause of male cancer death, is currently detected by screen-ing PSA and physical examination and confirmed withTRUS-guided prostate biopsy. Current diagnostic sensitivityis limited by poor visualization of tumor and inadequatesampling. Our fundamental hypothesis is that sonoelastogra-phy imaging can enable the detection of prostate cancer thatotherwise appears normal in conventional in-vivo US imag-ing. A corollary of this hypothesis is that 3D sonoelastogra-phy can demarcate and help to calculate the volume of asuspected tumor region. Sonoelastic ultrasound imaging willenable earlier prostate cancer diagnosis due to better biopsyguidance and fewer false negative biopsies. Three-dimen-sional tumor volume analysis will provide quantification andlocalization for customized treatment, including tumor boostdose in brachytherapy. Our progress to date has led to newinformation regarding basic elements of sonoelastographyincluding aliasing and modal patterns, tissue frequency de-pendence and variable beam patterns; and the techniques of3D image pathology fusion. Our in-vivo work has similarlyidentified variables of gain, frequency, source beam patterns,and attenuation, which need to be controlled. Our next phaseof research will focus on the following three aims: Aim 1:Develop the (currently unknown) theoretical and experimen-tal characterization of the frequency dependent elastic prop-erties of the normal prostate and of the prostate with benignand malignant conditions of high prevalence. (Year 1, withlater extensions) Aim 2: Refine and advance our 3D Sono-elastography systems to increase the sensitivity, linearity,spatial resolution, and vibration frequency range so as toincrease the detectability of cancer. (Year 1: 25 patients)Aim 3: Apply the results of aims 1 and 2 to evaluate theclinical utility of in-vivo prostate cancer detection by sono-elastography. (Years 2-4: 90 patients)

Thesaurus Terms: diagnosis design /evaluation, digital im-
aging, neoplasm /cancer diagnosis, prostate neoplasm, three
dimensional imaging /topography, ultrasound imaging /scan-ning aging, computer simulation, diagnosis quality /standard,elasticity, image processing, prostate specific antigen bioim-aging /biomedical imaging, biopsy, clinical research, histopa-thology, human subject, male

Institution: University Of Rochester517 Hylan Bldg., Box 270140Rochester, NY 14627

Fiscal Year: 2005Department: RadiologyProject Start: 01-Dec-1998Project End: 30-Jun-2007ICD: National Institute On AgingIRG: ZRG1

National Institute ofMental Health

FMRI STUDIES OF VISUAL ATTENTION

Grant Number: 5R01MH071920-07PI Name: Corbetta, Maurizio M.

Abstract: Description (provided by applicant): The voluntarycontrol of visual attention allows people to selectively processinformation in the environment that is relevant to their currentbehavioral goals, whereas stimulus-driven re-orienting of atten-tion allows people to respond appropriately to unexpected con-tingencies. Previous work has indicated that brain regions playdifferent roles in these two functions. Regions in dorsal parietal,near/at the intraparietal sulcus (IPS), and frontal cortex, near/athuman frontal eye field (FEF), play a major role in voluntaryorienting to stimuli and responses. A right hemisphere ventralnetwork, consisting of the temporo-parietal junction (TPJ) andinferior frontal cortex, are inactive during task preparation, sug-gesting minimal involvement in the voluntary control of atten-tion, but are strongly activated by re-orienting to unexpected butbehaviorally important stimuli. In this grant we ask severalquestions concerning the functional significance of signals indorsal and ventral fronto-parietal regions. A first question iswhether preparatory orienting signals are predictive of behav-ioral performance for targets that are either attended or unat-tended. The topography of these signals in IPS and visual cor-tex as function of task (motion, shape discrimination), stimulusfeature (location, motion), or effector (eye, arm) is considered.A second question is how information is coded within the ven-tral network in terms of topography, hemispheric asymmetries,stimulus modality, and relationship to behavioral performance.A third question is how the input to this ventral network is con-trolled by signals coming from the dorsal network. Prior work
has indicated that TPJ activity is decreased in the presence of a
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task set. We propose that this decreased activity reflects a filter-ing of the input from unattended sensory areas to TPJ, whichprevents it from inappropriately responding to salient stimulithat are not task-relevant. Several experiments are proposed thattest predictions of this hypothesis.

Thesaurus Terms: attention, brain mapping, functionalmagnetic resonance imaging, neural information process-ing, visual perception form /pattern perception, motionperception, space perception, visual field, visual pathway,visual stimulus behavioral /social science research tag,bioimaging /biomedical imaging, clinical research, humansubject


Fiscal Year: 2005Department: RadiologyProject Start: 01-Feb-1999Project End: 30-Jun-2009ICD: National Institute Of Mental HealthIRG: COG

STUDY OF FIBER ANATOMY IN MOUSEDEVELOPMENT VIA MRI/DTI

Grant Number: 5R01MH070365-02PI Name: Davatzikos, Christos

Abstract: Description (provided by applicant): The maingoal of this project is to characterize the development ofthe murine brain, with emphasis on white matter anatomy,using magnetic resonance micro-imaging in conjunctionwith mathematical methodologies for quantitative imageanalysis. The traditionally used histological methods forexamination of murine brain sections are limited by tissuedistortion or loss, by difficulties in constructing a spatiallyconsistent volumetric image from sections, by extensiveeffort in preparation, and by lack of capability for in vivoexamination of the mouse brain. Magnetic resonance im-aging (MRI) is emerging as a technology with strengthscomplementary to histology, with respect to these limita-tions. In this project, we will develop methods for imag-ing and analysis of the murine brain, and we will usethem to generate normative data for brain development ofthe C57BL/6J mouse strain. Our emphasis will be on us-ing diffusion tensor imaging (DTI) to characterize thewhite matter architecture. Building upon current work byseveral groups in the Human Brain Project, we propose todevelop mathematical methodologies for computationalanatomy, which complement traditional analysis methods
in mainly two ways. First, they can identify very subtle
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and localized shape characteristics, without the need toknow the location of an affected brain region a priori.Second, they are highly automated and quantitative, thusenabling the examination of a large number of animalswith minimal effort, using statistical image analysis tech-niques. Our image analysis methodology will involveshape analysis methods for the reconstruction and spatialnormalization of murine brain structures, and it will uti-lize the well-established framework of stereotaxic spaceanalysis. After mass-preserving spatial normalization ofMRI images to a stereotaxic space of the respective devel-opmental stage, the normal anatomic variation of grey andwhite matter structures will be measured at a number ofdifferent developmental stages. This normative data willbe useful in subsequent DTI-based studies aiming to iden-tify regions of abnormal development in neurogeneticmice, by finding regions that fall outside this normalrange. We will test this methodology on a pilot study ofthe Emx-1 knockout mouse, a well-characterized strainwith abnormal cortical lamination and defasciculatedwhite matter fiber tracts, including the corpus callosum,and we will validate our MR-based measurements usinghistological sections.

Thesaurus Terms: axon, brain imaging /visualization /scan-ning, brain morphology, computational neuroscience, devel-opmental neurobiology, neuroanatomy, technology /techniquedevelopment, three dimensional imaging /topography corpuscallosum, developmental disease /disorder, image enhance-ment, mutant, neuronal guidance, white matter bioimaging/biomedical imaging, embryo /fetus, genetically modifiedanimal, laboratory mouse, magnetic resonance imaging, mor-phometry


Fiscal Year: 2005Department: RadiologyProject Start: 15-Jul-2004Project End: 31-Mar-2008ICD: National Institute Of Mental HealthIRG: ZRG1

TRAINING IN FUNCTIONALNEUROIMAGING

Grant Number: 5T32MH019992-08PI Name: Deyoe, Edgar A.

Abstract: Description (provided by applicant): Ten yearsago, the field of functional neuroimaging began a periodof unprecedented growth spurred by the development of
functional magnetic resonance imaging (fMRI) in concert


with previously developed imaging techniques and exper-tise. Since that time, the number of institutions involvedin neuroimaging has grown apace and that expansion con-tinues today as increasingly sophisticated applications de-velop in basic science and, more recently, in clinical prac-tice. Despite this exceptional growth, there has been ashortage of researchers who are well trained in the tech-nology, application and neuroscience of functional imag-ing. The proposed training program in functional neuroim-aging is designed to address this shortage by offering amultidisciplinary program of intensive instruction with anemphasis on the theory and practice of neuroimaging, thephysiological basis of imaging signals and neural func-tion, the design and implementation of neuroimaging stud-ies, the subsequent analysis, display and interpretation ofneuroimaging data and the application of these techniquesto fundamental problems of basic and clinical neuro-science. Applicants to the program are anticipated to havescientific interests ranging from strongly MR biophysicsto purely neuroscience. The training program is also de-signed to meet the needs of trainees at two different lev-els of career development. For predoctoral trainees, theprogram seeks to instill a broad understanding of the fun-damental principles and practice of neuroimaging and toteach the application of those principles to imaging-re-lated research. In contrast, the program for post-doctoraltrainees assumes that the student already has attained ex-pertise in research within a field that the trainee wishes tocombine with neuroimaging. The goal in the latter case, isto provide the trainee with the necessary neuroimagingtools and expertise to initiate a unique, long-term programof research incorporating a strong neuroimaging compo-nent. The training of students will be undertaken by aunique multidisciplinary team of faculty mentors repre-senting research interests ranging from MR biophysics tocognitive neuroscience and clinical practice. Through anintegrated curriculum of didactic course work, researchprojects, seminars, national and international presentationsas well as personal mentoring students will emerge pre-pared for a career and leadership role in neuroimaging.

Thesaurus Terms: There are no thesaurus terms on file forthis project.

Institution: Medical College Of Wisconsin8701 Watertown Plank RdMilwaukee, WI 532260509

Fiscal Year: 2005Department: RadiologyProject Start: 01-Jul-1997Project End: 30-Jun-2008ICD: National Institute Of Mental Health
IRG: ZMH1
HIGH ANGULAR RESOLUTIONDIFFUSION IMAGING WITH MRI

Grant Number: 5R01MH064729-02PI Name: Frank, Lawrence R.

Abstract: Description (provided by applicant): The diffusionanisotropy (DA) in the brain measured by diffusion weightedMRI (DW-MRI) is known to be related to the local whitematter (WM) structure and therefore can be used as an indi-cator for changes associated with degenerative WM diseases.The estimation of DA is also a necessary precursor to allfiber tract mapping methods, which hold the potential forunderstanding brain connectivity when used in conjunctionwith functional MRI (fMRI) studies. The current standardmethod for measuring DA is diffusion tensor imaging (DTI)in which magnetic field variations along multiple directionsencode complex patterns of microscopic water motion. Sig-nal variations as a function of the diffusion encoding direc-tion are related to the local tissue diffusion (LTD) fromwhich DA is estimated based upon a simplified model fortissue diffusion that require only a few encoding directions.However, recent studies have shown that the complexity ofLTD is not necessarily well fit by the standard model andhigh angular resolution diffusion (HARD) measurements areneeded to better characterize LTD. This poses two significantproblems: An increase in imaging time, making clinical ap-plications more difficult, and no general analysis scheme bywhich to characterize anisotropy. Ultimately, the assessmentof LTD and DA requires the development of more accuratephysical models for tissue diffusion that incorporate bound-aries and restrictions and increasingly sensitive methods ofmeasurement. The primary goal of this work is to furtherinvestigate our recently proposed solutions to these twoproblems. We have generalized the analysis currently usedfor DTI to incorporate more a general physical model, fordiffusion. This method, called the spherical harmonic decom-position (SHD), has been employed in a rapid numerical im-plementation efficient for clinical applications. The first spe-cific aim is to extend our SHD approach to an even moregeneral applicable to multiple b-values that we have devel-oped, called the spherical wave decomposition (SWD). Sec-ondly, we have described a novel DW-MRI method based onthe recently introduced concept of hyperechoes (HE) that hasthe potential to dramatically increased the diffusion sensitiv-ity per unit time of standard clinical applications, therebyfacilitating the extension to HARD measurements with mini-mal time penalty but greatly increased DA sensitivity. Whilehyperecho DW-MRI has a clear theoretical advantage overtraditional DW-MRI acquisition methods, it is prone tounique technical difficulties in its implementation that willbe addressed as our second specific aim to make it a clini-cally viable methodology. Both these two aims will be usedin the development of our third specific aim, which is to es-
tablish experimentally, through the use of variations of HE-
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HARD, in conjunction with SWD, the sensitivity of DWMRI to the structure of complex tissues. Motivated by ourrecent work showing changes in WM DA in alcoholic pa-tients, our proposal focuses on increasing the sensitivity ofDW-MRI to DA, our ultimate long term goal is to utilizethese methods in a clinical environment, specifically in ourongoing assessment of degenerate white matter diseases suchas Alzheimer’s, AIDS, and, in particular, alcoholism.

Thesaurus Terms: brain imaging /visualization /scanning,image processing, magnetic resonance imaging, white matterAIDS, Alzheimer’s disease, alcoholism /alcohol abuse, brainmapping, computer simulation, neural degeneration bioimag-ing /biomedical imaging, clinical research, electron micros-copy, histopathology, human subject, laboratory rat, terminalnick end labeling

Institution: University Of California San Diego9500 Gilman Dr, Dept. 0934La Jolla, CA 920930934

Fiscal Year: 2005Department: RadiologyProject Start: 01-Dec-2003Project End: 30-Nov-2008ICD: National Institute Of Mental HealthIRG: DMG

BRAIN IMAGING IN PANIC DISORDER ATHIGH-FIELD

Grant Number: 5K01MH069848-02PI Name: Friedman, Seth David.

Abstract: Description (provided by applicant): This five-yearcareer development proposal will establish Dr. Seth D. Fded-man as an independent researcher who can develop, apply,and integrate rapid high-field multinuclear magnetic reso-nance spectroscopy (MRS) and peripheral physiologicalmonitoring to study biological regulation in anxiety disor-ders. Towards this aim, a detailed curriculum of physics,digital signal processing, physiology, and statistical methodswill be undertaken. Regular training visits to centers withcritical expertise are also planned to facilitate technical andclinical skill development. The studies associated with thistraining experience will be conducted in three phases: (1)technical development and characterization of hyperventila-tion (HV) response in healthy control subjects, (2) clinicalinvestigation of HV dysregulation in panic disorder subjectscompared to healthy controls and social phobia subjects, and(3) pilot work focused on alternative challenges. In PD, anumber of peripheral alterations are found at rest (increasedsighing, low pCO2, and respiratory variability) and in re-sponse to HV, with delayed recovery of end-tidal pCO2
commonly demonstrated. Importantly, anxiety level per se is
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not sufficient to produce this delayed recovery, since SP sub-jects, who will be used as anxious controls in the proposedstudies, do not demonstrated altered pCO2 recovery follow-ing HV. Central nervous system alterations of lactate produc-tion are also demonstrated in response to HV challenge inPD, a response suggested to be in excess of the observedmetabolic alkalosis. By integrating time-resolved central andperipheral nervous system measures of physiological regula-tion, the components of altered physiology in PD will beelucidated.

Thesaurus Terms: brain imaging /visualization /scanning,neurophysiology, nuclear magnetic resonance spectroscopy,panic disorder, psychophysiology acid base balance, brainmetabolism, heart rate, hyperpnea, lactate, pulmonary respi-ration bioimaging /biomedical imaging, clinical research,galvanic skin response, human subject

Institution: University Of WashingtonOffice Of Sponsored ProgramsSeattle, WA 98105

Fiscal Year: 2005Department: RadiologyProject Start: 01-Dec-2003Project End: 30-Nov-2008ICD: National Institute Of Mental HealthIRG: BDCN

DEVELOPMENT AND APPLICATIONS OFNOVEL SERT PET LIGANDS

Grant Number: 4R33MH066622-04PI Name: Goodman, Mark M.

Abstract: Description (provided by applicant): Considerableevidence accrued over the last two decades have convinc-ingly implicated decreased serotonin transporter (SERT)binding in the pathophysiology of major depression and sui-cide. Although a tremendous amount of information regard-ing the SERT and its role in depression and suicide has beenobtained, this supporting evidence has, however, been indi-rect in being derived almost exclusively from the study ofpostmortem tissue and animal and peripheral cell models oftransporter cell function and pharmacology. The mechanismsresponsible for decreased brain SERT binding in depressionand suicide are still unknown. We propose to develop fluo-rine-18 and bromine-76 imaging agents as tools to the explo-ration of the mechanism of major depression by assessingthe functional status of SERT using Positron Emission To-mography (PET). This application wide focus on the devel-opment of positron emitting analogs of 2beta-carbome-thoxy-3 beta-(4=-(Z-2- iodoethenyl) phenyl)nortropane(ZIENT) that show high selectivity and affinity for the SERT
and low nonspecific binding. Our recent preliminary data


with iodine-123 labeled ZIENT indicate that structural fea-tures unique to ZIENT permit in vivo measurement of SERTdensity in cortical brain regions suggesting ZIENT is a suit-able lead compound for PET radiotracer development. Twogoals of this proposal are: 1) conduct a structure activity re-lationship study (SAR) to identify a sutiable fluorine-18 andbromine-76 radiotracer for in vivo imaging of the SERT inatients with mood disorders; the SAR study will involve: (a)the development of synthetic methods for the preparation ofnew 18F- and 76Br-labeled 2beta-carboalkoxy-3beta-(4=-(Z-2-haloethenyl)phenyl)nortropanes, (b) the in vitro determina-tion of relative affinity of 18F- and 76Br- candidates (c) exvivo estimation of brain penetrance and regional distributionin rats. (d) microPET studies defining time- activity curvesfor specific and nonspecific binding in brain regions-of-inter-est in rhesus monkeys. (e) ligand metabolite studies per-formed on arterial samples (f ) microPET studies of in vivobinding site selectivity assessed by “chase” competition inrhesus monkeys. (g) Graphical analysis of cerebral SERTsite binding using microPET in non-human primates with thelead radiolabeled analog; 2) To conduct toxicity studies onan optimized ligand that will support the submission of anRDRC and an IND application. Our hypotheses include: 1)the introduction of fluorine onto an alkyl group in the 2P-carboakoxy- position of ZIENT and replacement of iodinewith bromine on the 3beta-(4=-(Z-2-haloethenyl)phenyl)group will generate a PET ligand with imaging characteris-tics equivalent to ZIENT; 2) A 18F- and 76Br-analog ofZIENT provides substantial temporal and logistical benefitsfor SERT imaging as compared to a SERT [11C] radiotracerdue to the longer half-life of fluorine-18 (t1/2�110 min) andbromine-76 (t 1/2� 16 h) compared to carbon (tlI2�20min).After the best novel PET SERT ligand is identified, it willbe applied in humans to define the relationship betweenbrain SERT binding and depression and suicidal behavior.We will also begin to define SERT alterations in dimen-sional traits that are related to suicide, such as aggression,impulsivity and anxiety. The relationship between SERT5-HTTLPR promoter region and in vivo SERT expressionwill be explored. Once SERT binding is determined in de-pressed patients, we will be able to assess the relationship ofSERT binding and treatment response to SSRIs.

Thesaurus Terms: brain imaging /visualization /scanning,ligand, major depression, mental disorder diagnosis, methoddevelopment, positron emission tomography, protein binding,reagent /indicator, serotonin transporter bromine, fluorine,suicide Macaca mulatta, bioimaging /biomedical imaging,clinical research, laboratory rat, radiotracer

Institution: Emory University1784 North Decatur Road, Suite 510Atlanta, GA 30322

Fiscal Year: 2005
Department: Radiology
Project Start: 19-Sep-2002Project End: 31-Aug-2007ICD: National Institute Of Mental HealthIRG: ZRG1

OPIOID RECEPTOR IMAGING BY PET INBULIMIA NERVOSA

Grant Number: 5R01MH064115-03PI Name: Guarda, Angela S.

Abstract: Description (provided by applicant): The cause ofbulimia nervosa is incompletely understood however animaland human studies have implicated the endogenous opioidsystem in feeding behavior. We hypothesize that there areboth trait and state-related differences in the distribution andmodulation of the opioidergic system that underlie the rein-forcing quality inherent in this behavioral disorder. We pro-pose to use positron emission tomography (PET)-scanning tomeasure mu-opiate receptors in patients with bulimia nervosabefore and after treatment and in control women. Pilot datasuggest a relationship between opioid receptors and the etiol-ogy or symptoms of bulimia. We propose to elucidate thisrelationship and to examine its change with treatment, spe-cifically with normalization of eating behavior. The specificaims of this study are to: 1) Measure regional brain mu opi-oid receptors by PET in female patients with bulimia ner-vosa and matched normal controls. 2) Measure the change inregional mu opioid receptors by PET before and after cogni-tive behavioral therapy (CBT) of patients with bulimia ner-vosa. It is anticipated that elucidation of the role of the en-dogenous opioid system in bulimia nervosa will not onlyhelp elucidate the etiology of this disorder, but also bringabout new approaches to diagnosis, long-term risk assess-ment, and monitoring of treatment.

Thesaurus Terms: bulimia nervosa, imaging /visualization/scanning, opioid receptor, positron emission tomographybrain, cognitive behavior therapy, eating disorder behavioral/social science research tag, bioimaging /biomedical imaging,clinical research, female, human subject, interview, ultra-sound blood flow measurement, women’s health


Fiscal Year: 2005Department: RadiologyProject Start: 01-May-2003Project End: 30-Apr-2007ICD: National Institute Of Mental Health
IRG: ZRG1
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ENERGETICS OF NEURONALPOPULATIONS BY FMRI

Grant Number: 5R01MH067528-04PI Name: Hyder, Fahmeed

Abstract: Description (provided by applicant): In the pastfew years we investigated the neuroenergetic and neuro-chemical basis of blood-oxygenation level dependent(BOLD) functional MRI (fMRI) signal at 7T in rat brain.A major achievement in this research endeavor is that wecan now obtain high-resolution maps of energy metabo-lism (CMRO2) from calibrated fMRI an approach that hasbeen validated by independent 13C MRS measurements of“C glutamate turnover. We have found that the fMRI sig-nal-changes (DS/S) in the cortex are linked with alter-ations in energy metabolism (DCMR02/CMR02) of gluta-matergic synapses and the release of glutamate from pre-synaptic neurons. These results relate DS/S to excitatoryneurotransmission and energy metabolism of glutamatergicneurons. Although recent fMRI research efforts haveshown qualitative agreement between electrical activityand the fMRI signal, in terms of spatial location and rela-tive changes, the fundamental difference between the ori-gins of electrophysiological and fMRI signals has to beovercome in order for BOLD to become an accurate neu-roimaging tool. This research proposal is intended tobridge the gap between electrophysiological and fMRIdata of the rat brain. We will investigate whether local-ized functional activation of cerebral cortex uses total orincremental neuronal activity to process sensory inputs.We will explore if the localized neuronal activation is re-gionally in accord with the neurovascular response. Wewill then try to examine if there is a quantitative relation-ship between the rates of neuronal firing and energy me-tabolism. Our final objective will be to determine if thedynamic neuronal response can be modeled from dynamicfMRI measurements. The main consequence of this pro-posal is to relate DS/S to activity of a neuronal popula-tion, and therefore, create the link between neuronal activ-ity and fMRI (RFA-NS-02-009).

Thesaurus Terms: bioenergetics, cell population study, ce-rebral cortex, functional magnetic resonance imaging, neuro-imaging biological signal transduction, blood volume, brain,neural information processing, oxygen, respiratory oxygenbioimaging /biomedical imaging, electrophysiology, labora-tory rat

Institution: Yale University47 College Street, Ste 203New Haven, CT 065208047

Fiscal Year: 2005Department: Diagnostic Radiology
Project Start: 16-Aug-2002
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Project End: 31-Jul-2007ICD: National Institute Of Mental HealthIRG: ZNS1

PET IMAGING OF EXTRASTRIATIALDOPAMINE LEVELS

Grant Number: 5R21MH068757-03PI Name: Kessler, Robert M.

Abstract: Description (provided by applicant): Dopaminer-gic neurotransmission in cortex, limbic regions and thalamusis believed to be centrally involved in the pathophysiologyof schizophrenia, psychostimulant drug abuse, and attentiondeficit disorder. While there are PET and SPECT methodsfor evaluating striatal dopamine (DA) release and baselineextracellular DA levels in man, at present there are no wellvalidated methods for studying DA release and baseline ex-tracellular DA levels in extrastriatal regions in man. [18F]fallypride is an extremely potent and selective dopamine D2radioligand, i.e., a KD of 31 pM for the dopamine D2 recep-tor, which can be used do delineate and quantitate striatal,thalamic, limbic and cortical dopamine D2 receptors in man.Studies in primates demonstrate that [18F] fallypride is sen-sitive to levels of d-amphetamine released dopamine in bothstriatum and extrastriatal regions. We propose to perform[18F] fallypride PET studies in 12 normal subjects (ages 18-40, 6M, 6F) prior to and following d-amphetamine adminis-tration (0.43mg/kg orally) to study d-amphetamine induceddopamine release in extrastriatal regions. This dose of reald-amphetamine produces decrements in striatal [11C] raclo-pride binding potentials similar to those seen with a 0.2-0.3mg/kg IV dose of d-amphetamine with similar variability,but with fewer and less severe side effects. We propose toperform additional [18F] fallypride PET studies in 12 normalsubjects (ages 18-40, 6M, 6F) prior to and following a 36-hour course of 56.6 mg/kg alphamethylparatyrosine/24 hours(6 grams over 36 hours for a 70 kg subject) to estimatebaseline extracellular dopamine levels in extrastriatal regions.The development of methods for estimating DA release andbaseline extracellular DA levels in extrastriatal regions willallow important new research studies in a number of psychi-atric and neurological disorders which may allow design andevaluation of new therapeutic interventions.

Thesaurus Terms: corpus striatum, dopamine, fluorine,method development, neurotransmitter transport, positronemission tomography, radionuclide, radiotracer, substantianigra dextroamphetamine, dopamine receptor, limbic system,neurochemistry, thalamus bioimaging /biomedical imaging,clinical research, human subject, young adult human (21-34)

Institution: Vanderbilt UniversityMedical Center
Nashville, TN 372036869


Fiscal Year: 2005Department: Radiology & Radiological ScisProject Start: 10-Sep-2003Project End: 31-Jul-2007ICD: National Institute Of Mental HealthIRG: ZRG1

LOCALIZATION OF FUNCTION IN THEBRAIN

Grant Number: 5R01MH005286-43PI Name: Mccarthy, Gregory

Abstract: Description:(provided by applicant) In this com-peting renewal, we propose to continue two research themesconcerned with the study of the visual processing of com-plex forms that were established during the current period offunding. The first concerns visual processing within the ven-tral occipitotemporal region of the human brain. We proposea series of experiments to investigate the degree to whichprocessing in this region is category specific, and the degreeto which processing is influenced by expertise. These studieswill further attempt to determine whether processing withinputative category specific regions are influenced by cognitiveand attentional factors and, if so, when in time these factorsinfluence processing. These latter studies will help determinethe validity of our assertion that strong modularity may betemporally limited. The second line of inquiry concerns pro-cessing along the lateral temporal-parietal region - particu-larly within and near the superior temporal sulcus (STS).Our prior studies and those of other groups have indicatedthat this region is sensitive to the perception of biologicalmotion such as shifts in eye gaze and mouth movements. Wepropose to systematically map this region to determine ifindeed it is selectively influenced by biological as comparedto complex non-biological motion and, if so, whether there isan organizational principle along the STS for the type ofmotion perceived, such as a somatotopic organization. Fi-nally we will investigate whether activity in this region issensitive to the social relevance of the perceived motion -whether the action is intentional, and whether the action isgoal directed within the established context. As in our priorperiod of funding, we will conduct parallel studies usingfunctional magnetic resonance imaging (functional MRI, orfMRI) and intracranial event-related potential (ERP) record-ing. This proposal will benefit from technological develop-ments in high-field (4 Tesla or 4 T) neuroimaging that im-prove functional resolution, and from recent developments inpulse-sequence design that recover susceptibility-related sig-nal loss in ventral temporal regions.

Thesaurus Terms: brain mapping, cerebral cortex, motionperception, neural information processing, neuropsychology,
visual perception brain electrical activity, brain imaging /vi-
sualization /scanning, evoked potential, neural plasticity, vi-sual stimulus behavioral /social science research tag, clinicalresearch, electrocorticography, functional magnetic resonanceimaging, human subject

Institution: Duke University2424 Erwin Rd.Durham, NC 27705

Fiscal Year: 2005Department: RadiologyProject Start: 01-Dec-1977Project End: 30-Nov-2006ICD: National Institute Of Mental HealthIRG: IFCN

IMAGING SEROTONERGICTRANSMISSION IN HIV DEPRESSION

Grant Number: 1R21MH076591-01PI Name: Pomper, Martin G.

Abstract: Description (provided by applicant): Nearlyone-half of patients infected with the human immunodefi-ciency virus (HIV) have depression. The effect of depres-sion on this population has profound implications for dis-ease progression, in part related to adherence to antiviralmedication. However, neither the unique mechanism(s) bywhich depression may arise, nor exploration of appropri-ate antidepressant regimens has been adequately ad-dressed. Untreated depression in HIV� individuals canpromote risk-taking behavior leading to further spread ofthe disease. As with depression due to other causes, anattractive hypothesis involves a deficit in serotonergic (5-HT) transmission. The 5-HT deficiency-related disorders,i.e., aggressive and suicidal behavior, alcoholism, affec-tive disorders, sexual dysfunction and dementia, havebeen widely reported in HIV� individuals. One explana-tion may be that cytokines released in the periphery frommacrophages and from activated microglia within the cen-tral nervous system (CNS), may provoke hyperactivity ofthe kynurenine pathway, an alternative route of tryptophanmetabolism that effectively depletes CNS 5-HT levels andproduces quinolinic acid, an excitotoxin, that may damage5-HT neurons. We intend to assess the integrity of the5-HT system in HIV� individuals who are depressed us-ing positron emission tomography (PET) and [11C]DASB, a new, selective ligand for the 5-HT transporter(5-HTT). We will compare 5-HTT levels in HIV� indi-viduals who are depressed with those who are not and tohealthy controls. Relative to healthy controls, we expectto find a 5-HTT deficit in HIV� individuals who are notdepressed, but not to the extent seen in those who are. Wewill recruit patients to our study groups carefully, includ-
ing only individuals who possess the short (s) allele due
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to the polymorphism at the 5= end of the promoter regionof 5-HTT. The small sample size will also enable us tocontrol easily for co-morbid drug abuse and differences inantiretroviral regimens. In addition to investigating 5-HTTas a possible imaging biomarker, the overall goal of thisproof-of-principle study is to provide sufficient prelimi-nary data to undertake a more complete assessment of5-HT transmission in HIV-related depression that will in-clude longitudinal studies of treatment effects in a wider,more heterogeneous population of affected individuals.

Thesaurus Terms: HIV infection, brain metabolism, depres-sion, mental health epidemiology, neurotransmitter metabo-lism, serotonin transporter biomarker, brain imaging /visual-ization /scanning, comorbidity, genetic polymorphism, ge-netic promoter element, host organism interaction, humanimmunodeficiency virus, ligand, mental disorder diagnosisclinical research, human subject, patient oriented research,positron emission tomography


Fiscal Year: 2005Department: RadiologyProject Start: 30-Sep-2005Project End: 31-May-2007ICD: National Institute Of Mental HealthIRG: ZMH1

SIMPLE IN VIVO PET MEASURE OFAMYLOID BINDING IN AD

Grant Number: 5R01MH070729-02PI Name: Price, Julie C.

Abstract: Description (provided by applicant): At present,the definitive diagnosis of Alzheimer’s disease (AD) is basedon the pathologic confirmation of amyloid plaques and neu-rofibrillary tangles in the cerebral cortex. Over many years,our research efforts have been directed toward the develop-ment of non-invasive methods for the in vivo measurementof amyloid plaques. Toward this goal, our group recentlycollaborated with researchers in Uppsala, Sweden, to per-form the first human positron emission tomography (PET)studies of a new amyloidbinding radiotracer, named PIB(Pittsburgh Compound B). These first human studies demon-strated high PIB retention in AD subjects (n�9) in brainareas known to have high amyloid levels in AD (relative tocontrols, n�5). The next step in our efforts is to establishthe validity of the PIB PET methodology and to determine avalid and simple method for potential clinical use. The cen-tral goal of this application is to validate the PIB PET meth-
odology and identify a simple PIB measure of amyloid-bind-
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ing that is feasible for routine use. Toward this goal, PIBPET studies will be acquired in 3 subject groups: mild-to-moderate AD dementia (n�12), mild cognitive impairment(n�12), and elderly controls (n�12). PIB localization willbe related to measures of brain glucose metabolism (using[18F]FDG), which has been extensively used as a metabolicindex of AD. Validation will include acquisition of [15O]wa-ter PET data to exclude the influence of variations in bloodflow on PIB binding. Structural MRI data will be acquired inall subjects to provide anatomical guidance for the PET dataanalyses. Our first aim is to identify an optimal fully-quanti-tative (arterial blood) PIB PET method. The second aim is tochoose a valid and simple (no blood sampling) PIB PETmethod based upon the fully-quantitative data and an itera-tive evaluation of observed and computer-simulated PIBdata. The simple method will allow rapid generation of ro-bust image maps of amyloid binding throughout brain. Thefinal aim is to relate anatomically standardized maps of amy-loid binding to maps of cerebral metabolism. This researchwill provide important groundwork to support the use of thePIB measure of amyloid binding in early and pre-clinicaldiagnosis of AD and potentially accelerate the developmentand evaluation of important new therapies for dementia.

Thesaurus Terms: amyloid protein, brain imaging /visual-ization /scanning, method development, positron emissiontomography, protein binding, radiotracer Alzheimer’s dis-ease, biomarker, brain mapping, brain metabolism, dementia,early diagnosis, glucose metabolism, hemodynamics bioim-aging /biomedical imaging, clinical research, computer simu-lation, human subject, magnetic resonance imaging, patientoriented research

Institution: University Of Pittsburgh At Pittsburgh350 Thackeray HallPittsburgh, PA 15260

Fiscal Year: 2005Department: RadiologyProject Start: 13-May-2004Project End: 30-Apr-2007ICD: National Institute Of Mental HealthIRG: RNM

NEUROIMAGING MEDICAL ILLNESS INELDERLY DEPRESSION

Grant Number: 5K01MH001976-05PI Name: Price, Julie C.

Abstract: Description: (provided by applicant) This is a K-award resubmission (Mentored Research Scientist DevelopmentAward, KOl) that is designed to enable the applicant to acquirea richer clinical understanding of the complex interplay between
psychiatric and medical illness, to integrate clinical knowledge


with quantitative expertise, and to develop neuroimaging meth-ods that are more clinically useful. The candidate is an Assis-tant Professor of Radiology and physicist in the positron emis-sion tomography (PET) facility at the University of Pittsburgh.The applicant’s primary research experience has been in kineticmodeling and methods development for PET imaging and thisquantitative expertise has acted as a bridge between differentclinical disciplines. Past and present collaborations include PETstudies of medically healthy depressed subjects and skeletalmuscle function in subjects with diabetes. These experiences ledthe candidate to become interested in the link between depres-sion and diabetes. The KOl research will use PET imaging tostudy diabetes as a co-existing medical illness in elderly depres-sives. PET measures of serotonin 5-HT1A receptor binding({11C]WAY 100635) wifi be obtained in subjects with adult-onset type 2 diabetes, 40-80 years of age, who are (n�25) andare not (n�25) depressed. Data interpretation will be facilitatedby cerebral blood flow (�l50]water) data that also will be ac-quired for each subject and by the availability of 5-HT1A andcerebral blood flow measures in medically healthy mid-life andelderly subjects, without and with depression (through ongoingUniversity of Pittsburgh collaborations).

Thesaurus Terms: aging, clinical depression, comorbidity,neuroimaging, noninsulin dependent diabetes mellitus,positron emission tomography, technology /technique devel-opment geriatric medicine, human middle age (35-64), hu-man old age (65�), psychological aspect of aging bioimag-ing /biomedical imaging, clinical research, human subject

Institution: University Of Pittsburgh At Pittsburgh350 Thackeray HallPittsburgh, PA 15260

Fiscal Year: 2005Department: RadiologyProject Start: 01-Apr-2001Project End: 31-Mar-2007ICD: National Institute Of Mental HealthIRG: ZRG1

A DIFFUSION TENSOR IMAGING STUDYOF HIV-DEMENTIA

Grant Number: 5K23MH066705-04PI Name: Ragin, Ann B.

Abstract: Description (provided by applicant): This K23application requests a period of career development to studyadvanced methods in Magnetic Resonance (MR) imagingand exploit them to study HIV-Dementia (HIV-D). EmergingMR methods provide microstructural information concerningwhite matter that cannot be obtained using other imagingtechniques. Diffusion Tensor Imaging (DTI) is a non-inva-
sive technique that may be useful in studying white matter
integrity in normal, diseased or degenerating tissue in vivo.HIV-Dementia (HIV-D) is characterized by various patholo-gies involving white matter. This study represents an oppor-tunity to evaluate information uniquely revealed by DTI inthe context of other meaningful biological and clinical pa-rameters. Subjects in this investigation will include well-characterized patients from a large, longitudinal cohortstudy_ef HIV-D. Extensive data is available from semi-an-nual evaluations over a number of years, including biologicalmarkers derived from plasma and CSF, as well as informa-tion concerning neurocognitive and psychiatric functioning.This study will determine whether microstructural measuresof white matter integrity, derived using DTI, bear a relationto measures of advancing HIV infection (e.g. viral load andimmune activation), severity of dementia and specific neuro-psychiatric sequelae. In addition, the DTI findings will beevaluated in the context of biological markers of theoreticalinterest, including select measures of inflammation (e.g.TNF) and endothelial integrity (e.g. MMP-9). These findingswill contribute to an understanding of the pathogenesis ofHIV-D and may provide insights concerning other CNS dis-orders. Experience gained during the proposed award willlay the foundation for further independent investigations ofneurobiological factors in HIV-D.

Thesaurus Terms: AIDS dementia complex, dementia,magnetic resonance imaging biomarker, blood brain barrier,cerebrospinal fluid, longitudinal human study, neural degen-eration, neuropsychology, plasma, tumor necrosis factor al-pha clinical research, human subject, patient oriented re-search

Institution: Northwestern University750 N. Lake Shore Drive, 7thChicago, IL 60611

Fiscal Year: 2005Department: RadiologyProject Start: 01-Aug-2002Project End: 31-Jul-2007ICD: National Institute Of Mental HealthIRG: AARR

RESEARCH TRAINING IN CHILDPSYCHOPATHOLOGY & TREATMENT

Grant Number: 5T32MH020033-07PI Name: Riddle, Mark A.

Abstract: Description (provided by applicant): This is a 5-yearcompetitive renewal of an institutional post-doctoral researchtraining program in interventions research in children and ado-lescents with major mental disorders. The program will serve toaddress the shortage of well-trained clinical researchers in this
field. The specific aims of the proposed program are to train
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clinical researchers in the following areas of interventions re-search with youth: efficacy studies evaluating new medicationand/or psychosocial treatments; effectiveness studies of empiri-cally supported treatments applied in diverse populations andsettings; evaluation of safety and adverse effects of psychotropicmedications, particularly during long-term treatment; and relatedareas of study as they pertain to interventions research--instru-ment development, functional neuroimaging, and outcomes as-sessment strategies. The program faculty includes 6 primarymentors and 6 secondary mentors who have extensive experi-ence in training and mentoring post-doctoral fellows and anestablished funded research portfolio. The training program islocated in the Division of Child and Adolescent Psychiatry,with active collaborations elsewhere in the School of Medicine,the School of Public Health and the Kennedy Krieger Institute,an institution devoted to children with developmental disabili-ties. The training program, which draws upon our experienceover the past 4 years, will have 5 positions, and will includePh.D.s (for 2 years of training) and M.D.s (for 3 years). Re-cruitment of underrepresented minorities will be emphasized.Training consists of: 1) core coursework to ensure a basic un-derstanding of the principles of research methods, design andstatistics; 2) supervised clinical research in collaboration with aprimary mentor, 3) an individual research project to generatepilot data for a successful career development award or otherNIH grant application, 4) research seminars that involve studyproposal reviews/critiques, didactics/formal presentations, and ajournal club; and 5) attendance and presentations at nationalprofessional meetings. The training will occur in a supportiveenvironment of multidisciplinary researchers who are committedto research mentoring. This training program is thoughtfullyorganized to produce a cadre of graduates who will becomeproductive independent interventions researchers in child andadolescent major mental disorders.

Thesaurus Terms: There are no thesaurus terms on file forthis project.


Fiscal Year: 2005Department: Radiology And Radiological SciencesProject Start: 01-Jul-1999Project End: 30-Jun-2009ICD: National Institute Of Mental HealthIRG: ZMH1

PROJECT TITLE: QUANTIFICATION OFFACIAL EXPRESSIONS FORNEUROPSYCHIATRY

Grant Number: 1R01MH073174-01
PI Name: Verma, Ragini
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Abstract: Description (provided by applicant): The maingoal of this project is to develop methods for quantificationof facial expressions. Facial expression analysis is being in-creasingly used in clinical investigations of neuropsychiatricdisorders including affective disorders and schizophrenia,which cause deficits in the perception and expression ofemotion. However, clinicians still rely on methods of expres-sion rating that are manual, largely qualitative and typicallyof low reproducibility. This project seeks to develop objec-tive and automated tools, which will significantly augmentcurrent capabilities for reliable clinical diagnosis and follow-up. The proposed tools perform a morphometric analysis offine-grained structural deformations of the face during anexpression change. Faces will be represented using deform-able models, as a complex combination of elastic regionsthat deform (expand and contract) as the expression changes.The deformation between two faces with different expres-sions will be estimated through a high-dimensional shapetransformation that will be used to define the quantificationmeasure, using the neutral expression or a standardized tem-plate as reference units, depending on the study design. Invideo sequences, the shape transformation between subse-quent frames will be temporally propagated, thereby combin-ing the spatial and temporal information. These methods willbe validated against clinically accepted scales of expressionrating, in terms of their ability to replicate clinically estab-lished results, with emphasis on quantifying difference inexpressions between patients with affective disorders andhealthy controls. It is expected that upon completion of theproject, an integrated collection of expression quantificationtools will be provided to clinicians, which will improve diag-nostic accuracy in affect-related disorders and provide quan-tification measures beyond the scope of currently existingclinical techniques. These tools are expected to provide neu-ropsychiatrists the ability to quantify the degree of impair-ment in affect expression, quantitatively assess response tomedication, obtain behavioral predictors of violence and ag-gression and find endophenotypic markers in children, ado-lescents, and family members of patients, which could poten-tially predict the future onset of the disorder. The long-termgoal of the project is to provide methods for expressionquantification that are reliable, objective, reproducible andeasily usable by clinicians and that will significantly influ-ence the procedures used for accurately diagnosing clinicalconditions that cause deficits in emotional expressiveness,such as schizophrenia, affective disorders, Parkinson’s dis-ease and senile dementias.

Thesaurus Terms: bioimaging /biomedical imaging, compu-tational biology, computer assisted diagnosis, face expres-sion, mental disorder diagnosis, method development, mor-phometry, neuropsychology, schizophrenia computer dataanalysis, disease /disorder classification behavioral /social
science research tag, clinical research, human subject, mag-


netic resonance imaging, neuropsychological test, patientoriented research, video recording system


Fiscal Year: 2005Department: RadiologyProject Start: 01-Jan-2005Project End: 31-Dec-2008ICD: National Institute Of Mental HealthIRG: ZRG1

fMRI ABILITY TO MAP COLUMNARSTRUCTURES IN HUMANS

Grant Number: 5R01MH070800-02PI Name: Yacoub, Essa

Abstract: Description (provided by applicant): Functionalmagnetic resonance imaging offers an unmatched combi-nation of spatial and temporal resolution that continues tobe pushed to new levels. Recently, the limits of BOLDfMRI have been challenged to the level of sub-millimeterstructures. The reliability and reproducibility of thesemaps, as well as the optimization of the fMRI methods toacquire these maps has not yet been established, espe-cially in humans. Differential mapping using gradient ech-oes, which may not be reliable in the general case be-cause of the well known large vessel artifacts (more sig-nificantly at low fields), has been used in humans. Wehave recently demonstrated, made possible by fundingfrom an R21 proposal, at sub-millimeter spatial resolu-
tions, the advantages of high field Hahn spin echo (HSE)
BOLD signals. Differences in specificity to neural activitybetween GE and HSE BOLD signals at high fields has notyet been addressed. Optimized BOLD signals to map brainfunction could allow for mapping of functional architecturewithout apriori knowledge of orthogonal conditions (i.e. sin-gle condition mapping). This would be an invaluable tool formany neuroscience applications where orthogonal conditionsand columnar organizations in general are not known. Thiswork will advance the foundation of our previous R21 pro-posal which investigated T2 weighted fMRI at high magneticfields. The central hypothesis of this application is that HSEbased BOLD fMRI signals at high fields (7 Tesla) can beused to attain a higher spatial specificity and therefore morereliable maps of cortical columns, in awake humans, than atlower fields (4 Tesla) and/or with gradient echoes. Finally,the existence of orientation columns in humans, which hasnever been shown, can be addressed using fMRI techniquesdeveloped in this work.

Thesaurus Terms: brain mapping, functional magnetic reso-nance imaging, neurophysiology, technology /technique de-velopment, visual cortex electrophysiology, hemodynamics,magnetic field, visual stimulus bioimaging /biomedical imag-ing, cat, clinical research, human subject

Institution: University Of Minnesota Twin Cities450 McNamara Alumni CenterMinneapolis, MN 554552070

Fiscal Year: 2005Department: RadiologyProject Start: 01-Apr-2004Project End: 31-Mar-2009ICD: National Institute Of Mental Health
IRG: DMG
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Abstracts of Funded National Institutes of Health Grants

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