Abstracts of Funded National Institutes of Health Grants

National Institute of Diabetesand Digestive and Kidney

Diseases

DATA COORDINATING AND IMAGINGANALYSIS CENTER (DCIAC)

Grant Number: 5U01DK056961-02PI Name: Bae, Kyongtae T.

Abstract: Polycystic kidney disease (PKD) is a commonhereditary disease and ranks fourth as a leading cause ofend-stage renal failure. The primary goal of this study is toexploit volumetric imaging methods to identify and quantifymorphologic measures that are associated with the PKDstage and the rate of PKD progression. 200 subjects, dividedinto three cohorts (GFR�30-50, 70- 90 ml/min) will be fol-lowed for a four-year period. Two participating clinical cen-ters (PCC) will each contribute data on approximately 100subjects. Each PCC will collect clinical data and specimens,perform renal functional tests, and obtain MR and US im-ages for each subject at specific follow-up intervals. The datawill be delivered or electronically transferred to the data co-ordinating and imaging analysis center (DCIAC) proposed inthis application. Our specific aims are (1) to validate mag-netic resonance (MR) volumetric imaging methods for accu-rate and reliable morphometric assessment of the renal pa-renchyma and renal/hepatic/pancreatic cysts in PKD patients;(2) to compare morphologic measures obtained from MRimaging data with renal functional measures in PKD patients

to determine which morphologic measures are associatedwith the extent of renal functional impairment and with therate of disease progression; and structural changes, whileconsidering clinical-effectiveness, cost- effectiveness andpatient acceptability. Statistical methods appropriate forgrowth curve estimation with a heterogeneous populationwill be developed and applied to characterize the PKD pro-gression for each cohort and for the sample as a whole. Thelong-term goal of this project is to develop methods thatwould facilitate shortening the observation period necessaryto determine efficacy of treatment interventions in PKD pa-tients.

Thesaurus Terms: data management, histopathology, kidneyimaging /visualization, morphology, pathologic process,polycystic kidney cooperative study, kidney function, longi-tudinal human study, method development, phantom model,statistics /biometry, ultrasonography bioimaging /biomedicalimaging, clinical research, human subject, magnetic reso-nance imaging

Institution: Washington UniversityLindell and Skinker BlvdSt. Louis, MO 63130

Fiscal Year: 2001Department: RadiologyProject Start: 30-Sep-1999Project End: 30-Nov-2004ICD: National Institute of Diabetes and

Digestive and Kidney DiseasesIRG: ZDK1

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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 of radiology.These abstracts are listed on the NIH Web page (http://www-commons.cit.nih.gov/crisp/) and are printed here verbatim.

The grant identification number (eg, 1RO1AI12345-01) contains a three-digit activity code (in the previous example, RO1)that identifies a specific category of extramural activity. All current NIH activity code titles and definitions can be ob-tained 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) re-fers to the NIH funding source.

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

http://www.commons.cit.nih.gov/crisp/

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

MODEL B CELLS FOR USE IN DIABETESTREATMENT

Grant Number: 3R29DK047858-05S1PI Name: Constantinidis, Ioannis

Abstract: Transplantation of islets or Beta-cells offers a re-alistic possibility for physiological control of blood glucosein diabetics. All reports agree that euglycemia can beachieved for a limited time period (less than 1 year) follow-ing transplantation. A major limitation to using normal isletsor Beta-cells in implantable bioartificial pancreata is avail-ability. Normal cells isolated from mammalian glands exhibitlittl growth, and rapidly lose their differentiated properties inculture. With an estimated 300,000 cases of insulin depen-dent diabetes mellitus and an additional 30,000 new casesper year in the USA, alone, the deman for islets would beenormous. Consequently, cell lines which retain in culturethe differentiated properties of normal islets in vivo areneede for the development of a bioartificial pancreas. Sinceall living systems need energy to sustain their life and func-tion, knowledge about their energy metabolism as it respondsto expected physiologic changes is crucial in assessing theviability and function of these bioartificia devices. In thisapplication, we propose to study the bioenergetic stability ofthe continuous Beta cell line, BetaTC3, in an immunopro-tected environment under repetitive glucose stimulations andhypoxic stresses. Furthermore, we will implant immunopro-tected BetaTC3 cells in streptozotocin-induced diabetic rats,and investigate their ability to restore glucose regulation inthese animals. This type of information is currently unavail-able, and will add greatly to the understanding of the capa-bilities and limitations of an implantable bioartificial pan-creas. We propose to use the non-invasive modality of Nu-clear Magnetic Resonance spectroscopy, for both in vitro andin vivo studies. 31P NMR will assess intracellular levels ofhigh and low energ phosphates, and 13C NMR will deter-mine the relative fluxes through glycolysis and the tricarbox-ylic acid cycle. Enzymatic assays of the perfusion mediumeffluent, perchloric acid extract of the cells, and histologicexaminations of the beads will be performed in support ofthe in vitro studies. Changes in tissue biochemistry and keyphysiological parameters including blood glucose and insulinlevels will be monitored to assess the success of the implant.This proposal is the beginning of an interdisciplinary projectthat has brought together expertise from engineering, chemis-try, physics and medicine. Our long range goal is to developa clinically useful implantable bioartificial pancreas for thetreatment of diabetes mellitu in human patients.

Thesaurus Terms: artificial endocrine pancreas, bioenerget-ics, nonhuman therapy evaluation, pancreatic islet, tissueengineering blood glucose, brain metabolism, disease /disor-der model, glycosuria, hypoxia, streptozotocin alginate, labo-ratory rat, medical implant science, nuclear magnetic reso-nance spectroscopy, tissue /cell culture

Institution: Emory UniversityAtlanta, GA 30322

Fiscal Year: 2000Department: RadiologyProject Start: 01-Mar-1995Project End: 31-Mar-2002ICD: National Institute of Diabetes and

Digestive and Kidney DiseasesIRG: SB

ULTRASOUND TECHNIQUES FOR TUMORPERFUSION MEASUREMENTS

Grant Number: 5R01DK056658-02PI Name: Fowlkes, Jeffrey B.

Abstract: DESCRIPTION (Adapted from applicant’s ab-stract): This proposal will investigate the use of three relatedultrasound techniques for the evaluation of blood flow. Thesemethods will be applied specifically in the assessment ofliver hemodynamics in which there are various vascular sup-plies that provide some complicating factors. In addition,these techniques may provide some additional diagnosticinformation in the evaluation of liver lesions such as metas-tasis. Three methods will be tested. Contrast interruptionuses transcutaneously applied ultrasound to create high tem-poral resolution boluses in the vessels following simple in-travenous infusion of microbubble-based ultrasound contrastagent. These boluses are created without arterial catheteriza-tion and yet provide similar washin-washout. Perhaps evenmore important is the ability to repeated interrupt the flow ofagent for both multiple boluses during continuous IV fusion.Interruption in specific vessels can determine relative flowcontribution and be used during other types of perfusionmeasures. Contrast decorrelation measures the motion ofcontrast through the ultrasound beam by examining the grad-ual loss of speckle coherence at a given location. The tech-nique has the property of directly estimating a mean transittime, and at least in preliminary studies, appears to be quiteangle independent. With certain modifications, the techniquemay directly yield perfusion in a real-time imaging applica-tion of flow in ultrasound accessible tissues. Finally flash-echo imaging (FEI) is a technique which has already beenimplemented on a specific scanner. FEI uses higher intensitypulses on ultrasound to destroy contrast agent from the im-aging plane and then monitor the rate at which the contrastagent is returned to the tissue being imaged. In contrast tocontrast interruption, FEI provides the local blood flow infor-mation without selectivity for vascular supply but is a veryconvenient measurement that is already available. In combi-nation with contrast interruption, considerably more informa-tion can be obtained in liver flow than would be possiblewith FEI alone. The research will investigate the use of thesetechniques in three specific hepatic applications. 1) Measure-

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ment of the relative flow contributions from the hepatic arte-rial and portal venous systems. 2) Measurement of the meantransit time for these same vascular supplied (The combina-tion of information from 1 and 2 should provide a measurewhich is analogous to perfusion. And 3) Examine whetherdifferentiation of liver lesions can be achieved. These tech-niques should not only improve diagnosis of liver diseasebut should be applicable to a wide variety of hemodynamicmeasures throughout the body.

Thesaurus Terms: blood flow measurement, computed axialtomography, contrast media, liver circulation, liver neoplasm,ultrasound imaging /scanning carcinoma, disease /disordermodel, isolation perfusion, longitudinal human study, metas-tasis, method development, prognosis bioimaging /biomedi-cal imaging, clinical research, human subject, injection /infu-sion, laboratory rabbit, magnetic resonance imaging, micro-capsule

Institution: University of Michigan at Ann ArborAnn Arbor, MI 48109

Fiscal Year: 2001Department: RadiologyProject Start: 30-Sep-2000Project End: 30-Jun-2004ICD: National Institute of Diabetes and

Digestive and Kidney DiseasesIRG: RNM

ULTRASONIC BUBBLE GENERATION FORUROLOGIC DIAGNOSIS

Grant Number: 5R01DK042290-09PI Name: Fowlkes, Jeffrey B.

Abstract: In the previous grant period, experiments wereperformed to develop an understanding of the bubble genera-tion process in the urinary tract and our knowledge of theacoustic field requirements for contrast production hasgreatly improved. Excise canine urinary bladders and initialin vivo trails demonstrated that single acoustic bursts of 6.6Mpa and 250 ms duration produced, in a few in vitro and invivo cases, clouds of bubbles with apparently quite sufficientechogenicity and duration for reflux diagnosis. However,such bursts, even up to 14 Mpa, would not reliably producenoticeable cavitation under these conditions where both theparticulate and gas content is low. However, the thresholdwas lower (8.9 �/� 1.7 Mpa with 125 ms bursts) and reli-ability of bubble generation was significantly greater (7 or 8animals) in a rabbit model where naturally occurring particu-lates may have reduced the threshold to an obtainable levelwith the employed pulsed system. This allowed a study ofthe effects of natural gas content variation on echogenicityyield which indicated that copious quantities of cavitationcould be produced in vivo and that CO2 content was impor-

tant in threshold and echogenicity. Controlled experiments inwater were also performed, which again indicated that underconditions where threshold could be reached reliably, physio-logically relevant gas contents could produce copious bubbleproduction. The implication is that with sufficient acousticamplitude to reach the cavitation threshold, bubbles can beproduced in fluids with gas contents similar to that of urine.Recent canine experiments indicate that the goal of reliablegeneration has now been achieved using a short pulse systemwith up to twice the amplitude and with pulse sequences ononly 1/4000 as much on-time as the earlier 250 ms pulses.Cavitation was repeatedly produced in the canine bladderwith apparently no gross damage to the bladder wall. Whilethe amount of echogenicity was lower than that found forthe rabbit model, the repeated pulsing which can be per-formed with this system, or a low amplitude growth pulseshould produce the requisite echogenicity and bubble dura-tion, particularly if physiologic manipulation of CO2 in theurine is sufficiently safe for cases of low gas content. Giventhis level of success, it is the objective of the research pro-posed to develop a system to generate, collect and grow mi-crobubbles to the degree necessary for diagnosis of urinaryreflux. To this end, the proposed research focuses on lowparticle content systems where the effects of pulse parame-ters affecting safety, and contrast longevity and detectabilitycan be addressed to develop a working in vivo system.

Thesaurus Terms: biomedical equipment development, clin-ical biomedical equipment, contrast media, diagnosis design/evaluation, ultrasonography, urinary tract disorder diagnosiscarbon dioxide, disease /disorder model, noninvasive diagno-sis, urinary bladder bioimaging /biomedical imaging, cystos-copy, dog, human tissue, respiratory gas analyzer, urinalysis,urinary tract visualization

Institution: University of Michigan at Ann ArborAnn Arbor, MI 48109

Fiscal Year: 2000Department: RadiologyProject Start: 01-Jan-1991Project End: 30-Nov-2002ICD: National Institute of Diabetes and


IN VIVO STUDIES OF BRAIN GLYCOGENIN HYPOGLYCEMIA

Grant Number: 5R21DK058004-02PI Name: Gruetter, Rolf

Abstract: Hypoglycemia unawareness is a complication ofintensive insulin therapy often encountered after episodes ofiatrogenic hypoglycemia. The mechanisms by which thebrain detects low blood sugar concentrations are uncertain.

NIDDK Academic Radiology, Vol 9, No 8, August 2002

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The brain contains 3-10 muol/g glycogen that may serve as afuel during moderate hypoglycemia. Glycogen metabolism isinsulin-and glucose-sensitive. Brain glycogen thus providesan aspect of cerebral carbohydrate metabolism that is sensi-tive to alterations in glucose homeostasis such as those seenin diabetic patients. The purpose of this project is to explorethe potential role brain glycogen may have in modulating thesymptoms of hypoglycemia. Upon completion of this project,we expect to have a better understanding of the role of brainglycogen during and following hypoglycemic episodes. Thehypotheses of this project are a) That brain glycogen concen-tration and metabolism are modulated by plasma glucoseand/or insulin concentrations in vivo. b) That the brain gly-cogen concentration serves as a reservoir of glucose equiva-lents that are used during hypoglycemia in vivo. c) That fol-lowing a hypoglycemic episode, the brain stores more brainglycogen such that longer and deeper subsequent hypoglyce-mia is necessary to deplete brain glycogen, which may pro-vide a mechanism leading to hypoglycemia unawareness,with the following specific aims: 1. To explore in vivo brainglycogen metabolism non-invasively using 13C NMR local-ization methods during hyperglycemia and at different plasmainsulin levels. 2. To establish that brain glycogen serves as areservoir of glucosyl units during hypoglycemia and to deter-mine the control of brain glycogen following hypoglycemia andto correlate these changes with perfusion-based functional MRI(fMRI) measurements of cerebral blood flow changes. Theseaims will be achieved in rat brain using localized 1H and 13CNMR spectroscopy and perfusion-based fMRI.

Thesaurus Terms: brain metabolism, brain visualization,glycogen, glycogenesis, glycogenolysis, hypoglycemia bloodglucose, brain circulation, cerebral circulation, glucose me-tabolism, glycogen synthase, hyperglycemia, insulin bioimag-ing /biomedical imaging, functional magnetic resonance im-aging, laboratory rat, nuclear magnetic resonance spectros-copy

Institution: University of Minnesota Twin CitiesTwin CitiesMinneapolis, MN 55455

Fiscal Year: 2000Department: RadiologyProject Start: 30-Sep-1999Project End: 31-Aug-2002ICD: National Institute of Diabetes and

Digestive and Kidney DiseasesIRG: ZNS1

RACE, RENIN, GENES, RISK, ANDDIABETIC NEPHROPATHY

Grant Number: 1R01DK054668-01PI Name: Hollenberg, Norman K.

Abstract: African Americans carry a 3-6 fold increased riskof developing nephropathy as a complication of diabetesmellitus (DM), essential hypertension (HTN), and probablyother conditions. Although an increased frequency and sever-ity of HTN and socioeconomic factors that limit health careprobably contribute, multiple observations indicate that moreimportant alternative factors are also involved. Fields rangingfrom epidemiology and therapeutic trials to molecular biol-ogy and genetics indicate that the renin-angiotensin system(RAS) contributes to the risk of nephropathy via mechanismsthat include but go beyond HTN, perhaps involving the con-tribution of the RAS to growth and repair hyperplasia, andhypertrophy. Our application is based on several unantici-pated observations. First, in healthy African Americans, age-adjusted renal plasma flow (RPF) was substantially less thanin Caucasians, assessed in an identical protocol. Moreover,despite a high salt diet, African Americans displayed an en-hanced renal vasodilator response to angiotensin-convertingenzymic (ACE) inhibition with captopril, which enhancedrenal vascular responsiveness to angiotensin II (Ang II). Thispattern (which clearly differs from that in Caucasians and issimilar to our preliminary observations in patients with DM)suggests activation of the RAS. Second, in our non-insulin-dependent Type 2 DM patients, our preliminary data suggesta range of hitherto unrecognized RAS abnormalities reflect-ing inappropriate activation and autonomous renin release.Most surprising is the paradoxical extreme RAS activation atthe renal tissue level Type 2 DM patients with very lowplasma renin activity (PRA) and nephropathy. Evidence for afunctional contribution comes from hemodynamic measure-ments made during pharmacological interruption of the RASwith ACE inhibitors and Ang II antagonists, and during AngII infusion. In Type 2 DM, race is a critical determinant ofrisk. Third, we have made observations which indicate thatacute hyperglycemia activates the intrarenal system and in-duces striking Ang II-dependent vasoconstriction. Our hy-pothesis is that the increase in risk of nephropathy representsan interaction between genetic predisposition based on theincreased frequency of an angiotensinogen (AGT) gene poly-morphism that favors renin system activation, an action ofobesity and insulin resistance to amplify the effect of thepolymorphism on AGT; and the renal effects of hyperglyce-mia to activate the intrarenal system in a setting whichwould favor local intrarenal Ang II production. Our goal inthis study is to explore preliminary evidence that RAS acti-vation accounts for many Type 2 DM features involving re-nal risk, and racial differences in risk.

Thesaurus Terms: African American, diabetic nephropathy,disease /disorder proneness /risk, genetic susceptibility, non-insulin dependent diabetes mellitus, racial /ethnic difference,renin /angiotensin system angiotensin II, angiotensinogen,captopril, clearance rate, genetic polymorphism, hemodynam-ics, hyperglycemia, kidney function, p aminohippurate, reninclinical research, human subject


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Institution: Brigham and Women’s Hospital75 Francis StBoston, MA 02115

Fiscal Year: 1998Department:Project Start: 17-Aug-1998Project End: 31-Jul-2003ICD: National Institute of Diabetes and


FUNCTIONAL IMAGING & MASSANALYSIS OF PANCREATIC B CELLS

Grant Number: 5R01DK058512-02PI Name: Krohn, Kenneth A.

Abstract: DESCRIPTION (adapted from the application)We propose a collaboration of imaging scientists and expertsin B-cell biology to develop new imaging technology andagents to assess B-cell mass and function. Advances in invivo imaging methods have not yet made an impact on studyof the endocrine pancreas. Our premise is that this inherentlychemical organ needs to be imaged with chemical resolutionas well as structural resolution in order to advance researchin B-cell biology and the pathophysiology of diabetes. Com-plementary nuclear medicine (PET) and magnetic resonance(MRS) methods will be applied to an in vitro artificial organsystem and to small animal in vivo imaging studies ofhealthy and diabetic animals. New imaging tools will be de-veloped and validated to answer some fundamental questionsabout the biology of normal and injured B-cells. In SA1 wewill use principally MRS to determine the amount of viablecell mass in our in vitro organ and compare this measurewith oxygen metabolism and insulin release. We anticipatethat the 31P peak ratios will be a robust indicator of B-cellviable mass that is more sensitive than the insulin releaseassay and will permit direct comparisons between imagingagents for B cells and islets. In SA2 we will also use theartificial organ model to evaluate a series of compounds fortheir potential as imaging agents to quantitative B-cell massin vivo. Because only a small fraction of the pancreas is B-cells, a successful imaging agent will require a high level ofselectivity over acinar cells as well as cells of neighboringorgans. Selectivity could derive from chemical specificity ofa radiotracer and/or from a unique time course of the tracerin B-cells, as analyzed by mathematical models. Becausethere is no existing literature on radiopharmaceuticals withthe desired specificity for the endocrine pancreas, we havesearched broadly to find good candidate imaging agents forradiolabeling. We have identified selective B-cell toxins,dyes for in vitro staining of islets, unique B-cell surface re-ceptors, and molecules that play a role in the cell’s specificbiochemical function related to insulin production and re-

lease. Good candidate molecules will be labeled with PETnuclides and used in SA3 to image the natural history ofB-cell mass in animal models of both spontaneous and toxin-induced diabetes. Imaging using the small animal PET willbe compared with functional measures, including insulin re-lease and other assays developed in SA1. The application ofnon-invasive islet imaging will allow investigators to answerquestions about the etiology and natural history of type Idiabetes, to improve ways to predict who will develop clini-cal disease, and to various drugs in preventing progressivebeta cell destruction.

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

Institution: University of Washington3935 University Way NESeattle, WA 98195



COMPREHENSIVE MR EVALUATION OFRENOVASCULAR DISEASE

Grant Number: 5K23DK002814-02PI Name: Lee, Vivian S.

Abstract: DESCRIPTION (adapted from the application)Broad, long-term objectives: To acquire research skills in arichly mentored environment that will foster the developmentof a career in patient-oriented research. In conjunction withtraining in renal physiology, magnetic resonance (MR) phys-ics, image analysis, and biostatistics, the research focus willbe to improve methods for the diagnosis of renovascular dis-ease. Health relatedness: Renovascular disease (RVD) is themost common potentially reversible cause of hypertensionand progressive renal insufficiency in the US, yet presentdiagnostic tests are limited to either anatomic or physiologictests. The degree of renal artery stenosis (RAS) detected atangiography does not directly correlate with the physiologicsignificance of the narrowing and hence does not accuratelypredict response to revascularization. MR angiography canprovide an accurate minimally invasive method for identify-ing RAS, but is presently limited to anatomic assessments.We hypothesize that the development of MR techniques thatcan measure the physiologic consequences of stenoses willlead to improved diagnostic accuracy. Specific Aims/Meth-ods: 1) To measure blood flow in the renal arteries usingnewly developed faster MR phase contrast flow quantifica-tion techniques (validated in phantoms) and to correlate pat-


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terns of velocity waveforms (akin to Doppler tracings) withseverity of renal artery stenosis. 2) To develop MR methodsto measure parameters of renal function including whole kid-ney and regional (cortex, medulla, collecting system) perfu-sion, glomerular filtration rate, and tracer kinetic parameterssuch as mean transit time. Ultra-low doses of Gd-DTPA con-trast permit quantitative determinations of contrast concentra-tion. To evaluate renal response independent of variation incardiac output, injection rate, and dose, deconvolution ofrenal Gd-DTPA concentration-time curves will be performedusing measured aortic input function. MR results will becompared with scintigraphic measures of renal function us-ing gamma camera and blood sample methods with Tc-99m-DTPA. 3) To investigate the effects of angiotensin convert-ing enzyme-inhibitor on renal artery flow and perfusionmeasurements. Following a period of technique optimiza-tion and validation, a comprehensive MR protocol will betested in a population of patients with suspected RVD,and the diagnostic accuracy of MR measures of renal ar-tery velocity waveforms, GFR, and intrarenal tracer kinet-ics will be compared with anatomic evaluation by renalMR angiography.

Thesaurus Terms: cardiovascular disorder diagnosis, diag-nosis design /evaluation, kidney disorder diagnosis, magneticresonance imaging ACE inhibitor, kidney circulation, kidneyfunction, training angiography, bioimaging /biomedical imag-ing, clinical research, contrast media, human subject, scintil-lation camera, technetium

Institution: New York University School ofMedicine

550 1st AveNew York, NY 10016

Fiscal Year: 2001Department: RadiologyProject Start: 01-Apr-2000Project End: 31-Mar-2005ICD: National Institute of Diabetes and

Digestive and Kidney DiseasesIRG: DDK

EARLY DIAGNOSIS AND TREATMENT OFDIALYSIS GRAFT STENOSIS

Grant Number: 5R01DK054240-03PI Name: Robbin, Michelle L.

Abstract: The broad long-term objective of this proposal isto improve vascular access longevity in chronic renal failurepatients on hemodialysis using ultrasound evaluation. Syn-thetic graft failure after the first month is primarily due toclotting (thrombosis). After the graft thromboses, an underly-ing graft or draining vein stenosis is found in greater than 85percent of patients, despite aggressive clinical monitoring for

stenosis. Patent grafts with stenoses treated with percutane-ous transluminal angioplasty (PTA) or surgical revision tech-niques have longer patency than thrombosed grafts afterthrombectomy. Therefore, early stenosis detection with treat-ment of the hemodynamically significant stenoses found (inpatent grafts) should increase graft longevity, thereby de-creasing the substantial costs associated with graft failure.We propose to actively test two graft surveillance strategies.This study will test the hypothesis that triannual ultrasoundmonitoring and percutaneous treatment of detected stenoseswill improve hemodialysis graft longevity compared to ag-gressive clinical monitoring. Specific Aims: To test the hy-pothesis that: 1). Triannual color flow ultrasound (US) sur-veillance of hemodialysis grafts can diagnose stenoses thatare not detected during aggressive clinical monitoring. 2).PTA of hemodynamically significant stenoses detected byultrasound surveillance will approximately double graft lon-gevity, from the current 16 months. 3). To determine theultrasound and angiographic measurement parameters thatmost accurately predict the longevity of the PTA result. 4).To assess the cost-effectiveness of early color flow US graftstenoses detection and intervention versus aggressive clinicalmonitoring. Health Relatedness: If color flow US monitoringin addition to aggressive clinical monitoring increases graftlongevity and is cost effective as compared to aggressiveclinical monitoring alone, this would have important implica-tions for patient management. Increased graft longevityshould lead to improved patient quality of life, secondary toa decreased need for thrombectomies, temporary access cath-eters and surgical placement of new grafts. Research Designand Methods: A randomized, prospective clinical trial willcompare triannual color flow US graft monitoring in addi-tion to aggressive clinical monitoring, to aggressive clini-cal monitoring alone. PTA or surgical revision of hemo-dynamically significant stenoses detected will be per-formed. Access patency will be followed for at least 2years, or until placement of a new access. All other as-pects of the patients’ medical and dialysis care will followusual medical standards.


Institution: University of Alabama at BirminghamUAB StationBirmingham, AL 35294


Digestive and Kidney DiseasesIRG: GMB


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MRI OF RENAL ANATOMY ANDFUNCTION IN CHRONIC ISCHEMIA

Grant Number: 5R01DK048051-06PI Name: Sommer, F. G.

Abstract: The goal of this proposal is the development andin vivo validation of advanced MRI techniques designed toprovide a comprehensive anatomic and functional evaluationof the kidney in a single examination, and the subsequentapplication of these techniques to the diagnosis of patientswith renal artery stenosis and chronic renal ischemia. De-tailed anatomic information will be obtained through furtherdevelopment of successful existing techniques for ultrafastcontrast-enhanced magnetic resonance angiography (MRA).In addition to high- resolution imaging of the renal vascula-ture, the MRA sequence will be employed to obtain 3- di-mensional images of the renal parenchyma; accurate depic-tion of the renal cortex and medulla will also be achieved bycorrelation imaging, and volumes of these zones will be rap-idly calculated using semi-automated computerized tech-niques. Building on our successful techniques for the in vivomeasurement of renal blood flow with breathing- resolvedcine phase-contrast techniques using spiral k-space trajecto-ries, we will design and validate a sequence for the determi-nation of the extraction fraction (EF) of gadolinium-DTPAfrom the kidney. EF will be measured by determining sys-temic and renal venous T1 values, which will allow determi-nation of the difference in gadolinium-DTPA concentration.Using these EF determinations and renal blood flow valuesdetermined by our existing spiral phase-contrast techniques,we will compute single-kidney values of glomerular filtrationrate (GFR), the standard measure of renal function. All theabove techniques, following validation in vivo in normalpigs, will form the components of a single comprehensiveMRI exam which will be used to diagnose patients withchronic renal ischemia. The utility of the comprehensiveexam will be determined by correlating pre- interventionMRI-determined parameters with both clinical outcome mea-sures and post-intervention MRI-determined parameters.

Thesaurus Terms: angiography, diagnosis design /evalua-tion, magnetic resonance imaging, renal ischemia /hypoxiablood flow measurement, contrast media, diethylenetriamine-pentaacetate, digital imaging, gadolinium, kidney disorderdiagnosis, kidney function, kidney visualization, method de-velopment, noninvasive diagnosis bioimaging /biomedicalimaging, clinical research, glomerular filtration rate, humansubject, swine

Institution: Stanford UniversityStanford, CA 94305

Fiscal Year: 2001Department: RadiologyProject Start: 01-Jan-1995Project End: 31-Mar-2003

ICD: National Institute of Diabetes andDigestive and Kidney Diseases

IRG: RNM

DEVELOPMENT OF TC-99M RENALTUBULAR AGENTS

Grant Number: 2R01DK038842-14PI Name: Taylor, Andrew T.

Abstract: DESCRIPTION (Verbatim from the Applicant’sAbstract): We seek support to develop a new non-invasive,cost effective, accurate, and reproducible measure of effec-tive renal plasma flow (ERPF) to enhance the care of pa-tients with impaired renal function and to facilitate researchinto the mechanisms and treatment of renal diseases. Ourobjective is to develop new anionic and cationic Tc-99mrenal agents with a clearance higher than that of the discon-tinued tracer, I-131 ortho-iodohippuran (OIH) and equivalentto the gold standard of ERPF, para-aminohippurate (PAH).The feasibility of our approach is demonstrated by the factthat our NIH-funded program has already led to the identifi-cation of two of the best first-generation tubular imagingtracers in humans, one patent, and the development of fivepromising new agents comparable in rats to Tc99m mercap-toacetyltriglycine (MAG3), the best agent commerciallyavailable in the U.S. MAG3 has serious limitations. Its clear-ance does not measure a standard renal functional parameterand is less than half that of PAH; moreover, MAG3 cannotreliably detect changes in renal function as great as 35 per-cent. We hypothesize that an optimal tracer will be mini-mally bound to red cells and plasma proteins and will havekey chemical features shown by experience to give a highrenal clearance. To test these hypotheses, we will utilize amultifaceted approach. We propose (Aim 1) three classes ofagents, including the largely unexplored cationic renal trac-ers, which offer the potential for breakthrough research andenhanced diagnostic accuracy. Most Tc-99m agents in thethree classes will utilize novel ligands, each designed by aninnovative approach to yield (via kit preparation) only onerobust solution species at physiological pH. For all agentswe will determine the biodistribution, rate and specificity ofrenal excretion in streamlined animal models (Aim 2); thebest tracers will be assessed in human studies (Aim 3). Re-sults from Aims 2 and 3 will iteratively direct modificationsof agent design in Aim 1. The dosimetry of the best tracersat least equivalent to OIH in humans will be determined(Aim 4). An accurate measure of ERPF will have a signifi-cant impact on the diagnosis and management of patientswith prerenal azotemia. This condition occurs in 3-5 percentof hospitalized patients and, when sustained, is the mostcommon cause of ischemic tubular necrosis. A superiorERPF tracer will also improve the management of patientswith renal insufficiency, especially those with unstable renalfunction, including conditions such as renal transplantation,


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diabetes, and drug nephrotoxicity. Finally, our recent successidentifying tracers with high clearance has depended on ouradvances in technetium and rhenium chemistry and in liganddesign and synthesis. These advances and additional ad-vances expected from the proposed work are significant be-cause they will also aid others in the development of non-renal Tc-99m diagnostic agents and of p-emitting Re-186and Re-188 therapeutic agents.

Thesaurus Terms: clearance rate, glomerular filtration rate,kidney disorder diagnosis, kidney imaging /visualization,reagent /indicator, renal tubular transport chemical synthesis,diagnosis design /evaluation, diagnosis quality /standard, di-agnostic test, drug metabolism, glomerular filtration, pharma-cokinetics, radiation dosage, radionuclide diagnosis, radio-pharmacology, radiotracer, renal ischemia /hypoxia, uremiabioimaging /biomedical imaging, clinical research, humansubject, laboratory rat, technetium


Fiscal Year: 2001Department: RadiologyProject Start: 01-Sep-1986Project End: 30-Apr-2004ICD: National Institute of Diabetes and


MEMBRANE TRANSLOCATION SIGNALSFOR GENE DELIVERY

Grant Number: 5R21DK055713-02PI Name: Tung, Ching-Hsuan

Abstract: The overall goal of this proposal is to investigateand further develop peptide based membrane translocationsignals (MTS) in an effort to improve non-viral mediatedgene transfer. Non-viral gene delivery systems have attrac-tive features such as low toxicity and unlimited DNA load-ing capacity but on the contrary typically are associated witha low transfection efficiency. The low efficiency has largelybeen attributed to 1) physical barriers which impede DNAtransport through cell membranes and 2) lysosomal degrada-tion of vectors when internalized through receptor mediateduptake. Solutions to bypass these obstacles have includedlipid based carriers that may fuse with membranes or the useMTS proteins which are capable of ferrying plasmid pay-loads into cells while avoiding lysosomal pathways. We havesystematically explored a variety of natural and syntheticMTS and have recently found unique peptides consisting ofonly 5-7 amino acids, the shortest MTS reported so far. Wehave tested several of these peptides in murine and humancell lines and have shown them to be very efficient in inter-nalizing small and large (greater than 20 kDa) molecules,

and even particles (greater than 30 nm) into cytoplasmic andnuclear compartments. Apart from vastly improved intracel-lular delivery, we have also shown that prototype MTS-oli-gomer/plasmid DNA complexes significantly improve thetransfection efficiency in cell culture. The proposed experi-ments are a logical extension of our preliminary data to fur-ther evaluate the potential of the developed MTS. Specifi-cally, we will compare the efficacy of different MTS oli-gomers for improving gene expression and will alsoinvestigate the potential mechanisms of action through whichthe developed MTS operate. In a first step, several arborizingMTS will be synthesized, purified and then characterized.Subsequently, model preparation will undergo the in vitroand in vivo. We believe that the developed systems mayhave as substantial impact on cellular delivery of complexdrug systems and because of their efficiency demonstrated sofar, may offer great promise for gene therapy.

Thesaurus Terms: intracellular transport, synthetic peptide,technology /technique development, transfection, transfection/expression vector, transport protein endocytosis, gene ther-apy, plasmid, protein binding, protein sequence, proteintransport HeLa cell, biotechnology, fluorescence microscopy,green fluorescent protein, laboratory mouse, peptide chemicalsynthesis, tissue /cell culture

Institution: Massachusetts General Hospital55 Fruit StBoston, MA 02114

Fiscal Year: 2000Department:Project Start: 01-Jul-1999Project End: 30-Jun-2001ICD: National Institute of Diabetes and


MEMBRANE TRANSLOCATION SIGNALSFOR GENE DELIVERY

Grant Number: 5R21DK055713-02PI Name: Tung, Ching-Hsuan

Abstract: The overall goal of this proposal is to investigateand further develop peptide based membrane translocationsignals (MTS) in an effort to improve non-viral mediatedgene transfer. Non-viral gene delivery systems have attrac-tive features such as low toxicity and unlimited DNA load-ing capacity but on the contrary typically are associated witha low transfection efficiency. The low efficiency has largelybeen attributed to 1) physical barriers which impede DNAtransport through cell membranes and 2) lysosomal degrada-tion of vectors when internalized through receptor mediateduptake. Solutions to bypass these obstacles have includedlipid based carriers that may fuse with membranes or the use


981

MTS proteins which are capable of ferrying plasmid pay-loads into cells while avoiding lysosomal pathways. We havesystematically explored a variety of natural and syntheticMTS and have recently found unique peptides consisting ofonly 5-7 amino acids, the shortest MTS reported so far. Wehave tested several of these peptides in murine and humancell lines and have shown them to be very efficient in inter-nalizing small and large (greater than 20 kDa) molecules,and even particles (greater than 30 nm) into cytoplasmic andnuclear compartments. Apart from vastly improved intracel-lular delivery, we have also shown that prototype MTS-oli-gomer/plasmid DNA complexes significantly improve the trans-fection efficiency in cell culture. The proposed experiments area logical extension of our preliminary data to further evaluatethe potential of the developed MTS. Specifically, we will com-pare the efficacy of different MTS oligomers for improvinggene expression and will also investigate the potential mecha-nisms of action through which the developed MTS operate. In afirst step, several arborizing MTS will be synthesized, purifiedand then characterized. Subsequently, model preparation willundergo the in vitro and in vivo. We believe that the developedsystems may have as substantial impact on cellular delivery ofcomplex drug systems and because of their efficiency demon-strated so far, may offer great promise for gene therapy.

Thesaurus Terms: intracellular transport, synthetic peptide,technology /technique development, transfection, transfection/expression vector, transport protein endocytosis, gene ther-apy, plasmid, protein binding, protein sequence, proteintransport HeLa cell, biotechnology, fluorescence microscopy,green fluorescent protein, laboratory mouse, peptide chemicalsynthesis, tissue /cell culture


Fiscal Year: 2000Department:Project Start: 01-Jul-1999Project End: 30-Jun-2001ICD: National Institute of Diabetes and


National Institute of Arthritisand Musculoskeletaland Skin Diseases

SOLID STATE MR OF BONE MINERAL

Grant Number: 5R01AR042258-07PI Name: Ackerman, Jerome L.

Abstract: Description (Adapted from Applicant’s abstract):The central idea of this project is that solid state magneticresonance (SSMR) imaging and spectroscopy can provideunique solutions to problems related to the chemistry of bio-mineralization. In this continuation of the development ofSSMR methodology for bone mineral characterization, invivo and high resolution SSMR techniques are applied tostudy the remodeling of synthetic calcium phosphate bioma-terials in vivo, and to elucidate the structural chemical prop-erties of bone mineral crystals. The work focused on mea-surements that can be made in no other way with existingtechnology. In Specific Aim 1, the conversion of a non-pro-prietary beta-tricalcium phosphate (TCP) implant into thehost bone in a rabbit bone defect model is follow with invivo and high resolution SSMR. Although much effort hasbeen expended in the study of this and similar increasinglyused calcium phosphate based materials, these materials haverarely been studied by solid state MR, and never in vivo bythis method. Forty-five rabbits will be implanted, and thetime course of the remodeling of the implant material will becharacterized by in vivo SSMR imaging, and by high fieldhigh resolution cross polarization/magic angle spinning (CP/MAS) spectroscopy, chemical analysis and histomorphom-etry on harvested specimens. This study is expected to eluci-date details of the chemistry of the remodeling process thathave so far remained obscure. In Specific Aim 2, specializedCP/MAS and other solid state MR techniques in conjunctionwith computer modeling are applied to characterize bonemineral crystals in order to develop detailed model of thestructural chemistry of the crystal interior as well as the sur-face. Specimens of trabecular bone from normal and ovariec-tomized rats, treated and not treated with alendronate, a typi-cal diphosphonate anti-resorptive pharmaceutical of rapidlyincreasing importance in the treatment of osteoporosis, willbe analyzed. Because the action of diphosphonates includesphysicochemical effects involving binding to bone mineralcrystals, enhanced understanding of the structural chemistryof bone mineral crystals and their diphosphonate bindingproperties will be important in the design of improved anti-resorptive drugs.

Thesaurus Terms: biomaterial evaluation, bone prosthesis,bone scanning, magnetic resonance imaging, normal ossifica-tion, nuclear magnetic resonance spectroscopy, osteoporosis,physiologic bone resorption alendronate, biomedical equip-ment development, calcium phosphate, clinical biomedicalequipment, computer simulation, image processing, implant,method development, model design /development, phantommodel, solid state, structural model bioengineering /biomedi-cal engineering, bioimaging /biomedical imaging, digital im-aging, laboratory rabbit, laboratory rat, light microscopy,medical implant science, medical rehabilitation related tag


NIAMS Academic Radiology, Vol 9, No 8, August 2002

982

Fiscal Year: 2000Department:Project Start: 01-Jun-1994Project End: 31-Jul-2002ICD: National Institute of Arthritis and

Musculoskeletal and Skin DiseasesIRG: RNM

RESPIRATION AND GLYCOLYSIS—INTEGRATION IN ACTIVE MUSCLE

Grant Number: 5R01AR045184-04PI Name: Conley, Kevin E.

Abstract: DESCRIPTION (Adapted from the applicant’sabstract): Glycolysis and respiration are independently regu-lated in the cell, and their interaction is critical for activemuscle. Glycolysis provides the majority of substrate forrespiration (i.e., oxidative phosphorylation) in exercise. How-ever, glycolysis can also limit oxidative phosphorylation bygenerating H� and lactate under aerobic conditions whichreduces intracellular pH and inhibits mitochondrial respira-tion. The PI’s working hypothesis is that the interaction ofglycolysis with respiration limits muscle respiration in exer-cise to well below the mitochondrial capacity. Newly devel-oped magnetic resonance methods are applied to characterizethe contractile, oxidative and glycolytic fluxes during in vivoexercise. Human and animal muscle groups differing in thesemetabolic properties will be used to evaluate the interactionof these pathways. Specific Aim 1 determines the limit tooxidative phosphorylation in exercise. Activation of respira-tion prior to the onset of glycolysis is used to elicit higheroxidative phosphorylation rates than measured under steadystate conditions. The range of metabolic properties amongmuscles is used to determine how the interaction of thesepathways limits oxidative phosphorylation. Specific Aim 2uses physiological methods to reduce or enhance glycolyticacidification during exercise. These manipulations of intra-cellular pH are used to determine the role of H� accumula-tion in limiting oxidative phosphorylation. Specific Aim 3determines how altering the ratio of glycolytic to oxidativecapacities in a muscle affects the limit to oxidative phos-phorylation during exercise. Endurance training is used toincrease oxidative capacity vs. glycolytic flux, while sprinttraining is used to enhance glycolytic relative to oxidativeflux. The results may demonstrate and quantify importantways by which glycolytic flux can limit oxygen consumptionin skeletal muscle. This project has clinical relevance be-cause many muscle disorders show functional deficits andreflect poor integration of metabolic systems, e.g., diabetes.An understanding of the integration of metabolism in healthytissue is the first step to understanding how failure of inte-gration limits function in diseased muscle.

Thesaurus Terms: exercise, glycolysis, muscle metabolism,oxidative phosphorylation, striated muscle acidity /alkalinity,adenosine diphosphate, blood flow, intracellular, lactate clini-cal research, human subject, magnetic resonance imaging,nuclear magnetic resonance spectroscopy, snake, ultrasoundblood flow measurement


Fiscal Year: 2001Department: RadiologyProject Start: 01-May-1998Project End: 30-Apr-2003ICD: National Institute of Arthritis and

Musculoskeletal and Skin DiseasesIRG: RAP

SUN VALLEY SKELETAL TISSUEWORKSHOP

Grant Number: 1R13AR047801-01PI Name: Jee, Webster S.

Abstract: Description (Taken from the applicant’s abstract):This application requests support for three years for the an-nual meeting of the Sun Valley Workshop on Skeletal Biol-ogy held in Sun Valley, Idaho, 2001- 2003. Participation willbe limited to 150 attendees to maintain the small group,workshop atmosphere. The Sun Valley Workshops have a 30year tradition and originally grew out of an attempt to pro-vide multidisciplinary training to younger scientists. TheWorkshops continue to emphasize active participation of jun-ior faculty and students. The Workshops have promoted in-terdisciplinary communication and the discussion time equalsor exceeds time allotted for formal presentation. The goals ofthese efforts are (1) to provide additional funds to supportstudent and junior investigator attendance and (2) to stimu-late junior and senior investigator interactions. The goals ofthe Workshop are to (1) work toward a multidisciplinarybasic and clinical synthesis of molecular, tissue and biome-chanical processes related to the pathogenesis, preventionand treatment of bone disease; (2) develop dialogue betweenbasic and clinical investigators; (3) provide training work-shops for junior faculty and students that help bridge thegaps between disciplines; (4) provide a forum for studenttraining and the opportunity for junior faculty and studentsto talk with more senior scientists in a small group setting.The theme of the 31st Sun Valley Workshop is New Direc-tions for In Vivo Research, with five topics covering Osteo-porosis in Men and Women, Genetics and Mechanical Load-ing Sensitivity, Osteocyte Roles in Cell Signaling, SkeletalDevelopment and Tissue Regeneration, and NeurotransmitterFunctions and Bone Remodeling, followed by a general dis-


983

cussion in which new directions will be identified and poten-tial collaborations and experiments developed. Session chairsand speakers have been identified. The Advisory Panel iscomposed of session chairs. A plan is presented for support-ing junior scientists and for encouraging interaction withother junior and senior scientists. There are plans to adver-tise and distribute a summary of the workshop, partly usingWeb-based, resources.

Thesaurus Terms: bone disorder, disease /disorder preven-tion /control, pathology, workshop

Institution: University of Utah110 Park BldgSalt Lake City, UT 84112

Fiscal Year: 2001Department: RadiologyProject Start: 16-Jul-2001Project End: 30-Jun-2004ICD: National Institute of Arthritis and

Musculoskeletal and Skin DiseasesIRG: AMS

MR DIAGNOSIS OF MUSCLEMETABOLISM AND FUNCTION

Grant Number: 5R01AR041928-09PI Name: Kushmerick, Martin J.

Abstract: Description: The goal of this project is to developdiagnostic procedures for human muscle function using 31-P/1-H NMR spectroscopy and 1-H NMR imaging togetherwith principles of energy balance developed in the first grantperiod. The applicants working hypothesis is that integrationof energy balance provides mechanistic information essentialto define normal and to interpret abnormal muscle functionin the intact human limb. The first three specific aims de-velop the notions of an integrative mass and energy balance.PCr content measures the supply-demand balance betweenmuscle ATPases and oxidative phosphorylation. Myoglobindesaturation measures the supply-demand balance betweenoxidative phosphorylation and muscle perfusion. IntracellularpH and lactate measures the balance between net glycolyticflux and washout by perfusion. The contractile economy inhuman limb muscles will be quantified by characterizing theATPase due to myofibrillar force generation and to excita-tion-contraction coupling. Whether PCr level during exerciseis the link between local perfusion and O2 demand will betested and the magnitude and time course of the glycogeno-lytic flux during exercise will be quantified. The fourth spe-cific aim will probe two clinical problems for imbalances inone or more components of muscle energetics. Patients withcongestive heart failure will be probed for abnormalities inATP, H� and oxygen balances and patients with type 1 dia-betes will be probed for a trade-off in abnormalities resulting

in lower functional, but near-normal integration of muscleenergetics.

Thesaurus Terms: bioenergetics, diagnosis design /evalua-tion, muscle disorder diagnosis, muscle function, muscle me-tabolism, nuclear magnetic resonance spectroscopy adenosinetriphosphate, adenosinetriphosphatase, chromium, congestiveheart failure, exercise, glycogenolysis, hydrogen ion, insulindependent diabetes mellitus, muscle contraction, myoglobin,oxidative phosphorylation, oxygen, perfusion blood flowmeasurement, clinical research, electromyography, humansubject


Fiscal Year: 2001Department: RadiologyProject Start: 01-Feb-1993Project End: 31-Jan-2003ICD: National Institute of Arthritis and


CELLULAR RESPIRATION IN MUSCLEENERGY BALANCE

Grant Number: 5R01AR036281-16PI Name: Kushmerick, Martin J.

Abstract: Description (Adapted from the applicant’s ab-stract): The number of identified human degenerative dis-eases with involvement of mitochondrial malfunction issteadily increasing. Therefore, the need for a detailed under-standing of the physiologic controls of mitochondrial func-tion in the living cell has become urgent. The experimentsand analyses proposed in this application aim to develop aquantitative and integrated understanding of mitochondrialperformance in the living cell, with emphasis on the sensitiv-ity to cytosolic (ADP), to metabolic state influenced by thetype of substrate, and to altered cytosolic (Ca��). Non-invasive spectroscopic and oxygen polarographic measure-ments of mitochondrial function will be made in excisedmouse EDL (fast-twitch) and SOL (slow-twitch) muscles atrest and during contractile activity. The mitochondrial (ADP)response functions will be determined under control andphysiologically and pharmacologically altered conditions.Completion of the stated aims will establish a paradigm forapproaching similar quantitative questions in other cells andtissues. Further, the energy balance algorithm developed willprovide a general predictive and analytical tool in the studyof cell energetics and the relation to normal cell function anddisease.

Thesaurus Terms: bioenergetics, cellular respiration, musclecell, muscle metabolism adenosine diphosphate, adenosine


984

triphosphate, adenosinetriphosphatase, calcium ion, mito-chondria, muscle contraction, muscle relaxation, oxygen con-sumption, striated muscle fluorescence microscopy, labora-tory mouse, nuclear magnetic resonance spectroscopy


Fiscal Year: 2001Department: RadiologyProject Start: 01-Oct-1988Project End: 31-Mar-2005ICD: National Institute of Arthritis and

Musculoskeletal and Skin DiseasesIRG: RAP

MRI TO STUDY CARTILAGE-BONEINTERACTIONS

Grant Number: 5R01AR046905-03PI Name: Majumdar, Sharmila

Abstract: Description (Adapted from Applicant’s Descrip-tion): This proposal focusses on using Magnetic Resonance(MR) imaging to study injury induced joint degeneration andsubsequent repair mechanisms and the manifested changes inarticular cartilage, subchondral bone and peri-articular tra-becular bone. It aims to establish the relative role and inter-action between cartilage and bone changes in injury inducedosteoarthrosis (OA). Osteoarthrosis, often caused by injuriesto the knee joint, alters mechanical joint loading, and all themajor joint tissues, including the articular cartilage, syno-vium, subchondral and trabecular bone and muscle havebeen implicated. The condition is characterized by a longasymptomatic phase when articular cartilage degenerates,reparative changes occur and radiographic changes develop.A symptomatic or painful stage then develops after irrevers-ible cartilage damage has occurred and radiographic changesprogress. It has been hypothesized that articular degenerationand progression of OA may be preceded by changes in sub-chondral and trabecular bone. Although trabecular bone in-teractions are implicated in early OA, the changes in the tra-becular bone adjoining the articular cartilage associated withOA, are unclear and the trend of changes has not been de-fined conclusively. In this context, magnetic resonance imag-ing (MR), which has recently been used to depict trabecularbone structure may potentially be a valuable tool, particu-larly since MR images may also be used to quantify the car-tilage volume, thickness, water diffusion and relaxation timewhich characterize the biochemical status of the cartilage, aswell as measure trabecular bone. The investigators proposeto make use of recent advances in MR to accurately quantify(1) the 3-D morphology and relaxation time and water diffu-sion characteristics of articular cartilage, and (2) the 3-D

architecture of the trabecular bone network adjoining thearticular cartilage, subchondral bone thickness, and densityin normal and osteoarthritic (mild and severe or Kellgren-Lawrence scale 1 and 4) subjects. They aim to derive therelation of these measures to clinical measures such as painand disability (WOMAC scale, Health Activity Question-naire, etc.) and radiographic evidence of osteoarthrosis asdemonstrated by Kellgren-Lawrence Scores. Subjects withmild OA and normals will also be followed longitudinally todetermine the progression of joint degeneration, the relativechronological occurrence of bone and cartilage changes, andthe ability of MR to predict joint degeneration and reflect therepair mechanisms postinjury.

Thesaurus Terms: articular cartilage, bone, injury, jointdisorder, osteoarthritis, pathologic process bone density, bonedevelopment, bone metabolism, cartilage development, carti-lage metabolism, synovial fluid bioimaging /biomedical im-aging, clinical research, human subject, magnetic resonanceimaging

Institution: University of California San Francisco500 Parnassus AveSan Francisco, CA 94143

Fiscal Year: 2001Department: RadiologyProject Start: 17-Sep-1999Project End: 31-Aug-2004ICD: National Institute of Arthritis and

Musculoskeletal and Skin DiseasesIRG: ZHD1

ENERGY SAVING MECHANISMS INMUSCLE

Grant Number: 5F32AR008590-02PI Name: Moon, Brad R.

Abstract: Description Human and animal movement oftenuses energy more efficiently than expected from the effi-ciency of muscle alone. The extra efficiency often resultsfrom recovery of energy by elastic recoil of muscles andtendons after being stretched, Understanding such energysaving mechanisms requires examining the relationship be-tween intracellular metabolism and extracellular mechanicaloutput. Rattlesnake tailshaker muscle is an ideal model sys-tem for studying the relationship between energy supply anddemand, including energy saving mechanisms, in muscle.Tailshaker muscle contracts at higher rates without fatigue;its single motor unit and simple all or none contractions fa-cilitate experiments on physiology and mechanisms. Thisresearch will address (1) the force and mechanical work ofmuscle contraction. (2) The mechanisms for minimizing thecost of contraction, including elastic recycling, (3) Muscleefficiency with and without energy saving mechanisms. This


985

work will employ force transducers for measuring musclesforces, sonomicrometry for measuring muscle lengthchanges, and nuclear magnetic resonance spectroscopy formeasuring muscle energetics in vivo. Together, these experi-ments will promote understanding of the relationships amongmuscle metabolism, biomechanics, and performance, as wellas of muscle function during exercise, training, and recoveryfrom injury or surgery.

Thesaurus Terms: bioenergetics, biomechanics, muscle con-traction, muscle metabolism adenosine triphosphate, biologi-cal model, elasticity, muscle relaxation, muscle tension elec-tromyography, nuclear magnetic resonance spectroscopy,snake


Fiscal Year: 2001Department: RadiologyProject Start: 01-Mar-2001Project End:ICD: National Institute of Arthritis and

Musculoskeletal and Skin DiseasesIRG: GRM

MEASUREMENT OF THICKNESS/DENSITYOF THE PROXIMAL FEMUR

Grant Number: 5R03AR046859-02PI Name: Prevrhal, Sven

Abstract: DESCRIPTION (Taken from the application): Hipfracture is one of the most severe implication of Osteoporo-sis, a disease affecting millions of elderly people world-wide. The clinically established method to predict a person’ship fracture risk, bone densitometry, cannot separately mea-sure the status of trabecular and cortical bone but only re-ports overall bone density. There is evidence that both com-partments individually contribute to bone strength but aredifferently affected by aging or osteoporotic changes andtherapeutic regimens. This research effort will approach thefollowing questions: Can the density and the thickness ofcortical bone in the proximal femur be measured accuratelywith volumetric Quantitative Computed Tomography(vQCT)? Does the knowledge of these parameters aid in pre-dicting mechanical integrity in addition to standard bonedensitometry? To what extent is the technique applicable invivo? To assess the accuracy of vQCT, a comparison to Mi-cro-CT is planned. Micro-CT is a Computed Tomographytechnique on microscopic level (the spatial resolution is 25mm for the instrument being used) and has recently beenextended to scan whole proximal femora. It can therefore beused as a gold standard to evaluate vQCT. Out of a total of25 excised cadaveric proximal femora from elderly women

who did not have diseases known to affect bone, 5 will bescanned with vQCT and Micro-CT. The analysis tools,which will comprise segmentation of the cortical wall andlocal measurement of cortical bone mineral density andthickness, will be applied to both data sets. The other 20specimens will be subjected to vQCT, standard bone densi-tometry and mechanical testing. During the latter, bone elas-ticity and ultimate failure load will be recorded. The gath-ered data will allow to estimate the relative contribution ofthe cortical thickness and density to mechanical integrity andto locate the most sensitive regions of the cortex. The ques-tion of whether a vQCT scan of cortical bone can add infor-mation to standard bone densitometry can also be an-swered. The third part of the study will focus on clinicalfeasibility of vQCT of cortical bone. Its specific aim isreducing the radiation exposure by limiting the CT scanvolume and decreasing the amount of radiation used. Byanalyzing the impact of the consequential increase of im-age noise and loss of spatial resolution on the measurabil-ity of cortical density and thickness optimal CT imagingparameters will be derived.

Thesaurus Terms: biomechanics, bone density, computedaxial tomography, femur, photon absorptiometry phantommodel female, postmortem


Fiscal Year: 2001Department: RadiologyProject Start: 01-Apr-2000Project End: 31-Mar-2003ICD: National Institute of Arthritis and

Musculoskeletal and Skin DiseasesIRG: ZAR1

PROTEOGLYCAN MEASUREMENT INOSTEOARTHRITIS IN VIVO

Grant Number: 5R01AR045404-03PI Name: Reddy, Ravinder

Abstract: DESCRIPTION (Adapted from Applicant’s Ab-stract): Osteoarthritis is a major cause of morbidity in thepopulation over 50, affecting more than 40 million Ameri-cans. It also imposes considerable expense on the health caresystem. There is currently no cure for this debilitating dis-ease and the effective treatment is, at best, focused on symp-tomatic relief. Cartilage degeneration is thought to be theprimary pathology associated with the disease. Recent devel-opments in chondro-protective drugs and gene therapy havegenerated substantial demand for noninvasive techniques fordetecting changes in cartilage. These developments and anyother potential therapies can effectively work only if the dis-


986

ease is detected early. Among the most significant earlychanges in articular cartilage in osteoarthritis is the loss ofproteoglycans (PG). However, currently there is no reliablequantitative noninvasive method available for detecting andevaluating these early changes. The applicants proposed toquantitatively evaluate the potential of sodium magnetic res-onance imaging (MRI) for detecting and quantifying proteo-glycan (PG) changes in an in vivo model of early osteoar-thritis. To accomplish this task, the applicants proposed tofirst characterize the technique in bovine cartilage specimenstreated with a known mediator of extracellular matrix degra-dation. Secondly, they would inject to cytokine injectionbased model of PG degradation in the dog knee to createartificial osteoarthritic condition and measure dose dependentchanges in cartilage degeneration. Specifically, they proposedto inject the cytokine into the intra-articular space of thehind limb knee, using the contralateral knee as control. Afterthe appropriate time interval, the applicants proposed to per-form sodium MR on both the treated and control knee tomeasure changes in sodium content. After the MRI experi-ments, harvested cartilage tissue would be subjected to spec-trophotometric, histologic, and immunohistochemistry deter-mination of PG content and its spatial distribution. Thechanges in sodium content as measured from MRI and thechanges in PG content (measured by spectrophotometry, his-tology and immunohistochemistry) would be correlated.These measurements would establish the capability of so-dium MR in determining the changes that occur during earlydegeneration of cartilage in vivo. Since it is possible to per-form sodium MR in a noninvasive clinical setting, thismethod can be immediately exploited in human studies fordetecting early changes due to QA. Once developed, thismethod would have a major impact on the ability to make anearly and appropriate therapeutic intervention, monitor theclinical outcome, and aid in evaluating new treatment modal-ities.

Thesaurus Terms: articular cartilage, diagnosis design/evaluation, magnetic resonance imaging, osteoarthritis, pro-teoglycan, skeletal disorder diagnosis biomarker, cytokine,diagnostic test, disease /disorder model, noninvasive diagno-sis, sodium ion animal tissue, bioimaging /biomedical imag-ing, dog, histology, immunocytochemistry, spectrometry

Institution: University of PennsylvaniaPhiladelphia, PA 19104-6380


Musculoskeletal and Skin DiseasesIRG: ZRG1

EARLY DETECTION OF OSTEOARTHRITIS

Grant Number: 5R01AR045242-03PI Name: Reddy, Ravinder

Abstract: Description (Adapted from Applicant’s Abstract):Osteoarthritis (OA) is one of the most common disorders ofhumans. Osteoarthritis is a major cause of morbidity in thepopulation over 50 and affects more than 40 million Ameri-cans. It also imposes considerable expense on the health caresystem. Although evidence implicates cartilage degenerationas the primary cause for OA, no cure exists as yet. Currenttreatments relieve symptoms but do not inhibit disease pro-gression. Therefore, the development of new treatments is ofutmost importance. Ideally, methods should target the earlystages of the disease. However, the development of promis-ing new therapies is hindered by the lack of noninvasivemethods to detect early stages of cartilage degeneration. Inorder to address this, one needs to understand the structuraland biochemical changes that occur during degeneration andto correlate these properties to measurable parameters ob-tained by a noninvasive method. The applicants proposed toexploit MR properties of sodium to monitor structural andbiochemical changes in cartilage in order to determine theextent of the cartilage degeneration. They proposed to mea-sure MR properties of sodium by imaging and by spectros-copy. The measurements will be made on normal bovinecartilage, on bovine cartilage (in which proteoglycans areremoved selectively to mimic the structural and biochemicalchanges that occur in OA), and on human cartilage plugswith different stages of OA. The results obtained from theenzymatically degraded studies will be correlated to the os-teoarthritic human specimens which have been histologicallygraded to assess the extent of degeneration. The measuredMR properties rely not only on tissue sodium content andthereby contrast, but are also dependent on structural andbiochemical changes. Therefore, this proposed research willaid in the early diagnosis of OA as well as aid in the devel-opment of drugs and treatment therapies.

Thesaurus Terms: articular cartilage, diagnosis design/evaluation, early diagnosis, osteoarthritis, skeletal disorderdiagnosis interleukin 1, proteoglycan, sodium animal tissue,clinical research, human subject, magnetic resonance imag-ing, spectrometry


Fiscal Year: 2000Department: RadiologyProject Start: 01-Jun-1998Project End: 31-May-2002ICD: National Institute of Arthritis and

Musculoskeletal and Skin DiseasesIRG: DMG


987

BIOMECHANICS OF FOOT/ANKLEINJURIES USING 3D IMAGING

Grant Number: 5R01AR046902-02PI Name: Udapa, Jayaram K.

Abstract: Description (Adapted from the Applicant’s Ab-stract): The broad goal of this research is to apply advancedimaging techniques to develop, in a patient-specific manner,a quantitative understanding of how the joints function, andof how they are affected by soft-tissue injuries and by theirsurgical treatment. The central hypothesis is that this under-standing will lead to reliable, early and improved diagnosticand therapeutic procedures for joint ailments involving soft-tissue injuries. The focus of this proposal is on the anklejoint and its ligament injuries. The Specific Aims are: (1) toinvestigate ankle flexibility characteristics associated withspecific ligament injuries; (2) to determine relative internalbone movements at the ankle and subtalar joints associatedwith ligament injuries; (3) to develop stress radiography andstress slice MRI that are optimum to show bone displace-ments associated with specific ligament injuries; and (4) toobjectively assess the stabilization achieved by surgical re-construction techniques for treating ligament damage. Tofulfill Aim 1, a special mechanical device will be builtand flexibility data will be gathered from normal injured,and post-surgical joints. To fulfill Aim 2, methods of MRIimaging under stress, image segmentation, 3-D reconstruc-tion, and 3-D analysis will be developed. The resultinginjury-specific internal displacement data will be utilizedto devise simple, cost-effective methods, such as stressradiography and stress slice MRI, that best show the ef-fect of injury (Aim 3). Such data will be used to objec-tively assess surgical reconstruction techniques based onpre- and post-operative scans and measurements (Aim 4).The expected outcomes of this research are twofold: (1)simple, cost-effective and high specificity methods of di-agnosing ankle ligament injuries; and (2) new knowledgeabout the exact displacements occurring at the ankle andsubtalar joints as a result of ligament injuries or their sur-gical repair.

Thesaurus Terms: ankle, biomechanics, foot, magnetic res-onance imaging, method development, skeletal imaging /vi-sualization, skeletal injury joint ligament, skeletal disorderdiagnosis bioimaging /biomedical imaging, clinical research,human subject


Fiscal Year: 2001Department: RadiologyProject Start: 04-Apr-2000Project End: 31-Mar-2003

ICD: National Institute of Arthritis andMusculoskeletal and Skin Diseases

IRG: ORTH

NMR IMAGING AND STEREOLOGICANALYSIS OF TRABECULAR BONE

Grant Number: 5R01AR041443-08PI Name: Wehrli, Felix W.

Abstract: Most osteoporotic fractures occur at skeletal loca-tions rich in cancellous (trabecular) bone. The most widelyused criterion for risk assessment is bone mineral density(BMD). However, it is well known that BMD is not a satis-factory predictor of fracture risk. Indeed, there is now com-pelling theoretical, experimental and clinical evidence for therole of architecture as an additional predictor of the bone’smechanical competence. During the past cycles of thisproject we have shown both in the laboratory and in patientstudies that magnetic resonance micro-imaging (mu-MRI), inconjunction with image analysis, can predict the trabecularbone’s mechanical behavior and clinical outcome, respec-tively. In preliminary work we have conceived a new ap-proach toward a complete quantification of cancellous bonearchitecture based on three-dimensional digital topologicalanalysis and have shown that this techniques accurately de-scribes the conversion of trabecular plates to rods, a processwell known to occur during aging and, in particular, in os-teoporosis. Paralleling these developments we have madesignificant progress in data acquisition, processing and analy-sis, which improved both sensitivity and precision of mu-MRI to the extent that longitudinal studies are now feasible.During the next phase of the project we propose (i) to fur-ther develop and evaluate digital topological analysis andadditional structural analysis tools; (ii) to determine the pre-cision of the mu-MRI-derived topological and scale parame-ters in specimens and representative patients; (iii) to assessthe sensitivity of the method to detect architectural changesduring early menopause in a pilot project involving womentreated with estrogen and their controls; (iv) to compare sen-sitivity and precision of mu-MRI with DEXA and p-QCT.The overall hypothesis to be tested is that mu-MRI-basedcancellous bone structural analysis is sensitive and reproduc-ible and capable of detecting changes in cancellous bonearchitecture as they occur over time, either as a result of nor-mal changes or in response to treatment. The long-term goalof the work proposed is to establish “virtual bone biopsy,”analogous to physical bone biopsy, by three-dimensional ar-chitectural analysis of mu-MRI data collected in vivo, as ameans to follow patients longitudinally, either as a methodfor assessing osteoporosis risk or for evaluating treatmentefficacy.



988


Fiscal Year: 2001Department: RadiologyProject Start: 01-Jan-1993Project End: 31-Mar-2004ICD: National Institute of Arthritis and


IN VIVO ASSESSMENT OF STEROID-INDUCED OSTEOPENIA


Abstract: Calcium homeostasis is governed by the interplayof intestinal calcium absorption, renal excretion and skeletalexchange of calcium. In the adult skeleton, bone formationand resorption are closely coupled. Supraphysiological levelsof corticosteroids can interfere with calcium metabolismthrough various pathways, resulting in decreased bone for-mation and enhanced bone resorption, and thus leading toaccelerated osteopenia. The resulting fractures typically oc-cur at sites rich in trabecular bone, though cortical thinningis known to occur as well. Further, the architectural changesparalleling the reduction in mass density are different fromthose in involutional osteoporosis and there are indicationsthat steroid-induced osteopenia compromises skeletalstrength at higher mass density. The present project seeks toinvestigate the effects of corticosteroids on trabecular mor-phology and the biomechanical consequences of these archi-tectural changes by means of magnetic resonance (MR) mi-cro-imaging and dual-energy X-ray absorptiometry (DEXA)in vivo and in vitro in a rabbit model. The rabbit is particu-larly suited as model; in its mature skeleton remodeling pre-vails over modeling and significant bone loss occurs uponexposure to corticosteroids in comparatively short times.Most prior work has been done post mortem by means ofdensitometric and histomorphometric techniques. Using newultrahigh-resolution magnetic resonance (MR) imaging andcomputer-based image analysis we propose to evaluate thesteroid-induced skeletal changes serially in vivo. Specifically,we propose to test the following hypotheses: (1) The reduc-tion in bone mass results in changes of the trabecular micro-structure, which can be characterized quantitatively by invivo 3D MR imaging and image processing. (2) The timecourse of the changes in trabecular bone mass and architec-ture, in response to administration of dexamethasone, can beevaluated by serial quantitative MRI measurements in vivoin a rabbit model. (3) Discontinuation of corticosteroid ad-ministration leads to partial re-establishment of skeletal in-tegrity and mechanical competence. (4) Supplementation ofcorticosteroid treatment with gonadal steroids alleviates bone

loss. (5) The corticosteroid-induced changes in trabecularmicroarchitecture are accompanied by a predictable reductionin the bone’s elastic modulus.

Thesaurus Terms: corticosteroid, hormone regulation /con-trol mechanism, osteopenia bone density, dexamethasone,diet therapy, dietary supplement, elasticity, estrogen, femur,hormone therapy, pathologic bone resorption, substantiaspongiosa, testosterone densitometry, laboratory rabbit, mag-netic resonance imaging, nutrition related tag, radiography




IN VIVO ASSESSMENT OF STEROID-INDUCED OSTEOPENIA


Abstract: Calcium homeostasis is governed by the interplayof intestinal calcium absorption, renal excretion and skeletalexchange of calcium. In the adult skeleton, bone formationand resorption are closely coupled. Supraphysiological levelsof corticosteroids can interfere with calcium metabolismthrough various pathways, resulting in decreased bone for-mation and enhanced bone resorption, and thus leading toaccelerated osteopenia. The resulting fractures typically oc-cur at sites rich in trabecular bone, though cortical thinningis known to occur as well. Further, the architectural changesparalleling the reduction in mass density are different fromthose in involutional osteoporosis and there are indicationsthat steroid-induced osteopenia compromises skeletalstrength at higher mass density. The present project seeks toinvestigate the effects of corticosteroids on trabecular mor-phology and the biomechanical consequences of these archi-tectural changes by means of magnetic resonance (MR) mi-cro-imaging and dual-energy X-ray absorptiometry (DEXA)in vivo and in vitro in a rabbit model. The rabbit is particu-larly suited as model; in its mature skeleton remodeling pre-vails over modeling and significant bone loss occurs uponexposure to corticosteroids in comparatively short times.Most prior work has been done post mortem by means ofdensitometric and histomorphometric techniques. Using newultrahigh-resolution magnetic resonance (MR) imaging andcomputer-based image analysis we propose to evaluate thesteroid-induced skeletal changes serially in vivo. Specifically,we propose to test the following hypotheses: (1) The reduc-


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tion in bone mass results in changes of the trabecular micro-structure, which can be characterized quantitatively by invivo 3D MR imaging and image processing. (2) The timecourse of the changes in trabecular bone mass and architec-ture, in response to administration of dexamethasone, can beevaluated by serial quantitative MRI measurements in vivoin a rabbit model. (3) Discontinuation of corticosteroid ad-ministration leads to partial re-establishment of skeletal in-tegrity and mechanical competence. (4) Supplementation ofcorticosteroid treatment with gonadal steroids alleviates boneloss. (5) The corticosteroid-induced changes in trabecularmicroarchitecture are accompanied by a predictable reductionin the bone’s elastic modulus.

Thesaurus Terms: corticosteroid, hormone regulation /con-trol mechanism, osteopenia bone density, dexamethasone,diet therapy, dietary supplement, elasticity, estrogen, femur,hormone therapy, pathologic bone resorption, substantiaspongiosa, testosterone densitometry, laboratory rabbit, mag-netic resonance imaging, nutrition related tag, radiography




MRI-BASED VIRTUAL BONE BIOPSY INRENAL OSTEODYSTROPHY


Abstract: Description (Taken from the application): Renalosteodystrophy (ROD) is a multifactorial disorder of boneremodeling, resulting in skeletal deformities and fractures.The histologic spectrum of ROD ranges from markedly in-creased bone turnover to absent bone turnover. High-turn-over disease [osteitis fibrosa (OF)] is caused by secondaryhyperparathyroidism, and was once a universal complicationof renal failure. OF is characterized by trabecular bone scle-rosis and severe cortical thinning. However, the incidence oflow-turnover disease [adynamic bone disease (AD)] is nowrapidly approaching that of OF. AD is characterized by de-creased bone formation and trabecular thinning. The emer-gence of AD may be due to therapies aimed at preventingOF, such as calcium-containing phosphate binders and activevitamin D sterols. Current studies are focusing on the devel-opment of new strategies to prevent OF without suppressingnormal bone remodeling. Knowledge of the underlying bonestructural abnormalities is essential for developing, selecting

and monitoring therapeutic regimens. To date, bone biopsy isthe only available tool for characterizing ROD. However, theinvasive nature of the procedure has limited its use in clini-cal care. In addition, bone biopsy is subject to sampling er-ror and provides little information regarding cortical struc-ture and bone’s mechanical competence. Non-invasive mea-sures of bone turnover have been disappointing. There issignificant overlap in serum PTH levels among patients withAD, OF and normal bone tumover states. Bone densitometrictechniques are rarely informative because the projected bonemass represents the integrated sum of the cortical and trabec-ular components. We hypothesize that a ’virtual bone bi-opsy’ (VBB) based on micro magnetic resonance imaging(u-MRI), in conjunction with image processing, will providea non-invasive technique to simultaneously assess trabecularstructure and cortical thinning. VBB is inherently three-di-mensional, is less subject to sampling error, and can be per-formed repeatedly in longitudinal studies. This pilotproject proposes (1) to design and construct a u-MRI coilsto assess trabecular structure in the distal tibia; (2) to de-velop MR-based measures of cortical thickness and cross-sectional area in the tibial diaphysis; and (3) to performthese measures VBB in healthy controls, and in dialysispatients with clinical evidence of extreme high-turnover orlow-turnover bone disease. The development of a nonin-vasive technique to assess cortical and trabecular structurein ROD will facilitate studies of the prevention, treatmentand assessment of the biomechanical implications of thisprevalent disease.

Thesaurus Terms: biopsy, computer assisted diagnosis,computer simulation, diagnosis design /evaluation, imageprocessing, magnetic resonance imaging, noninvasive diag-nosis, pathologic bone resorption, renal rickets, skeletal im-aging /visualization bioimaging /biomedical imaging, clinicalresearch, human subject



Musculoskeletal and Skin DiseasesIRG: ZAR1

QUANTITATIVE EVALUATION OFTRABECULAR BONE AND MARROW


Abstract: Osteoporosis is a debilitating disease causing skel-etal impairment resulting from loss of cancellous and cortical


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bone, eventually leading to fractures of the femur, vertebrae,wrist and humerus. Current methods for assessment of skele-tal competence rely almost entirely on bone mineral density(BMD), which is widely considered the primary risk factorfor the occurrence of fractures. However, the recognition thatmass density is an unsatisfactory predictor of bone strengthhas, more recently, spurred the search for alternative modali-ties focusing on ’bone quality,’ notably architecture. The P.I.and his co-workers have, during the prior phases of thisproject, shown theoretically and experimentally that the sus-ceptibility-induced MR signal decay rate (R2’) is related tothe density and orientation of the trabeculae and that thisparameter is able to predict the bone’s elastic modulus invitro. Further, clinical evidence was provided that decreasedtrabecular bone marrow R2’ augments the probability for theoccurrence of vertebral fractures and that BMD and R2’jointly improve fracture prediction. The central hypothesis tobe tested is that, along with improved methodology and anew MR-based measurement of trabecular bone volume frac-tion (BVF), a single-modality examination that evaluatesboth R2’ and BVF, better predicts fractures than bone densi-tometry. We shall examine the above hypothesis by pursuingthe aims below; specifically, we shall 1. Further develop andvalidate improved methodology for acquiring and processingquantitative MR data for measuring R2’, conceived duringthe current cycle of the project. 2. Evaluate a new MRmethod for measuring cancellous bone volume fraction andassess its relationship to R2’ in cancellous bone models andspecimens. 3. Measure both R2’ and BVF in a cohort ofperi- and postmenopausal normal, osteopenic and osteopo-rotic women and determine the association between the twoindependently measured parameters and DEXA BMD. 4.Determine the diagnostic accuracy of the techniques of Aims1 and 2 relative to DEXA BMD z-scores as a means to as-sess fracture status in the spine in the subjects examined un-der Aim 3.

Thesaurus Terms: diagnosis design /evaluation, diagnosisquality /standard, hip fracture, osteoporosis, skeletal disorderdiagnosis bone density, female, magnetic resonance imaging,pathologic bone resorption, postmenopause, tensile strength,vertebrae clinical research, densitometry, human subject,photon absorptiometry


Fiscal Year: 2000Department: RadiologyProject Start: 01-Jul-1991Project End: 31-Jul-2002ICD: National Institute of Arthritis and


National Institute on AlcoholAbuse and Alcoholism

PET IMAGING OF BRAIN OPIOIDRECEPTORS IN ALCOHOLISM

Grant Number: 5R01AA011872-03PI Name: Frost, James J.

Abstract: Alcohol abuse and alcoholism is a major publichealth problem in the United States, but little is known of theneurochemical pathways in the human brain that mediate thereinforcing and other properties of ethanol. The brain’s endoge-nous opioid system is known to play an important role in re-ward mechanisms and recently it has been targeted in treatmentefforts using the opiate antagonist naltrexone. The rationale forusing opioid blockade in the treatment of alcoholism is wellfounded in experimental animal models of human alcohol useand abuse, but we know little about the underlying differencesin the endogenous opioid system between healthy individualsand alcoholics. Positron emission tomography (PET) is a non-invasive imaging method that can be used to image and quanti-tate a number of neuromarkers and mu opioid receptors can beimaged in the human brain by PET using the well-validatedligand C-11 carfentanil. Our long-term goal is to better under-stand the function of the endogenous brain opioid system inalcohol use and abuse, and determine if it is involved in in-creasing the risk of alcoholism. The use of PET to measureregional mu opioid receptors is an approach that could providenew insight into the role of the endogenous opioid system inalcoholism. The specific aims of this study are: l) Measure re-gional mu opioid receptor binding by PET in non-alcoholic menand women with a positive family history of alcoholism.; 2)Measure regional brain mu opioid receptor binding by PET inFHP and FHN alcoholic men and women and relate regionalbinding to behavioral measures of alcohol abuse; and 3) Mea-sure the change in regional mu opioid receptor binding duringone month controlled abstinence from ethanol in alcoholic menand women.

Thesaurus Terms: alcoholism /alcohol abuse, brain metabo-lism, opioid receptor, positron emission tomography, receptorbinding craving, drug withdrawal, emotion, relapse /recurrence,substance abuse related behavior bioimaging /biomedical imag-ing, clinical research, human subject, statistics /biometry

Institution: Johns Hopkins University3400 N Charles StBaltimore, MD 21218

Fiscal Year: 2001Department: RadiologyProject Start: 01-Jul-1999Project End: 31-Mar-2003


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ICD: National Institute on Alcohol Abuseand Alcoholism

IRG: ZRG1

PET IMAGING OF THE 5HTTRANSPORTER IN ALCOHOLISM

Grant Number: 5R01AA011653-03PI Name: Szabo, Zsolt

Abstract: Impaired serotonin (5-HT) function has been impli-cated as a possible factor in the biological vulnerability for al-coholism, but most studies of the 5-HT system have been per-formed in animals or, if performed in humans, they involvedonly indirect measurements to assess the 5-HT system in thebrain. The status of the 5-HT neurons in the brain of living al-cohol dependent individuals remains unknown. To investigatethe 5-HT system of the brain, quantitative PET studies of thebrain 5-HT transporter (5-HTT; an established marker of seroto-nin neuron integrity) are proposed using [11C] McN5652 asradioligand for four groups of human subjects: family historynegative (FHN) controls, family history positive (FHP) controls,FHN recovering alcoholics, and FHP recovering alcoholics. Thehypothesis to be tested is that radioligand binding to the 5-HTtransporter is significantly reduced as a function of both alco-holism and family history of alcoholism. Serotonin function willalso be measured by quantification of plasma prolactin and cor-tisol increase in response to fluoxetine. The genetic aspectof 5-HT impairment will be investigated by measuring thefrequency of specific polymorphisms of the 5-HTT gene.The hypothesis is that FHP alcoholics and FHP controlswill have a higher frequency of the s-variant allele, theallele which has been associated with reduced 5-HTT ex-pression/function in in vitro studies. The frequency of thes- variant allele is predicted to be higher in subjects withreduced 5-HTT densities (as determined by PET) and withreduced hormonal responses to fluoxetine. The results ofthis project will lead to better understanding of the role ofserotonin in the biological vulnerability for alcoholismand may lead to improved approaches to prevent and treatalcoholism.

Thesaurus Terms: alcoholism /alcohol abuse, brain imaging/visualization /scanning, brain scanning, family genetics, positronemission tomography, serotonin transporter cortisol, fluoxetine,functional ability, genetic polymorphism, hormone regulation/control mechanism, isoquinoline, mental disorder diagnosis,neural transmission, neuroendocrine system, prolactin affinitylabeling, bioimaging /biomedical imaging, blood chemistry,clinical research, human subject, magnetic resonance imaging,polymerase chain reaction, radioimmunoassay, radiotracer

Institution: Johns Hopkins University3400 N Charles StBaltimore, MD 21218

Fiscal Year: 2001

Department: Radiology and Radiological SciProject Start: 01-Jan-1999Project End: 31-Dec-2003ICD: National Institute on Alcohol Abuse

and AlcoholismIRG: ZRG4

CHRONIC ALCOHOL ABUSE—EFFECTSON HIV CNS MORBIDITY

Grant Number: 3P01AA011493-02S1PI Name: Weiner, Michael W.

Abstract: The HIV epidemic is a major public health prob-lem in the United States and the world. Nervous disease is afrequent cause of morbidity and mortality for the more than1 million people infected with HIV in the U.S. Recently,with the success of protease inhibitor therapy in the treat-ment of systemic HIV disease and the limited penetration ofprotease inhibitors into the nervous system, there is a devel-oping awareness that CNS disease may become of evenmore importance in the clinical management of HIV diseaseand the HIV epidemic. Although heavy alcohol use, whichhas its own CNS and PNS toxicity, is common in popula-tions at high risk for HIV infection, almost no research di-rectly addresses the effect of heavy alcohol use on HIV dis-ease severity and progression. The primary goal of this Pro-gram Project is to determine the effect of chronic heavyalcohol use on CNS and PNS morbidity in HIV disease. Thiseffect may result from behavioral and biological effects ofchronic alcohol use increasing the rapidity of the progressionof the overall HIV disease process or decreasing the re-sponse to HIV treatment and from alcohol’s own nervoussystem toxicity. These mechanisms and their effects will beevaluated in a longitudinal study of HIV� and HIV-chronicheavy drinkers (HIV� HDs & HIV-HDs) and light/non-drinkers (HIV � L/NDs & HIV-L/NDs). The ProgramProject goals are to: Determine whether HIV� HDs havedecrease care seeking and HIV treatment adherence, an in-creased prevalence of unprotected sex, poorer nutrition,and/or decreased drug levels of HIV treatment medications.Determine whether a) HIV � HDs have a greater rate ofHIV systemic disease progression or reduced treatment re-sponse, and b) the degree to which the behavioral and drugmetabolism effects of chronic heavy drinking underlie anyincreased rate of HIV systemic disease progression or re-duced treatment response. . Determine whether HIV� HDshave greater CNS and PNS morbidity and progression ofsuch morbidity than HIV� LDs. Determine whether theseeffects of chronic heavy alcohol use are additive or exceedadditive effects. Determine the impact of CNS and PNS mor-bidity on the quality of life of HIV� individuals. In HIV�subjects, determine the association of CNS and PNS morbidityand its progression with systemic measures of viral load, im-mune suppression and nutritional status, and with CSF measures

NIAAA Academic Radiology, Vol 9, No 8, August 2002

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of CNS disease, and determine whether these associations differbetween heavy chronic alcohol drinkers and light/non-drinkers.We will study four groups of subjects: 120 HIV� HDs, 120HIV� L/NDs, 60 HIV-HDs, and 60 HIV-L/NDs.

Thesaurus Terms: AIDS /HIV neuropathy, alcoholism /al-cohol abuse

Institution: Northern California Institute Res &Educ

For Research and EducationSan Francisco, CA 94121

Fiscal Year: 2000Department:Project Start: 07-Sep-1998Project End: 31-Aug-2003ICD: National Institute on Alcohol Abuse

and AlcoholismIRG: ZAA1

National Library of Medicine

INTERACTIVE 4D VISUALIZATION OFCONGENITAL HEART DISEASE

Grant Number: 5R29LM006486-05PI Name: Brummer, Marijn

Abstract: Description (Taken from application abstract):Development and clinical testing of a new family of soft-ware display techniques for cardiovascular magnetic reso-nance imaging (MRI) data are proposed. These efforts areanticipated to enhance the diagnostic process and facilitatecurrently challenging decisions on therapy and patient man-agement of children with severe congenital heart disease. Inparticular, assessment of hypoplastic left and right heart syn-dromes and univentricular heart require improved visualiza-tion and function quantification tools for evaluation andmonitoring of severity and functional status. The initial de-sign of the system is largely completed. Design features ofthe software system are footed on recent improvements inwidely available 3-D rendering hardware and on observa-tions made during 11 years of clinical experience with car-diac MRI at the investigation site During the first year of theproject a clinically usable prototype can be delivered fortesting and user feedback, including a highly streamlinedimage data pipeline, sophisticated contemporary user inter-face, and other features essential for extensive clinical evalu-ation. The proposed dynamic 3-D display technique com-bines a maximum of anatomical information available in amulti-slice ECG-triggered cine-MRI scan of the heart, bydisplaying all slice images simultaneously in correct 3-Dgeometric perspective in dynamic fashion (a cyclic movie of

the beating heart). A user can manipulate in real-time thedisplayed slice objects to improve visualization of regionalanatomy, generate reformatted views along cutting planeson-the-fly, and annotate the display for other observers byhighlighting 3-D regions of interest. The proposed effort in-cludes (1) development of first prototype using extensivepreexisting in-house developed software libraries, (2) clinicalevaluation of the technique from the second year of theproject onwards, (3) implementation of enhancements includ-ing quantitation and display of essential cardiac function pa-rameters including hemodynamic data and follow-up on userfeedback, and adding limited DICOM I/O functionality.

Thesaurus Terms: child (0-11), computer assisted diagno-sis, congenital heart disorder, diagnosis design /evaluation,heart imaging /visualization /scanning, interactive multimediacomputer program /software, computer system design /evalu-ation, congenital cardiovascular disorder, functional magneticresonance imaging, image enhancement, infant human (0-1year) bioimaging /biomedical imaging, cardiovascular imag-ing /visualization, clinical research, human subject


Fiscal Year: 2001Department: RadiologyProject Start: 01-May-1997Project End: 30-Apr-2002ICD: National Library of MedicineIRG: BLR

DIGITAL HAND ATLAS IN ASSESSMENTOF SKELETAL DEVELOPMENT

Grant Number: 5R01LM006270-05PI Name: Huang, H. K.

Abstract: Description (adapted from the Abstract): Bone ageassessment is a procedure frequently performed on pediatricpatients to evaluate their growth. It is an important procedurein the diagnosis and management of endocrine disorders,diagnostic evaluation of metabolic and growth abnormalities,deceleration of maturation in a variety of syndromes, malfor-mations, and bone dysplasias. It is also used for consultationin planning orthopedic procedures. A simple method forbone age assessment is atlas matching by a left-hand wristradiograph against a small reference set of atlas patterns ofnormal standards developed by Greulich and Pyle in the1950s. However, these reference radiographs do not reflectskeletal development in children and adolescents of today’sEuropean, African, Hispanic or Asian descent. Because racialdiversity and racial mixing in the United States are increasing,reevaluation of the use of skeletal age standards when appliedto children of diverse ethnicity is needed. This proposal is thesecond phase of a six-year continuing effort and intends to


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complete the development of a digital hand atlas with a largestandard set of normal hand and wrist images of children offour diverse ethnic groups, and to implement a Web-basedcomputer-aided diagnostic system for bone age assessment. Thedigital atlas, comprising a large set of 1,120 reference imagesand computer-extracted bone objects and quantitative features,removes the disadvantages of the currently out-of-date Greulich-Pyle atlas and allows the bone age assessment to be computer-ized. These images are collected from evenly distributed normalnewborn to 18 years of age, male and female, European, Afri-can, Hispanic, and Asian descent. Quantitative features on apatient examined hand image are extracted on the Web serverand then compared with patterns from the atlas database to as-sess the bone age.

Thesaurus Terms: bone development, computer assisteddiagnosis, computer program /software, digital imaging,hand, information system, racial /ethnic difference archive,bone imaging /visualization /scanning, computer system de-sign /evaluation, gender difference, image enhancement, ra-diodiagnosis, wrist African American, Asian American, His-panic American, bioimaging /biomedical imaging, caucasianAmerican, child (0-11), clinical research, data collectionmethodology /evaluation, human subject


Fiscal Year: 2001Department: RadiologyProject Start: 01-May-1997Project End: 30-Apr-2003ICD: National Library of MedicineIRG: ZLM1

COMPONENT BASED TOOLS FORCONNECTIONIST CLASSIFICATION

Grant Number: 1R01LM006538-01PI Name: Ohno-Machado, Lucila

Abstract: DESCRIPTION (Taken from application abstract):We propose to develop automated techniques to facilitate classi-fication and pattern recognition in biomedical data sets. Thesetechniques will involve development of novel neural networkarchitectures, as well as formulation of principles governingtheir creation and explanation of results. Specifically, as a solu-tion to the problem of recognizing infrequent categories, wewill develop hierarchical and sequential systems of feedforwardneural networks that make use of information such as (a) priorknowledge of the domain, and/or (b) natural clusters defined byclustering or unsupervised learning methods to develop interme-diate classification goals and utilize a divide-and-conquer ap-proach to complex classification problems. Additionally, wewill develop generic tools for pre-processing input data by mak-

ing transformations of original data, reducing dimensionality,and producing training and test sets suitable for cross-validationand bootstrap. We will build tools for evaluating results thatmeasure calibration, resolution, importance of variables, andcomparisons between different models. Furthermore, we willdevelop standardized interfaces for certain existing classificationmodels. We will use a component-based architecture to buildour neural network and write interfaces to existing classificationmodels (e.g., regression trees, logistic regression models) so thatthey can be interchanged in a user-friendly manner. We will useour preprocessing modules to prepare data to be entered in avariety of classification models. The results will be evaluated inisolation, and later combined to test the hypothesis that thecombined system performs better in real biomedical data sets interms of calibration, resolution, and explanatory power. Thisresearch will (a) quantify improvement in performance when aclassification problem is broken down into subproblems in asystematic way, (b) quantify the advantages of combining dif-ferent types of classifiers, create a library of reusable neuralnetwork classification models, data pre-processing, and evalua-tion tools that use standardized interfaces, and (d) foster dissem-ination of classification models and the use of pre-processingand evaluation tools by making them available to other re-searchers through the World-Wide-Web. We will test four hy-potheses: (1) Combinations of different modalities of classifiersperform significantly better than isolated models. (2) Hierarchi-cal and sequential neural networks perform better than standardneural networks. (3) Unsupervised models can decompose aproblem for hierarchical or sequential neural networks betterthan models that use prior knowledge. (4) It is possible to builda Classification Tool Kit composed of data pre-processing mod-ules, classification models, and evaluation modules in whichcomponents are independent, reusable, and interchangeable.

Thesaurus Terms: artificial intelligence, classification, com-puter assisted medical decision making, computer systemdesign /evaluation Internet, mathematical model, model de-sign /development

Institution: Brigham and Women’s Hospital75 Francis StBoston, MA 02115

Fiscal Year: 1998Department:Project Start: 30-Sep-1998Project End: 31-Aug-2000ICD: National Library of MedicineIRG: BLR

SHAPE-BASED RETRIEVAL IN MEDICALIMAGE DATABASES

Grant Number: 5R01LM006911-02PI Name: Tagare, Hemant D.

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Abstract: DESCRIPTION (adapted from the Abstract): Re-trieval in Medical Image Databases is greatly facilitated byqueries which use visual and graphical examples. In suchqueries, the user points to features of interest in an exampleimage and the database is expected to retrieve other imageswhich have similar features. This proposal seeks to createthe capacity for retrieval by shape similarity in an echocar-diographic image database. The proposal has three aims. Thefirst aim is to create robust shape features. Much of the pre-vious work on shape analysis uses shape features which areinvariant to certain image transformations. Unfortunatelythese features are very susceptible to noise and are not prac-tically useful. A primary aim of this proposal is to seek alter-nate and more robust shape features. Preliminary work by theinvestigators and others suggests that there are non-invariantfeatures which satisfy these demands, and the proposal seeks toinvestigate these in more detail. The second aim is to createnovel structures and algorithms for indexing these features.Classical indexing techniques, such as indexing trees, are appli-cable for indexing invariant features. The proposal seeks to ex-tend these techniques substantially for indexing non-invariantshape features. The extension is based on the application of thetheory of interval valued arithmetic to indexing. Finally, theproposal seeks to validate the mechanism of retrieval by shapesimilarity in echocardiography. First, the robustness of the newshape features will be compared to the robustness of old shapefeatures by adding noise to the data. Second, the efficiency ofretrieval with the new indexing mechanisms will be measuredby simulations and by evaluating the performance for the echo-cardiographic image database. Lastly, the utility of shape simi-larity retrieval will be evaluated by measuring the performanceof the database to that of expert cardiac radiologists.

Thesaurus Terms: digital imaging, echocardiography, infor-mation retrieval, information system image processing, in-dexing human data

Institution: Yale UniversityNew Haven, CT 06520

Fiscal Year: 2001Department: Diagnostic RadiologyProject Start: 01-Jun-2000Project End: 31-May-2003ICD: National Library of MedicineIRG: BLR

MULTIMODALITY NEUROIMAGINGDATABASE SYSTEM

Grant Number: 5R29LM006300-04PI Name: Wong, Stephen T.

Abstract: DESCRIPTION (Taken from application abstract):The past-three decades have witnessed a remarkable growthof medical imaging modalities in patient care. Ironically,

however, the field of medical imaging is threatened by itsown success in that the sheer mass of information availableis becoming unmanageable. The long-term objective of thisapplication is to develop the next generation of medical im-age information systems. This five-year FIRST award projectwill focus on the design and implementation of a prototypeneuroimaging database management system (NI-DBMS) formanaging and indexing multimodality brain images, includ-ing MRI, PET, MR spectroscopy, and MEG. This new im-age DBMS intends to support flexible search and browsingof picture archiving and communication systems (PACS)image library, as well as clinical applications in epilepsy andmultiple sclerosis. The hypothesis of this research is thatdifferent kinds of three-dimensional (3D) brain images andassociated clinical data can be modeled, correlated, queried,and analyzed by computers on the World Wide Web (WWW)to aid neurologic education, practice, and research. The specificaims to investigate this hypothesis are: (I) design a new frame-work for multimodality neuroimage management; (ii) developtools for extracting structural, functional, and temporal featuresof different brain images; (iii) investigate new content basedsearch algorithms for epilepsy and multiple sclerosis imaging;(iv) develop a neuroimaging data model to allow access fromthe Web; and (v) evaluate system performance with well-de-fined experiments in epilepsy and multiple sclerosis imaging.The neuroimaging DBMS will be built on top of the large im-age archives in hospitals and will add values to the existingPACS with content-based information management and Webaccessibility. The software product developed in this research willbe generalizable and extensible so that it can be put into wide useby other medical centers and hospitals. Its open systems architec-ture will ensure image databases developed by the medical com-munity will be sharable through the ubiquitous Web.

Thesaurus Terms: abstracting /text searching, brain visual-ization, computer graphics /printing, computer program /soft-ware, computer system design /evaluation, image processing,information system, interactive multimedia Internet, datamanagement, epilepsy, health care professional practice,health science research, information retrieval, medical educa-tion, multiple sclerosis bioimaging /biomedical imaging, hu-man data, magnetic resonance imaging, magnetoencephalog-raphy, nuclear magnetic resonance spectroscopy, positronemission tomography


Fiscal Year: 2001Department: RadiologyProject Start: 01-Feb-1998Project End: 31-Jan-2003ICD: National Library of MedicineIRG: BLR


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