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MRI indicates that bone marrow stem cells remain grafted in the infarcted rat heart for sixteen weeks,but do not improve cardiac functionStuckey DJ 1 , Carr CA 1 , Martin-Rendon E 2 , Tyler DJ 1 , Willmott C 2 , Cassidy PJ 1 , Hale SJM 2 , Schneider JE 1 , Tatton L 2 ,Harding SE 3 , Radda GK 1 , Watt S 2 , Clarke K 11 Cardiac Metabolism Research Group, Laboratory of Physiology, Anatomy and Genetics, University of Oxford.2 Stem Cell Research Laboratory, National Blood Service, John Radcliffe Hospital. Oxford.3 National Heart and Lung Institute, Imperial College School of Science, Technology and Medicine, London.O21IntroductionA promising, novel approach to the treatment of myocardial infarction(MI) and prevention of heart failure is cell grafting in the damagedmyocardium 1 To optimise stem cell therapy a non-invasive methodthat can show the tissue distribution of the administered cells andmonitor cardiac function is required 2 . We have used iron-labelling ofbone marrow stromal cells (BMSCs) to non-invasively track celllocation in the infarcted rat heart over 16 weeks using cine-MRI andto isolate the donor cells from the grafted hearts using the magneticproperties of the injected BMSCs. Cardiac function was measuredfrom 1 to 16 weeks post MI and BMSC administration.MethodsBMSCs were isolated from rat bone marrow, characterised by flowcytometry, transduced with lentiviral vectors expressing GFP andlabelled with 0.9 µm iron particles (Bangs Laboratories Inc). Ratswere anaesthetized and MI was induced by ligation of the left anteriordescending coronary artery. Ten minutes post MI, either a total of 5 ×10 5 BMSCs (n = 8), or saline (n = 7), was injected into 4 separatelocations in the infarct periphery. Cardiac cine-MRI was performed at1, 4, 10 and 16 weeks post MI using an 11.7 T MR system with aBruker console and a 60 mm birdcage coil as described previously 3 .A stack of contiguous 1.5 mm true short axis ECG and respiratorygated cine images (FOV, 51.2 mm 2 ; matrix size 256×256; TE/TR,1.43/4.6 ms; 17.5° pulse; 25 to 35 frames per cardiac cycle) wereacquired to cover the entire left ventricle. Cell distribution andcardiac function were measured in each slice. At 16 weeks, heartswere removed, fixed and imaged ex vivo using high resolution 3D MRmicroscopy (fast gradient echo, FOV, 20 mm 3 ; matrix size,256×256×512; TR/TE, 1.8/30 ms), then sectioned for histology ordigested to single cells using collagenase for donor cell re-isolation.ResultsSignal voids in the cardiac MR images caused by the iron particles inthe BMSCs were detected in all rats at all times (Fig 1A). MRmicroscopy identified hypointense regions at the same position asthose identified in vivo (Fig 1B). In mildly infarcted hearts, thevolume of the signal void decreased over the 16 weeks (Fig 1C),whilst the signal void volume did not decrease significantly inseverely infarcted hearts. When non-labelled BMSCs or naked Bangsiron particles were injected into the heart, no signal voids wereidentified after the first week. Donor cells containing iron particlesand expressing GFP were identified in MR-targeted heart sections andafter magnetic cell separation from digested hearts. Approximately1.5% of administered BMSCs were identified at 16 weeks. Themajority of donor cells maintained their BMSC phenotype, but on rareoccasions, fluorescently labelled cells with a cardiomyocytephenotype were identified.No improvements in left ventricular ejection fraction (Fig 2), strokevolume, cardiac output or reduction in non-contractile scar regionwere found between the control and BMSC treated animals at any ofthe time points studies.Ejection Fraction (%)80706050400 5 10 15WeeksMI +BMSCsn = 8MIn = 7shamn = 6Figure 2: Left ventricular ejection fraction from rats that underwenteither MI, MI + BMSC injection, or sham operation.ConclusionMRI can be used to track cells labelled with iron particles in damagedtissue for at least 16 weeks after injection and to guide tissuesectioning by accurately identifying regions of cell engraftment. Themagnetic properties of the iron labelled donor cells can be used fortheir isolation from host tissue to enable future characterisation. Inthis study, although the grafted BMSCs remained present in theinfarcted hearts for 16 weeks, they were unable to improve cardiacfunction.References1 Mather & Martin, 2004, Lancet 364 p 183-922 Bartunek et al, 2006, Eur Heart J, 11, p1338-403Tyler et al, 2006, J Cardiovas Magn Reson, 8, 327-33This project was funded by the British Heart FoundationFigure 1: In vivo (A) and ex vivo (B) MR images of iron labelled BMSCs in the infarcted rat heart 16 weeks after administration. By tenweeks the signal void volume arising from the donor cells was significantly larger in the hearts with greater damage (C).
Longitudinal Short TE Proton Magnetic Resonance Spectroscopy and Disease Progression in Inherited Prion DiseaseHyare H 1,2 , Siddique D 2, 3 , Webb T 2, 3 , Wroe S 2, 3 , Collinge J 2, 3 , Thornton JS 1 , Yousry T 11 Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery,2 MRC Prion Unit, Department of Neurodegenerative Diseases, Institute of Neurology, UCL,3National Prion Clinic, National Hospital for Neurology and Neurosurgery, Queen Square, London, UKO22IntroductionInherited prion disease is a progressive neurodegenerativedisease characterised by different mutations within theprion protein (PRNP) gene 1 . Conventional MR sequencesare often unremarkable but with a therapeutic trialunderway, non-invasive monitoring of disease progressionis vital. To date, proton magnetic resonance spectroscopy( 1 H-MRS) studies in inherited prion disease have beenlimited to case reports and small series 2-4 . The purpose ofthis study was to determine longitudinal changes in cerebral1 H-MRS metabolite-ratios in inherited prion disease andinvestigate their value as surrogate markers of diseaseprogression.MethodsFive symptomatic patients (3 male, 2 female, mean age 46years) with inherited prion disease, referred to the NationalPrion Clinic, National Hospital for Neurology andNeurosurgery, for treatment with quinacrine as part of theMRC Prion 1 Trial, were studied. Short echo time (TE),single voxel 1 H-MRS was performed using an automatedpoint-resolved spin-echo localisation (PRESS) technique,with TE 35ms, TR 3000, NEX 8 at 1.5T (GE MedicalSystems, Milwaukee, WI). Spectra were acquired fromtwo voxels (volume 3.3ml-4.4ml) centred on the right headof caudate (RHC) to include the anterior right putamen, andthe right thalamus (RTH) (Fig 1). Signal ratios for themetabolites N-acetylaspartate (NAA), choline containingcompounds (Cho) and myo-inositol (MI) relative to totalcreatine (Cr) were determined using LCModel software 5 .Spectra were obtained serially using the same protocol inall patients at 3 month intervals to a maximum of 9 monthsfollow up.ResultsClinically all patients demonstrated disease progressionwith a decrease in mini mental state examination (MMSE)and activities of daily living (ADL) clinical scores.Appearances on conventional MRI were unremarkableexcept for mild volume loss. In the RHC voxel, all patientsdemonstrated a decrease in NAA/Cr and an increase inMI/Cr with time (Figs. 2 and 3). Linear regression analysisdemonstrated a mean slope of -0.0520 (SE 0.013) permonth for NAA/Cr (p=0.018) and 0.0975 (SE 0.025) permonth for MI/Cr (p=0.018). No significant change wasseen for Cho/Cr in the RHC voxel, or any metabolite-ratioin the RTH voxel.ConclusionAnatomically specific changes in NAA/Cr and MI/Cr wereobserved concomitant with clinical deterioration.Spongiosis, gliosis and neuronal loss are histopathologicalfeatures of inherited prion disease and changes are oftenextensive in the caudate and putamen 6 . Elevated MI/Cr isthought to be associated with gliosis, and reduced NAA/Crwith neuronal loss in neurodegenerative conditions 7 .In the RHC voxel we observed a proportionally greaterchange in MI/Cr than NAA/Cr, suggesting that MI/Cr maybe a more sensitive index of pathological changes.As opposed to conventional MR imaging, longitudinalshort TE1 H-MRS may provide important surrogatemarkers of disease progression in patients with inheritedforms of prion disease.Fig 1: Axial T2 FSE images demonstrating positions of the RHC voxel(A) and RTH voxel (B).NAA/Cr21.81.61.41.210.80.60.40.20Right head of caudate and right putamen voxel0 1 2 3 4 5 6 7 8 9Time (months)Fig 2: NAA/Cr versus time in RHC voxelMI/Cr1.41.210.80.60.40.20ARight head of caudate and right putamen voxel0 1 2 3 4 5 6 7 8 9Time (months)Fig 3: MI/Cr versus time in the RHC voxelPatient 1Patient 2Patient 3Patient 4Patient 5Patient 1Patient 2Patient 3Patient 4Patient 5References(1) Malluci G et al. Curr Opin Neurol. 17(6), 641-647 (2004)(2) Shyu W-C et al.. J Neurol Sci. 138, 157-160 (1996)(3) Konaka K et al. Neuroradiology. 42, 662-665 (2000)(4) Waldmann AD et al. Neuroradiology. 48(6), 428-33 (2006)(5).Provencher SW et al. Magn Reson Med. 30, 672-679 (1993)(6) Nicholl D et al. J Neurol Neurosurg Pyschiatry. 58, 65-69 (1995)(7) Valenzuela et al. Neurology. 56, 592-598 (2001)This project was funded by the Medical Research Council.B
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