Molecular and cellular MR imaging: Potentials and challenges for neurological applications

This review presents the state of the art of molecular MRI and its application to experimental neurology and neuroscience. We do not repeat a broad, comprehensive overview over the rapidly growing literature in the field of “molecular MRI,” which is achieved by several recent reviews. Instead, we focus here on the potential of this imaging technique and its challenges to achieve useful new information in various fields of application with the aim of visualizing cellular processes in the brain, in both the physiological and pathophysiological context. Particular attention will be given to the visualization of cells grafted into the brain. For this goal, the recent most exciting studies are selected as the best examples to elucidate the method's fast expanding potentials. Attention is also given to the aspects of producing synergies by combining molecular MRI with other molecular imaging modalities, thus generating the most complex pictures of cellular and molecular events in the brain under in vivo conditions. J. Magn. Reson. Imaging 2008. © 2008 Wiley‐Liss, Inc.

[1]  Mathias Hoehn,et al.  Monitoring of implanted stem cell migration in vivo: A highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Heather Kalish,et al.  Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. , 2004, Blood.

[3]  M E Phelps,et al.  Positron emission tomography provides molecular imaging of biological processes. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Anna Moore,et al.  In vivo magnetic resonance imaging of transgene expression , 2000, Nature Medicine.

[5]  S. Gambhir,et al.  Gene Therapy Progress and Prospects: Noninvasive imaging of gene therapy in living subjects , 2004, Gene Therapy.

[6]  J A Frank,et al.  Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Trevor Douglas,et al.  MR microscopy of magnetically labeled neurospheres transplanted into the Lewis EAE rat brain , 2003, Magnetic resonance in medicine.

[8]  Thomas J. Meade,et al.  Synthesis and visualization of a membrane-permeable MRI contrast agent , 2003, JBIC Journal of Biological Inorganic Chemistry.

[9]  A. Blamire,et al.  MRI detection of early endothelial activation in brain inflammation , 2004, Magnetic resonance in medicine.

[10]  G. Stoll,et al.  In Vivo Detection of Developing Vessel Occlusion in Photothrombotic Ischemic Brain Lesions in the Rat by Iron Particle Enhanced MRI , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  Stefano Colagrande,et al.  Persistent contrast enhancement by sterically stabilized paramagnetic liposomes in murine melanoma , 2004, Magnetic resonance in medicine.

[12]  S. Gambhir,et al.  Molecular imaging in living subjects: seeing fundamental biological processes in a new light. , 2003, Genes & development.

[13]  Mathias Hoehn,et al.  Cellular MR Imaging , 2005, Molecular imaging.

[14]  J. Bulte,et al.  Instant MR labeling of stem cells using magnetoelectroporation , 2005, Magnetic resonance in medicine.

[15]  Mathias Hoehn,et al.  Central nervous system inflammatory response after cerebral infarction as detected by magnetic resonance imaging , 2004, NMR in biomedicine.

[16]  Stephen J. Blackband,et al.  Nuclear magnetic resonance imaging of a single cell , 1986, Nature.

[17]  Klaas Nicolay,et al.  Lipid‐based nanoparticles for contrast‐enhanced MRI and molecular imaging , 2006, NMR in biomedicine.

[18]  Patrick J. Gaffney,et al.  Quantitative “magnetic resonance immunohistochemistry” with ligand‐targeted 19F nanoparticles , 2004 .

[19]  Mathias Hoehn,et al.  MRI detection of macrophage activity after experimental stroke in rats: New indicators for late appearance of vascular degradation? , 2005, Magnetic resonance in medicine.

[20]  J. Bulte,et al.  Tagging of T cells with superparamagnetic iron oxide: uptake kinetics and relaxometry. , 1996, Academic radiology.

[21]  C. Contag,et al.  Advancing animal models of neoplasia through in vivo bioluminescence imaging. , 2002, European journal of cancer.

[22]  Brian K Rutt,et al.  Cellular MRI contrast via coexpression of transferrin receptor and ferritin , 2006, Magnetic resonance in medicine.

[23]  Shelton D Caruthers,et al.  Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI , 2004, Magnetic resonance in medicine.

[24]  Ralph Weissleder,et al.  Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells , 2000, Nature Biotechnology.

[25]  Ichio Aoki,et al.  Manganese‐enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations , 2004, NMR in biomedicine.

[26]  Enzo Terreno,et al.  Effect of the intracellular localization of a Gd‐based imaging probe on the relaxation enhancement of water protons , 2006, Magnetic resonance in medicine.

[27]  Eva Syková,et al.  Imaging the fate of implanted bone marrow stromal cells labeled with superparamagnetic nanoparticles , 2003, Magnetic resonance in medicine.

[28]  Brian K Rutt,et al.  In vivo MRI of cancer cell fate at the single‐cell level in a mouse model of breast cancer metastasis to the brain , 2006, Magnetic resonance in medicine.

[29]  Shelton D Caruthers,et al.  Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. , 2003, Circulation.

[30]  J. Bulte,et al.  Serial in vivo MR tracking of magnetically labeled neural spheres transplanted in chronic EAE mice , 2007, Magnetic resonance in medicine.

[31]  A. Fischman,et al.  Polyclonal human immunoglobulin G labeled with polymeric iron oxide: antibody MR imaging. , 1991, Radiology.

[32]  Michael Chopp,et al.  Magnetic resonance imaging and neurosphere therapy of stroke in rat , 2003, Annals of neurology.

[33]  Rika Takikawa,et al.  [In-vivo visualization of gene expression using magnetic resonance imaging]. , 2007, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[34]  Jeff W M Bulte,et al.  Chondrogenic differentiation of mesenchymal stem cells is inhibited after magnetic labeling with ferumoxides. , 2004, Blood.

[35]  Ergin Atalar,et al.  In Vivo Magnetic Resonance Imaging of Mesenchymal Stem Cells in Myocardial Infarction , 2003, Circulation.

[36]  Eric T Ahrens,et al.  In vivo imaging platform for tracking immunotherapeutic cells , 2005, Nature Biotechnology.

[37]  E. Haacke,et al.  Theory of NMR signal behavior in magnetically inhomogeneous tissues: The static dephasing regime , 1994, Magnetic resonance in medicine.

[38]  Scott E. Fraser,et al.  Mapping transplanted stem cell migration after a stroke: a serial, in vivo magnetic resonance imaging study , 2004, NeuroImage.

[39]  R Weissleder,et al.  High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. , 1999, Bioconjugate chemistry.

[40]  M. Neeman,et al.  Labeling fibroblasts with biotin‐BSA‐GdDTPA‐FAM for tracking of tumor‐associated stroma by fluorescence and MR imaging , 2005, Magnetic resonance in medicine.

[41]  R Weissleder,et al.  Measuring transferrin receptor gene expression by NMR imaging. , 1998, Biochimica et biophysica acta.

[42]  Jeff W M Bulte,et al.  In Vivo Magnetic Resonance Tracking of Magnetically Labeled Cells after Transplantation , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[43]  David A. Cheresh,et al.  Detection of tumor angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging , 1998, Nature Medicine.

[44]  M. Bednarski,et al.  Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging. , 1998, Nature medicine.

[45]  C. Wiessner,et al.  Three‐dimensional MRI of cerebral projections in rat brain in vivo after intracortical injection of MnCl2 , 2003, NMR in biomedicine.

[46]  Afonso C. Silva,et al.  In vivo neuronal tract tracing using manganese‐enhanced magnetic resonance imaging , 1998, Magnetic resonance in medicine.

[47]  Eliana Gianolio,et al.  Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations , 2002, Journal of magnetic resonance imaging : JMRI.

[48]  Mathias Hoehn,et al.  Histochemical detection of ultrasmall superparamagnetic iron oxide (USPIO) contrast medium uptake in experimental brain ischemia , 2004, Magnetic resonance in medicine.

[49]  Martin Bendszus,et al.  in Vivo Monitoring of Macrophage Infiltration in Experimental Ischemic Brain Lesions by Magnetic Resonance Imaging , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[50]  Mathias Hoehn,et al.  In vivo tracking of endogenous stem cells by MRI after intraparenchymal injection of iron oxide nanoparticles , 2005 .

[51]  Mehmet Bilgen,et al.  Electrical stimulation of cortex improves corticospinal tract tracing in rat spinal cord using manganese-enhanced MRI , 2006, Journal of Neuroscience Methods.

[52]  E. Ahrens,et al.  A new transgene reporter for in vivo magnetic resonance imaging , 2005, Nature Medicine.

[53]  Alan P. Koretsky,et al.  Magnetic resonance imaging of the migration of neuronal precursors generated in the adult rodent brain , 2006, NeuroImage.

[54]  Arend Heerschap,et al.  Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy , 2005, Nature Biotechnology.

[55]  Max A Viergever,et al.  Passive tracking exploiting local signal conservation: The white marker phenomenon , 2003, Magnetic resonance in medicine.

[56]  M. Rausch,et al.  Dynamic patterns of USPIO enhancement can be observed in macrophages after ischemic brain damage , 2001, Magnetic resonance in medicine.

[57]  P. Renshaw,et al.  Immunospecific NMR contrast agents. , 1986, Magnetic resonance imaging.

[58]  M. Rausch,et al.  In‐vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO , 2002, NMR in biomedicine.

[59]  E T Ahrens,et al.  Receptor‐mediated endocytosis of iron‐oxide particles provides efficient labeling of dendritic cells for in vivo MR imaging , 2003, Magnetic resonance in medicine.

[60]  M. Verhoye,et al.  In vivo manganese-enhanced magnetic resonance imaging reveals connections and functional properties of the songbird vocal control system , 2002, Neuroscience.

[61]  Scott E. Fraser,et al.  A SMART MAGNETIC RESONANCE IMAGING AGENT THAT REPORTS ON SPECIFIC ENZYMATIC ACTIVITY , 1997 .

[62]  Michal Neeman,et al.  Ferritin as an endogenous MRI reporter for noninvasive imaging of gene expression in C6 glioma tumors. , 2005, Neoplasia.

[63]  H. Kauczor,et al.  Manganese‐enhanced magnetic resonance imaging for in vivo assessment of damage and functional improvement following spinal cord injury in mice , 2006, Magnetic resonance in medicine.

[64]  Anna Devor,et al.  In vivo tracing of major rat brain pathways using manganese-enhanced magnetic resonance imaging and three-dimensional digital atlasing , 2003, NeuroImage.

[65]  Jeff W M Bulte,et al.  Feridex labeling of mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis , 2004, NMR in biomedicine.

[66]  Stefan Miltenyi,et al.  Specific MR imaging of human lymphocytes by monoclonal antibody‐guided dextran‐magnetite particles , 1992, Magnetic resonance in medicine.

[67]  J A Frank,et al.  Methods for magnetically labeling stem and other cells for detection by in vivo magnetic resonance imaging. , 2004, Cytotherapy.

[68]  Mathias Hoehn,et al.  Improved Stem Cell MR Detectability in Animal Models by Modification of the Inhalation Gas , 2005, Molecular imaging.

[69]  R Weissleder,et al.  Normal T-cell response and in vivo magnetic resonance imaging of T cells loaded with HIV transactivator-peptide-derived superparamagnetic nanoparticles. , 2001, Journal of immunological methods.

[70]  Ralph Weissleder,et al.  DNA-based magnetic nanoparticle assembly acts as a magnetic relaxation nanoswitch allowing screening of DNA-cleaving agents. , 2002, Journal of the American Chemical Society.

[71]  Lei Wang,et al.  MRI detects white matter reorganization after neural progenitor cell treatment of stroke , 2006, NeuroImage.

[72]  Jeff W M Bulte,et al.  Iron oxide MR contrast agents for molecular and cellular imaging , 2004, NMR in biomedicine.

[73]  Sophie Laurent,et al.  Magnetic resonance imaging of inflammation with a specific selectin‐targeted contrast agent , 2005, Magnetic resonance in medicine.

[74]  Fernando Nottebohm,et al.  Migration of young neurons in adult avian brain , 1988, Nature.

[75]  C. Lois,et al.  Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[76]  Silvio Aime,et al.  Visualization through Magnetic Resonance Imaging of DNA Internalized Following “In Vivo” Electroporation , 2005, Molecular imaging.

[77]  Samuel A. Wickline,et al.  Molecular Imaging of Angiogenesis in Early-Stage Atherosclerosis With &agr;v&bgr;3-Integrin–Targeted Nanoparticles , 2003 .

[78]  Samuel A Wickline,et al.  Targeted contrast agents for magnetic resonance imaging and ultrasound. , 2005, Current opinion in biotechnology.

[79]  Mathias Hoehn,et al.  Stem cell implantation in ischemic mouse heart: a high‐resolution magnetic resonance imaging investigation , 2005, NMR in biomedicine.

[80]  Luigi Biancone,et al.  Improved route for the visualization of stem cells labeled with a Gd‐/Eu‐Chelate as dual (MRI and fluorescence) agent , 2004, Magnetic resonance in medicine.

[81]  R. Tsien,et al.  Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein , 2004, Nature Biotechnology.

[82]  R Weissleder,et al.  Macrocyclic chelators with paramagnetic cations are internalized into mammalian cells via a HIV-tat derived membrane translocation peptide. , 2000, Bioconjugate chemistry.

[83]  Scott E. Fraser,et al.  Tracking Transplanted Stem Cell Migration Using Bifunctional, Contrast Agent-Enhanced, Magnetic Resonance Imaging , 2002, NeuroImage.

[84]  Piotr Walczak,et al.  Artificial reporter gene providing MRI contrast based on proton exchange , 2007, Nature Biotechnology.

[85]  Uwe Himmelreich,et al.  A responsive MRI contrast agent to monitor functional cell status , 2006, NeuroImage.

[86]  Ronald G Blasberg,et al.  Molecular-genetic imaging: current and future perspectives. , 2003, The Journal of clinical investigation.

[87]  C. Cepko,et al.  Multipotent neural cell lines can engraft and participate in development of mouse cerebellum , 1992, Cell.

[88]  E. Ritman,et al.  Molecular imaging in small animals—roles for micro‐CT , 2002, Journal of cellular biochemistry. Supplement.

[89]  M. Bednarski,et al.  Tumor Regression by Targeted Gene Delivery to the Neovasculature , 2002, Science.

[90]  Peter van Gelderen,et al.  Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells , 2001, Nature Biotechnology.

[91]  Markus Rudin,et al.  Feasibility and Limits of Magnetically Labeling Primary Cultured Rat T Cells with Ferumoxides Coupled with Commonly Used Transfection Agents , 2006, Molecular imaging.

[92]  Mathias Hoehn,et al.  In Vivo Molecular MR Imaging: Potential and Limits , 2006 .

[93]  R Weissleder,et al.  MR lymphography: study of a high-efficiency lymphotrophic agent. , 1994, Radiology.

[94]  C. Lois,et al.  Long-distance neuronal migration in the adult mammalian brain. , 1994, Science.