Tracking Superparamagnetic Iron Oxide Labeled Monocytes in Brain by High-Field Magnetic Resonance Imaging Marina L. Zelivyanskaya, 1,2 Jay A. Nelson, 1,3 Larissa Poluektova, 1,2 Mariano Uberti, 1,5 Melissa Mellon, 1,3 Howard E. Gendelman, 1,2,4 * and Michael D. Boska 1,3 1 Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 2 Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 3 Department of Radiology, University of Nebraska Medical Center, Omaha, Nebraska 4 Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 5 Department of Computer Science, PKI 170, University of Nebraska at Omaha, Omaha, Nebraska Inflammatory cells, most notably mononuclear phago- cytes (MP; macrophages and microglia), play a critical role in brain homeostasis, repair and disease. One im- portant event in cellular biodynamics is how MP move in and throughout the nervous system. Prior studies have focused principally on cell migration across the blood– brain barrier during neuroinflammatory processes with little work done on cell movement within the brain. During the past decade our laboratories have studied the role of MP in HIV-1-associated dementia (HAD). In HAD MP incite sustained glial inflammatory reactions causing sig- nificant neuronal damage. To extend these works we investigated cell movement in brain and its influence for disease in a novel co-registration system integrating neu- ropathology with high-field magnetic resonance imaging (MRI). Human monocytes labeled with superparamag- netic iron oxide particles were injected into the brain of severe combined immunodeficient (SCID) mice. MRI was recorded 1, 7, and 14 days after cell injection. MRI co- registered with histology verified that the MRI signal modification was due to the labeled cells. MRI showed human monocyte-derived macrophages along the injec- tion site, the corpus callosum, the ventricular system and in other brain sites. These data support the idea that cell migration can be monitored in vivo and provides an opportunity to assess monocyte mobility in brain and its affects on neurodegenerative processes and notably HAD. © 2003 Wiley-Liss, Inc. Key Words: monocyte-derived macrophages; Feridex; magnetic resonance imaging; histology MRI co-registra- tion; SCID mice; HIV-1-associated dementia Inflammatory cell trans migration is a critical com- ponent of the disease process for many neurodegenerative disorders (for example, Alzheimer’s and Parkinson’s dis- ease [AD and PD] and HIV-1-associated dementia [HAD]) (Gendelman, 1997; Al-Omaishi et al., 1999; Cot- ter et al., 1999b; Swindells et al., 1999; Diesing et al., 2002). Prior works have investigated cell migration across the blood– brain barrier with little known about leukocyte migration within the brain itself (Persidsky et al., 2000). During the past two decades, our laboratories have worked toward a better understanding of the role that mononuclear phagocytes (MP; circulating monocytes, monocyte-derived macrophages [MDM] and microglia) play in HIV-1-associated dementia (HAD) as well as in other lentiviral encephalopathies (Zink, 2002). It has been demonstrated that virus-infected immune activated MP directly affect the neurodegenerative disease process (McArthur et al., 1992; Glass et al., 1995; Williams et al., 2001; Gendelman, 2002). HAD, a late complication of HIV-1 infection, is an example of how immune compe- tent brain MP can affect neuronal and cognitive function. HAD is characterized by severe cognitive, motor or be- havior abnormalities (Navia et al., 1986a; McArthur et al., 1999). Pathologically, HAD is linked to an encephalitis where the infiltration, viral infection and immune activa- tion of infected MP (Navia et al., 1986b; Glass et al., 1993) and multinucleated giant cells abound (Sharer et al., 1985; Budka, 1986). MP are the principal productively infected cell in brain during disease (Gartner et al., 1986; Koenig et al., 1986; Wiley et al., 1986). It is accepted that macrophage secretory products may lead to neuronal death during HAD. These include pro-inflammatory cytokines, arachidonic acid and its me- tabolites, platelet activating factor, quinolinic acid, matrix Contract grant sponsor: National Institute of Health; Contract grant num- ber: R37NS 36126, PO1 NS31492, and P01AI050244. *Correspondence to: Howard E. Gendelman, MD, Center for Neurovi- rology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5215. E-mail: hegendel@unmc.edu Received 6 February 2003; Accepted 24 March 2003 Journal of Neuroscience Research 73:284 –295 (2003) © 2003 Wiley-Liss, Inc.