Multimodal Imaging Core
The Multimodal Imaging Core provides services to investigators locally, regionally, and nationally, encompassing scales that range from molecular to whole-animal imaging. The mission of the Core is to support the research of investigators and trainees in qualitative and quantitative imaging applications, and to assist with study design, data interpretation, extramural grant submissions, and to conduct preclinical and IND-enabling studies with nonhuman primates.
The Core provides in vivo imaging services including ultrasound imaging, optical imaging, computed tomography (CT), and positron emission tomography (PET) with a dedicated high-resolution brain scanner (πPET), total-body PET/CT µBioExplorer,, and a GE PET/CT scanner. In addition, radiochemistry services are provided through a partnership with the UC Davis Center for Molecular and Genomic Imaging.
Core faculty work in an integrated manner to implement the imaging goals of the program, and to ensure investigators have the depth and breadth of imaging opportunities to conduct their research and to submit NIH grants and IND applications. The Core provides a range of services (e.g., protocol development and optimization, operating all imaging systems, image processing, quantitative analysis) including daily operational management, data backup/sharing, preventative and routine maintenance, and quality assurance/quality control (QA/QC). The Multimodal Imaging Core faculty and staff work in an efficient manner to meet the imaging needs of investigators nationwide.
The Core also provides slide sectioning and staining services specific to nonhuman primates and whole slide scanning.
The Core provides services, expertise, and training, including advanced imaging applications that address innovative research questions across the lifespan. The in vivo imaging program provides a unique depth and breadth of services offered for high-resolution brain and total-body imaging that meets a broad spectrum of investigator needs. The Core has a long-standing history in providing research support to investigators, including assistance with extramural grant applications.
Innovative techniques and procedures have provided a means for investigators to incorporate non-invasive ultrasound-related techniques and procedures in their research programs, and to use non-surgical ultrasound-guided methods to develop and study new monkey models of human disease. Ultrasound imaging includes a spectrum of applications during pregnancy. Normative prenatal growth parameters are well established, including mean data tables, predicted values, and 95% confidence intervals for multiple head, abdominal, and limb measures, in addition to early gestational biometrics. Ultrasound is also used extensively as an adjunct for guiding the delivery of agents into various fetal compartments and for collecting fetal specimens.
Highly innovative methods for bioluminescence imaging have been developed and applied for a spectrum of gene therapy, somatic cell genome editing, and stem cell transplantation/regenerative medicine studies.
Core and Affiliate Scientists, along with a national collaborative team, developed EXPLORER, the world’s first total-body scanner for humans that allows all the tissues and organs of the body to be imaged simultaneously. This new technology enables total-body studies at 1/40th the current radiation dose used with conventional PET scanners, allowing imaging to be performed at fractions of the annual radiation dose humans receive from natural background sources. These capabilities have revolutionized the scope of PET applications to, for example, longitudinal studies for patients with chronic diseases and wider applications of PET in special populations such as infants and children. The first demonstration of use of this new total-body PET technology was performed with the mini-EXPLORER prototype designed for total-body imaging in nonhuman primates, which was recently replaced through S10 funding with the United Imaging µBioExplorer.
The state-of-the-art total-body PET scanner, the µBioExplorer, and a GE Discovery PET/CT are used for an array of studies including protocols that focus on somatic cell genome edited cells, radiolabeled antibodies for assessing cell and viral trafficking; fetal development using a combined ultrasound and CT imaging protocol; biodistribution of iodinated proteins; and inflation CT scans. Studies also address tissue engineered constructs with scaffolds and stem/progenitor cells to tailor the construct.
Emerging applications for PET, particularly for stem and progenitor cell trafficking and engraftment, requires the ability to image very low activity source distributions. The Core has developed methods for radiolabeling of cells for regenerative medicine purposes, and adapted these techniques to radiolabel viruses and monitor trafficking and viral sanctuaries.
New radiotracers are available in the Core (through partnership with the UC Davis Center for Molecular and Genomic Imaging) including those that bind to the translocator protein (TSPO) to monitor inflammation, including a third generation radiotracer 18F-DPA714. Other PET radioligands have been synthesized for targeting the tau protein (18F-T807) and synapse loss (18F-UCB-H and 18F-SDM8).
New radiotracers are introduced to Core users in parallel with new imaging protocols, methods, and algorithms. Rigor and research excellence are primary goals in parallel with transformative solutions that provide innovative technologies, tools, and biomarkers. For example, Affiliate Scientist, Dr. Julie Sutcliffe, developed an αvβ6-directed molecular imaging agent, which has high affinity and selectivity and demonstrated favorable pharmacokinetics in rhesus monkeys. Based on studies conducted in the Core the safety, biodistribution, and dosimetry properties are under evaluation in a first-in-human Phase I clinical trial (NCT03164486).
The Core has developed a complement of techniques including those used to explore the pharmacokinetics of novel radiopharmaceuticals with high performance liquid chromatography (HPLC). A laboratory is dedicated for this purpose, and staff provide the expertise for these services.
Quantitative Image Analysis (QIA) refers to the standardized extraction of meaningful, quantitative information from imaging data and uses computational algorithms. QIA methods ensure imaging biomarkers are reproducible and less subjective, and can provide imaging biomarkers for future application in human clinical trials.
Imaging plays a critical role in precision medicine, which is focused on early diagnostics and personalized treatments. The Core plays an important role in precision imaging through novel functional imaging techniques and developing new imaging biomarkers and tools.
The Core has the world’s first total-body PET scanner, EXPLORER, designed for humans that allows all the tissues and organs to be imaged simultaneously. In vivo imaging capabilities and novel models are provided by faculty in the School of Medicine and College of Engineering, that are members of the Reproductive Sciences and Regenerative Medicine Unit. The Core partnership with the Center for Molecular and Genomic Imaging, a campus core facility with a biomedical cyclotron, provides on-site synthesis of custom radiotracers for the Core.
Select publications from Multimodal Imaging Core activities
Baker CA, Swainson L, Lin DL, Wong S, Hartigan-O’Connor DJ, Lifson JD, Tarantal AF, and McCune JM. Exposure to SIV in utero results in reduced viral loads and altered responsiveness to postnatal challenge. Sci Transl Med. 2015;7(300):300ra125. PMCID: PMC5100009
Bakkour S, Baker CA, Tarantal AF, Wen L, Busch MP, Lee TH, and McCune JM. Analysis of maternal microchimerism in rhesus monkeys (Macaca mulatta) using real-time quantitative PCR amplification of MHC polymorphisms. Chimerism. 2014;5(1):6-15. PMCID: PMC3988117
Barger N, Keiter J, Kreutz A, Krishnamurthy A, Weidenthaler C, Martínez-Cerdeño V, Tarantal AF, and Noctor SC. Microglia: An intrinsic component of the proliferative zones in the fetal rhesus monkey (Macaca mulatta) cerebral cortex. Cereb Cortex. 2019;29(7):2782-2796. PMCID: PMC6611465
Batchelder CA, Duru N, Lee CI, Baker CA, Swainson L, McCune JM, and Tarantal AF. Myeloid-lymphoid ontogeny in the rhesus monkey (Macaca mulatta). Anat Rec (Hoboken). 2014;297(8):1392-406. PMCID: PMC4120262
Batchelder CA, Martinez ML, Duru N, Meyers FJ, and Tarantal AF. Three dimensional culture of human renal cell carcinoma organoids. PLoS One. 2015;10(8):e0136758. PMCID: PMC4552551
Batchelder CA, Martinez ML, and Tarantal AF. Natural scaffolds for renal differentiation of human embryonic stem cells for kidney tissue engineering. PLoS One. 2015;10(12):e0143849. PMCID: PMC4672934
Bauman MD, Lesh TA, Rowland DJ, Schumann CM, Smucny J, Kukis DL, Cherry SR, McAllister AK, Carter CS. Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation. Transl Psychiatry. 2019;9(1):135. PMCID: PMC6461624
Beckman D, Chakrabarty P, Ott S, Dao A, Zhou E, Janssen WG, Donis-Cox K, Muller S, Kordower JH, Morrison JH. A novel tau-based rhesus monkey model of Alzheimer’s pathogenesis. Alzheimers Dement. 2021;17(6):933-945. PMCID: PMC8252011
Berg E, Roncali E, and Cherry SR. Optimizing light transport in scintillation crystals for time-of-flight PET: an experimental and optical Monte Carlo simulation study. Biomed Opt Express. 2015;6(6):2220-30. PMCID: PMC4473755
Berg E, Roncali E, Hutchcroft W, Qi J, and Cherry SR. Improving depth, energy and timing estimation in PET detectors with deconvolution and maximum likelihood pulse shape discrimination. IEEE Trans Med Imaging. 2016; 35(11):2436-46. PMCID: PMC5119913
Berg E, Roncali E, Kapusta M, Du J, and Cherry SR. A combined time-of-flight and depth-of-interaction detector for total-body positron emission tomography. Med Phys. 2016;43(2):939-50. PMCID: PMC4733082
Berg E, Cherry SR. Innovations in instrumentation for positron emission tomography. Semin Nucl Med. 2018;48(4):311-331. PMCID: PMC5986096
Berg E, Gill H, Marik J, Ogasawara A, Williams S, van Dongen G, Vugts D, Cherry SR, and Tarantal AF. Total-Body PET and highly stable chelators together enable meaningful 89Zr-antibody PET studies up to 30 days after Injection. J Nucl Med. 2020;61:453-460. PMCID: PMC7067524
Berg E, Zhang X, Bec J, Judenhofer MS, Patel B, Peng Q, Kapusta M, Schmand M, Casey ME, Tarantal AF, Qi J, Badawi RD, and Cherry SR. Development and evaluation of mini-EXPLORER: a long axial field-of-view PET scanner for nonhuman primate imaging. J Nucl Med. 2018;59(6):993-998. PMCID: PMC6004556
Carbonaro Sarracino D, Tarantal AF, Lee CC, Martinez M, Jin X, Wang X, Hardee CL, Geiger S, Kahl CA, and Kohn DB. Effects of vector backbone and pseudotype on lentiviral vector-mediated gene transfer: studies in infant ADA-deficient mice and rhesus monkeys. Mol Ther. 2014;22(10):1803-16. PMCID: PMC4428412
Chaffin CL, Latham KE, Mtango NR, Midic U, and VandeVoort CA. Dietary sugar in healthy female primates perturbs oocyte maturation and in vitropreimplantation embryo development. Endocrinology. 2014; 155(7):2688-95. PMCID: PMC4060180
Cherry SR, Badawi RD, Karp JS, Moses WW, Price P, and Jones T. Total-body imaging: Transforming the role of positron emission tomography. Sci Transl Med. 2017;9:381. PMCID: PMC5629037
Conlon T, Mah C, Pacak C, Rucker Henninger M, Erger K, Jorgensen M, Lee C, Tarantal AF, and Byrne BJ. Transfer of therapeutic genes into fetal rhesus monkeys using recombinant adeno-associated type 1 viral vectors. Hum Gene Ther Clin Dev. 2016;27(4):152-9. PMCID: PMC5310237
Corti M, Cleaver B, Clément N, Conlon TJ, Faris KJ, Wang G, Benson J, Tarantal AF, Fuller D, Herzog RW, and Byrne BJ. Evaluation of readministration of a recombinant adeno-associated virus vector expressing acid alpha-glucosidase in Pompe disease: Preclinical to clinical planning. Hum Gene Ther Clin Dev. 2015; 26(3):185-93. PMCID: PMC4606909
Deng P, Halmai JANM, Beitnere U, Cameron D, Martinez ML, Lee CC, Waldo JJ, Thongphanh K, Adhikari A, Copping N, Petkova SP, Lee RD, Lock S, Palomares M, O’Geen H, Carter J, Gonzalez CE, Buchanan FKB, Anderson JD, Fierro FA, Nolta JA, Tarantal AF, Silverman JL, Segal DJ, and Fink KD. An in vivo Cell-Based Delivery Platform for Zinc Finger Artificial Transcription Factors in Pre-clinical Animal Models. Front Mol Neurosci. 2022;14:789913. PMCID: PMC8829036
Du J, Yang Y, Bai X, Judenhofer MS, Berg E, Di K, Buckley S, Jackson C, and Cherry SR. Characterization of large-area SiPM array for PET applications. IEEE Trans Nucl Sci. 2016;63(1):8-16. PMCID: PMC4281963
Engle JR, Machado CJ, Permenter MR, Vogt JA, Maurer AP, Bulleri AM, and Barnes CA. Network patterns associated with navigation behaviors are altered in aged nonhuman primates. J Neurosci. 2016;36(48):12217-27. PMCID: PMC5148220
Gong K, Cherry SR, and Qi J. On the assessment of spatial resolution of PET systems with iterative image reconstruction. Phys Med Biol. 2016;61(5):N193-202. PMCID: PMC4890626
Huang J, Lee CCI, Sutcliffe JL, Cherry SR, and Tarantal AF. Radiolabeling rhesus monkey CD34+ hematopoietic and mesenchymal stem cells with 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) for microPET imaging. Mol Imaging. 2008;7(1):1-11.
Hinde K, Muth C, Maninger N, Ragen BJ, Larke RH, Jarcho MR, Mendoza SP, Mason WA, Ferrer E, Cherry SR, Fisher-Phelps ML, and Bales KL. Challenges to the pair bond: Neural and hormonal effects of separation and reunion in a monogamous primate. Front Behav Neurosci. 2016;10:221. PMCID: PMC5107580
Hinderer C, Bell P, Louboutin JP, Zhu Y, Yu H, Lin G, Choa R, Gurda BL, Bagel J, O’Donnell P, Sikora T, Ruane T, Wang P, Tarantal AF, Casal ML, Haskins ME, and Wilson JM. Neonatal systemic AAV induces tolerance to CNS gene therapy in MPS I dogs and nonhuman primates. Mol Ther. 2015;23(8):1298-307. PMCID: PMC4817868
Kwon SI, Ferri A, Gola A, Berg E, Piemonte C, Cherry SR, and Roncali E. Reaching 200-ps timing resolution in a time-of-flight and depth-of-interaction positron emission tomography detector using phosphor-coated crystals and high-density silicon photomultipliers. J Med Imaging (Bellingham). 2016;3(4):043501. PMCID: PMC5120149
Kwon SI, Gola A, Ferri A, Piemonte C, and Cherry SR. Bismuth germanate coupled to near ultraviolet silicon photomultipliers for time-of-flight PET. Phys Med Biol. 2016;61(18):L38-L47. PMCID: PMC5056849
Newman CM, Tarantal AF, Miller CJ, and O’Connor DH. Early embryonic loss following intravaginal Zika virus challenge in rhesus macaques. Front Immunol. 2021;12:686437. PMCID: PMC8165274
Nicol LE, O’Brien TD, Dumesic DA, Grogan T, Tarantal AF, and Abbott DH. Abnormal infant islet morphology precedes insulin resistance in PCOS-like monkeys. PLoS One. 2014;9(9):e106527. PMCID: PMC4160158
Noctor SC, Shepherd H, Penna E, Chelson C, Barger N, Martínez-Cerdeño V, and Tarantal AF. Periventricular microglial cells interact with dividing precursor cells in the nonhuman primate and rodent prenatal cerebral cortex. J Comp Neurol. 2019;527(10):1598-1609. PMCID: PMC6800177
Qu Y, Frazer LC, O’Connell CM, Tarantal AF, Andrews CW Jr, O’Connor SL, Russell AN, Sullivan JE, Poston TB, Vallejo AN, and Darville T. Comparable genital tract infection, pathology, and immunity in rhesus macaques inoculated with wild-type or plasmid-deficient Chlamydia trachomatis serovar D. Infect Immun. 2015; 83(10):4056-67. PMCID: PMC4567646
Rossano S, Toyonaga T, Berg E, Lorence I, Fowles K, Nabulsi N, Ropchan J, Li S, Ye Y, Felchner Z, Kukis D, Huang Y, Benveniste H, Tarantal AF, Groman S, and Carson RE. Imaging the fetal nonhuman primate brain with SV2A positron emission tomography (PET). Eur J Nucl Med Mol Imaging 2022 May 28. PMC Journal-in-Progress
Smith AL, Freeman SM, Barnhart TE, Abbott DH, Ahlers EO, Kukis DL, Bales KL, Goodman MM, and Young LJ. Initial investigation of three selective and potent small molecule oxytocin receptor PET ligands in New World monkeys. Bioorg Med Chem Lett. 2016;26(14):3370-3375. PMCID: PMC4928571
Tai DS, Hu C, Lee CC, Martinez M, Cantero G, Kim EH, Tarantal AF, and Lipshutz GS. Development of operational immunologic tolerance with neonatal gene transfer in nonhuman primates: preliminary studies. Gene Ther. 2015;22(11):923-30. NIHMSID: NIHMS867303
Tarantal AF. Ultrasound imaging in rhesus (Macaca mulatta) and long-tailed (Macaca fascicularis) macaques: Reproductive and research applications. In: The Laboratory Primate, Elsevier Academic Press, Chapter 20, 2005;317-351.
Tarantal AF, Hartigan-O’Connor DJ, Penna E, Kreutz A, Martinez ML, and Noctor SC. Fetal rhesus monkey first trimester Zika virus infection impacts cortical development in the second and third trimesters. Cereb Cortex. 2021;31(5):2309-21. PMCID: PMC8023859
Tarantal AF and Lee CCI. Long-term luciferase expression monitored by bioluminescence imaging after adeno-associated virus-mediated fetal gene delivery in rhesus monkeys (Macaca mulatta). Hum Gene Ther. 2010;21(12):143-148. PMCID: PMC2829449
Tarantal AF, Lee CCI, Batchelder CA, Christensen JE, Martinez ML, and Cherry SR. Radiolabeling and in vivo imaging of transplanted renal lineages differentiated from human embryonic stem cells in fetal monkeys. Mol Imaging Biol. 2012;14(2):197-204. PMCID: PMC4224287
Tarantal AF, Lee CCI, and Itkin-Ansari P. Real-time bioluminescence imaging of macroencapsulated fibroblasts reveal allograft protection in rhesus monkeys (Macaca mulatta). Transplantation 2009;88(1):38-41. PMCID: PMC2744215
Tarantal AF, Lee CCI, Jimenez DF, and Cherry SR. Fetal gene transfer using lentiviral vectors: In vivo detection of gene expression by microPET and optical imaging in fetal and infant monkeys. Hum Gene Ther. 2009;17(12):1254-1261.
Tarantal AF, Lee CCI, Kukis D, and Cherry SR. Radiolabeling to monitor cell trafficking and engraftment of human peripheral blood stem cells by PET in young rhesus monkeys. PLoS One 2013;8(10):e77148. PMCID: PMC3789702
Tarantal AF, Lee CCI, Martinez ML, Asokan A, and Samulski RJ. Systemic and persistent muscle gene expression in rhesus monkeys with a liver de-targeted adeno-associated virus (AAV) vector. Hum Gene Ther. 2017;28(5):385-391. PMCID: PMC5444483
VandeVoort CA, Gerona RR, Vom Saal FS, Tarantal AF, Hunt PA, Hillenweck A, and Zalko D. Maternal and fetal pharmacokinetics of oral radiolabeled and authentic bisphenol A in the rhesus monkey. PLoS One. 2016; 11(12):e0165410. PMCID: PMC5145146
VandeVoort CA, Grimsrud KN, Midic U, Mtango N, and Latham KE. Transgenerational effects of binge drinking in a primate model: implications for human health. Fertil Steril. 2015;103(2):560-9. PMCID: PMC4314404
Wang Y, Li E, Cherry SR, and Wang G. Total-Body PET kinetic modeling and potential opportunities using deep learning. PET Clin. 2021;16(4):613-625. PMCID: PMC8453049