Faculty Bibliography

Introduction: Progranulin (PGRN), is a multifunctional growth factor that directly binds to tumor necrosis factor alpha (TNF-alpha) receptors (TNFR), and inhibits TNF-alpha activity [1]. It is well-accepted that TNF signaling plays an important role in impaired fracture healing as observed in diabetes mellitus. Importantly, we have previously demonstrated that PGRN has a protective and therapeutic effect in bone healing that is mediated, at least partially, through modulation of the TNF-alpha signaling pathway [2]. These previous data promoted us to determine whether PGRN also has therapeutic effects in impaired diabetic fracture healing, and if so what is the molecular mechanism involved. Methods: Murine bone fracture models were established alongside induction of the streptozotocin (STZ)-induced Type 1 diabetes model in wild type mice and in mice deficient for PGRN in order to determine the role of endogenous and recombinant PGRN in diabetic fracture healing. Thereafter, the bone healing process of those mice was analyzed through radiological assays including X-ray and micro CT, and morphological analysis including histology, and RT-PCR and western blotting. Results: 1. Deletion of PGRN further delays diabetic bone fracture healing. To investigate the role of PGRN in the course of diabetic bone regeneration, a nonunion segmental radial defect model was employed in the streptozotocin (STZ)-induced, diabetic wild type (WT) and PGRN knockout (KO) mice. Bone healing was impaired in the diabetic mice relative to healthy controls and fracture healing was further delayed in diabetic PGRN deficient mice relative to diabetic WT mice (Fig.1A). Analysis of radiographic evidence of bone healing revealed a significantly larger residual gap size in PGRN KO mice with diabetes (Fig.1B). A unicortical drill-hole model was also established and microCT imaging demonstrated that diabetic PGRN KO mice exhibit markedly less callus formation (Fig. 1C). Statistical analysis of callus mineralized volume fraction (BV/TV) indicates that deficiency of PGRN led to significantly impaired new bone quality (Fig.1D). HE staining of samples revealed that KO mice exhibited dramatically less newly formed bone tissue than the other two groups (Fig. 1E). 2. Recombinant PGRN promotes diabetic bone healing process In order to determine whether the therapeutic effect of PGRN upon bone healing is maintained under diabetic conditions, PGRN was locally delivered to diabetic WT mice via implantation of a collagen sponge containing 10ug of PGRN/PBS into the fracture site coincident with fracture generation. PGRN administration dramatically promoted diabetic bone healing in the nonunion model (Fig.2A). Histological analysis of PGRN-treated mice subjected to the drill-hole model revealed more bone formation and less cortical bone gap (Fig.2B). Western blot and RT-PCR showed expression of NOS-2, IL-1beta, and COX-2 was inhibited by PGRN treatment in the callus of diabetic mice induced under the drill-hole model (Fig.2C-F). Safranin O staining, at day 10, day 16, and day 22 after surgery, revealed the induction of chrondrogenesis following PGRN administration in diabetic mice Einhorn model of impact bone fracture showed chondrogenesis induced by PGRN(Fig.2G). Conclusion: PGRN, a growth factor known to inhibit TNF activity and to induce chondrogenesis, effectively promotes fracture healing in murine diabetic fracture models. (Figure Presented)

PURPOSE: To examine the possibility that MR-induced RF power deposition (SAR) and the resulting effects on temperature-dependent metabolic rates or perfusion rates might affect observed 18FDG signal in PET/MR. METHODS: Using numerical simulations of the SAR, consequent temperature increase, effect on rates of metabolism or perfusion, and [18FDG] throughout the body, we simulated the potential effect of maximum-allowable whole-body SAR for the entire duration of an hour-long PET/MR scan on observed PET signal for two different 18FDG injection times: one hour before onset of imaging and concurrent with the beginning of imaging. This was all repeated three times with the head, the heart, and the abdomen (kidneys) at the center of the RF coil. RESULTS: Qualitatively, little effect of MR-induced heating is observed on simulated PET images. Maximum relative increases in PET signal (26% and 31% increase, respectively, for the uptake models based on metabolism and the perfusion) occur in regions of low baseline metabolic rate (also associated with low perfusion and, thus, greater potential temperature increase due to high local SAR), such that PET signal in these areas remains comparatively low. Maximum relative increases in regions of high metabolic rate (and also high perfusion: heart, thyroid, brain, etc.) are affected mostly by the relatively small increase in core body temperature and thus are not affected greatly (10% maximum increase). CONCLUSIONS: Even for worst-case heating, little effect of MR-induced heating is expected on 18FDG PET images during PET/MR for many clinically relevant applications. For quantitative, dynamic MR/PET studies requiring high SAR for extended periods, it is hoped that methods like those introduced here can help account for such potential effects in design of a given study, including selection of reference locations that should not experience notable increase in temperature.

OBJECTIVE: Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [11C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age. METHODS: Forty-two healthy control subjects (9 females, 33 males; age range 19-55years) were scanned with [11C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BPND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images. RESULTS: Regional [11C](+)PHNO BPND displayed a negative correlation between receptor availability and age in the caudate (r=-0.56, corrected p=0.0008) and putamen (r=-0.45, corrected p=0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions. CONCLUSION: In accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [11C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.

INTRODUCTION: The basis for SWEDD is unclear, with most cases representing PD mimics but some later developing PD with a dopaminergic deficit. METHODS: We studied a patient initially diagnosed with SWEDD (based on 18 F-dopa PET) who developed unequivocal PD associated with a leucine-rich repeat kinase 2 p.G2019S mutation. Repeat multitracer PET was performed at 17 years' disease duration, including (+)[11C]dihydrotetrabenazine, [11C](N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (which binds the serotonin transporter), and 18 F-dopa. RESULTS: The patient showed bilateral striatal dopaminergic denervation (right putamen 28% of age-matched normal, left putamen 33%). 18 F-dopa uptake was decreased, particularly on the left (mean 31% of normal vs. 45% on the more affected right side). Serotonin transporter binding was relatively preserved in the putamen (right mean 90% of normal, left 81%) and several cortical regions. CONCLUSIONS: SWEDD can occur in genetically determined PD and may, in some cases, be the result of compensatory nondopaminergic mechanisms operating in early disease. (c) 2015 International Parkinson and Movement Disorder Society.

OBJECTIVE: This review article explores recent advancements in PET/MRI for clinical oncologic imaging. CONCLUSION: Radiologists should understand the technical considerations that have made PET/MRI feasible within clinical workflows, the role of PET tracers for imaging various molecular targets in oncology, and advantages of hybrid PET/MRI compared with PET/CT. To facilitate this understanding, we discuss clinical examples (including gliomas, breast cancer, bone metastases, prostate cancer, bladder cancer, gynecologic malignancy, and lymphoma) as well as future directions, challenges, and areas for continued technical optimization for PET/MRI.

BACKGROUND: Previous work in healthy non-human primates and humans has shown that social status correlates positively with dopamine 2/3 receptor (D2/3R) availability imaged with antagonist radioligands and positron emission tomography (PET). Further work in non-human primates suggests that this relationship is disrupted by chronic cocaine administration. This exploratory study examined the relationship between social status and D2/3R availability in healthy (HH) and cocaine dependent (CD) humans using the D3-preferring, agonist radioligand, [11C](+)PHNO. METHODS: Sixteen HH and sixteen CD individuals completed the Barratt Simplified Measure of Social Status (BSMSS) and underwent [11C](+)PHNO scanning to measure regional brain D2/3R binding potentials (BPND). Correlations between BPND and BSMSS scores were then assessed within each group. RESULTS: Within HH and CD groups, inverse associations between BSMSS score and BPND were observed in the substantia nigra/ventral tegmental area (SN/VTA) and the ventral striatum, and for the CD group alone, the amygdala. After adjusting for body mass index and age, negative correlations remained significant in the SN/VTA for HH and in the amygdala for CD subjects. CONCLUSION: These preliminary data utilizing a dopamine agonist tracer demonstrate, for the first time, an inverse association between social status and D2/3R availability in the D3R rich extrastriatal regions of HH and CD humans.

PURPOSE: [(18)F]FPEB is a promising PET radioligand for the metabotropic glutamate receptor 5 (mGluR5), a potential target for the treatment of neuropsychiatric diseases. The purpose of this study was to evaluate the test-retest reproducibility of [(18)F]FPEB in the human brain. METHODS: Seven healthy male subjects were scanned twice, 3 - 11 weeks apart. Dynamic data were acquired using bolus plus infusion of 162 +/- 32 MBq [(18)F]FPEB. Four methods were used to estimate volume of distribution (V T): equilibrium analysis (EQ) using arterial (EQA) or venous input data (EQV), MA1, and a two-tissue compartment model (2 T). Binding potential (BP ND) was also estimated using cerebellar white matter (CWM) or gray matter (CGM) as the reference region using EQ, 2 T and MA1. Absolute test-retest variability (aTRV) of V T and BP ND were calculated for each method. Venous blood measurements (C V) were compared with arterial input (C A) to examine their usability in EQ analysis. RESULTS: Regional V T estimated by the four methods displayed a high degree of agreement (r (2) ranging from 0.83 to 0.99 among the methods), although EQA and EQV overestimated V T by a mean of 9 % and 7 %, respectively, compared to 2 T. Mean values of aTRV of V T were 11 % by EQA, 12 % by EQV, 14 % by MA1 and 14 % by 2 T. Regional BP ND also agreed well among the methods and mean aTRV of BP ND was 8 - 12 % (CWM) and 7 - 9 % (CGM). Venous and arterial blood concentrations of [(18)F]FPEB were well matched during equilibrium (C V = 1.01 . C A, r (2) = 0.95). CONCLUSION: [(18)F]FPEB binding shows good TRV with minor differences among analysis methods. Venous blood can be used as an alternative for input function measurement instead of arterial blood in EQ analysis. Thus, [(18)F]FPEB is an excellent PET imaging tracer for mGluR5 in humans.

INTRODUCTION: Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with (11)C-MRB ((S,S)-(11)C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. METHODS: Ten healthy, Caucasian subjects (5 M: age 24.6+/-2.6, BMI 21.6+/-2.7kg/m(2); 5 F: age 25.4+/-2.1, BMI 22.1+/-1.0kg/m(2)) underwent (11)C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15 degrees C) compared to (18)F-FDG PET-CT imaging. Uptake of (11)C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. RESULTS: As expected, (18)F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT (11)C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0+/-0.3 vs. cold 1.1+/-0.3, p=0.31; BAT/muscle DVR: RT 2.3+/-0.7 vs. cold 2.5+/-0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of (11)C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with (18)F-FDG (p=0.63). Furthermore, there were gender differences in (11)C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in (11)C-MRB as a function of both body composition and body temperature. CONCLUSIONS: Unlike (18)F-FDG, the uptake of (11)C-MRB in BAT offers a unique opportunity to investigate the role of BAT in humans under basal, room temperature conditions.