Quantitative pharmacologic MRI: Mapping the cerebral blood volume response to cocaine in dopamine transporter knockout mice

The use of pharmacologic MRI (phMRI) in mouse models of brain disorders allows noninvasive in vivo assessment of drug-modulated local cerebral blood volume changes (ΔCBV) as one correlate of neuronal and neurovascular activities. In this report, we employed CBV-weighted phMRI to compare cocaine-modulated neuronal activity in dopamine transporter (DAT) knockout (KO) and wild-typemice. Cocaine acts to block the dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT) that clear their respective neurotransmitters from the synapses, helping to terminate cognate neurotransmission. Cocaine consistently reduced CBV, with a similar pattern of regional ΔCBV in brain structures involved inmediating reward in both DAT genotypes. The largest effects (−20% to −30% ΔCBV) were seen in the nucleus accumbens and several cortical regions. Decreasing response amplitudes to cocaine were noted in more posterior components of the cortico-mesolimbic circuit. DAT KO mice had significantly attenuated ΔCBV amplitudes, shortened times to peak response, and reduced response duration in most regions. This study demonstrates that DAT knockout does not abolish the phMRI responses to cocaine, suggesting that adaptations to loss of DAT and/or retained cocaine activity in other monoamine neurotransmitter systems underlie these responses in DAT KO mice

Simultaneous in vivo positron emission tomography and magnetic resonance imaging

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are widely used in vivo imaging technologies with both clinical and biomedical research applications. The strengths of MRI include high-resolution, high-contrast morphologic imaging of soft tissues; the ability to image physiologic parameters such as diffusion and changes in oxygenation level resulting from neuronal stimulation; and the measurement of metabolites using chemical shift imaging. PET images the distribution of biologically targeted radiotracers with high sensitivity, but images generally lack anatomic context and are of lower spatial resolution. Integration of these technologies permits the acquisition of temporally correlated data showing the distribution of PET radiotracers and MRI contrast agents or MR-detectable metabolites, with registration to the underlying anatomy. An MRI-compatible PET scanner has been built for biomedical research applications that allows data from both modalities to be acquired simultaneously. Experiments demonstrate no effect of the MRI system on the spatial resolution of the PET system and <10% reduction in the fraction of radioactive decay events detected by the PET scanner inside the MRI. The signal-to-noise ratio and uniformity of the MR images, with the exception of one particular pulse sequence, were little affected by the presence of the PET scanner. In vivo simultaneous PET and MRI studies were performed in mice. Proof-of-principle in vivo MR spectroscopy and functional MRI experiments were also demonstrated with the combined scanner

Serial Diffusion MRI to Monitor and Model Treatment Response of the Targeted Nanotherapy CRLX101

Purpose: Targeted nanotherapies are being developed to improve tumor drug delivery and enhance therapeutic response. Techniques that can predict response will facilitate clinical translation and may help define optimal treatment strategies. We evaluated the efficacy of diffusion-weighted magnetic resonance imaging to monitor early response to CRLX101 (a cyclodextrin-based polymer particle containing the DNA topoisomerase I inhibitor camptothecin) nanotherapy (formerly IT-101), and explored its potential as a therapeutic response predictor using a mechanistic model of tumor cell proliferation. Experimental Design: Diffusion MRI was serially conducted following CRLX101 administration in a mouse lymphoma model. Apparent diffusion coefficients (ADCs) extracted from the data were used as treatment response biomarkers. Animals treated with irinotecan (CPT-11) and saline were imaged for comparison. ADC data were also input into a mathematical model of tumor growth. Histological analysis using cleaved-caspase 3, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, Ki-67, and hematoxylin and eosin (H&E) were conducted on tumor samples for correlation with imaging results. Results: CRLX101-treated tumors at day 2, 4, and 7 posttreatment exhibited changes in mean ADC = 16 ± 9%, 24 ± 10%, 49 ± 17%, and size (TV) = −5 ± 3%, −30 ± 4%, and −45 ± 13%, respectively. Both parameters were statistically greater than controls [p(ADC) ≤ 0.02, and p(TV) ≤ 0.01 at day 4 and 7], and noticeably greater than CPT-11–treated tumors (ADC = 5 ± 5%, 14 ± 7%, and 18 ± 6%; TV = −15 ± 5%, −22 ± 13%, and −26 ± 8%). Model-derived parameters for cell proliferation obtained using ADC data distinguished CRLX101-treated tumors from controls (P = 0.02). Conclusions: Temporal changes in ADC specified early CRLX101 treatment response and could be used to model image-derived cell proliferation rates following treatment. Comparisons of targeted and nontargeted treatments highlight the utility of noninvasive imaging and modeling to evaluate, monitor, and predict responses to targeted nanotherapeutics

Quantitative pharmacologic MRI in mice

Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a noninvasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (ΔCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in deferring brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique, with temporal resolution of one min at high magnetic field. The tissue half-life of the USPIOs was studied using a nonlinear detrending model. The three USPIOs are candidates for CBV weighted phMRI experiments, with r_2/r_1 ratios ≥ 20 and apparent half-lives ≥ 1.5 h at the described doses. An echo-time of about 10 ms or longer results in a functional contrast to noise ratio (fCNR) > 75 after USPIO injection, with negligible decrease between 1.5-2 h. phMRI experiments were conducted at 7 T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin-norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters, and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI results showed that CBV was reduced in the normal mouse brain after cocaine challenge, with the largest effects in the nucleus accumbens, whereas after acetazolamide, blood volume was increased in both cerebral and extracerebral tissue

Quantitative, Simultaneous PET/MRI for Intratumoral Imaging with an MRI-Compatible PET Scanner

Noninvasive methods are needed to explore the heterogeneous tumor microenvironment and its modulation by therapy. Hybrid PET/MRI systems are being developed for small-animal and clinical use. The advantage of these integrated systems depends on their ability to provide MR images that are spatially coincident with simultaneously acquired PET images, allowing combined functional MRI and PET studies of intratissue heterogeneity. Although much effort has been devoted to developing this new technology, the issue of quantitative and spatial fidelity of PET images from hybrid PET/MRI systems to the tissues imaged has received little attention. Here, we evaluated the ability of a first-generation, small-animal MRI-compatible PET scanner to accurately depict heterogeneous patterns of radiotracer uptake in tumors. Methods: Quantitative imaging characteristics of the MRI-compatible PET (PET/MRI) scanner were evaluated with phantoms using calibration coefficients derived from a mouse-sized linearity phantom. PET performance was compared with a commercial small-animal PET system and autoradiography in tumor-bearing mice. Pixel and structure-based similarity metrics were used to evaluate image concordance among modalities. Feasibility of simultaneous PET/MRI functional imaging of tumors was explored by following ^(64)Cu-labeled antibody uptake in relation to diffusion MRI using cooccurrence matrix analysis. Results: The PET/MRI scanner showed stable and linear response. Activity concentration recovery values (measured and true activity concentration) calculated for 4-mm-diameter rods within linearity and uniform activity rod phantoms were near unity (0.97 ± 0.06 and 1.03 ± 0.03, respectively). Intratumoral uptake patterns for both ^(18)F-FDG and a ^(64)Cu-antibody acquired using the PET/MRI scanner and small-animal PET were highly correlated with autoradiography (r > 0.99) and with each other (r = 0.97 ± 0.01). On the basis of these data, we performed a preliminary study comparing diffusion MRI and radiolabeled antibody uptake patterns over time and visualized movement of antibodies from the vascular space into the tumor mass. Conclusion: The MRI-compatible PET scanner provided tumor images that were quantitatively accurate and spatially concordant with autoradiography and the small-animal PET examination. Cooccurrence matrix approaches enabled effective analysis of multimodal image sets. These observations confirm the ability of the current simultaneous PET/MRI system to provide accurate observations of intratumoral function and serve as a benchmark for future evaluations of hybrid instrumentation

A robust coregistration method for in vivo studies using a first generation simultaneous PET/MR scanner

Purpose: Hybrid positron emission tomography (PET)/magnetic resonance (MR) imaging systems have recently been built that allow functional and anatomical information obtained from PET and MR to be acquired simultaneously. The authors have developed a robust coregistration scheme for a first generation small animal PET/MR imaging system and illustrated the potential of this system to study intratumoral heterogeneity in a mouse model. Methods: An alignment strategy to fuse simultaneously acquired PET and MR data, using the MR imaging gradient coordinate system as the reference basis, was developed. The fidelity of the alignment was evaluated over multiple study sessions. In order to explore its robustness in vivo, the alignment strategy was applied to explore the heterogeneity of glucose metabolism in a xenograft tumor model, using ^(18)F-FDG-PET to guide the acquisition of localized ^1H MR spectra within a single imaging session. Results: The alignment method consistently fused the PET/MR data sets with subvoxel accuracy (registration error mean=0.55 voxels, <0.28 mm); this was independent of location within the field of view. When the system was used to study intratumoral heterogeneity within xenograft tumors, a correlation of high ^(18)F-FDG-PET signal with high choline/creatine ratio was observed. Conclusions: The authors present an implementation of an efficient and robust coregistration scheme for multimodal noninvasive imaging using PET and MR. This setup allows time-sensitive, multimodal studies of physiology to be conducted in an efficient manner

Rapid dramatic alterations to the tumor microstructure in pancreatic cancer following irreversible electroporation ablation.

AimNanoKnife(®) (Angiodynamics, Inc., NY, USA) or irreversible electroporation (IRE) is a newly available ablation technique to induce the formation of nanoscale pores within the cell membrane in targeted tissues. The purpose of this study was to elucidate morphological alterations following 30 min of IRE ablation in a mouse model of pancreatic cancer.Materials &amp; methodsImmunohistochemistry markers were compared with diffusion-weighted MRI apparent diffusion coefficient measurements before and after IRE ablation.ResultsImmunohistochemistry apoptosis index measurements were significantly higher in IRE-treated tumors than in controls. Rapid tissue alterations after 30 min of IRE ablation procedures (structural and morphological alterations along with significantly elevated apoptosis markers) were consistently observed and well correlated to apparent diffusion coefficient measurements.DiscussionThis imaging assay offers the potential to serve as an in vivo biomarker for noninvasive detection of tumor response following IRE ablation