Imaging readouts as biomarkers or surrogate parameters for the assessment of therapeutic interventions

Surrogate markers and biomarkers based on imaging readouts providing predictive information on clinical outcome are of increasing importance in the preclinical and clinical evaluation of novel therapies. They are primarily used in studies designed to establish evidence that the therapeutic principle is valid in a representative patient population or in an individual. A critical step in the development of (imaging) surrogates is validation: correlation with established clinical endpoints must be demonstrated. Biomarkers must not fulfill such stringent validation criteria; however, they should provide insight into mechanistic aspects of the therapeutic intervention (proof-of-mechanism) or document therapy efficacy with prognostic quality with regard to the long-term clinical outcome (proof of concept). Currently used imaging biomarkers provide structural, physiological and metabolic information. Novel imaging approaches annotate structure with molecular signatures that are tightly linked to the pathophysiology or to the therapeutic principle. These cellular and molecular imaging methods yield information on drug biodistribution, receptor expression and occupancy, and/or intra- and intercellular signaling. The design of novel target-specific imaging probes is closely related to the development of the therapeutic agents and should be considered early in the discovery phase. Significant technical and regulatory hurdles have to be overcome to foster the use of imaging biomarkers for clinical drug evaluatio

Analytic image concept combined to SENSE reconstruction

Object: Two approaches of reconstructing undersampled partial k-space data, acquired with multiple coils are compared: homodyne detection combined with SENSE (HM_SENSE) and analytic image reconstruction combined with SENSE (AI_SENSE). The latter overcomes limitations of HM_ SENSE by considering aliased images as analytic thus avoiding the need for phase correction required for HM_SENSE. Materials and methods: In vivo imaging experiments were carried out in male Lewis rats using both gradient echo and spin echo sequences. Accelerated images obtained by using the various reconstruction algorithms were compared to fully sampled reference images both qualitatively and quantitatively. Results: For the various sampling patterns evaluated, both HM_SENSE and AI_SENSE were found to yield robust image reconstruction with small deviations from the reference image. Even for high acceleration factors AI_SENSE still provided useful results and was found superior compared to HM_SENSE. Conclusion: Combination of partial k-space sampling and parallel image acquisition allows for further acceleration of data acquisition as compared to each method alone. Image reconstruction from undersampled data sets using the AI_SENSE algorithm was found to considerably reduce reconstruction errors and artifacts observed for HM_SENSE reconstruction caused by errors in phase estimatio

Improving the accuracy of a solid spherical source radius and depth estimation using the diffusion equation in fluorescence reflectance mode

BACKGROUND: Non-invasive planar fluorescence reflectance imaging (FRI) is used for accessing physiological and molecular processes in biological tissue. This method is efficiently used to detect superficial fluorescent inclusions. FRI is based on recording the spatial radiance distribution (SRD) at the surface of a sample. SRD provides information for measuring structural parameters of a fluorescent source (such as radius and depth). The aim of this article is to estimate the depth and radius of the source distribution from SRD, measured at the sample surface. For this reason, a theoretical expression for the SRD at the surface of a turbid sample arising from a spherical light source embedded in the sample, was derived using a steady-state solution of the diffusion equation with an appropriate boundary condition. METHODS: The SRD was approximated by solving the diffusion equation in an infinite homogeneous medium with solid spherical sources in cylindrical geometry. Theoretical predications were verified by experiments with fluorescent sources of radius 2-6 mm embedded at depths of 2-4 mm in a tissue-like phantom. RESULTS: The experimental data were compared with the theoretical values which shows that the root mean square (RMS) error in depth measurement for nominal depth values d = 2, 2.5, 3, 3.5, 4 mm amounted to 17%, 5%, 2%, 1% and 5% respectively. Therefore, the average error in depth estimation was < or = 4% for depths larger than the photon mean free path. CONCLUSIONS: An algorithm is proposed that allows estimation of the location and radius of a spherical source in a homogeneous tissue-like phantom by accounting for anisotropic light scattering effect using FRI modality. Surface SRD measurement enabled accurate estimates of fluorescent depth and radius in FRI modality, and can be used as an element of a more general tomography reconstruction algorithm

Accelerated cardiovascular magnetic resonance of the mouse heart using self-gated parallel imaging strategies does not compromise accuracy of structural and functional measures

BACKGROUND: Self-gated dynamic cardiovascular magnetic resonance (CMR) enables non-invasive visualization of the heart and accurate assessment of cardiac function in mouse models of human disease. However, self-gated CMR requires the acquisition of large datasets to ensure accurate and artifact-free reconstruction of cardiac cines and is therefore hampered by long acquisition times putting high demands on the physiological stability of the animal. For this reason, we evaluated the feasibility of accelerating the data collection using the parallel imaging technique SENSE with respect to both anatomical definition and cardiac function quantification. RESULTS: Findings obtained from accelerated data sets were compared to fully sampled reference data. Our results revealed only minor differences in image quality of short- and long-axis cardiac cines: small anatomical structures (papillary muscles and the aortic valve) and left-ventricular (LV) remodeling after myocardial infarction (MI) were accurately detected even for 3-fold accelerated data acquisition using a four-element phased array coil. Quantitative analysis of LV cardiac function (end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and LV mass) in healthy and infarcted animals revealed no substantial deviations from reference (fully sampled) data for all investigated acceleration factors with deviations ranging from 2% to 6% in healthy animals and from 2% to 8% in infarcted mice for the highest acceleration factor of 3.0. CNR calculations performed between LV myocardial wall and LV cavity revealed a maximum CNR decrease of 50% for the 3-fold accelerated data acquisition when compared to the fully-sampled acquisition. CONCLUSIONS: We have demonstrated the feasibility of accelerated self-gated retrospective CMR in mice using the parallel imaging technique SENSE. The proposed method led to considerably reduced acquisition times, while preserving high spatial resolution at sufficiently high CNR. The accuracy of measurements of both structural and functional parameters of the mouse heart was not compromised by the application of the proposed accelerated data acquisition method

Increasing temporal resolution of DSC perfusion MRI using the analytic image concept

Object: Dynamic susceptibility contrast MRI (DSC-MRI) is increasingly being used to evaluate cerebral microcirculation. In this study, the use of the analytic image reconstruction (AIR), with the aim to increase the temporal resolution, is evaluated for DSC-MRI in small animals. Materials and methods: Imaging was performed using a T 2*- weighted sequence to acquire male Lewis rats raw data. Results show that AIR satisfactory reconstructs DSC-MRI while preserving a good reconstruction quality and the image characteristics compared to the full k-space and keyhole reconstructed images. The combination of the choice of the baseline image and the proposed asymmetric acquisition schema enables an increase in temporal resolution, by a factor of four, thus having more sample points for better estimating perfusion parameters. Results: Computer simulations result in a mean cerebral blood volume of 1.22 that deviates from the full k-space value by −3% and a mean cerebral blood flow of 1.97 deviating from the full k-space value by −3% when the mean transit time did not change. Even if these deviations increase when achieving real acquisitions, AIR still better computes quantitative values than keyhole. Conclusion: AIR allows a good reconstruction of the dynamic stage of the image series thus leading to better dynamic effects analysi

Hepatic lipid composition differs between ob/ob and ob/+ control mice as determined by using in vivo localized proton magnetic resonance spectroscopy

Object: Hepatic lipid accumulation is associated with nonalcoholic fatty liver disease, and the metabolic syndrome constitutes an increasing medical problem. In vivo proton magnetic resonance spectroscopy (1H MRS) allows the assessment of hepatic lipid levels noninvasively and also yields information on the fat composition due to its high spectral resolution. Materials and methods: We applied 1H MRS at 9.4T to study lipid content and composition in eight leptin-deficient ob/ob mice as a model of obesity and in four lean ob/+ control mice at 24weeks of age. PRESS sequence was used. For accurate estimation of signal intensity, differences in relaxation behavior of individual signals were accounted for each mouse individually. Also, in order to minimize spectral degrading due to motion artifacts, respiration gating was applied. Results: Significant differences between ob/ob and ob/+ control mice were found in both lipid content and composition. The mean chain length was found to be significantly longer in ob/ob mice with a higher fraction of monounsaturated lipids. Conclusion: 1H MRS enables accurate assessment in hepatic lipids in mice, which is attractive for mechanistic studies of altered metabolism given the large number of genetically engineered mouse models availabl

Accurate assessment of carotid artery stenosis in atherosclerotic mice using accelerated high-resolution 3D magnetic resonance angiography

Object: High-resolution magnetic resonance angiography (MRA) enables non-invasive detection and longitudinal monitoring of atherosclerosis in mouse models of human disease. However, MRA is hampered by long acquisition times putting high demands on the physiological stability of the animal. Therefore, we evaluated the feasibility of accelerated MRA using the parallel imaging technique SENSE with regard to both lesion detection and quantification. Materials and methods: MRA acquisitions of supra-aortic vessels were performed in ApoE −/− mice that have been shown to develop atherosclerotic plaques. Findings obtained from accelerated data sets were compared to fully sampled reference data sets and histology. Results: Our results revealed only minor differences in detecting vascular lesions for data collections accelerated by factors of up to 3.3 using a four-element coil array. For vessels with a mean lumen diameter of 500μm, morphometry of stenotic lesions revealed no substantial deviations from reference (fully sampled) data for all investigated acceleration factors. For the highest acceleration factor of 3.3, an average deviation of the degree of stenosis of 4.9 ± 3.6% was found. Common carotid stenoses assessed by in vivo MRA displayed a good correlation with histological analyses (slope of linear regression = 0.97, R 2 = 0.98). Conclusion: According to the results of this work, we have demonstrated the feasibility and accuracy of accelerated high-resolution 3D ToF MRA in mice suitable for detailed depiction of mouse supra-aortic vessels and amenable to non-invasive quantification of small atherosclerotic lesion

Structural Basis of Large-Scale Functional Connectivity in the Mouse

Translational neuroimaging requires approaches and techniques that can bridge between multiple different species and disease states. One candidate method that offers insights into the brain's functional connectivity (FC) is resting-state fMRI (rs-fMRI). In both humans and nonhuman primates, patterns of FC (often referred to as the functional connectome) have been related to the underlying structural connectivity (SC; also called the structural connectome). Given the recent rise in preclinical neuroimaging of mouse models, it is an important question whether the mouse functional connectome conforms to the underlying SC. Here, we compared FC derived from rs-fMRI in female mice with the underlying monosynaptic structural connectome as provided by the Allen Brain Connectivity Atlas. We show that FC between interhemispheric homotopic cortical and hippocampal areas, as well as in cortico-striatal pathways, emerges primarily via monosynaptic structural connections. In particular, we demonstrate that the striatum (STR) can be segregated according to differential rs-fMRI connectivity patterns that mirror monosynaptic connectivity with isocortex. In contrast, for certain subcortical networks, FC emerges along polysynaptic pathways as shown for left and right STR, which do not share direct anatomical connections, but high FC is putatively driven by a top-down cortical control. Finally, we show that FC involving cortico-thalamic pathways is limited, possibly confounded by the effect of anesthesia, small regional size, and tracer injection volume. These findings provide a critical foundation for using rs-fMRI connectivity as a translational tool to study complex brain circuitry interactions and their pathology due to neurological or psychiatric diseases across species.A comprehensive understanding of how the anatomical architecture of the brain, often referred to as the "connectome," corresponds to its function is arguably one of the biggest challenges for understanding the brain and its pathologies. Here, we use the mouse as a model for comparing functional connectivity (FC) derived from resting-state fMRI with gold standard structural connectivity measures based on tracer injections. In particular, we demonstrate high correspondence between FC measurements of cortico-cortical and cortico-striatal regions and their anatomical underpinnings. This work provides a critical foundation for studying the pathology of these circuits across mouse models and human patients

Non-invasive visualization of amyloid-beta deposits in Alzheimer amyloidosis mice using magnetic resonance imaging and fluorescence molecular tomography

Abnormal cerebral accumulation of amyloid-beta peptide (Aβ) is a major hallmark of Alzheimer's disease. Non-invasive monitoring of Aβ deposits enables assessing the disease burden in patients and animal models mimicking aspects of the human disease as well as evaluating the efficacy of Aβ-modulating therapies. Previous in vivo assessments of plaque load have been predominantly based on macroscopic fluorescence reflectance imaging (FRI) and confocal or two-photon microscopy using Aβ-specific imaging agents. However, the former method lacks depth resolution, whereas the latter is restricted by the limited field of view preventing a full coverage of the large brain region. Here, we utilized a fluorescence molecular tomography (FMT)-magnetic resonance imaging (MRI) pipeline with the curcumin derivative fluorescent probe CRANAD-2 to achieve full 3D brain coverage for detecting Aβ accumulation in the arcAβ mouse model of cerebral amyloidosis. A homebuilt FMT system was used for data acquisition, whereas a customized software platform enabled the integration of MRI-derived anatomical information as prior information for FMT image reconstruction. The results obtained from the FMT-MRI study were compared to those from conventional planar FRI recorded under similar physiological conditions, yielding comparable time courses of the fluorescence intensity following intravenous injection of CRANAD-2 in a region-of-interest comprising the brain. In conclusion, we have demonstrated the feasibility of visualizing Aβ deposition in 3D using a multimodal FMT-MRI strategy. This hybrid imaging method provides complementary anatomical, physiological and molecular information, thereby enabling the detailed characterization of the disease status in arcAβ mouse models, which can also facilitate monitoring the efficacy of putative treatments targeting Aβ