A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPI-ONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebralvascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.

The data in this article provide detail regarding the rat brain atlas measurements discussed in our research article, “Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function” (Gharagouzloo et al., 2017) [1]. This article provides datasets of quantitative cerebral blood volume (qCBV) measurements across 173 regions of the rat brain in 11 healthy rats. State-changes from this baseline during isoflurane and CO2 administration are provided for all regions and all animals.

Cerebrovascular abnormality is linked to Alzheimer’s disease and related dementias (ADRDs). ApoE-Ɛ4 (APOE4) is known to play a critical role in neurovascular dysfunction, however current medical imaging technologies are limited in quantification. This cross-sectional study tested the feasibility of a recently established imaging modality, quantitative ultra-short time-to-echo contrast-enhanced magnetic resonance imaging (QUTE-CE MRI), to identify small vessel abnormality early in development of human APOE4 knock-in female rat (TGRA8960) animal model. At 8 months, 48.3% of the brain volume was found to have significant signal increase (75/173 anatomically segmented regions; q<0.05 for multiple comparisons). Notably, vascular abnormality was detected in the tri-synaptic circuit, cerebellum, and amygdala, all of which are known to functionally decline throughout AD pathology and have implications in learning and memory. The detected abnormality quantified with QUTE-CE MRI is likely a result of hyper-vascularization, but may also be partly, or wholly, due to contributions from blood-brain-barrier leakage. Further exploration with histological validation is warranted to verify the pathological cause. Regardless, these results indicate that QUTE-CE MRI can detect neurovascular dysfunction with high sensitivity with APOE4 and may be helpful to provide new insights into health and disease.

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Introduction: We have developed a new method of Quantitative MRI named QUTE-CE MRI that yields images of the vasculature with unparalleled clarity and definition and is quantitative. QUTE-CE MRI can produce contrast enhanced magnetic resonance angiograms (CE-MRA) using super paramagnetic iron-oxide nanoparticle (SPION), including the FDA approved ferumoxytol, with high contrast in cardiovascular, cerebral, and tumor imaging. Based upon principles of magnetic nanoparticle interactions with neighboring water molecules, the method achieves robust, reproducible results by utilizing rapid signal acquisition at ultra-short time-to-echo (UTE) to produce positive-contrast images with pure T1 weighting and little T2* decay. The spoiled gradient echo equation (SPGR) is used to transform UTE intensities directly into concentration using experimentally determined relaxivity constants and image acquisition parameters. Methods: All animal experiments were conducted in accordance with the Northeastern University Division of Laboratory Animal Medicine and Institutional Animal Care and Use Committee. MRI images were obtained at ambient temperature (∼25°C) using a Bruker Biospec 7.0T/20-cm USR horizontal magnet (Bruker, Billerica, Massachusetts, USA) equipped with a 20-G/cm magnetic field gradient insert (ID =12 cm, Bruker) and the same quadrature 300 MHz, 30 mm Mouse MRI coil was used for all in vivo work as previously utilized for mouse experiments in Section 3.8 (Animal Imaging Research, LLC, Holden, Massachusetts, USA). PC 3 cells were injected into the right flank of immunocompromised FoxNu1 mice (n=5, Charles River Laboratories). After tumors reached about 0.5-1.0cm3, animals underwent three separate imaging sessions: Session 1 - pre-contrast T1, T2 and QUTE-CE measurements, Session 2 - immediate post-contrast QUTE-CE measurement and Session 3 - 24h post-contrast T1, T2 and QUTE-CE measurements. For contrast, 100μl of ferumoxytol diluted to 6mg/ml was injected i.v. to render a blood concentration of ~200μg/ml Fe (2x clinical dose). Results: Contrary to more standard MRI techniques, QUTE-CE pre-contrast images render a nearly homogenous signal with a Gaussian distribution in the tumor. The immediate post-contrast images render the vasculature clearly and skew the distribution of voxels within the whole tumor to the left, however also increases the overall mean of the signal intensity because the movement of voxels within the tumor is to the right, leaving a long bright tail with the brightest voxels represented by those containing 100% blood. 24h after the initial administration of ferumoxytol the vasculature is no longer visible, but the locations within the tumor that have passively accumulated SPIONs resulting from the EPR effect becomes apparent. While the distribution of voxels within the tumor becomes less skewed, the overall shape is still slightly skewed to the left and the mean of the distribution has moved to the right. Nanoparticle accumulation in the post-contrast image is heterogeneous and unambiguous. Angiography and TBV in tumors Assuming a partial 2-volume model of blood and tissue, we determine the tumor blood volume (TBV) across the entire tumor volume. The resultant TBV heatmaps show a clear range of TBV values are apparent, delineating areas of the tissue with high contrast in regard to overall vascular health, including apparently necrotic tissue. Nanoparticle accumulation Next, a unique feature of the methodology to produce high-contrast images of purely T1-weighted signal is employed to unambiguously delineate nanoparticle accumulation in a PC3 subcutaneous tumor model with ferumoxytol accumulation 24 hours after just one dose. From this, contrast efficiency was produced compared to standard techniques with the additional benefit that pre-contrast images are not necessitated. A major advantage of delineating SPION accumulation using QUTE-CE, compared to ΔT2 or ΔT1 imaging, is that the post-contrast image contains sufficient information for nanoparticle localization, eliminating the need for pre-contrast images. Conclusion: QUTE-CE MRI exploits physical principles of magnetic relaxation modulated by SPIONs to achieve quantitative MRI yielding exceptional vascular images. This ability to longitudinally quantify blood pool CA concentration is unique to the QUTE-CE method, and makes QUTE-CE MRI competitive with nuclear imaging. Quantitative tumor blood volume distributions are obtained at short times, while nanoparticle accumulation maps are obtained at long times. QUTE-CE MRI is a new method that can be used to study tumor properties longitudinally. The technique is immediately translatable to the clinic using the FDA approved contrast agent ferumoxytol and is expected to have a major impact on clinical tumor imaging. Work supported by NSF-DGE- 0965843. Citation Format: Gharagouzloo Codi, Ju Qiao, Liam Timms, Anne van de Ven, Srinivas Sridhar. Quantitative tumor imaging using magnetic nanoparticles. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B22.

A ferumoxytol-enhanced MRA technique using Ultrashort Time-to-Echo (UTE) sequences is demonstrated for kidney vasculature mapping and renal mass assessment. The blood volume (BV) map is calculated by scaling the post- and pre-contrast subtraction image from 0 to 1. BV is measured in one cystic mass (-6&plusmn;7)% and one complex mass (17&plusmn;8)% with sub-regions BV up to (32&plusmn;10)% and (30&plusmn;7)%. The quantification of BV provides a measurement of the distribution of micro-vessel density, reflecting the vascularity of the kidneys and masses. This technique potentially benefits surgical planning, renal mass characterization, and disease progression in patients with impaired renal function.