Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function

Abstract

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.

Imaging the effect of the circadian light–dark cycle on the glymphatic system in awake rats

“…Blood Vessel Distribution. To evaluate blood vessel distribution across the whole brain, three-dimensional (3D) quantitative ultrashort time-to-echo contrast-enhanced (QUTE-CE) MRI was performed using ferumoxytol, a superparamagnetic iron oxide nanoparticle contrast agent (25,26). The rat was anesthetized and given a tail vein injection of heparinized saline followed by a volume of ferumoxytol calculated to produce a concentration of 200 μg/mL Fe in the blood immediately after administration.…”

“…2, Top and was created in 3D Slicer. Thresholding was applied to the vascular density map to get vasculature that reflected small, medium, and large arteries and veins, essentially omitting the microvasculature as described previously (26).…”

Evaluating blood-brain barrier permeability in a rat model of type 2 diabetes

“…Numerous clinical MRI studies using ferumoxytol have been conducted in children and adults, demonstrating no major adverse effects, thus QUTE-CE can be readily used in the clinic to study BBB permeability (9). We recently published a study mapping the absolute physiological cerebral blood volume (CBV) of the awake rat brain, including measurements of microvasculature density and vascular functional reserve (10). QUTE-CE MRI can be used for identifying hyper-or hypovascularization, small vessel density, BBB permeability and vascular reserve and vascular responsivity to CO2 challenge at the individual voxel and regional levels using our rat 3D MRI atlas.…”

“…The pre-contrast UTE images were set as the baseline. For each rat in each imaging session, the voxel wise percentage change of signal intensity for each scan time point (post-con) was calculated as (post-con -baseline)/(blood intensity change) *100% as described in our previous work (10), where blood intensity change is a normalization factor calculated by the post-con blood signal intensity minus baseline blood signal intensity. A 173-region rat brain atlas (Ekam Solutions LLC, Boston, MA, US) was fit to T2-weighted RARE anatomical data set for each rat data set taken at each imaging session, using software developed at Northeastern University Center for Translational Neuroimaging (CTNI), considering the variations in brain size and positions.…”

Evaluating blood-brain barrier permeability in a rat model of type 2 diabetes

“…Numerous clinical MRI studies using ferumoxytol have been conducted in children and adults, demonstrating no major adverse effects, thus QUTE-CE can be readily used in the clinic to study bloodbrain barrier permeability (10). We recently published a study mapping the absolute physiological cerebral blood volume (CBV) of the awake rat brain, including measurements of microvasculature density and vascular functional reserve (8). QUTE-CE MRI can be used for identifying hyper-or hypovascularization, small vessel density, blood-brain barrier permeability and vascular reserve and vascular responsivity to CO2 challenge at the individual voxel and regional levels using our rat 3D MRI atlas.…”