Quantification of Myelinated Nerve Fraction and Degeneration in Spinal Cord Neuropil by SHIFT MRI.

BACKGROUND: Neurodegeneration is a complex cellular process linked to prompt changes in myelin integrity and gradual neuron loss. Current imaging techniques offer estimations of myelin volumes in lesions/remyelinated areas but are limited to detect subtle injury. PURPOSE: To investigate whether measurements detected by a signal hierarchically isolated as a function of time-to-echo (SHIFT) MRI technique can determine changes in myelin integrity and fiber axolemma. STUDY TYPE: Prospective animal model. ANIMAL MODEL: Surgically demyelinated spinal cord (SC) injury model in rodents (n = 6). FIELD STRENGTH/SEQUENCE: Gradient-echo spin-echo at 3T. ASSESSMENT: Multicompartment T2 relaxations were computed by SHIFT MRI in 75-microns-resolution images of the SC injury penumbra region 2 weeks post-trauma. G-ratio and axolemma delamination were assessed by transmission electron microscopy (TEM) in intact and injured samples. SC myelinated nerve fraction was computed by SHIFT MRI prospectively and assessed histologically. STATISTICAL TESTS: Relations between SHIFT-isolated T2 -components and TEM measurements were studied using linear regression and t-tests. Pearson's correlation and significance were computed to determine the SHIFT's sensitivity to detect myelinated fibers ratio in gray matter. Regularized least-squares-based ranking analysis was employed to determine SHIFT MRI's ability to discern intact and injured myelinated nerves. RESULTS: Biexponential signals isolated by SHIFT MRI for intact vs. lesion penumbra exhibited changes in T2 , shifting from intermediate components (25 ± 2 msec) to long (43 ± 11 msec) in white matter, and similarly in gray matter regions-of-interest (31 ± 2 to 46 ± 16 msec). These changes correlated highly with TEM g-ratio and axon delamination measurements (P < 0.05). Changes in short T2 components were observed but not statistically significant (8.5 ± 0.5 to 7 ± 3 msec, P = 0.445, and 4.0 ± 0.9 to 7 ± 3 msec, P = 0.075, respectively). SHIFT MRI's ability to detect myelinated fibers within gray matter was confirmed (P < 0.001). DATA CONCLUSION: Changes detected by SHIFT MRI are associated with abnormal intermembrane spaces formed upon mild injury, directly correlated with early neuro integrity loss. Level of Evidence 1 Technical Efficacy Stage 2.

Real-time in vivo monitoring of magnetic nanoparticles in the bloodstream by AC biosusceptometry.

BACKGROUND: We introduce and demonstrate that the AC biosusceptometry (ACB) technique enables real-time monitoring of magnetic nanoparticles (MNPs) in the bloodstream. We present an ACB system as a simple, portable, versatile, non-invasive, and accessible tool to study pharmacokinetic parameters of MNPs, such as circulation time, in real time. We synthesized and monitored manganese doped iron oxide nanoparticles in the bloodstream of Wistar rats using two different injection protocols. Aiming towards a translational approach, we also simultaneously evaluated cardiovascular parameters, including mean arterial pressure, heart rate, and episodes of arrhythmia in order to secure the well-being of all animals. RESULTS: We found that serial injections increased the circulation time compared with single injections. Immediately after each injection, we observed a transitory drop in arterial pressure, a small drop in heart rate, and no episodes of arrhythmia. Although some cardiovascular effects were observed, they were transitory and easily recovered in both protocols. CONCLUSIONS: These results indicate that the ACB system may be a valuable tool for in vivo, real-time MNP monitoring that allows associations with other techniques, such as pulsatile arterial pressure and electrocardiogram recordings, helping ensuring the protocol safety, which is a fundamental step towards clinical applications.

Real-time liver uptake and biodistribution of magnetic nanoparticles determined by AC biosusceptometry.

We describe the development of a joint in vivo/ex vivo protocol to monitor magnetic nanoparticles in animal models. Alternating current biosusceptometry (ACB) enables the assessment of magnetic nanoparticle accumulation, followed by quantitative analysis of concentrations in organs of interest. We present a study of real-time liver accumulation, followed by the assessment of sequential biodistribution using the same technique. For quantification, we validated our results by comparing all of the data with electron spin resonance (ESR). The ACB had viable temporal resolution and accuracy to differentiate temporal parameters of liver accumulation, caused by vasculature extravasation and macrophages action. The biodistribution experiment showed different uptake profiles for different doses and injection protocols. Comparisons with the ESR system indicated a correlation index of 0.993. We present the ACB system as an accessible and versatile tool to monitor magnetic nanoparticles, allowing in vivo and real-time evaluations of distribution and quantitative assessments of particle concentrations.

Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer.

The microRNA (miR)-200s and their negative regulator ZEB1 have been extensively studied in the context of the epithelial-mesenchymal transition. Loss of miR-200s has been shown to enhance cancer aggressiveness and metastasis, whereas replacement of miR-200 miRNAs has been shown to inhibit cell growth in several types of tumors, including lung cancer. Here, we reveal a novel function of miR-200c, a member of the miR-200 family, in regulating intracellular reactive oxygen species signaling and explore a potential application for its use in combination with therapies known to increase oxidative stress such as radiation. We found that miR-200c overexpression increased cellular radiosensitivity by direct regulation of the oxidative stress response genes PRDX2, GAPB/Nrf2, and SESN1 in ways that inhibits DNA double-strand breaks repair, increase levels of reactive oxygen species, and upregulate p21. We used a lung cancer xenograft model to further demonstrate the therapeutic potential of systemic delivery of miR-200c to enhance radiosensitivity in lung cancer. Our findings suggest that the antitumor effects of miR-200c result partially from its regulation of the oxidative stress response; they further suggest that miR-200c, in combination with radiation, could represent a therapeutic strategy in the future.

Dynamic cerebral perfusion parameters and magnetic nanoparticle accumulation assessed by AC biosusceptometry.

Cerebral blood flow (CBF) assessment is mainly performed by scintigraphy, computed tomography (CT) and magnetic resonance imaging (MRI). New approaches to assess the CBF through the passage of magnetic nanoparticles (MNPs) to blood-brain barrier (BBB) are convenient to help decrease the use of ionizing radiation and unleash the required MRI schedule in clinics. The development of nanomedicine and new biomedical devices, such as the magnetic particle imaging (MPI), enabled new approaches to study dynamic brain blood flow. In this paper, we employed MNPs and the alternating current biosusceptometry (ACB) to study the brain perfusion. We utilized the mannitol, before the MNPs, injection to modulate the BBB permeability and study its effects on the circulation time of the MNPs in the brain of rats. Also, we characterized a new ACB sensor to increase the systems' applicability to study the MNPs' accumulation, especially in the animals' brain. Our data showed that the injection of mannitol increased the circulation time of MNPs in the brain. Also, the mannitol increased the accumulation of MNPs in the brain. This paper suggests the use of the ACB as a tool to study brain perfusion and accumulation of MNPs in studies of new nano agents focused on the brain diagnostics and treatment.

Albumin Coating Prevents Cardiac Effect of the Magnetic Nanoparticles.

We have showed that surface layer can determine cardiac effects of the magnetic nanoparticles (MNPs). Considering the high binding capacity of albumin and low side-effects, the aim of this study was to evaluate the influence of albumin coating on the cardiovascular effects of two manganese ferrite-based MNPs: citrate-coated and bare MNPs. Isolated rat hearts were perfused with citrate-coated magnetic nanoparticles (CiMNPs), citrate albumin-coated magnetic nanoparticles (CiAlbMNPs), bare magnetic nanoparticles (BaMNPs), and albumin-coated magnetic nanoparticles (AlbMNPs). CiMNPs induce a transient decrease in the left ventricular end-systolic pressure, +dP/dt and -dP/dt. These effects were not worsened by albumin coating. BaMNPs significantly increased the left ventricular end-diastolic pressure and perfusion pressure and decreased the +dP/dt and -dP/dt. These effects were completely absent in hearts perfused with AlbMNPs. None of the MNPs changed heart rate or arterial blood pressure in conscious rats. Magnetic signals in isolated hearts perfused with BaMNPs were significantly higher than AlbMNPs perfused hearts. However, the magnetic signal in heart tissue was similar when the MNPs were infused in conscious rats. These data indicate that albumin-coated can reduce cardiovascular effects of MNPs. These findings suggest a protective effect of albumin surface in MNPs, favoring its future therapeutic applications.

Multichannel AC Biosusceptometry System to Map Biodistribution and Assess the Pharmacokinetic Profile of Magnetic Nanoparticles by Imaging.

In this paper, the application of a technique to evaluate in vivo biodistribution of magnetic nanoparticles (MNP) is addressed: the Multichannel AC Biosusceptometry System (MC-ACB). It allows real-time assessment of magnetic nanoparticles in both bloodstream clearance and liver accumulation, where a complex network of inter-related cells is responsible for MNP uptake. Based on the acquired MC-ACB images, we propose a mathematical model which helps to understand the distribution and accumulation pharmacokinetics of MNP. The MC-ACB showed a high time resolution to detect and monitor MNP, providing sequential images over the particle biodistribution. Utilizing the MC-ACB instrument, we assessed regions corresponding to the heart and liver, and we determined the MNP transfer rates between the bloodstream and the liver. The pharmacokinetic model resulted in having a strong correlation with the experimental data, suggesting that the MC-ACB is a valuable and accessible imaging device to assess in vivo and real-time pharmacokinetic features of MNP.

Employment of a noninvasive magnetic method for evaluation of gastrointestinal transit in rats.

AC Biosusceptometry (ACB) was previously employed towards recording gastrointestinal motility. Our data show a reliable and successful evaluation of gastrointestinal transit of liquid and solid meals in rats, considering the methods scarcity and number of experiments needed to endorsement of drugs and medicinal plants. ACB permits real time and simultaneous experiments using the same animal, preserving the physiological conditions employing both meals with simplicity and accuracy.

A novel device with 36 channels for imaging and signal acquisition of the gastrointestinal tract based on AC biosusceptometry.

The alternate current biosusceptometry (ACB) is a biomagnetic technique used to study some physiological parameters associated with gastrointestinal (GI) tract. For this purpose it applies an AC magnetic field and measures the response originating from magnetic marks or tracers. This paper presents an equipment based on the ACB which uses anisotropic magnetoresistive (AMR) sensors and an inexpensive electronic support. The ACB-AMR developed consists of a square array of 6×6 sensors arranged in a first-order gradiometer configuration with one reference sensor. The equipment was applied to capture magnetic images of different phantoms and to acquire gastric contraction activity of healthy rats. The results show a reasonable sensitivity and spatial-temporal resolution, so that it may be applied for imaging of phantoms and signal acquisition of the GI tract of small animals.