Magnetic Resonance Imaging Tracer Research Articles

Current Trends and Applications of PET/MRI Hybrid Imaging in Neurodegenerative Diseases and Normal Aging.

Dementia is a significant global health issue that is exacerbated by an aging population. Imaging plays an established role in the evaluation of patients with neurocognitive disorders such as dementia. In current clinical practice, magnetic resonance imaging (MRI) and positron emission tomography (PET) are primary imaging modalities used separately but in concert to help diagnose and classify dementia. The clinical applications of PET/MRI hybrid imaging in dementia are an active area of research, particularly given the continued emergence of functional MRI (fMRI) and amyloid PET tracers. This narrative review provides a comprehensive overview of the rationale and current evidence for PET/MRI hybrid dementia imaging from 2018 to 2023. Hybrid imaging offers advantages in the accuracy of characterizing neurodegenerative disorders, and future research will need to address the cost of integrated PET/MRI systems compared to stand-alone scanners, the development of new biomarkers, and image correction techniques.

Identification of direct connections between the dura and the brain.

The arachnoid barrier delineates the border between the central nervous system and dura mater. Although the arachnoid barrier creates a partition, communication between the central nervous system and the dura mater is crucial for waste clearance and immune surveillance1,2. How the arachnoid barrier balances separation and communication is poorly understood. Here, using transcriptomic data, we developed transgenic mice to examine specific anatomical structures that function as routes across the arachnoid barrier. Bridging veins create discontinuities where they cross the arachnoid barrier, forming structures that we termed arachnoid cuff exit (ACE) points. The openings that ACE points create allow the exchange of fluids and molecules between the subarachnoid space and the dura, enabling the drainage of cerebrospinal fluid and limited entry of molecules from the dura to the subarachnoid space. In healthy human volunteers, magnetic resonance imaging tracers transit along bridging veins in a similar manner to access the subarachnoid space. Notably, in neuroinflammatory conditions such as experimental autoimmune encephalomyelitis, ACE points also enable cellular trafficking, representing a route for immune cells to directly enter the subarachnoid space from the dura mater. Collectively, our results indicate that ACE points are a critical part of the anatomy of neuroimmune communication in both mice and humans that link the central nervous system with the dura and its immunological diversity and waste clearance systems.

A stable, highly concentrated fluorous nanoemulsion formulation for in vivo cancer imaging via 19F-MRI.

Magnetic resonance imaging (MRI) is a routine diagnostic modality in oncology that produces excellent imaging resolution and tumor contrast without the use of ionizing radiation. However, improved contrast agents are still needed to further increase detection sensitivity and avoid toxicity/allergic reactions associated with paramagnetic metal contrast agents, which may be seen in a small percentage of the human population. Fluorine-19 (19F)-MRI is at the forefront of the developing MRI methodologies due to near-zero background signal, high natural abundance of 100%, and unambiguous signal specificity. In this study, we have developed a colloidal nanoemulsion (NE) formulation that can encapsulate high volumes of the fluorous MRI tracer, perfluoro-[15-crown-5]-ether (PFCE) (35% v/v). These nanoparticles exhibit long-term (at least 100 days) stability and high PFCE loading capacity in formulation with our semifluorinated triblock copolymer, M2F8H18. With sizes of approximately 200 nm, these NEs enable in vivo delivery and passive targeting to tumors. Our diagnostic formulation, M2F8H18/PFCE NE, yielded in vivo 19F-MR images with a high signal-to-noise ratio up to 100 in a tumor-bearing mouse model at clinically relevant scan times. M2F8H18/PFCE NE circulated stably in the vasculature, accumulated in high concentration of an estimated 4-9 × 1017 19F spins/voxel at the tumor site, and cleared from most organs over the span of 2 weeks. Uptake by the mononuclear phagocyte system to the liver and spleen was also observed, most likely due to particle size. These promising results suggest that M2F8H18/PFCE NE is a favorable 19F-MR diagnostic tracer for further development in oncological studies and potential clinical translation.

Development and in functional study of a bi-specific sustained release drug-loaded nano-liposomes for hepatocellular carcinoma.

Lenvatinib (LEN) is a first-line therapy for patients with hepatocellular carcinoma (HCC), but has a larger adverse effect profile. In this study, we developed a liposome with drug-carrying function and magnetic resonance imaging (MRI) imaging function to investigate the targeted drug-carrying function and MRI tracing ability of liposome for HCC. Magnetic nano-liposomes (MNL) with dual targeting function of epithelial cell adhesion molecule (EpCAM) and vimentin and capable of encapsulating LEN drugs were prepared. The characterization performance, drug loading efficiency and cytotoxicity of EpCAM/vimentin-LEN-MNL were tested, and the dual-targeting slow release drug loading function and MRI tracing ability were investigated in cellular and animal models. EpCAM/vimentin-LEN-MNL has a mean particle size of 218.37 ± 5.13nm and a mean potential of 32.86 ± 4.62mV, and is spherical in shape and can be uniformly dispersed in solution. The encapsulation rate was 92.66 ± 0.73% and the drug loading rate was 9.35 ± 0.16%. It has low cytotoxicity, can effectively inhibit HCC cell proliferation and promote HCC cell apoptosis, and has specific targeting function and MRI tracing ability for HCC cells. In this study, an HCC-specific dual-targeted sustained-release drug delivery liposome with dual-targeted recognition and sensitive MRI tracer was successfully prepared, which provides an important scientific basis for maximizing the multiple effects of nano-carriers in tumor diagnosis and treatment.

Boosting luminescence and MRI evolution via regulation of GdPO4:5%Eu3+ morphologies by H3PO4

A series of GdPO4:5%Eu3+ micro/nanomaterials with different morphologies and crystal structures were successfully prepared by the one-step solvothermal method using only the gadolinium source, the phosphoric acid source and ethanol as solvents, without any surfactants or templates, without further calcination and by adjusting only the ratio of phosphoric acid and gadolinium sources. They all have good dispersion and homogeneity. The morphology of the products was mainly regulated by the ratio of H3PO4 to Gd(NO3)3·6H2O, with ratios of 2:1, 8:1, 16:1, 24:1, 32:1, 40:1 and 48:1 mL/g resulting in the formation of square, pillow, star, carambola, hollow cylinder, drum and jujube shaped GdPO4:5%Eu3+ micro/nanomaterials, respectively. Ratios of 2:1–24:1 and 32:1–48:1 allow for the direct solvothermal synthesis of monoclinic and hexagonal phase gadolinium phosphate, simultaneously. In addition to their crystal structure and morphology, chemical bonding, thermal stability and specific surface area, their luminescence properties and magnetic resonance imaging (MRI) tracing properties have also been studied in comparison. Interestingly, the GdPO4:5%Eu3+ micro/nanoparticles in the carambola shape had a higher photoluminescence intensity and relaxation rate of 0.7709 mM−1 s−1 (r1) among all the morphologies. The possible mechanisms by which various morphologies of GdPO4:5%Eu3+ were prepared in different ratios were analyzed, and the reasons for their effects on the fluorescence and MRI tracer properties were further investigated. This study is of reference significance for the simple-regulated synthesis of rare earth inorganic gadolinium-containing micro/nanomaterials and provides a reliable guarantee for the expansion of their multifunctional applications in UV–Vis luminescence and MRI tracing for implants.

Thermoresponsive Triblock Copolymers as Widely Applicable 19F Magnetic Resonance Imaging Tracers

Fluorine-19 magnetic resonance imaging (19F MRI) has emerged as a promising noninvasive diagnostic tool, broadening the diagnostic possibilities of commonly used proton MRI. Despite the potential of 19F MRI, an ideal tracer paving the way toward the entry of this method into common medical practice is yet to be developed. In this study, we report on a series of polymeric systems based on thermoresponsive poly[N-(2,2-difluoroethyl)acrylamide] (PDFEA), a polymer considered to be an ideal tracer for 19F MRI. The described systems are designed as BAB triblock copolymers, where B corresponds to thermoresponsive PDFEA blocks and A is a hydrophilic poly(ethylene glycol) block. These BAB triblock copolymers are able to form nanoparticles in dilute aqueous solutions, which undergo a transition into physically cross-linked hydrogels upon increasing the polymer concentration. Since thermoresponsive particle- and hydrogel-based systems are applicable in a wide range of biomedical applications, we created a diagnostic system with potential therapeutic properties (theranostic) as a widely tunable platform through straightforward synthesis while serving a multitude of applications. We analyzed the effect of the BAB block ratio on the self-assembly, thermoresponsiveness, and mechanical properties of the studied hydrogels, together with their suitability for 19F MRI. Finally, their biocompatibility was assessed on a relevant cell line.

Quantitative results for the direct participation of the parenchymal vascular system in cerebral waste removal

Background: Impaired cerebral waste clearance (CWC) has been associated with a broad range of both physiological and pathophysiological neurologic conditions.1,2 Because of the unique anatomy of the brain parenchyma, theoretically, in the brain parenchyma, biochemically inert waste such as magnetic resonance imaging (MRI) contrast agents can only be removed through two possible pathways: cerebrospinal fluid (CSF) pathway, and/or vascular pathway. Despite the controversy, there seems to be a solid consensus on the participation of the CSF pathway in CWC.3 In contrast to the CSF system, the current consensus is that the parenchymal vascular system does not participate in CWC. Considering there is a big difference in flow rate between the blood (2 mL/min) and the CSF (3.7 µL/min) and the brain is the most bioactive, energy-consuming organ (20% nutrition for about 5% of body weight) in the body, it is illogical that the brain would rely on the slow CSF circulation for CWC while less bioactive tissues outside the brain require both the fast vascular and slow lymphatic systems to remove waste in a timely manner.4,5
 Methods: Superparamagnetic iron oxide–enhanced susceptibility-weighted imaging (SPIO-SWI) and quantitative susceptibility mapping (QSM) methods were used to simultaneously study 7 T MRI signal changes in parenchymal veins, arteries, and their corresponding para-vascular spaces in 26 rats, following intra-cisterna magna (ICM) infusion of different CSF tracers (FeREX, ferumoxytol, Fe-Dextran) to determine the amount of tracer in the artery and vein quantitatively.
 Results: The parenchymal venous system participated in CSF tracer clearance following ICM infusion of different MRI tracers with different concentrations of iron. Parenchymal venous participation was more obvious when 75 μg iron was injected. In the parenchymal veins, the relative mean (±SE) value of the susceptibility increased by 13.5±1.0% at 15 min post-tracer infusion (p<0.01), and 33.6±6.7% at 45 min post-tracer infusion (p=0.01), compared to baseline. In contrast to the parenchymal veins, a negligible amount of CSF tracer entered the parenchymal arteries: 1.3±2.6% at 15 min post-tracer infusion (p=0.6), and 12±19% at 45 min post-tracer infusion (p=0.5), compared to baseline.
 Conclusions: MRI tracers can enter the parenchymal vascular system and more MRI tracers were observed in the cerebral venous than arterial vessels, suggesting the direct participation of parenchymal vascular system in CWC.

Unique Random-Block Polymer Architecture for Site-Specific Mitochondrial Sequestration-Aided Effective Chemotherapeutic Delivery and Enhanced Fluorocarbon Segmental Mobility-Facilitated 19F Magnetic Resonance Imaging.

The elevation of the chemotherapeutic efficacy and attenuation of its side effects on healthy cells and tissues become one of the prime targets for the treatment of cancer. Toward this direction, a sequential receptor and mitochondria dual-targeting strategy was implemented in the DX TP PG BN 19F theranostic polymer that was anchored with the chemotherapeutic agent doxorubicin, receptor-targeting biotin, and mitochondria-targeting triphenylphosphonium cations. The polymer was flourished with a unique 19F magnetic resonance imaging (MRI) tracer that exhibited high segmental mobility and eventually led to prolonged T2 relaxation time. Furthermore, for the sake of amphiphilicity, the DX TP PG BN 19F polymer spontaneously aggregated into nano-sphere with positive zeta potential, where the MRI tracer and biotin embedded at the exterior and displayed site-specific targeting and remarkable 19F MRI capability simultaneously. The mitochondria-targeting competency of the DX TP PG BN 19F theranostic polymer was investigated by comparing the non-mitochondrial-targeting DX PG BN 19F polymer using fluorescence microscopic cell imaging in human cervical, HeLa, and breast MCF-7 carcinoma cell lines. Moreover, cytotoxicity experiments of the aforementioned theranostic polymers clarified the enhancement of the chemotherapeutic efficacy of DX TP PG BN 19F theranostic polymers through effective and precise mitochondrial doxorubicin delivery that forced to follow the apoptotic path.

Gross tumor volume (GTV) : Basics, methods, registration, limitations

Gross tumor volume (GTV) denotes the macroscopic tumor which as the central target volume needs to be correctly identified for successful radiotherapy. In precision radiotherapy, GTV is outlined on 3D tomographic images. The basis is computed tomography (CT), which is often supplemented by additional diagnostic information, e. g. magnetic resonance imaging (MRI) and positron emission tomography (PET). New developments like dual-energy CT, functional MRI and specific PET tracers facilitate acontinuously better differentiation between tumor and surrounding normal tissue. The concept of GTV is acentral part of radiotherapy and the basis of radiation treatment planning. Studies regarding the interobserver variability are performed in order to analyze the impact of different imaging modalities, interventions and observer qualifications, and to deduce steps to constantly improve the practical realization. Each tumor entity presents specific challenges which are demonstrated here using examples.

Non-invasively differentiating extent of liver fibrosis by visualizing hepatic integrin αvβ3 expression with an MRI modality in mice.

To explore the potential of a dendrimer nanoprobe labeled with cyclic arginine-glycine-aspartic acid pentapeptide (cRGDyK) as a magnetic resonance imaging (MRI) tracer to non-invasively differentiate the extent of liver fibrosis. Synthetic dendrimer nanoprobes were labeled with cRGDyK (Den-RGD) to form a formulation of hepatic stellate cell (HSC)-specific MRI tracer. An MRI modality was employed to visualize hepatic Den-RGD deposition in a mouse model of liver fibrosis caused by thioacetamide treatment. Den-RGD bound to activated HSCs via integrin αvβ3 receptors. The labeling of nanoprobes with cRGDyK increased their affinity to and accelerated their uptake by activated HSCs. Most of intravenously administrated Den-RGD nanoprobes deposited in the fibrotic areas, and the deposited amount was paralleled with the severity of liver fibrosis. Majority of cells taking-up Den-RGD was found to be activated HSCs in fibrotic livers. An MRI modality using Den-RGD as a tracer demonstrated that the relative hepatic T1-weighed MR signal value was increased in parallel with the severity of liver fibrosis. The extent of Den-RGD deposition reflects integrin αvβ3 expression in activated HSCs, and Den-RGD appears to be a useful formulation of MRI tracer and may non-invasively and quantitatively assess the extent of liver fibrosis.

Direct labeling of 19F-perfluorocarbon onto multilayered cell sheet for MRI-based non-invasive cell tracking

Autologous stem cell transplantation for eye diseases is immunologically preferable to avoid allograft rejection. However, the fate of the grafted cells has never been studied. Here, we propose to use 19F-perfluorocarbon magnetic resonance imaging tracer agent, to label cell sheet in vitro. This labeling enables non-invasive visualization of possible migration of grafted cells. Oral mucosal epithelial cells were isolated from rabbit oral mucosal epithelium and were cultivated in a thermo-responsive surface to engineer a multilayer cell sheet. Different concentrations of 19F-perfluorocarbon were added to the cell sheet culture media, one or two times. Cells were analyzed in a 7 T nuclear magnetic resonance to determine the labeling efficiency. We found that 10 mg/mL and two incubations with 19F-perfluorocarbon were the optimal condition for labeling. H&E and immunocytochemistry showed that labeling did not affect the expression of cell sheets specific markers (CK4, CK13, connexin43, E-cadherin). Furthermore, no significant effects were observed on the number of cells and the cell viability, making 19F-perfluorocarbon suitable for cell tracking, with no side effects.

Noninvasive Imaging of Liposomal Delivery of Superparamagnetic Iron Oxide Nanoparticles to Orthotopic Human Breast Tumor in Mice

Magnetic resonance imaging (MRI) is widely used for diagnostic imaging in preclinical studies and in clinical settings. Considering the intrinsic low sensitivity and poor specificity of standard MRI contrast agents, the enhanced delivery of MRI tracers into tumors is an important challenge to be addressed. This study was intended to investigate whether delivery of superparamagnetic iron oxide nanoparticles (SPIONs) can be enhanced by liposomal SPION formulations for either "passive" delivery into tumor via the enhanced permeability and retention (EPR) effect or "active" targeted delivery to tumor endothelium via the receptors for vascular endothelial growth factor (VEGFRs). In vivo MRI of orthotopic MDA-MB-231 tumors was performed on a preclinical 9.4T MRI scanner following intravenous administration of either free/non-targeted or targeted liposomal SPIONs. In vivo MRI study revealed that only the non-targeted liposomal formulation provided a statistically significant accumulation of SPIONs in the tumor at four hours post-injection. The EPR effect contributes to improved accumulation of liposomal SPIONs in tumors compared to the presumably more transient retention during the targeting of the tumor vasculature via VEGFRs. A non-targeted liposomal formulation of SPIONs could be the optimal option for MRI detection of breast tumors and for the development of therapeutic liposomes for MRI-guided therapy.

MRI virtual biopsy and treatment of brain metastatic tumors with targeted nanobioconjugates: nanoclinic in the brain.

Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy, which can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections, or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. To develop a more precise noninvasive MRI diagnostic method, we have engineered a new class of poly(β-l-malic acid) polymeric nanoimaging agents (NIAs). The NIAs carrying attached MRI tracer are able to pass through the blood-brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative "MRI virtual biopsy" method is based on a nanoconjugate carrying MRI contrast agent gadolinium-DOTA and antibodies recognizing tumor-specific markers and extravasating through the BBB. In newly developed double tumor xenogeneic mouse models of brain metastasis this noninvasive method allowed differential diagnosis of HER2- and EGFR-expressing brain tumors. After MRI diagnosis, breast and lung cancer brain metastases were successfully treated with similar tumor-targeted nanoconjugates carrying molecular inhibitors of EGFR or HER2 instead of imaging contrast agent. The treatment resulted in a significant increase in animal survival and markedly reduced immunostaining for several cancer stem cell markers. Novel NIAs could be useful for brain diagnostic MRI in the clinic without currently performed brain biopsies. This technology shows promise for differential MRI diagnosis and treatment of brain metastases and other pathologies when biopsies are difficult to perform.

In Vivo Targeting of Cutaneous Melanoma Using an Melanoma Stimulating Hormone-Engineered Human Protein Cage with Fluorophore and Magnetic Resonance Imaging Tracers.

Nanoparticle (NP)-based materials are promising agents for enhancing cancer diagnosis and treatment. Once functionalized for selective targeting of tumor-expressed molecules, they can specifically deliver drugs and diagnostic molecules inside tumor cells. In the present work, we evaluated the in vivo melanoma-targeting ability of a nanovector (HFt-MSH-PEG) based on human protein ferritin (HFt), functionalized with both melanoma-targeting melanoma stimulating hormone (α-MSH) and stabilizing poly(ethylene glycol) (PEG) molecules. Independent and complementary techniques, such as whole-specimen confocal microscopy and magnetic resonance imaging, were used to detect in vivo localization of NP constructs with suitable tracers (i.e., fluorophores or magnetic metals). Targeted HFt-MSH-PEG NPs accumulated persistently at the level of primary melanoma and with high selectivity with respect to other organs. Melanoma localization of untargeted HFt-PEG NPs, which lack the α-MSH moiety, was less pronounced. Furthermore, HFt-MSH-PEG NPs accumulated to a significantly lower extent and with a different distribution in a diverse type of tumor (TS/A adenocarcinoma), which does not express α-MSH receptors. Finally, in a spontaneous lung metastasis model, HFt-MSH-PEG NPs localized at the metastasis level as well. These results suggest that HFt-MSH-PEG NPs are suitable carriers for selective in vivo delivery of diagnostic or therapeutic agents to cutaneous melanoma.

Imaging neuroinflammation in vivo in a neuropathic pain rat model with near-infrared fluorescence and ¹⁹F magnetic resonance.

Chronic neuropathic pain following surgery represents a serious worldwide health problem leading to life-long treatment and the possibility of significant disability. In this study, neuropathic pain was modeled using the chronic constriction injury (CCI). The CCI rats exhibit mechanical hypersensitivity (typical neuropathic pain symptom) to mechanical stimulation of the affected paw 11 days post surgery, at a time when sham surgery animals do not exhibit hypersensitivity. Following a similar time course, TRPV1 gene expression appears to rise with the hypersensitivity to mechanical stimulation. Recent studies have shown that immune cells play a role in the development of neuropathic pain. To further explore the relationship between neuropathic pain and immune cells, we hypothesize that the infiltration of immune cells into the affected sciatic nerve can be monitored in vivo by molecular imaging. To test this hypothesis, an intravenous injection of a novel perfluorocarbon (PFC) nanoemulsion, which is phagocytosed by inflammatory cells (e.g. monocytes and macrophages), was used in a rat CCI model. The nanoemulsion carries two distinct imaging agents, a near-infrared (NIR) lipophilic fluorescence reporter (DiR) and a 19F MRI (magnetic resonance imaging) tracer, PFC. We demonstrate that in live rats, NIR fluorescence is concentrated in the area of the affected sciatic nerve. Furthermore, the 19F MRI signal was observed on the sciatic nerve. Histological examination of the CCI sciatic nerve reveals significant infiltration of CD68 positive macrophages. These results demonstrate that the infiltration of immune cells into the sciatic nerve can be visualized in live animals using these methods.

Performances d’un outil d’interrogatoire standardisé médicalisé pour faciliter l’amorce au dépistage de l’infection à Chlamydia trachomatis

An efficient mutual information (MI) based automatic registration method is introduced to align the rat brain tissues in magnetic resonance imaging (MRI) time-series, which is critical to the MRI tracer method for quantitative analysis of brain extracellular space (ECS). The method is specially designed to address the specific properties of contrast-enhanced MRI time-series. Firstly, a segmentation method is proposed to extract the brain tissue mask which is used in MI computing to avoid the adverse effects of surrounding deformed tissues. Secondly, a two-stage registration framework is proposed, where the images are first aligned using deformable registration and then finally matched by rigid registration. A series of experiments are conducted to evaluate the registration method qualitatively and quantitatively. The experimental results show that the proposed method has a high degree of accuracy and reliability, and is adequate to the task of three-dimensional registration of rat brain MRI time-series.

19F MRI Tracer Preserves in Vitro and in Vivo Properties of Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) have numerous therapeutic applications including immune reconstitution, enzyme replacement, regenerative medicine, and immunomodulation. The trafficking and persistence of these cells after administration is a fundamental question for future therapeutic applications of HSCs. Here, we describe the safe and efficacious labeling of human CD34(+) HSCs with a novel, self-delivering perfluorocarbon ¹⁹F magnetic resonance imaging (MRI) tracer, which has recently been authorized for use in a clinical trial to track therapeutic cells. While various imaging contrast agents have been used to track cellular therapeutics, the impact of this MRI tracer on HSC function has not previously been studied. Both human CD34(+) and murine bone marrow (BM) HSCs were effectively labeled with the MRI tracer, with only a slight reduction in viability, relative to mock-labeled cells. In a pilot study, ¹⁹F MRI enabled the rapid evaluation of HSC delivery/retention following administration into a rat thigh muscle, revealing the dispersal of HSCs after injection, but not after surgical implantation. To investigate effects on cell functionality, labeled and unlabeled human HSCs were tested in in vitro colony forming unit (CFU) assays, which resulted in equal numbers of total CFU as well as individual CFU types, indicating that labeling did not alter multipotency. Cobblestone assay forming cell precursor frequency was also unaffected, providing additional evidence that stem cell function was preserved after labeling. In vivo tests of multipotency and reconstitution studies in mice with murine BM containing labeled HSCs resulted in normal development of CFU in the spleen, compared to unlabeled cells, and reconstitution of both lymphoid and myeloid compartments. The lack of interference in these complex biological processes provides strong evidence that the function and therapeutic potential of the HSCs are likely maintained after labeling. These data support the safety and efficacy of the MRI tracer for clinical tracking of human stem cells.

Mutual information based three-dimensional registration of rat brain magnetic resonance imaging time-series

An efficient mutual information (MI) based automatic registration method is introduced to align the rat brain tissues in magnetic resonance imaging (MRI) time-series, which is critical to the MRI tracer method for quantitative analysis of brain extracellular space (ECS). The method is specially designed to address the specific properties of contrast-enhanced MRI time-series. Firstly, a segmentation method is proposed to extract the brain tissue mask which is used in MI computing to avoid the adverse effects of surrounding deformed tissues. Secondly, a two-stage registration framework is proposed, where the images are first aligned using deformable registration and then finally matched by rigid registration. A series of experiments are conducted to evaluate the registration method qualitatively and quantitatively. The experimental results show that the proposed method has a high degree of accuracy and reliability, and is adequate to the task of three-dimensional registration of rat brain MRI time-series.

Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

Previous authors have shown that the transverse relaxivity R(2)* and frequency shifts that characterize gradient echo signal decay in magnetic resonance imaging are closely associated with the distribution of iron and myelin in the brain's white matter. In multiple sclerosis, iron accumulation in brain tissue may reflect a multiplicity of pathological processes. Hence, iron may have the unique potential to serve as an in vivo magnetic resonance imaging tracer of disease pathology. To investigate the ability of iron in tracking multiple sclerosis-induced pathology by magnetic resonance imaging, we performed qualitative histopathological analysis of white matter lesions and normal-appearing white matter regions with variable appearance on gradient echo magnetic resonance imaging at 7 Tesla. The samples used for this study derive from two patients with multiple sclerosis and one non-multiple sclerosis donor. Magnetic resonance images were acquired using a whole body 7 Tesla magnetic resonance imaging scanner equipped with a 24-channel receive-only array designed for tissue imaging. A 3D multi-gradient echo sequence was obtained and quantitative R(2)* and phase maps were reconstructed. Immunohistochemical stainings for myelin and oligodendrocytes, microglia and macrophages, ferritin and ferritin light polypeptide were performed on 3- to 5-µm thick paraffin sections. Iron was detected with Perl's staining and 3,3'-diaminobenzidine-tetrahydrochloride enhanced Turnbull blue staining. In multiple sclerosis tissue, iron presence invariably matched with an increase in R(2)*. Conversely, R(2)* increase was not always associated with the presence of iron on histochemical staining. We interpret this finding as the effect of embedding, sectioning and staining procedures. These processes likely affected the histopathological analysis results but not the magnetic resonance imaging that was obtained before tissue manipulations. Several cellular sources of iron were identified. These sources included oligodendrocytes in normal-appearing white matter and activated macrophages/microglia at the edges of white matter lesions. Additionally, in white matter lesions, iron precipitation in aggregates typical of microbleeds was shown by the Perl's staining. Our combined imaging and pathological study shows that multi-gradient echo magnetic resonance imaging is a sensitive technique for the identification of iron in the brain tissue of patients with multiple sclerosis. However, magnetic resonance imaging-identified iron does not necessarily reflect pathology and may also be seen in apparently normal tissue. Iron identification by multi-gradient echo magnetic resonance imaging in diseased tissues can shed light on the pathological processes when coupled with topographical information and patient disease history.

Greatly improved neuroprotective efficiency of citicoline by stereotactic delivery in treatment of ischemic injury

Limited penetration of neuroprotective drug citicoline into the central nervous system (CNS) by systemic administration led to poor efficiency. A novel method of stereotactic drug delivery was explored to make citicoline bypass the blood brain barrier (BBB) and take effect by direct contact with ischemic neurons. A permanent middle cerebral artery occlusion (pMCAO) model of rats was prepared. To get the optimal conditions for citicoline administration by the novel stereotactic delivery pathway, magnetic resonance imaging (MRI) tracer method was used, and a dose-dependent effect was given. Examinations of MRI, behavior evaluation, infarct volume assessment and histological staining were performed to evaluate the outcome. This MRI-guided stereotactic delivery of citicoline resulted in a notable reduction (>80%) in infarct size and a delayed ischemic injury in cortex 12 hours after onset of acute ischemia when compared with the systematic delivery. The improved neuroprotective efficiency was realized by a full distribution of citicoline in most of middle cerebral artery (MCA) territory and an adequate drug reaction in the involved areas of the brain. Brain lesions of treated rats by stereotactic delivery of citicoline were well predicted in the lateral ventricle and thalamus due to a limited drug deposition by MRI tracer method. Our study realized an improved neuroprotective efficiency of citicoline by stereotactic delivery, and an optimal therapeutic effect of this administration pathway can be achieved under MRI guidance.