Search

Microvascular rarefaction, or the decrease in vascular density, has been described in the cerebrovasculature of aging humans, rats, and, more recently, mice in the presence and absence of age-dependent diseases. Given the wide use of mice in modeling age-dependent human diseases of the cerebrovasculature, visualization, and quantification of the global murine cerebrovasculature is necessary for establishing the baseline changes that occur with aging. To provide in vivo whole-brain imaging of the cerebrovasculature in aging C57BL/6 mice longitudinally, contrast-enhanced magnetic resonance angiography (CE-MRA) was employed using a house-made gadolinium-bearing micellar blood pool agent. Enhancement in the vascular space permitted quantification of the detectable, or apparent, cerebral blood volume (aCBV), which was analyzed over 2 years of aging and compared to histological analysis of the cerebrovascular density. A significant loss in the aCBV was detected by CE-MRA over the aging period. Histological analysis via vessel-probing immunohistochemistry confirmed a significant loss in the cerebrovascular density over the same 2-year aging period, validating the CE-MRA findings. While these techniques use widely different methods of assessment and spatial resolutions, their comparable findings in detected vascular loss corroborate the growing body of literature describing vascular rarefaction aging. These findings suggest that such age-dependent changes can contribute to cerebrovascular and neurodegenerative diseases, which are modeled using wild-type and transgenic laboratory rodents.

Microvascular rarefaction, or the decrease in vascular density, has been described in the cerebrovasculature of aging humans, rats, and, more recently, mice in the presence and absence of age-dependent diseases. Given the wide use of mice in modeling age-dependent human diseases of the cerebrovasculature, visualization, and quantification of the global murine cerebrovasculature is necessary for establishing the baseline changes that occur with aging. To provide in vivo whole-brain imaging of the cerebrovasculature in aging C57BL/6 mice longitudinally, contrast-enhanced magnetic resonance angiography (CE-MRA) was employed using a house-made gadolinium-bearing micellar blood pool agent. Enhancement in the vascular space permitted quantification of the detectable, or apparent, cerebral blood volume (aCBV), which was analyzed over 2 years of aging and compared to histological analysis of the cerebrovascular density. A significant loss in the aCBV was detected by CE-MRA over the aging period. Histological analysis via vessel-probing immunohistochemistry confirmed a significant loss in the cerebrovascular density over the same 2-year aging period, validating the CE-MRA findings. While these techniques use widely different methods of assessment and spatial resolutions, their comparable findings in detected vascular loss corroborate the growing body of literature describing vascular rarefaction aging. These findings suggest that such age-dependent changes can contribute to cerebrovascular and neurodegenerative diseases, which are modeled using wild-type and transgenic laboratory rodents. [ABSTRACT FROM AUTHOR]

Blood-pool agents (BPAs) are MRI contrast agents (CAs) characterized by their long circulation in the vascular system to provide an extended time window for high-resolution MR angiography (MRA). Prolonged vascular retention, however, impedes the excretion of BPAs. Therefore, chemical strategy to regulate the balance between retention and clearance is important to reach optimal pharmacokinetics. We recently developed MnP2, the first Mn(III)-porphyrin (MnP) based BPA. MnP2 shows high T1 relaxivity (r1) and high affinity to human serum albumin (HSA) that leads to up to 48-h vascular retention in rats. However, upon albumin binding, the r1 is decreased. To modulate vascular retention time and plasma r1, a regioisomer of MnP2, m-MnP2, was synthesized. The free m-MnP2 exhibits lower r1 than that of MnP2 at magnetic fields above 2 MHz, which agrees with their relative hydrodynamic sizes. The HSA binding of m-MnP2 was evaluated using UV-Vis spectroscopy and found to have tuned-down affinity in comparison with MnP2. Upon HSA binding, the protein complex of m-MnP2 exhibits an r1 of 11.8 mM−1 s−1 at 3 T, which is higher than that of MnP2 bound to HSA. Taken together, this demonstrated the role of molecular geometry in optimizing the pharmacokinetics of albumin-targeting BPAs.

Abstract: Ultra‐small superparamagnetic iron oxide (USPIO) nanoparticles provide a safer alternative to gadolinium‐based contrast agents (GBCAs) in T1‐weighted MR imaging. MRI contrast behavior of USPIOs depends on their magnetic properties, which in turn depend on their physicochemical composition. Identifying and tailoring USPIO structural characteristics that influence proton relaxation in MRI is crucial to developing effective gadolinium‐free T1 contrast agents. Here, we present a systematic empirical evaluation of the relationship between USPIO size and MRI relaxivity (r1 and r2 values). Monodisperse USPIO cores, with precisely controlled core diameter (dC) were synthesized via the thermal decomposition of iron(III)‐oleate precursor. USPIOs with dC = 6.34, 7.58, 8.58, and 9.50nm, were dispersed in aqueous phase via ligand exchange with silane or dopamine‐modified polyethylene glycol (PEG) polymers. Relaxivity characterization in a 1.5 T clinical MRI scanner showed the r2/r1 ratio increased linearly with USPIO core diameter (R2 = 0.95), but varied little with both hydrodynamic diameter (dH) and PEG molecular weight. One sample, DOPA‐6‐20 (6.34nm USPIO cores coated with 20 kDa dopamine‐modified PEG), provided the lowest r2/r1 value (3.44) and thus promise as a potential T1 contrast agent. In a preliminary study, we evaluated DOPA‐6‐20 for in vivo angiography imaging in a mouse with a 7 T scanner and observed strong T1‐weighted enhancement of the mouse blood pool. Key anatomical features in the vascular network were visible even 5 min after intravenous administration. Using empirical data, we have presented the basis of a structure–property relationship that can help develop optimized USPIO‐based T1 contrast agents. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2440–2447, 2018. [ABSTRACT FROM AUTHOR]

Despite significant advances in contrast enhanced-magnetic resonance angiography, the lack of truly blood-pool agents with long circulating property is limiting the clinical impact of this imaging technique. The terminal half-life for blood elimination of most small molecular weight gadolinium (Gd) based extracellular fluid agents is about 1.5 h when administered intravenously to subjects with normal renal function. The small size of these extracellular fluid agents does not prevent them from extravasating, especially from damaged vessels which are generally hyperpermeable. Therefore, the development of novel, clinically relevant blood pool contrast agents is critically needed to improve outcomes in the prevention, detection, and treatment of vascular diseases. We have demonstrated the fusion strategies in which the Gd-liposome without any stealth property radically fuses with red blood cells (RBCs) forming MR glowing Gd-RBC with the order of magnitude enhancements in circulation half-life (t 1/2 = 50 h) and r 1 relaxivity (r 1 = 19.0 mM −1 s −1 ) of Gd. The in vivo contrast enhancement of Gd-RBC was studied by using 3T clinical MR scanner for extended period of time, which clearly visualized the abdominal aorta. In summary, the vascular delivery of blood pool agents may benefit from carriage by RBCs because it naturally stays within the vascular lumen. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the safety and feasibility of off-label use of ferumoxytol as an intravenous MRI contrast agents in pediatric patients and young adults. Materials and methods With HIPAA compliance and IRB approval, 86 consecutive patients who had undergone 3 T or 1.5 T MRI with ferumoxytol were retrospectively identified. The blood pressure and heart rate of patients before and after ferumoxytol injection were compared. The overall image quality was evaluated independently by two radiologists with a four-point scale. Interobserver agreement was calculated using weighted kappa statistics. Results The mean ± standard deviation (SD) pre and post-contrast systolic blood pressures (SBP) were 101 ± 18 and 95 ± 20, respectively. There was a statistically significant difference between pre-SBP and post-SBP (P = 0.003). The pre-contrast diastolic blood pressure (DBP) and the post-contrast diastolic blood pressure (DBP) were 60 ± 14 and 51 ± 17, respectively. There was a statistically significant difference between pre-DBP and post-DBP (P < 0.001). The number of patients with SBP and DBP increase, SBP increase and DBP decrease, SBP decrease and DBP increase, SBP and DBP decrease, SBP increase and DBP unchanged were 14 (16%), 9 (10%), 6 (7%), 56 (65%), 1 (1%), respectively. There was moderate agreement on all individual assessments of image quality (kappa = 0.45). Eighty-two of 86 (95.4%) studies were scored 3 or above (at least diagnostic quality) by both readers, with 90% confidence interval of 92–99%. Conclusion Ferumoxytol is effective as an MR contrast agent. In our sample, there was on average a small but clinically insignificant drop in SBP and DBP post-contrast injection. Large, randomized, controlled trials are needed to establish optimal dosing, imaging procedures, and safety monitoring. [ABSTRACT FROM AUTHOR]

Purpose: To compare steady-state magnetic resonance angiography (SS-MRA), using a blood pool contrast agent, with the established technique of time-resolved MRA (TR-MRA), in pulmonary vein mapping and left atrial patency.Materials and Methods: Twenty-one patients (12 males, age 58.3 ± 8.4 years; 9 females; 57 ± 10 years) undergoing pulmonary vein mapping were evaluated with TR-MRA (TWIST) and SS-MRA. Orthogonal measurements and areas for four veins per patient per technique were assessed by Friedman's test.Results: Overall intertechnique mean difference for any pulmonary vein orthogonal measurement and area was 0.02 ± 0.34 cm (P = 0.705), and 0.2 ± 0.08 cm(2) (P < 0.001). Interobserver correlation was strong for diameter and area measurements using the three methods with a range of 0.72-0.94, and 0.87-0.97, respectively. Left atrial appendage image quality score for TR-MRA was significantly lower than the other two methods (P < 0.001). Both observers detected more stenosis on inversion recovery (IR)-True FISP compared to TR-MRA and IR-FLASH.Conclusion: SS-MRA with a blood pool agent compared favorably to the established technique of TR-MRA for quantitative assessment of pulmonary venous anatomy. SS-MRA offers greater spatial resolution than TR-MRA with increased confidence for ruling out left atrial appendage filling defect. [ABSTRACT FROM AUTHOR]

Objective: To compare performance of single-injection blood pool agent (gadofosveset trisodium, BPA) against dual-injection extracellular contrast (gadopentetate dimeglumine, ECA) for MRA/MRV in assessment of suspected vascular TOS. Materials and methods: Thirty-one patients referred for vascular TOS evaluation were assessed with BPA (n =18) or ECA (n =13) MRA/MRV in arm abduction and adduction. Images were retrospectively assessed for: image quality (1=non-diagnostic, 5=excellent), vessel contrast (1=same signal as muscle, 4=much brighter than muscle) and vascular pathology by two independent readers, with a separate experienced reader providing reference assessment of vascular pathology. Results: Median image quality was diagnostic or better (score ≥3) for ECA and BPA at all time points, with BPA image quality superior at abduction late (BPA 4.5, ECA 4, p =0.042) and ECA image quality superior at adduction-early (BPA 4.5; ECA 4.0, p =0.018). High qualitative vessel contrast (mean score ≥3) was observed at all time points with both BPA and ECA, with superior BPA vessel contrast at abduction-late (BPA 3.97±0.12; ECA 3.73±0.26, p =0.007) and ECA at adduction-early (BPA 3.42±0.52; ECA 3.96±0.14, p <0.001). Readers readily identified arterial and venous pathology with BPA, similar to ECA examinations. Conclusion: Single-injection BPA MRA/MRV for TOS evaluation demonstrated diagnostic image quality and high vessel contrast, similar to dual-injection ECA imaging, enabling identification of fixed and functional arterial and venous pathology. [ABSTRACT FROM AUTHOR]

Abstract: Stable gadolinium chelates are widely used as the contrast agents (CAs) for magnetic resonance imaging (MRI). Conjugation of the chelates onto macromolecular carriers forms macromolecular CAs (mCAs). Compared with small molecule MRI CAs, mCAs have advantages of high relaxivity and prolonged retention in blood circulation. Variants of mCAs have been synthesized and tested using animal models, showing their great potential applications in angiography, cancer imaging, kidney imaging, liver imaging, lymphatic imaging, and noninvasive visualization of drug delivery. Herein, the state of the art of mCAs, including their structures, properties, and applications is reviewed and future directions for developing mCAs are suggested. [Copyright &y& Elsevier]

Purpose: To investigate enhancement of hepatic lesions with gadofosveset trisodium (Gdfos) (Ablavar) (blood pool agent) compared with the extracellular gadolinium contrast agent (EcGd) gadobutrol (Gadovist). Materials and Methods: The prospective study was approved by the Institutional Research Ethics Board with informed consent. Twelve patients underwent magnetic resonance imaging (MRI) with EcGd followed by MRI with Gdfos. For each agent qualitative analysis described the pattern of enhancement and quantitative analysis was performed using lesion-to-liver contrast-to-noise (CNR) ratio. Paired and unpaired Student's t-test used. Results: Twelve hemangiomas, four metastases, one cyst, two focal nodular hyperplasia (FNH), and three adenomas were found. Cyst, FNH, adenomas, and hemangiomas demonstrated the classic pattern of enhancement with both agents. Hemangiomas demonstrated retention of contrast with both agents and their CNR was not statistically different ( P > 0.05). Metastases demonstrated retention of contrast on delayed phase with EcGd. Retention of contrast was not seen in metastases with Gdfos. CNR of metastases with Gdfos was statistically lower than CNR of metastases with EcGd ( P = 0.005). CNR of hemangiomata and metastases on delayed phase were significantly different ( P = 0.0008) with Gdfos, but similar with EcGd ( P = 0.4). Conclusion: Hemangiomas accumulate Gdfos on delayed phase and metastases do not, a key additional differentiating feature. Liver imaging with Gdfos may improve characterization of liver lesions. J. Magn. Reson. Imaging 2012;36:738-742. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Gadofosveset trisodium (Ablavar®, formerly Vasovist®) is the first intravascular contrast agent approved for clinical use in peripheral vascular disease. The purpose of this review is to illustrate the clinical uses of gadofosveset-enhanced magnetic resonance angiography in patients referred for assessment of arteriovenous disease. Superior T1 shortening enables first pass renal and peripheral arteriography of quality comparable with larger doses of extracellular agents. In applications such as thoracic outlet syndrome, there may be other advantages such as superior venous imaging and need for only one injection. Steady-state delayed imaging provides high resolution mapping of both arterial and venous systems and imaging of multiple territories. A combination of dynamic and delayed steady-state imaging can provide detailed anatomy and flow characteristics of vascular malformations and mapping for percutaneous sclerotherapy at one investigation. The ability to image in the steady state can provide minimally invasive imaging of thrombo-occlusive disease of central veins. [ABSTRACT FROM AUTHOR]

We have developed a magnetic resonance imaging (MRI) method for improved detection of cancer with a new class of cancer-specific contrast agents, containing vanadyl (VO2+)-chelated organic ligands, specifically bis(acetylacetonato)oxovanadium(IV) [VO(acac)2]. Vanadyl compounds have been found to accumulate within cells, where they interact with intracellular glycolytic enzymes. Aggressive cancers are metabolically active and highly glycolytic; an MRI contrast agent that enters cells with high glycolytic activity could provide high-resolution functional images of tumor boundaries and internal structure, which cannot be achieved by conventional contrast agents. The present work demonstrates properties of VO(acac)2 that may give it excellent specificity for cancer detection. A high dose of VO(acac)2 did not cause any acute or short-term adverse reactions in murine subjects. Calorimetry and spectrofluorometric methods demonstrate that VO(acac)2 is a blood pool agent that binds to serum albumin with a dissociation constant Kd ~ 2.5 ± 0.7 × 10−7 M and a binding stoichiometry n = 1.03 ± 0.04. Owing to its prolonged blood half-life and selective leakage from hyperpermeable tumor vasculature, a low dose of VO(acac)2 (0.15 mmol/kg) selectively enhanced in vivo magnetic resonance images of tumors, providing high-resolution images of their interior structure. The kinetics of uptake and washout are consistent with the hypothesis that VO(acac)2 preferentially accumulates in cancer cells. Although VO(acac)2 has a lower relaxivity than gadolinium-based MRI contrast agents, its specificity for highly glycolytic cells may lead to an innovative approach to cancer detection since it has the potential to produce MRI contrast agents that are nontoxic and highly sensitive to cancer metabolism. [ABSTRACT FROM AUTHOR]

Vasovist is a newly developed blood pool contrast agent for MR angiogiography (MRA). It consists of a low molecular weight molecule, chelated to Gadolinium, that strongly binds to plasma proteins, thus increasing its relaxivity and retention time in the vascular system. Due to its high efficiency, a smaller dose compared to existing Extracellular Fluid Contrast Agents is sufficient for diagnostic purposes, resulting in a lower injection volume. With appropriate adjustments of standard extracellular contrast injection protocols, a dynamic phase MRA can be achieved using routine MRA parameters. For extended phase imaging, ('steady-state') starting approximately 3 to 5 min post injection, repetition time (TR) and flip angle may be adjusted for optimization of intravascular signal. Preliminary technical recommendations for the optimization of contrast-enhanced MRA with Vasovist can be deducted from current clinical trial experience in various vessel beds. [ABSTRACT FROM AUTHOR]

Rationale and Objectives. To compare the diagnostic performance of the blood pool agent feruglose and the standard extracellular contrast agent gadopentetate in their abilities to differentiate benign and malignant breast tumors.Patients and Methods. Fourteen women, aged 35–77 years (mean, 55 years), with 19 breast lesions underwent dynamic fast field echo 14/1/30° (TR/TE/α) magnetic resonance imaging of the breast after bolus injection of feruglose (Clariscan; Amersham Health, Amersham, UK: dose, 2 mg Fe/kg) and an additional, comparative gadopentetate (dose, 0.2 mmol gadolinium/kg)-enhanced fast field echo 10/4/30° (TR/TE/ α) magnetic resonance study within 1–11 days (mean, 4.8 days) before or after the feruglose study. All breast tumors were surgically excised within 1–6 days (mean, 2.5 days) after completion of the magnetic resonance studies. Data were analyzed by measuring quantitative enhancement data and qualitatively by categorizations of the shape of the tumor enhancement curves. Group differences between quantitative data of the two contrast agents and between benign and malignant tumors were evaluated using a two-tailed paired-sample t test. Differences in curve type distribution between benign and malignant tumors were tested with the χ2 test.Results. Histopathology showed a spectrum of 10 benign and nine malignant breast lesions: five mastopathies, two fibroadenomas, two chronic inflammations, and one papillomatosis, as well as five invasive ductal carcinomas and four invasive lobular carcinomas. Substantial differences were observed between feruglose- and gadopentetate-enhanced images: the mean tumor ΔSI(%) peak enhancement and wash-in rate were significantly higher for gadopentetate- as compared with feruglose-enhanced images (P < .05). Using either contrast agent, morphologic enhancement characteristics showed a considerable overlap between benign and malignant breast lesions. However, the kinetic enhancement profiles of benign and malignant lesions were significantly different based on feruglose-enhanced data (χ2 = 9.017; P = .0027) but not gadopentetate-enhanced data (χ2 = 2.239; P = .3264).Conclusion. Compared with gadopentetate, the new blood pool agent feruglose provided an improved characterization of the evaluated breast lesions; however, at the cost of weaker overall tumor enhancement. [Copyright &y& Elsevier]

A new isonitrile ligand 3,3,5-trimethyl cyclohexylisonitrile (TMCHI) and its copper salt [Cu(TMCHI)4BF4] were synthesized and characterized by IR and elemental analysis. 99mTc-TMCHI is prepared by direct labeling method with high RCP. In vitro protein binding in albumin, blood retention and biodistribution of 99mTc-TMCHI in mice indicated that it is mainly accumulated and maintained in blood with a high protein binding rate and low washout rate. The target/non-target ratios in mice are excellent and suggest its use as a cardiac blood pool agent. [Copyright &y& Elsevier]

Rationale and objectives: In this paper we discuss novel MR imaging blood pool agents characterized by new pharmacokinetic properties. Methods: The pharmacokinetics of the products were studied in a rabbit model. The potential of these new products was demonstrated in experimental MR imaging. Results and conclusion: Three main classes of blood pool agents have been defined and characterized according to their pharmacokinetic properties: low diffusion agents, rapid clearance blood pool agents, slow clearance blood pool agents. Each kind of blood pool agent is expected to have different diagnostic applications. [ABSTRACT FROM AUTHOR]

The parameters that govern water proton magnetic relaxation (e.g. water exchange rates, and rotational and electronic correlation times) of representatives of two classes of Gd(III) complexes have been estimated, using two different approaches and the results compared with those derived for known analogs. The complexes studied are: (i) the non-ionic GdDTPA-bis(methoxyethyl-amide) [Gd(DTPA-BMEA)], a typical small-molecule extracellular MR agent, and (ii) the ionic Gd(III) complex of 4-pentylbicyclo[2.2.2]octane-1-carboxyl-di- l-aspartyl-lysine-derived-DTPA [GdL]4−, a prototype MR blood pool agent, which binds to serum albumin in vivo through non-covalent hydrophobic interactions. An17O-NMR study of [Gd(DTPA-BMEA)] gives a water exchange rate constant of k =(0.39±0.02)×106 s−1, identical to that for the bismethylamide analog [Gd(DTPA-BMA)]. Both approaches yield longer rotational correlation times for [Gd(DTPA-BMEA)], consistent with its higher molecular weight. An17O-NMR study of [GdL]4− gives a water exchange rate constant of k =(4.2±0.1)×106 s−1, identical to that for [Gd(DTPA)]2−. The water exchange rate on [GdL]4− did not decrease considerably when bound to albumin, the lowest limit is k ex,GdL-BSA= k ex,GdL/2. Both approaches yield identical rotational correlation times for [GdL]4−, however, it was difficult to derive a consistent rotational constant for the albumin-bound [GdL]4− using the different approaches (values ranged between 1.0 and 23.0 ns). [ABSTRACT FROM AUTHOR]