Lipophilic Group-Modified Manganese(II)-Based Contrast Agents for Vascular and Hepatobiliary Magnetic Resonance Imaging.

Effective vascular and hepatic enhancement and better safety are the key drivers for exploring gadolinium-free hepatobiliary contrast agents. Herein, a facile strategy proposes that the high lipophilicity may be favorable to enhancing sequentially vascular and hepatobiliary signal intensity based on the structure-activity relationship that both hepatic uptake and interaction with serum albumins partly depend on lipophilicity. Therefore, 11 newly synthesized derivatives of manganese o-phenylenediamine-N,N,N',N'-tetraacetic acid (MnLs) were evaluated as vascular and hepatobiliary agents. The maximum signal intensities of the heart, liver, and kidneys were strongly correlated with log P, a key indicator of lipophilicity. The most lipophilic agent, MnL6, showed favorable relaxivity when binding with serum albumin, good vascular enhancement, rapid excretion, and reliable hepatobiliary phases comparable to a classic hepatobiliary agent, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) for in vivo liver tumor imaging. Inhibition experiments confirmed the hepatic targeting of MnL6 is mediated by organic anion-transporting polypeptides.

The Breakdown of Blood-Labyrinth Barrier Makes it Easier for Drugs to Enter the Inner Ear.

PURPOSE: This study aimed to investigate dynamic change of permeability of blood-labyrinth barrier (BLB) after noise exposure and its effect on the drug delivery efficiency of systemic administration. METHODS: Gadopentetate dimeglumine (Gd-DTPA) and dexamethasone (DEX) were used as tracers, and magnetic resonance imaging (MRI) and immunofluorescence were used to observe the change of the BLB after strong noise exposure in guinea pigs. High-performance liquid chromatography-mass spectrometry (LC-MS) was used to observe the effect of the breakdown of BLB after noise exposure on the drug delivery efficiency of intravenous DEX. The guinea pigs were divided into 6 groups: normal group (N), 1, 3, 5, 8, and 12 days after noise exposure groups (P1, P3, P5, P8, P12), with 5 animals in each group. RESULTS: The BLB changes dynamically after noise exposure. Increased permeability of the blood-endolymph barrier, the endolymph-perilymph barrier, and the blood-nerve barrier was observed at days 1-3, 1-5, and 1-8, respectively, after noise exposure in guinea pigs. Higher drug concentration in the cochlear tissue was obtained by intravenous administration of DEX in guinea pigs during the time window of increased permeability of the BLB. CONCLUSION: After noise exposure, the increased BLB permeability makes it easier for drugs to enter the inner ear from blood. In guinea pigs, 1-8 days after strong noise exposure, the drug delivery efficiency of systemic administration increased. After 8 days, the efficiency gradually returned to normal level. 1-8 days after noise exposure may be the best intervention time for systemic administration. LEVEL OF EVIDENCE: NA Laryngoscope, 134:2377-2386, 2024.

MRI-Based Interstitial Fluid Velocity Analysis for Drug Delivery Efficiency Evaluation in Tumor.

There are many flow behaviors in solid tumors, including intravascular, bloodstream, and interstitial convection. Studies have shown that tumor interstitial fluid (TIF) is an important part of tumor microenvironment regulation and affects drug delivery and metabolism between tumor cells. Magnetic resonance imaging (MRI) is suitable for detecting the flow rates of liquids in tissues. Clinical phase contrast PC-MRI technology has been designed to observe the blood flow in large vessels such as arteries and veins; however, it is not sensitive enough to deal with slow flow velocity. Our previously developed vertical plane echo PC-MRI technology, the Velocity Mapping sequence, improved the signal-to-noise ratio (SNR) for measuring slow interstitial fluid rate. In this study, this sequence was used to determine the TIF flow rate in MDA-MB-231 human breast tumor cells used in BALB/c nude male mice. Two different sizes of contrast agents were intravenously injected, and the relationship between their distribution and the TIF flow rate was studied for the first time. Combining the results of clinical scanning showed that small-molecule DTPA-Gd (diethylenetriaminepentaacetic acid-gadolinium) was distributed immediately around the tumor margin after the injection. This distribution was positively correlated to the high flow rate area of the TIF before administration. In contrast, nanoparticles NaGdF4-PEG (polyethylene glycol) entered the tumor and reached their peak at 3 h. Drug distribution was negatively correlated with the high-flow-rate region of the TIF. Investigation of the TIF velocity can help better understand the fluid behavior in tumors and its role in drug delivery.

Comparison of the biological effects of gadodiamide (Omniscan) and gadoteridol (ProHance) by means of multi-organ and plasma metabolomics.

Gadolinium-based contrast agents (GBCAs) are massively employed in radiology to increase the diagnostic power of MRI. However, investigations aiming at detecting possible metabolic perturbations or adverse health effects due to gadolinium deposition are still lacking. In this work, aqueous organs extract and plasma samples were analyzed by GC-MS and 1H-NMR, respectively, to investigate the effects of multiple administrations of one linear (Omniscan) and one macrocyclic (ProHance) GBCA, on the main metabolic pathways in healthy mice. Multivariate analysis revealed that plasma metabolome was not differently perturbed by the two GBCAs, while, the multiorgan analysis displayed a clear separation of the Omniscan-treated from the control and the ProHance-treated groups. Interestingly, the most affected organs were the brain, cerebellum and liver. Thus, this work paves the way to both the safest use of the commercially available GBCAs and the development of new GBCAs characterized by lower general toxicity.

The effect of a novel AQP4 facilitator, TGN-073, on glymphatic transport captured by diffusion MRI and DCE-MRI.

The glymphatic system is a low resistance pathway, by which cerebrospinal fluid enters the brain parenchyma along perivascular spaces via AQP4 channels. It is hypothesised that the resulting convective flow of the interstitial fluid provides an efficient mechanism for the removal of waste toxins from the brain. Therefore, enhancing AQP4 function might protect against neurodegenerative diseases such as Alzheimer's disease (AD), in which the accumulation of harmful proteins and solutes is a hallmark feature. Here, we test the effect of a putative AQP4 facilitator, TGN-073, on glymphatic transport in a normal rat brain by employing different MRI techniques. Surgical procedures were undertaken to catheterise the cisterna magna, thereby enabling infusion of the MRI tracer. Followed by the intraperitoneal injection of either TGN-073, or the vehicle. Using a paramagnetic contrast agent (Gd-DTPA) as the MRI tracer, dynamic 3D T1 weighted imaging of the glymphatic system was undertaken over two hours. Further, the apparent diffusion coefficient was measured in different brain regions using diffusion-weighted imaging (DWI). While physiological parameters and arterial blood gas analysis were monitored continuously. We found that rats treated with TGN-073 showed the distribution of Gd-DTPA was more extensive and parenchymal uptake was higher compared with the vehicle group. Water diffusivity was increased in the brain of TGN-073 treated group, which indicates greater water flux. Also, MRI showed the glymphatic transport and distribution in the brain is naturally heterogeneous, which is consistent with previous studies. Our results indicate that compounds such as TGN-073 can improve glymphatic function in the brain. Since glymphatic impairment due to AQP4 dysfunction is potentially associated with several neurological disorders such as AD, dementia and traumatic brain injury, enhancing AQP4 functionality might be a promising therapeutic target.

[Epidural photobiomodulation accelerates the drainage of brain interstitial fluid and its mechanism].

OBJECTIVE: To evaluate the effect of photobiomodulation (PBM) on the drainage of brain interstitial fluid (ISF) and to investigate the possible mechanism of the positive effect of PBM on Alzheimer's disease (AD). METHODS: Twenty-four SD male rats were randomly divided into PBM group (n=12), sham PBM group (n=6), and negative control group (n=6). According to the injection site of tracer, the PBM group was further divided into PBM-ipsilateral traced group (n=6) and PBM-contralateral traced group (n=6). Rats in the PBM group and the sham PBM group were exposed to the dura minimally invasively on the skull corresponding to the frontal cortical area reached by ISF drainage from caudate nucleus region. The PBM group was irradiated by using 630 nm red light (5-6 mW/cm2), following an irradiation of 5 min with a 2 min pause, and a total of 5 times; the sham PBM group was kept in the same position for the same time using the light without power. The negative control group was kept without any measure. After PBM, tracer was injected into caudate nucleus of each group. The changes of ISF drainage in caudate nucleus were observed according to the diffusion and distribution of tracer molecule by tracer-based magnetic resonance imaging, and the structural changes of brain extracellular space (ECS) were analyzed by diffusion rate in ECS-mapping (DECS-mapping) technique. Finally, parameters reflecting the structure of brain ECS and the drainage of ISF were obtained: volume fraction (α), tortuo-sity (λ), half-life (T1/2), and DECS. The differences of parameters among different groups were compared to analyze the effect of PBM on brain ECS and ISF. One-Way ANOVA post hoc tests and independent sample t test were used for statistical analysis. RESULTS: The parameters including T1/2, DECS, and λ were significantly different among the PBM-ipsilateral traced group, the PBM-contralateral traced group, and the sham PBM group (F=79.286, P < 0.001; F=13.458, P < 0.001; F=10.948, P=0.001), while there was no difference in the parameter α of brain ECS among the three groups (F=1.217, P=0.324). Compared with the sham PBM group and the PBM-contralateral traced group, the PBM-ipsilateral traced group had a significant decrease in the parameter T1/2 [(45.45±6.76) min vs. (76.01±3.44) min, P < 0.001; (45.45±6.76) min vs. (78.07±4.27) min, P < 0.001], representing a significant acceleration of ISF drainage; the PBM-ipsilateral traced group had a significant increase in the parameter DECS [(4.51±0.77)×10-4 mm2/s vs. (3.15±0.44)×10-4 mm2/s, P < 0.001; (4.51±0.77)×10-4 mm2/s vs. (3.01±0.38)×10-4 mm2/s, P < 0.001], representing a significantly increased molecular diffusion rate of in the brain ECS; the PBM-ipsilateral traced group had a significant decrease in the parameter λ (1.51±0.21 vs. 1.85±0.12, P=0.001; 1.51±0.21 vs. 1.89±0.11, P=0.001), representing a significant decrease in the degree of tortuosity in the brain ECS. CONCLUSION: PBM can regulate the brain ISF drainage actively, which may be one of the potential mechanisms of the effect of PBM therapy on AD. This study provides a new method for enhancing the brain function via ECS pathway.

Species-dependent interaction of Gd-based contrast agents with humic substances.

In this study, model experiments regarding species-dependent differences in the interaction of gadolinium-based contrast agents (GBCAs) with humic acids as potential binding partners in the aquatic environment are conducted. For this, the Gd content of different weight fractions obtained via ultracentrifugation of incubation solutions of humic acids with a linear (gadodiamide) and a macrocyclic GBCA (gadobutrol) were analyzed via inductively coupled plasma-mass spectrometry (ICP-MS). This enabled the fractionation of Gd-humic acid adducts and intact GBCAs, since Gd bound to macromolecules would be present in the macromolecular fraction of the filter residue while the low molecular weight Gd species can pass the filter with the filtrate. The Gd concentration in the different weight fractions was determined and a different reaction behavior for the examined GBCAs was observed. 73% of the total Gd amount was present in the macromolecular fraction of the linear GBCA compared to 0.41% in case of the macrocyclic GBCA. Speciation analysis of the macromolecular fractions by size exclusion chromatography-UV-ICP-MS confirmed that Gd-humic acid adducts were formed in case of the linear gadodiamide, but not with the macrocyclic gadobutrol. The findings of this study suggest that humic substance was able to react with the linear GBCA while the macrocyclic GBCA remained stable. Since free Gd ions are toxic, the question remains whether the humic acid bound Gd can be remobilized or if subsequent reactions with other molecules can take place. Furthermore, the persistence of macrocyclic GBCAs towards the humic substances indicates the potential accumulation of these compounds in the environment. However, more experiments regarding other binding partners and long term studies are needed to assess their ultimate fate after their release into the environment.

Outcomes of patients presenting with elevated tumor marker levels but negative gadoxetic acid-enhanced liver MRI after a complete response to hepatocellular carcinoma treatment.

PURPOSE: Hepatocellular carcinoma (HCC) patients usually achieve a complete response after treatment. This study was aimed to assess the clinical outcome of HCC patients who had achieved a complete response but later presented with elevated tumor marker levels without an identifiable recurrent tumor on gadoxetic acid-enhanced magnetic resonance imaging (MRI). METHODS: We retrospectively reviewed the clinical outcome of 58 HCC treated patients who had achieved a complete response but later was referred to our institution's multidisciplinary tumor board for a clinically suspected hidden HCC recurrence based on elevated tumor marker levels but negative gadoxetic acid-enhanced MRI. The imaging studies, tumor markers, and clinical information were reviewed. The total follow-up period was at least 15 months after the initial negative gadoxetic acid-enhanced MRI. RESULTS: Follow-up imaging studies detected an HCC lesion in 89.7% (n = 52/58) of the patients within the study period, and approximately half of the tumors (46.2%, n = 24/52) developed within 3 months. The most frequent site of recurrence was the liver (86.5%; n = 45/52), but extra-hepatic metastasis was also common (19.2%; n = 10/52). In 5.8% (n = 3/52), HCC reoccurred in the combined form of intra-hepatic and extra-hepatic recurrence. Extra-hepatic metastasis alone occurred in 13.5% (n = 7/52) of patients. CONCLUSIONS: HCC frequently recurred within a short interval in patients who achieved a complete response to treatment in the presence of increased tumor marker levels, even if gadoxetic acid-enhanced MRI was negative. Under such circumstances, we suggest a short-term follow-up including, but not limited to, gadoxetic acid-enhanced MRI along with systemic evaluation.

Simultaneous measurements of myocardial glucose metabolism and extracellular volumes with hybrid PET/MRI using concurrent injections of Gd-DTPA and [18F]FDG.

BACKGROUND: The aims of this study were to investigate the application of a constant infusion (CI) to mitigate the issue of constantly changing Gd-DTPA contrast levels in a bolus injection for extracellular volume (ECV) measurements by (a) comparing a CI alone to a bolus alone and a bolus followed by CI in healthy myocardium, (b) evaluating the impact of glucose suppression using heparin on ECV. METHODS: Five healthy canine subjects were imaged to compare three different protocols for injecting Gd-DTPA and FDG: bolus alone, CI alone, bolus followed by CI. Suppression of myocardial glucose uptake was induced using a continuous infusion of 20% lipid at a rate of 0.25 mL·min-1·kg-1 as well as 2000 units of intravenous heparin injected 20 minutes prior to FDG/Gd-DTPA injection. RESULTS: There was no significant effect on ECV measurement when heparin was used for glucose suppression at equilibrium irrespective of infusion protocol). Measurements of ECV in myocardium, regardless of infusion protocol showed no significant difference at all time points (P = 0.21) prior to washout. CONCLUSIONS: The suppression of myocardial uptake of [18F]FDG with heparin did not alter the determination of myocardial ECV though a larger sample size may show differences. Further, the infusion protocol (bolus or constant infusion) had no effect on the calculated ECV.

Quantification of contrast agent uptake in the hepatobiliary phase helps to differentiate hepatocellular carcinoma grade.

This study aimed to assess the degree of differentiation of hepatocellular carcinoma (HCC) using Gd-EOB-DTPA-assisted magnetic resonance imaging (MRI) with T1 relaxometry. Thirty-three solitary HCC lesions were included in this retrospective study. This study's inclusion criteria were preoperative Gd-EOB-DTPA-assisted MRI of the liver and a histopathological evaluation after hepatic tumor resection. T1 maps of the liver were evaluated to determine the T1 relaxation time and reduction rate between the native phase and hepatobiliary phase (HBP) in liver lesions. These findings were correlated with the histopathologically determined degree of HCC differentiation (G1, well-differentiated; G2, moderately differentiated; G3, poorly differentiated). There was no significant difference between well-differentiated (950.2 ± 140.2 ms) and moderately/poorly differentiated (1009.4 ± 202.0 ms) HCCs in the native T1 maps. After contrast medium administration, a significant difference (p ≤ 0.001) in the mean T1 relaxation time in the HBP was found between well-differentiated (555.4 ± 140.2 ms) and moderately/poorly differentiated (750.9 ± 146.4 ms) HCCs. For well-differentiated HCCs, the reduction rate in the T1 time was significantly higher at 0.40 ± 0.15 than for moderately/poorly differentiated HCCs (0.25 ± 0.07; p = 0.006). In conclusion this study suggests that the uptake of Gd-EOB-DTPA in HCCs is correlated with tumor grade. Thus, Gd-EOB-DTPA-assisted T1 relaxometry can help to further differentiation of HCC.

Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Disposition of Imaging Biomarker Gadoxetate in Rats.

Physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development to simulate changes in both systemic and tissue exposures that arise as a result of changes in enzyme and/or transporter activity. Verification of these model-based simulations of tissue exposure is challenging in the case of transporter-mediated drug-drug interactions (tDDI), in particular as these may lead to differential effects on substrate exposure in plasma and tissues/organs of interest. Gadoxetate, a promising magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). In this study, we developed a gadoxetate PBPK model and explored the use of liver-imaging data to achieve and refine in vitro-in vivo extrapolation (IVIVE) of gadoxetate hepatic transporter kinetic data. In addition, PBPK modeling was used to investigate gadoxetate hepatic tDDI with rifampicin i.v. 10 mg/kg. In vivo dynamic contrast-enhanced (DCE) MRI data of gadoxetate in rat blood, spleen, and liver were used in this analysis. Gadoxetate in vitro uptake kinetic data were generated in plated rat hepatocytes. Mean (%CV) in vitro hepatocyte uptake unbound Michaelis-Menten constant (Km,u) of gadoxetate was 106 µM (17%) (n = 4 rats), and active saturable uptake accounted for 94% of total uptake into hepatocytes. PBPK-IVIVE of these data (bottom-up approach) captured reasonably systemic exposure, but underestimated the in vivo gadoxetate DCE-MRI profiles and elimination from the liver. Therefore, in vivo rat DCE-MRI liver data were subsequently used to refine gadoxetate transporter kinetic parameters in the PBPK model (top-down approach). Active uptake into the hepatocytes refined by the liver-imaging data was one order of magnitude higher than the one predicted by the IVIVE approach. Finally, the PBPK model was fitted to the gadoxetate DCE-MRI data (blood, spleen, and liver) obtained with and without coadministered rifampicin. Rifampicin was estimated to inhibit active uptake transport of gadoxetate into the liver by 96%. The current analysis highlighted the importance of gadoxetate liver data for PBPK model refinement, which was not feasible when using the blood data alone, as is common in PBPK modeling applications. The results of our study demonstrate the utility of organ-imaging data in evaluating and refining PBPK transporter IVIVE to support the subsequent model use for quantitative evaluation of hepatic tDDI.

Highly Efficient Activatable MRI Probe to Sense Myeloperoxidase Activity.

Myeloperoxidase (MPO) is a key component of innate immunity but can damage tissues when secreted abnormally. We developed a new generation of a highly efficient MPO-activatable MRI probe (heMAMP) to report MPO activity. heMAMP has improved Gd stability compared to bis-5-HT-Gd-DTPA (MPO-Gd) and demonstrates no significant cytotoxicity. Importantly, heMAMP is more efficiently activated by MPO compared to MPO-Gd, 5HT-DOTA(Gd), and 5HT-DOTAGA-Gd. Molecular docking simulations revealed that heMAMP has increased rigidity via hydrogen bonding intramolecularly and improved binding affinity to the active site of MPO. In animals with subcutaneous inflammation, activated heMAMP showed a 2-3-fold increased contrast-to-noise ratio (CNR) compared to activated MPO-Gd and 4-10 times higher CNR compared to conventional DOTA-Gd. This increased efficacy was further confirmed in a model of unstable atherosclerotic plaque where heMAMP demonstrated a comparable signal increase and responsiveness to MPO inhibition at a 3-fold lower dosage compared to MPO-Gd, further underscoring heMAMP as a potential translational candidate.

Intracellular accumulation capacity of gadoxetate: initial results for a novel biomarker of liver function.

Previous studies have shown gadoxetate disodium's potential to represent liver function by its retention in the hepatobiliary phase. Additionally, in cardiac imaging, quantitative characterization of altered parenchyma is established by extracellular volume (ECV) calculation with extracellular contrast agents. Therefore, the purpose of our study was to evaluate whether intracellular accumulation capacity (IAC) of gadoxetate disodium derived from ECV calculation provides added scientific value in terms of liver function compared to the established parameter reduction rate (RR). After local review board approval, 105 patients undergoing standard MR examination with gadoxetate disodium were included. Modified Look-Locker sequences were obtained before and 20 min after contrast agent administration. RR and IAC were calculated and correlated with serum albumin, as a marker of synthetic liver function. Correlation was higher between IAC and albumin, than between RR and albumin. Additionally, capacity of both RR and IAC to distinguish between patients with or without liver cirrhosis was investigated, and differed significantly in their respective means between patients with cirrhosis and those without. We concluded, that the formula to calculate ECV can be transferred to calculate IAC of gadoxetate disodium in hepatocytes, and, thereby, IAC may possibly qualify as an imaging-based parameter to estimate synthetic liver function.

GAN and dual-input two-compartment model-based training of a neural network for robust quantification of contrast uptake rate in gadoxetic acid-enhanced MRI.

PURPOSE: Gadoxetic acid uptake rate (k1 ) obtained from dynamic, contrast-enhanced (DCE) magnetic resonance imaging (MRI) is a promising measure of regional liver function. Clinical exams are typically poorly temporally characterized, as seen in a low temporal resolution (LTR) compared to high temporal resolution (HTR) experimental acquisitions. Meanwhile, clinical demands incentivize shortening these exams. This study develops a neural network-based approach to quantitation of k1 , for increased robustness over current models such as the linearized single-input, two-compartment (LSITC) model. METHODS: Thirty Liver HTR DCE MRI exams were acquired in 22 patients with at least 16 min of postcontrast data sampled at least every 13 s. A simple neural network (NN) with four hidden layers was trained on voxel-wise LTR data to predict k1 . Low temporal resolution data were created by subsampling HTR data to contain six time points, replicating the characteristics of clinical LTR data. Both the total length and the placement of points in the training data were varied considerably to encourage robustness to variation. A generative adversarial network (GAN) was used to generate arterial and portal venous inputs for use in data augmentation based on the dual-input, two-compartment, pharmacokinetic model of gadoxetic acid in the liver. The performance of the NN was compared to direct application of LSITC on both LTR and HTR data. The error was assessed when subsampling lengths from 16 to 4 min, enabling assessment of robustness to acquisition length. RESULTS: For acquisition lengths of 16 min NRMSE (Normalized Root-Mean-Squared Error) in k1 was 0.60, 1.77, and 1.21, for LSITC applied to HTR data, LSITC applied to LTR data, and GAN-augmented NN applied to LTR data, respectively. As the acquisition length was shortened, errors greatly increased for LSITC approaches by several folds. For acquisitions shorter than 12 min the GAN-augmented NN approach outperformed the LSITC approach to a statistically significant extent, even with HTR data. CONCLUSIONS: The study indicates that data length is significant for LSITC analysis as applied to DCE data for standard temporal sampling, and that machine learning methods, such as the implemented NN, have potential for much greater resilience to shortened acquisition time than directly fitting to the LSITC model.

Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human.

OBJECTIVE: Aging is a major risk factor for numerous neurological disorders, and the mechanisms underlying brain aging remain elusive. Recent animal studies demonstrated a tight relationship between impairment of the glymphatic pathway, meningeal lymphatic vessels, and aging. However, the relationship in the human brain remains uncertain. METHODS: In this observational cohort study, patients underwent magnetic resonance imaging before and at multiple time points after intrathecal administration of a contrast agent. Head T1-weighted imaging was performed to assess the function of the glymphatic pathway and head high-resolution T2-fluid attenuated inversion recovery imaging to visualize putative meningeal lymphatic vessels (pMLVs). We measured the signal unit ratio (SUR) of 6 locations in the glymphatic pathway and pMLVs, defined the percentage change in SUR from baseline to 39 hours as the clearance of the glymphatic pathway and pMLVs, and then analyzed their relationships with aging. RESULTS: In all patients (N = 35), the SUR of the glymphatic pathway and pMLVs changed significantly after intrathecal injection of the contrast agent. The clearance of both the glymphatic pathway and pMLVs was related to aging (all p < 0.05). The clearance of pMLVs was significantly related to the clearance of the glymphatic pathway (all p < 0.05), and the clearance of the glymphatic pathway was significantly faster in patients with early filling of pMLVs than those with late filling (all p < 0.05). INTERPRETATION: We revealed that both the glymphatic pathway and pMLVs might be impaired in the aging human brain through the novel, clinically available method to simultaneously visualize their clearance. Our findings also support that in humans, pMLVs are the downstream of the glymphatic pathway. Ann Neurol 2020;87:357-369.

Gadolinium-conjugated CB86: a novel TSPO-targeting MRI contrast agent for imaging of rheumatoid arthritis.

TSPO is up-regulated in activated macrophages, and serves as an attractive target for macrophages molecular imaging and therapy. MRI may be an ideal technique in the clinical management of RA due to its excellent spatial resolution. In the present study, a novel TSPO-targeting MRI contrast agent was developed by conjugating a novel TSPO ligand CB86 with gadolinium chelate to visualise inflamed regions in RA mice model. A novel TSPO ligand CB86 was linked to DTPAA, followed by chelation with gadolinium to obtain MRI targeted contrast agent CB86-DTPA-Gd. CB86-DTPA-Gd was characterised by MRI relaxivity, cell cytotoxicity, cell specificity and in vitro stability analysis. The distribution and MRI intensity was evaluated in RA rat model. Synthesis of CB86-DTPA-Gd was completed successfully with MRI relaxivity of 11.05/mM/sec (9.4 T, 25 °C). CB86-DTPA-Gd exhibited a good stability in human serum, high RAW264.7 cells specificity and no cytotoxicity in RAW264.7 cells. The biodistribution and MRI studies showed that the accumulation and signal intensity of CB86-DTPA-Gd in the right RA ankles was higher and stronger than those of Gd­DTPA. This study demonstrates that CB86-DTPA-Gd can identify phagocytic active macrophages in the synovial joints, and has potential as a promising targeting MRI contrast agent for imaging of peripheral inflammation.

Evaluating differential nanoparticle accumulation and retention kinetics in a mouse model of traumatic brain injury via Ktrans mapping with MRI.

Traumatic brain injury (TBI) is a leading cause of injury-related death worldwide, yet there are no approved neuroprotective therapies that improve neurological outcome post-injury. Transient opening of the blood-brain barrier following injury provides an opportunity for passive accumulation of intravenously administered nanoparticles through an enhanced permeation and retention-like effect. However, a thorough understanding of physicochemical properties that promote optimal uptake and retention kinetics in TBI is still needed. In this study, we present a robust method for magnetic resonance imaging of nanoparticle uptake and retention kinetics following intravenous injection in a controlled cortical impact mouse model of TBI. Three contrast-enhancing nanoparticles with different hydrodynamic sizes and relaxivity properties were compared. Accumulation and retention were monitored by modelling the permeability coefficient, Ktrans, for each nanoparticle within the reproducible mouse model. Quantification of Ktrans for different nanoparticles allowed for non-invasive, multi-time point assessment of both accumulation and retention kinetics in the injured tissue. Using this method, we found that 80 nm poly(lactic-co-glycolic acid) nanoparticles had maximal Ktrans in a TBI when injected 3 hours post-injury, showing significantly higher accumulation kinetics than the small molecule, Gd-DTPA. This robust method will enable optimization of administration time and nanoparticle physicochemical properties to achieve maximum delivery.

The olfactory stimulation slows down the substance clearance in the extracellular space of the hippocampus in rat brain.

Accelerating the clearance of toxin in the brain extracellular space (ECS) has grown a promising strategy for treating some central nervous system diseases. As oldest sensory system, we know little about the influence of olfaction on the brain, but preclinical studies such as treatment of neurological diseases through it are in the ascendant. This makes it important to clarify the effects of olfaction on brain ECS and interstitial fluid (ISF) drainage. In this study, the effect of olfactory stimulation (eugenol, EUG) on ISF flow in hippocampus and its association with aquaporin 4 (Aqp4) had been investigated. The results show that eugenol can significantly increase the activity of hippocampal neurons, but reduce the clearance and diffusion rates of Gd-DTPA and A-594 in hippocampus. Similarly, eugenol inhalation slows down the rate of Gd-DTPA in CSF entering the hippocampus and its clearance. And knockout of Aqp4 gene aggravated these processes. In vitro results showed that after Aqp4 gene silencing, astrocytes grew slowly, with significantly decreased cells number, less nuclei, atrophied bodies and shorter processes. These results concluded that olfactory stimulation can change the ECS structure of the hippocampus, slow down the ISF drainage, and improve the function of neurons, while Aqp4 plays important roles.

Imaging biomarkers for well and moderate hepatocellular carcinoma: preoperative magnetic resonance image and histopathological correlation.

BACKGROUND: Our aim of the study is to investigate the feasibility of preoperative prediction for hepatocellular carcinoma (HCC) histological grading using gadoxetic acid-enhanced magnetic resonance imaging (MRI). METHODS: This study included one hundred and fifty-six patients with solitary HCC. Preoperative gadoxetic acid-enhanced MRI findings were retrospectively analyzed. MRI qualitative features such as tumor size, margin, capsule status, signal homogeneity, intratumoral vessels, peritumoral enhancement during mid-arterial phase, peritumoral hypointensity during the hepatobiliary phase (HBP) were investigated. Apparent diffusion coefficients (ADCs), T1 reduction ratio of pre- and post-contrast enhanced images of the tumors were calculated. HCC histological grading in surgical specimens were confirmed by Edmonson's criteria. Correlations between these MRI features and HCC histological grading were analyzed using multivariate logistic regression. The receiver operating characteristic (ROC) curve was used to assess the predictive efficacy of the model. RESULTS: Univariate analysis showed that maximum tumor diameter (p = 0.004), tumor margin (p = 0.006), intratumoral vessels (p = 0.001) and peritumoral hypointensity during HBP (p = 0.000), were significantly correlated with HCC histological grading. There was no relationship between capsule, tumor signal, venous thrombosis, peritumoral enhancement during mid-arterial phase, ADC value, T1 reduction ratio, and HCC histological grading. Multivariate logistic regression analysis demonstrated that the maximum tumor diameter (p = 0.012, odds ratio = 1.002, 95% confidence interval: 1.007-1.046)) was an independent risk factor for high grade HCC. CONCLUSIONS: Greater tumor size, a more irregular margin, presence of intratumoral vessels, and peritumoral hypointensity during HBP were indicators for high grade HCC. The maximum tumor diameter was an independent risk factor for high grade HCC.

Combined morphological and functional liver MRI using spin-lattice relaxation in the rotating frame (T1ρ) in conjunction with Gadoxetic Acid-enhanced MRI.

Noninvasive early detection of liver cirrhosis and fibrosis is essential for management and therapy. The aim was to investigated whether a combination of the functional parameter relative enhancement (RE) on Gadoxetic Acid magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) and the fibrosis parameter T1ρ distinguishes cirrhosis and healthy liver. We analyzed patients with Gd-EOB-DTPA-enhanced MRI and T1ρ mapping. Signal intensity was measured before and after contrast; RE was calculated. T1ρ was measured with circular regions of interest (T1ρ-cROI). A quotient of RE and T1ρ-cROI was calculated: the fibrosis function quotient (FFQ). Cirrhosis was evaluated based on morphology and secondary changes. 213 datasets were included. The difference between cirrhotic and noncirrhotic liver was 51.11 ms vs. 47.56 ms for T1ρ-cROI (p < 0.001), 0.59 vs. 0.70 for RE (p < 0.001), and 89.53 vs. 70.83 for FFQ (p < 0.001). T1ρ-cROI correlated with RE, r = -0.14 (p < 0.05). RE had an AUC of 0.73. The largest AUC had the FFQ with 0.79. The best cutoff value was 48.34 ms for T1ρ-cROI, 0.70 for RE and 78.59 ms for FFQ. In conclusion T1ρ and RE can distinguish between cirrhotic and noncirrhotic liver. The FFQ, which is the combination of the two, improves diagnostic performance.