Prospective T1 mapping to assess gadolinium retention in brain after intrathecal gadobutrol.

PURPOSE: A possible pathway behind gadolinium retention in brain is leakage of contrast agents from blood to cerebrospinal fluid and entry into brain along perivascular (glymphatic) pathways. The object of this study was to assess for signs of gadolinium retention in brain 4 weeks after intrathecal contrast enhanced MRI. METHODS: We prospectively applied standardized T1 mapping of the brain before and 4 weeks after intrathecal administration of 0.5 mmol gadobutrol in patients under work-up of cerebrospinal fluid circulation disorders. Due to methodological limitations, a safety margin for percentage change in T1 time was set to 3%. Region-wise differences were assessed by pairwise comparison using t-tests and forest plots, and statistical significance was accepted at .05 level (two-tailed). RESULTS: In a cohort of 76 participants (mean age 47.2 years ± 17.9 [standard deviation], 47 women), T1 relaxation times remained unchanged in cerebral cortex and basal ganglia 4 weeks after intrathecal gadobutrol. T1 was reduced from 1082 ± 46.7 ms to 1070.6 ± 36.5 ms (0.98 ±2.9%) (mean [standard deviation]) (p=0.001) in white matter, thus within the pre-defined 3% safety margin. The brain stem and cerebellum could not be assessed due to poor alignment of posterior fossa structures at scans from different time points. CONCLUSION: Gadolinium retention was not detected in the cerebral hemispheres 4 weeks after an intrathecal dose of 0.5 mmol gadobutrol, implying that presence of contrast agents in cerebrospinal fluid is of minor importance for gadolinium retention in brain.

Intrathecal Contrast-Enhanced Magnetic Resonance Imaging of Cerebrospinal Fluid Dynamics and Glymphatic Enhancement in Idiopathic Normal Pressure Hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease, characterized by cerebrospinal fluid (CSF) flow disturbance. Today, the only available treatment is CSF diversion surgery (shunt surgery). While traditional imaging biomarkers typically assess CSF space anatomy, recently introduced imaging biomarkers of CSF dynamics and glymphatic enhancement, provide imaging of CSF dynamics and thereby more specifically reveal elements of the underlying pathophysiology. The biomarkers address CSF ventricular reflux grade as well as glymphatic enhancement and derive from intrathecal contrast-enhanced MRI. However, the contrast agent serving as CSF tracer is administered off-label. In medicine, the introduction of new diagnostic or therapeutic methods must consider the balance between risk and benefit. To this end, we performed a prospective observational study of 95 patients with iNPH, comparing different intrathecal doses of the MRI contrast agent gadobutrol (0.10, 0.25, and 0.50 mmol, respectively), aiming at the lowest reasonable dose needed to retrieve diagnostic information about the novel MRI biomarkers. The present observations disclosed a dose-dependent enrichment of subarachnoid CSF spaces (cisterna magna, vertex, and velum interpositum) with dose-dependent ventricular reflux of tracer in iNPH, as well as dose-dependent glymphatic tracer enrichment. The association between tracer enrichment in CSF and parenchymal compartments were as well dose-related. Intrathecal gadobutrol in a dose of 0.25 mmol, but not 0.10 mmol, was at 1.5T MRI considered sufficient for imaging altered CSF dynamics and glymphatic enhancement in iNPH, even though 3T MRI provided better sensitivity. Tracer enrichment in CSF at the vertex and within the cerebral cortex and subcortical white matter was deemed too low for maintaining diagnostic information from a dose of 0.10 mmol. We conclude that reducing the intrathecal dose of gadobutrol from 0.50 to 0.25 mmol gadobutrol improves the safety margin while maintaining the necessary diagnostic information about disturbed CSF homeostasis and glymphatic failure in iNPH.

Off-label intrathecal use of gadobutrol: safety study and comparison of administration protocols.

PURPOSE: Magnetic resonance imaging (MRI) contrast agents have been used off-label for diagnosis of cerebrospinal fluid (CSF) leaks and lately also for assessment of the glymphatic system and meningeal lymphatic drainage. The purpose of this study was to further evaluate the short- and long-term safety profile of intrathecal MRI contrast agents. METHODS: In this prospective study, we compared the safety profile of different administration protocols of intrathecal gadobutrol (GadovistTM; 1.0 mmol/ml). Gadobutrol was administered intrathecal in a dose of 0.5 mmol, with or without iodixanol (VisipaqueTM 270 mg I/ml; 3 ml). In addition, a subgroup was given intrathecal gadobutrol in a dose of 0.25 mmol. Adverse events were assessed at 1 to 3 days, 4 weeks, and after 12 months. RESULTS: Among the 149 patients, no serious adverse events were seen in patients without history of prior adverse events. The combination of gadobutrol with iodixanol did not increase the occurrence of non-serious adverse events after days 1-3. Intrathecal gadobutrol in a dose of 0.25 mmol caused less severity of nausea, as compared with the dose of 0.5 mmol. The clinical diagnosis was the major determinant for occurrence of non-serious adverse events after intrathecal gadobutrol. CONCLUSION: This prospective study showed that intrathecal administration of gadobutrol in a dose of 0.5 mmol is safe. Non-serious adverse events were to a lesser degree affected by the administration protocols, though preliminary data are given that side effects of intrathecal gadobutrol are dose-dependent.

Effect of Drinking Oxygenated Water Assessed by in vivo MRI Relaxometry.

GRANT SUPPORT: This project was funded by the Research Council of Norway. BACKGROUND: Oxygen uptake through the gastrointestinal tract after oral administration of oxygenated water in humans is not well studied and is debated in the literature. Due to the paramagnetic properties of oxygen and deoxyhemoglobin, MRI as a technique might be able to detect changes in relaxometry values caused by increased oxygen levels in the blood. PURPOSE: To assess whether oxygen dissolved in water is absorbed from the gastrointestinal tract and transported into the bloodstream after oral administration. STUDY TYPE: A randomized, double-blinded, placebo-controlled crossover trial. POPULATION/SUBJECTS: Thirty healthy male volunteers age 20-35. FIELD STRENGTH/SEQUENCE: 3T/Modified Look-Locker inversion recovery (MOLLI) T1 -mapping and multi fast field echo (mFFE) T2 *-mapping. ASSESSMENT: Each volunteer was scanned in two separate sessions. T1 and T2 * maps were acquired repeatedly covering the hepatic portal vein (HPV) and vena cava inferior (VCI, control vein) before and after intake of oxygenated or control water. Assessments were done by placing a region of interest in the HPV and VCI. STATISTICAL TEST: A mixed linear model was performed to the compare control vs. oxygen group. RESULTS: Drinking caused a mean 1.6% 95% CI (1.1-2.0% P < 0.001) increase in T1 of HPV blood and water oxygenation attributed another 0.70% 95% confidence interval (CI) (0.07-1.3% P = 0.028) increase. Oxygenation did not change T1 in VCI blood. Mean T2 * increased 9.6% 95% CI (1.7-17.5% P = 0.017) after ingestion of oxygenated water and 1.2% 95% CI (-4.3-6.8% P = 0.661) after ingestion of control water. The corresponding changes in VCI blood were not significant. DATA CONCLUSION: Ingestion of water caused changes in T1 and T2 * of HPV blood compatible with dilution due to water absorption. The effects were enhanced by oxygen. Assessment of oxygen enrichment of HPV blood was not possible due to the dilution effect. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:720-728.

Determination of oxygen r1 at 3 Tesla using samples with a concentration range of dissolved oxygen.

OBJECTIVE: To investigate the sensitivity of modified Look-Locker inversion recovery (MOLLI) to measure changes in dissolved oxygen (DO) concentrations in water samples and to calculate sequence-specific relaxivity (r1m) and limit of detection (LOD). MATERIALS AND METHODS: Ten water samples with a range of DO concentrations were scanned at 3 T using two variations of MOLLI schemes. Using linear regression the r1 of DO was estimated from the measured DO concentrations and T1 relaxation rates (R1). The results were combined with previously reported values on in vivo stability measures of the MOLLI sequences and used to estimate a LOD. RESULTS: DO concentrations ranged from 0.5 to 21.6 mg L-1. A linear correlation between DO and R1 was obtained with both MOLLI sequences, with an average correlation coefficient (R2) 0.9 and an average estimated r1 ([Formula: see text]) of 4.45 × 10-3 s-1 mg-1 L. Estimated LOD was ≈ 10 mg L-1. CONCLUSION: MOLLI T1-mapping sequences may be used for detecting dissolved oxygen in vivo at 3 T with an [Formula: see text] in the range 4.18-4.8 × 10-3 s-1 mg-1 L and a corresponding LOD for dissolved oxygen of approximately 10 mg L-1. MOLLI-based T1 mapping may be a useful non-invasive tool for quantification of in vivo changes of DO concentration during oxygen challenges.

Precision of T1-relaxation time measurements in the hepatic portal vein: influence of measurement technique and sequence parameters.

OBJECTIVE: To investigate the effects of a range of parameter settings on T1 measurement stability in the portal vein using the T1-mapping sequences Look-Locker (LL) and Modified Look-Locker inversion recovery (MOLLI). MATERIALS AND METHODS: Ten different versions of LL and MOLLI sequences were tested and compared to a reference sequence provided by the MR manufacturer. Ten healthy volunteers were imaged multiple times on two separate scan days at 3T. The mean T1 values and coefficient of variation (CoV) were calculated for each of the ten sequences and compared to the reference sequence. RESULTS: Six of the tested sequences had T1 values close to the reference sequence; among those, three sequences achieved lower CoV than the reference sequence. Lowest CoV was achieved using a non-triggered LL sequence with 5 beat readout and a 45o flip angle (mean T1 1733 ms ± 89 ms, CoV 1.3% ± 0.58%). CONCLUSION: T1-measurements in the hepatic portal vein can be performed with high precision using either MOLLI or LL sequences provided that LL sampling duration is sufficiently long and flip angle sufficiently high. The advantage of constant timing outweighed the advantage of ECG-triggering.

Brain-wide glymphatic enhancement and clearance in humans assessed with MRI.

To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus). The MRI contrast agent gadobutrol, which is confined to the extravascular brain compartment by the intact blood-brain barrier, was used as a CSF tracer. Standardized T1-weighted MRI scans were performed before and after intrathecal gadobutrol at defined time points, including at 24 hours, 48 hours, and 4 weeks. All MRI scans were aligned and brain regions were segmented using FreeSurfer, and changes in normalized T1 signals over time were quantified as percentage change from baseline. The study provides in vivo evidence of access to all human brain subregions of a substance administered intrathecally. Clearance of the tracer substance was delayed in the dementia cohort. These observations translate previous findings in animal studies into humans and open new prospects concerning intrathecal treatment regimens, extravascular contrast-enhanced MRI, and assessment of brain clearance function.

Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes.

Pre-clinical research in rodents provides evidence that the central nervous system (CNS) has functional lymphatic vessels. In-vivo observations in humans, however, are not demonstrated. We here show data on CNS lymphatic drainage to cervical lymph nodes in-vivo by magnetic resonance imaging (MRI) enhanced with an intrathecal contrast agent as a cerebrospinal fluid (CSF) tracer. Standardized MRI of the intracranial compartment and the neck were acquired before and up to 24-48 hours following intrathecal contrast agent administration in 19 individuals. Contrast enhancement was radiologically confirmed by signal changes in CSF nearby inferior frontal gyrus, brain parenchyma of inferior frontal gyrus, parahippocampal gyrus, thalamus and pons, and parenchyma of cervical lymph node, and with sagittal sinus and neck muscle serving as reference tissue for cranial and neck MRI acquisitions, respectively. Time series of changes in signal intensity shows that contrast enhancement within CSF precedes glymphatic enhancement and peaks at 4-6 hours following intrathecal injection. Cervical lymph node enhancement coincides in time with peak glymphatic enhancement, with peak after 24 hours. Our findings provide in-vivo evidence of CSF tracer drainage to cervical lymph nodes in humans. The time course of lymph node enhancement coincided with brain glymphatic enhancement rather than with CSF enhancement.

Non-invasive assessment of pulsatile intracranial pressure with phase-contrast magnetic resonance imaging.

Invasive monitoring of pulsatile intracranial pressure can accurately predict shunt response in patients with idiopathic normal pressure hydrocephalus, but may potentially cause complications such as bleeding and infection. We tested how a proposed surrogate parameter for pulsatile intracranial pressure, the phase-contrast magnetic resonance imaging derived pulse pressure gradient, compared with its invasive counterpart. In 22 patients with suspected idiopathic normal pressure hydrocephalus, preceding invasive intracranial pressure monitoring, and any surgical shunt procedure, we calculated the pulse pressure gradient from phase-contrast magnetic resonance imaging derived cerebrospinal fluid flow velocities obtained at the upper cervical spinal canal using a simplified Navier-Stokes equation. Repeated measurements of the pulse pressure gradient were also undertaken in four healthy controls. Of 17 shunted patients, 16 responded, indicating high proportion of "true" normal pressure hydrocephalus in the patient cohort. However, there was no correlation between the magnetic resonance imaging derived pulse pressure gradient and pulsatile intracranial pressure (R = -.18, P = .43). Pulse pressure gradients were also similar in patients and healthy controls (P = .26), and did not differ between individuals with pulsatile intracranial pressure above or below established thresholds for shunt treatment (P = .97). Assessment of pulse pressure gradient at level C2 was therefore not found feasible to replace invasive monitoring of pulsatile intracranial pressure in selection of patients with idiopathic normal pressure hydrocephalus for surgical shunting. Unlike invasive, overnight monitoring, the pulse pressure gradient from magnetic resonance imaging comprises short-term pressure fluctuations only. Moreover, complexity of cervical cerebrospinal fluid flow and -pulsatility at the upper cervical spinal canal may render the pulse pressure gradient a poor surrogate marker for intracranial pressure pulsations.

Glymphatic MRI in idiopathic normal pressure hydrocephalus.

The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer's disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging.

Signal Enhancement of the Dentate Nucleus at Unenhanced MR Imaging after Very High Cumulative Doses of the Macrocyclic Gadolinium-based Contrast Agent Gadobutrol: An Observational Study.

Purpose To test for measurable visual enhancement of the dentate nucleus (DN) on unenhanced T1-weighted magnetic resonance (MR) images in a cohort of patients with a primary brain tumor who had not received linear gadolinium-based contrast agents (GBCAs) but had received many injections of macrocyclic GBCAs. Materials and Methods Seventeen patients with high-grade gliomas who had received 10-44 administrations of the macrocyclic GBCA gadobutrol (0.1 mmol/kg of body weight) were retrospectively included in this regional ethics committee-approved study. Two neuroradiologists inspected T1-weighted MR images with optimized window settings to visualize small differences in contrast at the baseline and at the last examination for the presence of visual DN signal enhancement. Signal intensity (SI) in the DN was normalized to the SI of the pons, and a one-sample t test was used to test for differences between baseline normalized SI (nSI) in the DN (nSIDN) and the average change in nSIDN of all postbaseline MR imaging sessions (ΔnSIDNavg) or the change in nSIDN from baseline to the last MR imaging session (ΔnSIDN). Linear and quadratic correlation analyses were used to examine the association between the number of macrocyclic GBCA administrations and ΔnSIDN or ΔnSIDNavg. Results The mean ± standard deviation number of macrocyclic GBCA administrations was 22.2 ± 10.6 administered throughout 706 days ± 454. Visually appreciable signal enhancement was observed in two patients who had received 37 and 44 macrocyclic GBCA injections. Mean ΔnSIDN was greater than zero (0.03 ± 0.05; P = .016), and there was a significant linear association between the number of macrocyclic GBCA injections and ΔnSIDN (r = 0.69, P = .002) and ΔnSIDNavg (r = 0.77, P < .001). Conclusion A small but statistically significant dose-dependent T1-weighted signal enhancement was observed in the DN after multiple macrocyclic GBCA injections. Visually appreciable enhancement in the DN was observed on contrast-optimized images in two patients who had received 37 and 44 standard doses of macrocyclic GBCAs. © RSNA, 2017 Online supplemental material is available for this article.

A theoretical framework for determining cerebral vascular function and heterogeneity from dynamic susceptibility contrast MRI.

Mapping the complex heterogeneity of vascular tissue in the brain is important for understanding cerebrovascular disease. In this translational study, we build on previous work using vessel architectural imaging (VAI) and present a theoretical framework for determining cerebral vascular function and heterogeneity from dynamic susceptibility contrast magnetic resonance imaging (MRI). Our tissue model covers realistic structural architectures for vessel branching and orientations, as well as a range of hemodynamic scenarios for blood flow, capillary transit times and oxygenation. In a typical image voxel, our findings show that the apparent MRI relaxation rates are independent of the mean vessel orientation and that the vortex area, a VAI-based parameter, is determined by the relative oxygen saturation level and the vessel branching of the tissue. Finally, in both simulated and patient data, we show that the relative distributions of the vortex area parameter as a function of capillary transit times show unique characteristics in normal-appearing white and gray matter tissue, whereas tumour-voxels in comparison display a heterogeneous distribution. Collectively, our study presents a comprehensive framework that may serve as a roadmap for in vivo and per-voxel determination of vascular status and heterogeneity in cerebral tissue.

Semiautomated Magnetic Resonance Imaging Assessment of Carotid Plaque Lipid Content.

BACKGROUND: The composition of a carotid plaque is important for plaque vulnerability and stroke risk. The main aim of this study was to assess the potential of semiautomated segmentation of carotid plaque magnetic resonance imaging (MRI) in the assessment of the size of the lipid-rich necrotic core (LRNC). METHODS: Thirty-four consecutive patients with carotid stenosis of 70% or higher, who were scheduled for carotid endarterectomy, underwent a clinical neurological examination, Color duplex ultrasound, 3-T MRI with an 8-channel carotid coil, and blood tests. All examinations were performed less than 24 hours prior to surgery and plaques were assessed histologically immediately following endarterectomy. Plaques were defined as symptomatic when associated with ipsilateral cerebral ischemic symptoms within 30 days prior to inclusion. The level of agreement between the size of the LRNC and calcification on MRI to the histological estimation of the same tissue components, plaque echolucency on ultrasound, and symptoms was assessed. RESULTS: The size of the LRNC on MRI was significantly correlated to the percentage amount of lipid per plaque on histological assessment (P = .010, r = .5), and to echogenicity on ultrasound with echolucent plaques having larger LRNC than echogenic plaques (P = .001, r = -.7). CONCLUSIONS: In this study, we found that semiautomated MRI assessments of the percentage LRNC in carotid plaques were significantly correlated to the percentage LRNC per plaque on histological assessment, and to echogenicity on ultrasound with echolucent plaques having larger LRNC than echogenic plaques.