Ultra-long-TE arterial spin labeling reveals rapid and brain-wide blood-to-CSF water transport in humans

The study of brain clearance mechanisms is an active area of research. While we know that the cerebrospinal fluid (CSF) plays a central role in one of the main existing clearance pathways, the exact processes for the secretion of CSF and the removal of waste products from tissue are under debate. CSF is thought to be created by the exchange of water and ions from the blood, which is believed to mainly occur in the choroid plexus. This exchange has not been thoroughly studied in vivo. We propose a modified arterial spin labeling (ASL) MRI sequence and image analysis to track blood water as it is transported to the CSF, and to characterize its exchange from blood to CSF. We acquired six pseudo-continuous ASL sequences with varying labeling duration (LD) and post-labeling delay (PLD) and a segmented 3D-GRASE readout with a long echo train (8 echo times (TE)) which allowed separation of the very long-T2 CSF signal. ASL signal was observed at long TEs (793 ms and higher), indicating presence of labeled water transported from blood to CSF. This signal appeared both in the CSF proximal to the choroid plexus and in the subarachnoid space surrounding the cortex. ASL signal was separated into its blood, gray matter and CSF components by fitting a triexponential function with T2s taken from literature. A two-compartment dynamic model was introduced to describe the exchange of water through time and TE. From this, a water exchange time from the blood to the CSF (Tbl->CSF) was mapped, with an order of magnitude of approximately 60 s

Cartilage inflammation and degeneration is enhanced by pro-inflammatory (M1) macrophages in vitro, but not inhibited directly by anti-inflammatory (M2) macrophages

Objective Macrophages play a crucial role in the progression of osteoarthritis (OA). Their phenotype may range from pro-inflammatory to anti-inflammatory. The aim of this study was to evaluate the direct effects of macrophage subtypes on cartilage by culturing macrophage conditioned medium (MCM) on human articular cartilage. Design Human OA cartilage explants were cultured with MCM of pro-inflammatory M(IFNγ+TNFα), or anti-inflammatory M(IL-4) or M(IL-10) human monocyte-derived macrophages. To assess effects of anti-inflammatory macrophages, the cartilage was cultured with a combination of MCM phenotypes as well as pre-stimulated with IFNγ+TNFα cartilage before culture with MCM. The reactions of the explants were assessed by gene expression, nitric oxide (NO) production and release of glycosaminoglycans (GAGs). Results M(IFNγ+TNFα) MCM affected OA cartilage by upregulation of IL1B (Interleukin 1β), IL6, MMP13 (Matrix Metalloproteinase-13) and ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin Motifs-5), while inhib

Combining T-2 measurements and crusher gradients into a single ASL sequence for comparison of the measurement of water transport across the blood-brain barrier

Purpose Arterial spin labeling can be used to assess the transition time of water molecules across the blood-brain barrier when combined with sequence modules, which allow a separation of intravascular from tissue signal. The bipolar gradient technique measures the intravascular fraction by removing flowing spins. The T-2-relaxation-under-spin-tagging (TRUST) technique modulates the TE to differentiate between intravascular and extravascular spins based on T-2. These modules were combined into a single time-encoded pseudo-continuous arterial spin labeling sequence to compare their mechanisms of action as well as their assessment of water transition across the blood-brain barrier.Methods This protocol was acquired on a scanner with 9 healthy volunteers who provided written, informed consent. The sequence consisted of a Hadamard-encoded pseudo-continuous arterial spin labeling module, followed by the TRUST module (effective TEs of 0, 40, and 80 ms) and bipolar flow-crushing gradients (2, 4, and infinity cm/s). An additional experiment was performed with TRUST and a 3D gradient and spin-echo readout.Results Gradients imperfectly canceled the intravascular signal, as evidenced by the presence of residual signal in the arteries at early postlabeling delays as well as the underestimation of the intravascular fraction as compared with the TRUST method. The TRUST module allowed us to detect the transport of water deeper into the vascular tree through changes in T-2 than the used crusher gradients could, with their limited b-value.Conclusion Of the implemented techniques, TRUST allowed us to follow intravascular signal deeper into the vascular tree than the approach with (relatively weak) crusher gradients when quantifying the transport time of water across the blood-brain barrier.Neuro Imaging Researc

Guiding synovial inflammation by macrophage phenotype modulation: An in vitro study towards a therapy for osteoarthritis

Objective: The aims of this study were to modulate inflammation in synovial explants with the compounds: dexamethasone, rapamycin, bone morphogenetic protein 7 (BMP-7) and pravastatin, and to investigate the mod

Real-life results of urate-driven pharmacotherapy with three urate lowering drugs in gout:allopurinol, febuxostat and benzbromarone

Aim:This study aims to assess outcomes of gout patients from the treat to target (T2T) perspective at 6 months and 12 months while using urate lowering therapy (ULT): allopurinol, febuxostat, and/or benzbromarone.Methods:All gout patients visiting the Rheumatology department between 2015 to 2021 were identified from the digital hospital system. The diagnosis of gout was based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2015 classification criteria. Patient outcomes were predefined intention to treat (ITT) categories: category 1: patients with serum uric acid (sUA) ≤ 0.360 mmol/L (ACR target for gout); category 2: patients with sUA ≤ 0.300 mmol/L (ACR/EULAR target for severe gout); category 3: patients with sUA > 0.360 (failure to meet ACR target).Results:Gout diagnoses were present in 1,186 patients: 986 (83.1%) males and 200 (16.9%) females. A follow-visit at 6 months was present in 76.9% (n = 856) out of 1,113 patients reaching sUA < 0.36 mmol/L, but 257 (23%) failed to reach the 0.36 mmol/L target. At 12 months, a follow-up visit was available in 792 (71.1%) patients, and from these, 710 (90%) had reached sUA < 0.36 mmol/L target. The use of benzbromarone was a strong predictor of reaching the sUA < 0.30 mmol/L target: odds ratio (OR) 3.2, 95% confidence interval (CI) (1.735, 6.017) at 6 months. Diabetic patients had the highest proportion of not reaching the target: 18%. Male patients needed higher dosages of allopurinol to reach the sUA target at 6 months compared to female patients.Conclusions:This is a large study on a T2T approach based in a real-life clinical setting. Only 42% reached the sUA target at 6 months with allopurinol 300 mg quaque die (QD) monotherapy. About 77% of gout patients reach the predefined sUA target of 0.36 mmol/L at 6 months with the availability of three ULTs. There is still a significant unmet need in gout as many patients failed to achieve predefined sUA targets

Arterial spin labeling signal in the CSF: implications for partial volume correction and blood-CSF barrier characterization

For better quantification of perfusion with arterial spin labeling (ASL), partial volume correction (PVC) is used to disentangle the signals from gray matter (GM) and white matter within any voxel. Based on physiological considerations, PVC algorithms typically assume zero signal in the cerebrospinal fluid (CSF). Recent measurements, however, have shown that CSF-ASL signal can exceed 10% of GM signal, even when using recommended ASL labeling parameters. CSF signal is expected to particularly affect PVC results in the choroid plexus. This study aims to measure the impact of CSF signal on PVC perfusion measurements, and to investigate the potential use of PVC to retrieve pure CSF-ASL signal for blood-CSF barrier characterization. In vivo imaging included six pCASL sequences with variable label duration and post-labeling delay (PLD), and an eight-echo 3D-GRASE readout. A dataset was simulated to estimate the effect of CSF-PVC with known ground-truth parameters. Differences between the results of CSF-PVC and non-CSF-PVC were estimated for regions of interest (ROls) based on GM probability, and a separate ROI isolating the choroid plexus. In vivo, the suitability of PVC-CSF signal as an estimate of pure CSF was investigated by comparing its time course with the long-TE CSF signal. Results from both simulation and in vivo data indicated that including the CSF signal in PVC improves quantification of GM CBF by approximately 10%. In simulated data, this improvement was greater for multi-PLD (model fitting) quantification than for single PLD (similar to 1-5% difference). In the choroid plexus, the difference between CSF-PVC and non-CSF-PVC was much larger, averaging around 30%. Long-TE (pure) CSF signal could not be estimated from PVC CSF signal as it followed a different time course, indicating the presence of residual macrovascular signal in the PVC. The inclusion of CSF adds value to PVC for more accurate measurements of GM perfusion, and especially for quantification of perfusion in the choroid plexus and study of the glymphatic system.Radiolog

Tracking of structural and functional cardiac measures from infancy into school-age

Objective Cardiac structure and function are important predictors for cardiovascular disease in adults. Not much is known about tracking of cardiac measures, other than left ventricular mass, from early life onwards. We examined whether and to what extent cardiac measures track from infancy into school-age. Methods We performed a population-based prospective cohort study among 1072 children. Aortic root diameter, left atrial diameter, left ventricular mass, relative wall thickness and fractional shortening were measured repeatedly by echocardiography. We explored tracking between infancy (1.5, six and 24 months) and school-age (six and 10 years). Results Of all cardiac measures, aortic root diameter, left atrial diameter and left ventricular mass were significantly correlated between infancy and school-age (r = 0.10-0.42, all p-values < 0.01), with the strongest correlations between 24 months and 10 years. Of the different structures, aortic root diameter showed the strongest correlations. Approximately 30% of children who were in the lowest or highest quartile of a measure at the age of 1.5 months remained in that quartile at the age of 10 years. When analysing the effects of the infant cardiac measures on the same outcomes at 10 years in conditional regression models, we observed ef

Ultra-long-TE arterial spin labeling reveals rapid and brain-wide blood-to-CSF water transport in humans

The study of brain clearance mechanisms is an active area of research. While we know that the cerebrospinal fluid (CSF) plays a central role in one of the main existing clearance pathways, the exact processes for the secretion of CSF and the removal of waste products from tissue are under debate. CSF is thought to be created by the exchange of water and ions from the blood, which is believed to mainly occur in the choroid plexus. This exchange has not been thoroughly studied in vivo.We propose a modified arterial spin labeling (ASL) MRI sequence and image analysis to track blood water as it is transported to the CSF, and to characterize its exchange from blood to CSF. We acquired six pseudo-continuous ASL sequences with varying labeling duration (LD) and post-labeling delay (PLD) and a segmented 3D-GRASE readout with a long echo train (8 echo times (TE)) which allowed separation of the very long-T-2 CSF signal. ASL signal was observed at long TEs (793 ms and higher), indicating presence of labeled water transported from blood to CSF. This signal appeared both in the CSF proximal to the choroid plexus and in the subarachnoid space surrounding the cortex. ASL signal was separated into its blood, gray matter and CSF components by fitting a triexponential function with T(2)s taken from literature. A two-compartment dynamic model was introduced to describe the exchange of water through time and TE. From this, a water exchange time from the blood to the CSF (Tbl->CSF) was mapped, with an order of magnitude of approximately 60 s.Neuro Imaging Researc

A split-label design for simultaneous measurements of perfusion in distant slices by pulsed arterial spin labeling

Purpose Multislice arterial spin labeling (ASL) MRI acquisitions are currently challenging in skeletal muscle because of long transit times, translating into low-perfusion SNR in distal slices when large spatial coverage is required. However, fiber type and oxidative capacity vary along the length of healthy muscles, calling for multislice acquisitions in clinical studies. We propose a new variant of flow alternating inversion recovery (FAIR) that generates sufficient ASL signal to monitor exercise-induced perfusion changes in muscle in two distant slices.Methods Label around and between two 7-cm distant slices was created by applying the presaturation/postsaturation and selective inversion modules selectively to each slice (split-label multislice FAIR). Images were acquired using simultaneous multislice EPI. We validated our approach in the brain to take advantage of the high resting-state perfusion, and applied it in the lower leg muscle during and after exercise, interleaved with a single-slice FAIR as a reference.Results We show that standard multislice FAIR leads to an underestimation of perfusion, while the proposed split-label multislice approach shows good agreement with separate single-slice FAIR acquisitions in brain, as well as in muscle following exercise.Conclusion Split-label FAIR allows measuring muscle perfusion in two distant slices simultaneously without losing sensitivity in the distal slice.Cardiovascular Aspects of RadiologyNeuro Imaging Researc

The self and others in the experience of pride

Pride is seen as both a self-conscious emotion as well as a social emotion. These categories are not mutually exclusive, but have brought forth different ideas about pride as either revolving around the self or as revolving around one’s relationship with others. Current measures of pride do not include intrapersonal elements of pride experiences. Social comparisons, which often cause experiences of pride, contain three elements: the self, the relationship between the self and another person, and the other person. From the literature on pride, we distilled three related elements; perceptions and feelings of self-inflation, other-distancing, and other-devaluation. In four studies, we explored whether these elements were present in pride experiences. We did so at an implicit (Experiment 1; N = 218) and explicit level (Experiment 2; N = 125), in an academic setting with in vivo (Experiment 3; N = 203) and imagined pride experiences (Experiment 4; N = 126). The data consistently revealed that the experience of pride is characterised by self-inflation, not by other-distancing nor other-devaluation