Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance.

Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8+ T cell-mediated immunity and promoted tolerogenic CD4+ regulatory T (Treg) cell expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6-specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimmunotherapy resulted in indefinite allograft survival. Together, we show that HDL-based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance.

Muscle fiber strain rates in the lower leg during ankle dorsi-/plantarflexion exercise.

Static quantitative magnetic resonance imaging (MRI) provides readouts of structural changes in diseased muscle, but current approaches lack the ability to fully explain the loss of contractile function. Muscle contractile function can be assessed using various techniques including phase-contrast MRI (PC-MRI), where strain rates are quantified. However, current two-dimensional implementations are limited in capturing the complex motion of contracting muscle in the context of its three-dimensional (3D) fiber architecture. The MR acquisitions (chemical shift-encoded water-fat separation scan, spin echo-echoplanar imaging with diffusion weighting, and two time-resolved 3D PC-MRI) wereperformed at 3 T. PC-MRI acquisitions and performed with and without load at 7.5% of the maximum voluntary dorsiflexion contraction force. Acquisitions (3 T, chemical shift-encoded water-fat separation scan, spin echo-echo planar imaging with diffusion weighting, and two time-resolved 3D PC-MRI) were performed with and without load at 7.5% of the maximum voluntary dorsiflexion contraction force. Strain rates and diffusion tensors were calculated and combined to obtain strain rates along and perpendicular to the muscle fibers in seven lower leg muscles during the dynamic dorsi-/plantarflexion movement cycle. To evaluate strain rates along the proximodistal muscle axis, muscles were divided into five equal segments. t-tests were used to test if cyclic strain rate patterns (amplitude > 0) were present along and perpendicular to the muscle fibers. The effects of proximal-distal location and load were evaluated using repeated measures ANOVAs. Cyclic temporal strain rate patterns along and perpendicular to the fiber were found in all muscles involved in dorsi-/plantarflexion movement (p < 0.0017). Strain rates along and perpendicular to the fiber were heterogeneously distributed over the length of most muscles (p < 0.003). Additional loading reduced strain rates of the extensor digitorum longus and gastrocnemius lateralis muscle (p < 0.001). In conclusion, the lower leg muscles involved in cyclic dorsi-/plantarflexion exercise showed cyclic fiber strain rate patterns with amplitudes that varied between muscles and between the proximodistal segments within the majority of muscles.

Cerebrospinal fluid turnover as a driver of brain clearance.

Cerebrospinal fluid (CSF) has historically been considered to function as a sink for brain-derived waste disposal. Recent work suggested that CSF interacts even more intensely with brain tissue than previously recognized, through perivascular spaces that penetrate the brain. Cardiac pulsations, vasomotion, and respiration have been suggested to drive CSF flow in these perivascular spaces, thereby enhancing waste clearance. However, the intrinsic role of CSF production in relation to its distribution volume (turnover) is not an explicit component of recent concepts on brain clearance. Here, we review the work on CSF turnover and volume, focusing on preclinical evidence. Herein, we highlight the use of MRI in establishing CSF-related parameters. We describe the impact of sleep, effect of anesthesia, aging, and hypertension on CSF turnover, and how this relates to brain clearance. Evaluation of the available evidence suggests that CSF turnover is a major determinant in brain clearance. In addition, we propose that several putative drivers of brain clearance, but also conditions associated with impaired clearance, such as aging, may actually relate to altered CSF turnover.

Diffusion tensor imaging and quantitative T2 mapping to monitor muscle recovery following hamstring injury.

MRI examinations are accurate for diagnosing sports-related acute hamstring injuries. However, sensitive imaging methods for assessing recovery of these injuries are lacking. Diffusion tensor imaging (DTI) and quantitative T2 (qT2) mapping have both shown promise for assessing recovery of muscle micro trauma and exercise effects. The purpose of this study was to explore the potential of DTI and qT2 mapping for monitoring the muscle recovery processes after acute hamstring injury. In this prospective study, athletes with an acute hamstring injury underwent a 3-T MRI examination of the injured and contralateral hamstrings including DTI and qT2 measurements at three time points: (1) within 1 week after sustaining the injury, (2) 2 weeks after time point 1, and (3) return to play (RTP). A linear mixed model was used for time-effect analysis and paired t-tests for the detection of differences between injured and uninjured muscles. Forty-one athletes (age 27.8 ± 7 years; two females and 39 males) were included. Mean RTP time was 50 (range 12-169) days. A significant time effect was found for mean diffusivity, radial diffusivity, and the second and third eigenvalues (p ≤ 0.001) in the injured muscles. Fractional anisotropy (p = 0.40), first eigenvalue (p = 0.02), and qT2 (p = 0.61) showed no significant time effect. All DTI indices, except for fractional anisotropy, were significantly elevated compared with control muscles right after the injury (p < 0.001). Values normalized during the recovery period, with no significant differences between control and injured muscles at RTP (p values ranged from 0.08 to 0.51). Mean qT2 relaxation times in injured muscles were not significantly elevated compared with control muscles at any time point (p > 0.04). In conclusion, DTI can be used to monitor recovery after an acute hamstring injury. Future work should explore the potential of DTI indices to predict RTP and recovery times in athletes after an acute strain injury.

Model-based reconstructions for intravoxel incoherent motion and diffusion tensor imaging parameter map estimations.

Intravoxel incoherent motion (IVIM) imaging and diffusion tensor imaging (DTI) facilitate noninvasive quantification of tissue perfusion and diffusion. Both are promising biomarkers in various diseases and a combined acquisition is therefore desirable. This comes with challenges, including noisy parameter maps and long scan times, especially for the perfusion fraction f and pseudo-diffusion coefficient D*. A model-based reconstruction has the potential to overcome these challenges. As a first step, our goal was to develop a model-based reconstruction framework for IVIM and combined IVIM-DTI parameter estimation. The IVIM and IVIM-DTI models were implemented in the PyQMRI model-based reconstruction framework and validated with simulations and in vivo data. Commonly used voxel-wise nonlinear least-squares fitting was used as the reference. Simulations with the IVIM and IVIM-DTI models were performed with 100 noise realizations to assess accuracy and precision. Diffusion-weighted data were acquired for IVIM reconstruction in the liver (n = 5), as well as for IVIM-DTI in the kidneys (n = 5) and lower-leg muscles (n = 6) of healthy volunteers. The median and interquartile range (IQR) values of the IVIM and IVIM-DTI parameters were compared to assess bias and precision. With model-based reconstruction, the parameter maps exhibited less noise, which was most pronounced in the f and D* maps, both in the simulations and in vivo. The bias values in the simulations were comparable between model-based reconstruction and the reference method. The IQR was lower with model-based reconstruction compared with the reference for all parameters. In conclusion, model-based reconstruction is feasible for IVIM and IVIM-DTI and improves the precision of the parameter estimates, particularly for f and D* maps.

Self-gated, dynamic contrast-enhanced magnetic resonance imaging with compressed-sensing reconstruction for evaluating endothelial permeability in the aortic root of atherosclerotic mice.

High-risk atherosclerotic plaques are characterized by active inflammation and abundant leaky microvessels. We present a self-gated, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) acquisition with compressed sensing reconstruction and apply it to assess longitudinal changes in endothelial permeability in the aortic root of Apoe-/- atherosclerotic mice during natural disease progression. Twenty-four, 8-week-old, female Apoe-/- mice were divided into four groups (n = 6 each) and imaged with self-gated DCE-MRI at 4, 8, 12, and 16 weeks after high-fat diet initiation, and then euthanized for CD68 immunohistochemistry for macrophages. Eight additional mice were kept on a high-fat diet and imaged longitudinally at the same time points. Aortic-root pseudo-concentration curves were analyzed using a validated piecewise linear model. Contrast agent wash-in and washout slopes (b1 and b2 ) were measured as surrogates of aortic root endothelial permeability and compared with macrophage density by immunohistochemistry. b2 , indicating contrast agent washout, was significantly higher in mice kept on an high-fat diet for longer periods of time (p = 0.03). Group comparison revealed significant differences between mice on a high-fat diet for 4 versus 16 weeks (p = 0.03). Macrophage density also significantly increased with diet duration (p = 0.009). Spearman correlation between b2 from DCE-MRI and macrophage density indicated a weak relationship between the two parameters (r = 0.28, p = 0.20). Validated piecewise linear modeling of the DCE-MRI data showed that the aortic root contrast agent washout rate is significantly different during disease progression. Further development of this technique from a single-slice to a 3D acquisition may enable better investigation of the relationship between in vivo imaging of endothelial permeability and atherosclerotic plaques' genetic, molecular, and cellular makeup in this important model of disease.

Venous Blood Oxygenation Measurements Using TRUST and T2-TRIR MRI During Hypoxic and Hypercapnic Gas Challenges.

BACKGROUND: Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) may serve as biomarkers in several diseases. OEF and CMRO2 can be estimated from venous blood oxygenation (Yv ) levels, which in turn can be calculated from venous blood T2 values (T2b ). T2b can be measured using different MRI sequences, including T2-relaxation-under-spin-tagging (TRUST) and T2-prepared-blood-relaxation-imaging-with-inversion-recovery (T2-TRIR). The latter measures both T2b and T1 (T1b ) but was found previously to overestimate T2b compared to TRUST. It remained unclear, however, if this bias is constant across higher and lower oxygen saturations. PURPOSE: To compare TRUST and T2-TRIR across a range of O2 saturations using hypoxic and hypercapnic gas challenges. STUDY TYPE: Prospective. POPULATION: Twelve healthy volunteers (four female, age 36 ± 10 years). FIELD STRENGTH/SEQUENCE: A 3T; turbo-field echo-planar-imaging (TFEPI), echo-planar-imaging (EPI), and fast-field-echo (FFE). ASSESSMENT: TRUST- and T2-TRIR-derived T2b , Yv , OEF, and CMRO2 were compared across different respiratory challenges. T1b from T2-TRIR was used to estimate Hct (HctTRIR ) and compared with venipuncture (HctVP ). STATISTICAL TESTS: Shapiro-Wilk, one-sample and paired-sample t-test, repeated measures ANOVA, Friedman test, Bland-Altman, and correlation analysis. Bonferroni multiple-comparison correction was performed. Significance level was 0.05. RESULTS: A significant bias was observed between TRUST- and T2-TRIR-derived T2b , Yv , and OEF values (-13 ± 11 msec, -5.3% ± 3.5% and 5.9 ± 4.1%, respectively). For Yv and OEF, this bias was constant across the range of measured values. T1b was significantly lower during severe hypoxia and hypercapnia compared to baseline (1712 ± 86 msec and 1634 ± 79 msec compared to 1757 ± 90 msec). While no significant bias was found between HctVP and HctTRIR (0.02% ± 0.06%, P = 0.20), the correlation between these Hct values was significant but weak (r = 0.19). DATA CONCLUSION: Given the constant bias, TRUST- and T2-TRIR-derived venous T2b values can be used interchangeably to estimate Yv , OEF, and CMRO2 across a broad range of oxygen saturations. Hct from T2-TRIR-derived T1-values only weakly correlated with Hct from venipuncture. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

A comparison of myocardial magnetic resonance extracellular volume mapping at 3 T against histology of tissue collagen in severe aortic valve stenosis and obstructive hypertrophic cardiomyopathy.

OBJECTIVE: Quantitative extracellular volume fraction (ECV) mapping with MRI is commonly used to investigate in vivo diffuse myocardial fibrosis. This study aimed to validate ECV measurements against ex vivo histology of myocardial tissue samples from patients with aortic valve stenosis or hypertrophic cardiomyopathy. MATERIALS AND METHODS: Sixteen patients underwent MRI examination at 3 T to acquire native T1 maps and post-contrast T1 maps after gadobutrol administration, from which hematocrit-corrected ECV maps were estimated. Intra-operatively obtained myocardial tissue samples from the same patients were stained with picrosirius red for quantitative histology of myocardial interstitial fibrosis. Correlations between in vivo ECV and ex vivo myocardial collagen content were evaluated with regression analyses. RESULTS: Septal ECV was 30.3% ± 4.6% and correlated strongly (n = 16, r = 0.70; p = 0.003) with myocardial collagen content. Myocardial native T1 values (1206 ± 36 ms) did not correlate with septal ECV (r = 0.41; p = 0.111) or with myocardial collagen content (r = 0.32; p = 0.227). DISCUSSION: We compared myocardial ECV mapping at 3 T against ex vivo histology of myocardial collagen content, adding evidence to the notion that ECV mapping is a surrogate marker for in vivo diffuse myocardial fibrosis.

Effect of two eccentric hamstring exercises on muscle architectural characteristics assessed with diffusion tensor MRI.

OBJECTIVES: To evaluate the effect of a Nordic hamstring exercise or Diver hamstring exercise intervention on biceps femoris long head, semitendinosus and semimembranosus muscle's fascicle length and orientation through diffusion tensor imaging (DTI) with magnetic resonance imaging. METHODS: In this three-arm, single-center, randomized controlled trial, injury-free male basketball players were randomly assigned to a Nordic, Diver hamstring exercise intervention or control group. The primary outcome was the DTI-derived fascicle length and orientation of muscles over 12 weeks. RESULTS: Fifty-three participants were included for analysis (mean age 22 ± 7 years). Fascicle length in the semitendinosus over 12 weeks significantly increased in the Nordic-group (mean [M]: 20.8 mm, 95% confidence interval [95% CI]: 7.8 to 33.8) compared with the Control-group (M: 0.9 mm, 95% CI: -7.1 to 8.9), mean between-groups difference: 19.9 mm, 95% CI: 1.9 to 37.9, p = 0.026. Fascicle orientation in the biceps femoris long head over 12 weeks significantly decreased in the Diver-group (mean: -2.6°, 95% CI: -4.1 to -1.0) compared with the Control-group (mean: -0.2°, 95% CI: -1.4 to 1.0), mean between-groups difference: -2.4°, 95% CI: -4.7 to -0.1, p = 0.039. CONCLUSION: The Nordic hamstring exercise intervention did significantly increase the fascicle length of the semitendinosus and the Diver hamstring exercise intervention did significantly change the orientation of fascicles of the biceps femoris long head. As both exercises are complementary to each other, the combination is relevant for preventing hamstring injuries.

Right atrial function is associated with right venticular diastolic stiffness: RA-RV interaction in pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. This study assessed the impact of RV diastolic stiffness on RA-RV interaction. METHODS: PAH patients with low or high end-diastolic elastance (Eed) (n=94) were compared with controls (n=31). Treatment response was evaluated in 62 patients. RV and RA longitudinal strain, RA emptying and RV filling were determined and diastole was divided into a passive and active phase. Vena cava backflow was calculated as RA active emptying-RV active filling and RA stroke work as RA active emptying×RV end-diastolic pressure. RESULTS: With increased Eed, RA and RV passive strain were reduced while active strain was preserved. In comparison to controls, patients had lower RV passive filling but higher RA active emptying and RA stroke work. RV active filling was lower in patients with high Eed, resulting in higher vena cava backflow. Upon treatment, Eed was reduced in ~50% of the patients with high Eed, which coincided with larger reductions in afterload, RV mass and vena cava backflow and greater improvements in RV active filling and stroke volume in comparison with patients in whom Eed remained high. CONCLUSIONS: In PAH, RA function is associated with changes in RV function. Despite increased RA stroke work, severe RV diastolic stiffness is associated with reduced RV active filling and increased vena cava backflow. In 50% of patients with high baseline Eed, diastolic stiffness remained high, despite treatment. A reduction in Eed coincided with a large reduction in afterload, increased RV active filling and decreased vena cava backflow.

Multi-parametric quantitative magnetic resonance imaging of the upper arm muscles of patients with spinal muscular atrophy.

Quantitative magnetic resonance imaging (qMRI) is frequently used to map the disease state and disease progression in the lower extremity muscles of patients with spinal muscular atrophy (SMA). This is in stark contrast to the almost complete lack of data on the upper extremity muscles, which are essential for carrying out daily activities. The aim of this study was therefore to assess the disease state in the upper arm muscles of patients with SMA in comparison with healthy controls by quantitative assessment of fat fraction, diffusion indices, and water T2 relaxation times, and to relate these measures to muscle force. We evaluated 13 patients with SMA and 15 healthy controls with a 3-T MRI protocol consisting of DIXON, diffusion tensor imaging, and T2 sequences. qMRI measures were compared between groups and related to muscle force measured with quantitative myometry. Fat fraction was significantly increased in all upper arm muscles of the patients with SMA compared with healthy controls and correlated negatively with muscle force. Additionally, fat fraction was heterogeneously distributed within the triceps brachii (TB) and brachialis muscle, but not in the biceps brachii muscle. Diffusion indices and water T2 relaxation times were similar between patients with SMA and healthy controls, but we did find a slightly reduced mean diffusivity (MD), λ1, and λ3 in the TB of patients with SMA. Furthermore, MD was positively correlated with muscle force in the TB of patients with SMA. The variation in fat fraction further substantiates the selective vulnerability of muscles. The reduced diffusion tensor imaging indices, along with the positive correlation of MD with muscle force, point to myofiber atrophy. Our results show the feasibility of qMRI to map the disease state in the upper arm muscles of patients with SMA. Longitudinal data in a larger cohort are needed to further explore qMRI to map disease progression and to capture the possible effects of therapeutic interventions.

Comparative Analysis of Blood T2 Values Measured by T2 -TRIR and TRUST.

BACKGROUND: Venous blood oxygenation (Yv), which can be derived from venous blood T2 (T2 b), combined with oxygen-extraction fraction (OEF) and cerebral metabolic rate of oxygen, is considered indicative for tissue viability and brain functioning and frequently assessed in patients with sickle cell disease. Recently, T2 -Prepared-Blood-Relaxation-Imaging-with-Inversion-Recovery (T2 -TRIR) was introduced allowing for simultaneous measurements of blood T2 and T1 (T1 b), potentially improving Yv estimation by overcoming the need to estimate hematocrit. PURPOSE: To optimize and compare T2 -TRIR with T2 -relaxation-under-spin-tagging (TRUST) sequence. STUDY TYPE: Prospective. POPULATION: A total of 12 healthy volunteers (six female, 27 ± 3 years old) and 7 patients with sickle cell disease (five female, 32 ± 12 years old). FIELD STRENGTH/SEQUENCE: 3 T; turbo field echo planar imaging (TFEPI), echo planar imaging (EPI), and fast field echo (FFE). ASSESSMENT: T2 b, Yv, and OEF from TRUST and T2 -TRIR were compared and T2 -TRIR-derived T1 b was assessed. Within- and between-session repeatability was quantified in the controls, whereas sensitivity to hemodynamic changes after acetazolamide (ACZ) administration was assessed in the patients. STATISTICAL TESTS: Shapiro-Wilk, one-sample and paired-sample t-test, repeated measures ANOVA, mixed linear model, Bland-Altman analysis and correlation analysis. Sidak multiple-comparison correction was performed. Significance level was 0.05. RESULTS: In controls, T2 b from T2 -TRIR (70 ± 11 msec) was higher compared to TRUST (60 ± 8 msec). In patients, T2 b values were lower pre- compared to post-ACZ administration (TRUST: 80 ± 15 msec and 106 ± 23 msec and T2 -TRIR: 95 ± 21 msec and 125 ± 36 msec). Consequently, Yv and OEF were lower and higher pre- compared to post-ACZ administration (TRUST Yv: 68% ± 7% and 77% ± 8%, T2 -TRIR Yv: 74% ± 8% and 80% ± 6%, TRUST OEF: 30% ± 7% and 21% ± 8%, and T2 -TRIR OEF: 25% ± 8% and 18% ± 6%). DATA CONCLUSION: TRUST and T2 -TRIR are reproducible, but T2 -TRIR-derived T2 b values are significantly higher compared to TRUST, resulting in higher Yv and lower OEF estimates. This bias might be considered when evaluating cerebral oxygen homeostasis. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Whole-Heart 4D Flow MRI for Evaluation of Normal and Regurgitant Valvular Flow: A Quantitative Comparison Between Pseudo-Spiral Sampling and EPI Readout.

BACKGROUND: Pseudo-spiral Cartesian sampling with compressed sensing reconstruction has facilitated highly accelerated 4D flow magnetic resonance imaging (MRI) in various cardiovascular structures. However, unlike echo planar imaging (EPI)-accelerated 4D flow MRI, it has not been validated in whole-heart applications. HYPOTHESIS: Pseudo-spiral 4D flow MRI (PROUD [PROspective Undersampling in multiple Dimensions]) is comparable to EPI in robustness of valvular flow measurements and remains comparable as the undersampling factor is increased and scan time reduced. STUDY TYPE: Prospective. POPULATION: Twelve healthy subjects and eight patients with valvular regurgitation. FIELD STRENGTH/SEQUENCE: 3.0 T; PROUD and EPI 4D flow sequences, 2D flow and balanced steady-state free precession sequences. ASSESSMENT: Valvular blood flow was quantified using valve tracking. PROUD- and EPI-based measurements of aortic (AV) and pulmonary (PV) flow volumes and left and right ventricular stroke volumes were tested for agreement with 2D MRI-based measurements. PROUD reconstructions with undersampling factors (R) of 9, 14, 28, and 56 were tested for intervalve consistency (per valve, compared to the other valves) and preservation of peak velocities and E/A ratios. STATISTICAL TESTS: We used repeated measures ANOVA, Bland-Altman, Wilcoxon signed rank, and intraclass correlation coefficients. P < 0.05 was considered statistically significant. RESULTS: PROUD and EPI intervalve consistencies were not significantly different both in healthy subjects (valve-averaged mean difference [limits of agreement width]: 3.2 ± 0.8 [8.7 ± 1.1] mL/beat for PROUD, 5.5 ± 2.9 [13.7 ± 2.3] mL/beat for EPI, P = 0.07) and in patients with valvular regurgitation (2.3 ± 1.2 [15.3 ± 5.9] mL/beat for PROUD, 0.6 ± 0.6 [19.3 ± 2.9] mL/beat for EPI, P = 0.47). Agreement between EPI and PROUD was higher than between 4D flow (EPI or PROUD) and 2D MRI for forward flow, stroke volumes, and regurgitant volumes. Up to R = 28 in healthy subjects and R = 14 in patients with valvular regurgitation, PROUD intervalve consistency remained comparable to that of EPI. Peak velocities and E/A ratios were preserved up to R = 9. CONCLUSION: PROUD is comparable to EPI in terms of intervalve consistency and may be used with higher undersampling factors to shorten scan times further. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Dynamic MRI of swallowing: real-time volumetric imaging at 12 frames per second at 3 T.

OBJECTIVE: Dysphagia or difficulty in swallowing is a potentially hazardous clinical problem that needs regular monitoring. Real-time 2D MRI of swallowing is a promising radiation-free alternative to the current clinical standard: videofluoroscopy. However, aspiration may be missed if it occurs outside this single imaged slice. We therefore aimed to image swallowing in 3D real time at 12 frames per second (fps). MATERIALS AND METHODS: At 3 T, three 3D real-time MRI acquisition approaches were compared to the 2D acquisition: an aligned stack-of-stars (SOS), and a rotated SOS with a golden-angle increment and with a tiny golden-angle increment. The optimal 3D acquisition was determined by computer simulations and phantom scans. Subsequently, five healthy volunteers were scanned and swallowing parameters were measured. RESULTS: Although the rotated SOS approaches resulted in better image quality in simulations, in practice, the aligned SOS performed best due to the limited number of slices. The four swallowing phases could be distinguished in 3D real-time MRI, even though the spatial blurring was stronger than in 2D. The swallowing parameters were similar between 2 and 3D. CONCLUSION: At a spatial resolution of 2-by-2-by-6 mm with seven slices, swallowing can be imaged in 3D real time at a frame rate of 12 fps.

Supervised segmentation framework for evaluation of diffusion tensor imaging indices in skeletal muscle.

Diffusion tensor imaging (DTI) is becoming a relevant diagnostic tool to understand muscle disease and map muscle recovery processes following physical activity or after injury. Segmenting all the individual leg muscles, necessary for quantification, is still a time-consuming manual process. The purpose of this study was to evaluate the impact of a supervised semi-automatic segmentation pipeline on the quantification of DTI indices in individual upper leg muscles. Longitudinally acquired MRI datasets (baseline, post-marathon and follow-up) of the upper legs of 11 subjects were used in this study. MR datasets consisted of a DTI and Dixon acquisition. Semi-automatic segmentations for the upper leg muscles were performed using a transversal propagation approach developed by Ogier et al on the out-of-phase Dixon images at baseline. These segmentations were longitudinally propagated for the post-marathon and follow-up time points. Manual segmentations were performed on the water image of the Dixon for each of the time points. Dice similarity coefficients (DSCs) were calculated to compare the manual and semi-automatic segmentations. Bland-Altman and regression analyses were performed, to evaluate the impact of the two segmentation methods on mean diffusivity (MD), fractional anisotropy (FA) and the third eigenvalue (λ3 ). The average DSC for all analyzed muscles over all time points was 0.92 ± 0.01, ranging between 0.48 and 0.99. Bland-Altman analysis showed that the 95% limits of agreement for MD, FA and λ3 ranged between 0.5% and 3.0% for the transversal propagation and between 0.7% and 3.0% for the longitudinal propagations. Similarly, regression analysis showed good correlation for MD, FA and λ3 (r = 0.99, p < 60; 0.0001). In conclusion, the supervised semi-automatic segmentation framework successfully quantified DTI indices in the upper-leg muscles compared with manual segmentation while only requiring manual input of 30% of the slices, resulting in a threefold reduction in segmentation time.

Double delay alternating with nutation for tailored excitation facilitates banding-free isotropic high-resolution intracranial vessel wall imaging.

The purpose of this study was to evaluate the use of a double delay alternating with nutation for tailored excitation (D-DANTE)-prepared sequence for banding-free isotropic high-resolution intracranial vessel wall imaging (IC-VWI) and to compare its performance with regular DANTE in terms of signal-to-noise ratio (SNR) as well as cerebrospinal fluid (CSF) and blood suppression efficiency. To this end, a D-DANTE-prepared 3D turbo spin echo sequence was implemented by interleaving two separate DANTE pulse trains with different RF phase-cycling schemes, but keeping all other DANTE parameters unchanged, including the total number of pulses and total preparation time. This achieved a reduction of the banding distance compared with regular DANTE enabling banding-free imaging up to higher resolutions. Bloch simulations assuming static vessel wall and flowing CSF spins were performed to compare DANTE and D-DANTE in terms of SNR and vessel wall/CSF contrast. Similar image quality measures were assessed from measurements on 13 healthy middle-aged volunteers. Both simulation and in vivo results showed that D-DANTE had only slightly lower vessel wall/CSF and vessel wall/blood contrast-to-noise ratio values compared with regular DANTE, which originated from a 10%-15% reduction in vessel wall SNR but not from reduced CSF or blood suppression efficiency. As anticipated, IC-VWI acquisitions showed that D-DANTE can successfully remove banding artifacts compared with regular DANTE with equal scan time or DANTE preparation length. Moreover, application was demonstrated in a patient with an intracranial aneurysm, indicating improved robustness to slow flow artifacts compared with clinically available 3D turbo spin echo scans. In conclusion, D-DANTE provides banding artifact-free IC-VWI up to higher isotropic resolutions compared with regular DANTE. This allows for a more flexible choice of DANTE preparation parameters in high-resolution IC-VWI protocols.

Retrospective Camera-Based Respiratory Gating in Clinical Whole-Heart 4D Flow MRI.

BACKGROUND: Respiratory gating is generally recommended in 4D flow MRI of the heart to avoid blurring and motion artifacts. Recently, a novel automated contact-less camera-based respiratory motion sensor has been introduced. PURPOSE: To compare camera-based respiratory gating (CAM) with liver-lung-navigator-based gating (NAV) and no gating (NO) for whole-heart 4D flow MRI. STUDY TYPE: Retrospective. SUBJECTS: Thirty two patients with a spectrum of cardiovascular diseases. FIELD STRENGTH/SEQUENCE: A 3T, 3D-cine spoiled-gradient-echo-T1-weighted-sequence with flow-encoding in three spatial directions. ASSESSMENT: Respiratory phases were derived and compared against each other by cross-correlation. Three radiologists/cardiologist scored images reconstructed with camera-based, navigator-based, and no respiratory gating with a 4-point Likert scale (qualitative analysis). Quantitative image quality analysis, in form of signal-to-noise ratio (SNR) and liver-lung-edge (LLE) for sharpness and quantitative flow analysis of the valves were performed semi-automatically. STATISTICAL TESTS: One-way repeated measured analysis of variance (ANOVA) with Wilks's lambda testing and follow-up pairwise comparisons. Significance level of P ≤ 0.05. Krippendorff's-alpha-test for inter-rater reliability. RESULTS: The respiratory signal analysis revealed that CAM and NAV phases were highly correlated (C = 0.93 ± 0.09, P < 0.01). Image scoring showed poor inter-rater reliability and no significant differences were observed (P ≥ 0.16). The image quality comparison showed that NAV and CAM were superior to NO with higher SNR (P = 0.02) and smaller LLE (P < 0.01). The quantitative flow analysis showed significant differences between the three respiratory-gated reconstructions in the tricuspid and pulmonary valves (P ≤ 0.05), but not in the mitral and aortic valves (P > 0.05). Pairwise comparisons showed that reconstructions without respiratory gating were different in flow measurements to either CAM or NAV or both, but no differences were found between CAM and NAV reconstructions. DATA CONCLUSION: Camera-based respiratory gating performed as well as conventional liver-lung-navigator-based respiratory gating. Quantitative image quality analysis showed that both techniques were equivalent and superior to no-gating-reconstructions. Quantitative flow analysis revealed local flow differences (tricuspid/pulmonary valves) in images of no-gating-reconstructions, but no differences were found between images reconstructed with camera-based and navigator-based respiratory gating. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Quantification of Myocardial Creatine and Triglyceride Content in the Human Heart: Precision and Accuracy of in vivo Proton Magnetic Resonance Spectroscopy.

BACKGROUND: Proton magnetic resonance spectroscopy (1 H-MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking. PURPOSE: To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized 1 H-MRS. STUDY TYPE: Test-retest repeatability and measurement validation study. SUBJECTS: Sixteen volunteers and 22 patients scheduled for open-heart aortic valve replacement or septal myectomy. FIELD STRENGTH/SEQUENCE: Prospectively ECG-triggered respiratory-gated free-breathing single-voxel point-resolved spectroscopy (PRESS) sequence at 3 T. ASSESSMENT: Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the 1 H-MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo 1 H-MRS measurements against biochemical assays in myocardial tissue from the same subjects. STATISTICAL TESTS: Intrasession and intersession repeatability was assessed using Bland-Altman analyses. Agreement between 1 H-MRS measurements and biochemical assay was tested with regression analyses. RESULTS: The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% ± 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% ± 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with 1 H-MRS: n = 22, r = 0.44; P < 0.05. Likewise, ex vivo myocardial triglyceride concentrations correlated with the in vivo myocardial triglyceride content: n = 20, r = 0.50; P < 0.05. DATA CONCLUSION: We validated the use of localized 1 H-MRS of the human heart at 3 T for quantitative assessments of in vivo myocardial tissue metabolite content by estimating the measurement precision and accuracy. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function.

Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline-which belongs to the tetracycline class-reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in Drosophila and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and Drosophila melanogaster hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction.

An iterative sparse deconvolution method for simultaneous multicolor 19 F-MRI of multiple contrast agents.

PURPOSE: 19 F-MRI is gaining widespread interest for cell tracking and quantification of immune and inflammatory cells in vivo. Different fluorinated compounds can be discriminated based on their characteristic MR spectra, allowing in vivo imaging of multiple 19 F compounds simultaneously, so-called multicolor 19 F-MRI. We introduce a method for multicolor 19 F-MRI using an iterative sparse deconvolution method to separate different 19 F compounds and remove chemical shift artifacts arising from multiple resonances. METHODS: The method employs cycling of the readout gradient direction to alternate the spatial orientation of the off-resonance chemical shift artifacts, which are subsequently removed by iterative sparse deconvolution. Noise robustness and separation was investigated by numerical simulations. Mixtures of fluorinated oils (PFCE and PFOB) were measured on a 7T MR scanner to identify the relation between 19 F signal intensity and compound concentration. The method was validated in a mouse model after intramuscular injection of fluorine probes, as well as after intravascular injection. RESULTS: Numerical simulations show efficient separation of 19 F compounds, even at low signal-to-noise ratio. Reliable chemical shift artifact removal and separation of PFCE and PFOB signals was achieved in phantoms and in vivo. Signal intensities correlated excellently to the relative 19 F compound concentrations (r-2 = 0.966/0.990 for PFOB/PFCE). CONCLUSIONS: The method requires minimal sequence adaptation and is therefore easily implemented on different MRI systems. Simulations, phantom experiments, and in-vivo measurements in mice showed effective separation and removal of chemical shift artifacts below noise level. We foresee applicability for simultaneous in-vivo imaging of 19 F-containing fluorine probes or for detection of 19 F-labeled cell populations.