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Current clinical MRI of patients with juvenile osteochondritis dissecans (JOCD) is limited by the low reproducibility of lesion instability evaluation and inability to predict which lesions will heal after nonoperative treatment and which will later require surgery. The aim of this study is to verify the ability of apparent diffusion coefficient (ADC) to detect differences in lesion microstructure between different JOCD stages, treatment groups, and healthy, unaffected contralateral knees. Pediatric patients with JOCD received quantitative diffusion MRI between January 2016 and September 2020 in this prospective research study. A disease stage (I-IV) and stability of each JOCD lesion was evaluated. ADCs were calculated in progeny lesion, interface, parent bone, cartilage overlying lesion, control bone, and control cartilage regions. ADC differences were evaluated using linear mixed models with Bonferroni correction. Evaluated were 30 patients (mean age, 13 years; 21 males), with 40 JOCD-affected and 12 healthy knees. Nine patients received surgical treatment after MRI. Negative Spearman rank correlations were found between ADCs and JOCD stage in the progeny lesion (ρ = -0.572; p 0.001), interface (ρ = -0.324; p = 0.041), and parent bone (ρ = -0.610; p 0.001), demonstrating the sensitivity of ADC to microstructural differences in lesions at different JOCD stages. We observed a significant increase in the interface ADCs (p = 0.007) between operative (mean [95% CI] = 1.79 [1.56-2.01] × 10

INTRODUCTION: Despite the high risk for suicide, relatively few studies have explored the relationship between suicide and brain imaging measures in bipolar disorder. In addition, fewer studies have explored the possibility that altered brain metabolism may be associated with suicide attempt. To begin to fill in these gaps, we evaluated functional (task based fMRI) and metabolic (quantitative T1ρ) differences associated with suicide attempt in participants with bipolar disorder. METHODS: Thirty-nine participants with bipolar disorder underwent fMRI during a flashing checkerboard task and 27 also underwent quantitative T1ρ. The relationship between neuroimaging and history of suicide attempt was tested using multiple regression while adjusting for age, sex, and current mood state. Differences between two measures of suicide attempt (binary: yes/no and continuous: number of attempts) were quantified using the corrected Akaike Information Criterion. RESULTS: Participants who had attempted suicide had greater fMRI task-related activation in visual areas and the cerebellum. The number of suicide attempts was associated with a difference in BOLD response in the amygdala, prefrontal cortex, and cerebellum. Increased quantitative T1ρ was associated with number of suicide attempts in limbic, basal ganglia, and prefrontal cortex regions. LIMITATIONS: This study is a secondary analysis with a modest sample size. Differences between measures of suicide history may be due to differences in statistical power. CONCLUSIONS: History of suicide was associated with limbic, prefrontal, and cerebellar alterations. Results comparing those with and without suicide attempts differed from results using number of suicide attempts, suggesting that these variables have different neurobiological underpinnings.

Background Respiratory syncytial virus (RSV) causes respiratory tract infections, which may require hospitalization especially in early infancy. Transplacental transfer of RSV antibodies could confer protection to infants in their first months of life. Methods In this first-in-human, placebo-controlled study, 502 healthy nonpregnant women were randomized 1:1:1:1 to receive a single dose of unadjuvanted vaccine containing 30/60/120 µg of RSV fusion (F) protein stabilized in the prefusion conformation (RSVPreF3) or placebo. Results Solicited local adverse events (AEs) were more frequently reported in the RSVPreF3 groups (4%–53.2%) versus placebo (0%–15.9%); most were mild/moderate. Unsolicited AEs were comparably reported among groups. Three serious AEs were reported; none was vaccination-related. Compared with prevaccination values, anti-RSV A neutralizing antibody geometric mean titers and anti-RSVPreF3 immunoglobulin G geometric mean concentrations increased 8- to 14-fold and 12- to 21-fold at day 8 and persisted 5- to 6-fold and 6- to 8-fold higher until day 91 in the RSVPreF3 groups versus 1-fold in placebo. Comparisons at day 8 and day 31 showed that the higher dose levels were significantly more immunogenic than the lowest one. Conclusions The RSVPreF3 vaccine was well tolerated and immunogenic. The 60 and 120 µg dose levels were selected for further investigation in pregnant women. Clinical Trials Registration NCT03674177.

Mucopolysaccharidosis VII is a genetic, lysosomal storage disease characterized by abnormal accumulation of glycosaminoglycans in cells and tissues. MPS VII patients exhibit multiple failures of endochondral ossification during postnatal growth, including markedly delayed cartilage-to-bone conversion in the vertebrae and long bones. Cartilage canals provide the template for vascularization at the onset of secondary ossification. The objective of this study was to investigate whether abnormal cartilage canal architecture and enzyme-mediated extracellular matrix (ECM) remodeling contribute to delayed cartilage-to-bone conversion in MPS VII. The epiphyseal cartilage canal networks of 9-day-old healthy control and MPS VII-affected dog vertebrae were characterized using high-resolution, contrast-free quantitative susceptibility mapping magnetic resonance imaging. Interestingly, the density, number, connectivity and thickness of canals was not significantly different between MPS VII and control vertebrae. Immunohistochemistry revealed diminished MMP-9, but normal MMP-13 and 14 expression by epiphyseal cartilage chondrocytes, while active ALP and TRAP enzyme expression by chondrocytes and chondroclasts, respectively, were both diminished. Our findings suggest that while the epiphyseal cartilage canal network in MPS VII is normal at the onset of secondary ossification, expression of enzymes required for cartilage resorption and replacement with mineralized ECM, and initiation of angiogenesis, is impaired.

Purpose To introduce a new approach called tailored variable flip-angle (VFA) scheduling for SNR-efficient 3D T1ρ mapping of the brain using a magnetization-prepared gradient-echo sequence. Methods Simulations were used to assess the relative SNR efficiency, quantitative accuracy, and spatial blurring of tailored VFA scheduling for T1ρ mapping of brain tissue compared with magnetization-prepared angle-modulated partitioned k-space spoiled gradient-echo snapshots (MAPSS), a state-of-the-art technique for accurate 3D gradient-echo T1ρ mapping. Simulations were also used to calculate optimal imaging parameters for tailored VFA scheduling versus MAPSS, without and with nulling of CSF. Four participants were imaged at 3T MRI to demonstrate the feasibility of tailored VFA scheduling for T1ρ mapping of the brain. Using MAPSS as a reference standard, in vivo data were used to validate the relative SNR efficiency and quantitative accuracy of the new approach. Results Tailored VFA scheduling can provide a 2-fold to 4-fold gain in the SNR of the resulting T1ρ map as compared with MAPSS when using identical sequence parameters while limiting T1ρ quantification errors to 2% or less. In vivo whole-brain 3D T1ρ maps acquired with tailored VFA scheduling had superior SNR efficiency than is achievable with MAPSS, and the SNR efficiency improved with a greater number of views per segment. Conclusions Tailored VFA scheduling is an SNR-efficient GRE technique for 3D T1ρ mapping of the brain that provides increased flexibility in choice of imaging parameters compared with MAPSS, which may benefit a variety of applications.

The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. Increasing evidence suggests that IVD degeneration is a disease of the whole joint that is associated with significant inflammation. Moreover, studies show elevated macrophage accumulation within the IVD with increasing levels of disease severity; however, we still need to understand the roles, be they causative or consequential, of macrophages during the degenerative process. In this narrative review, we discuss hallmarks of IVD degeneration, showcase evidence of macrophage involvement during disc degeneration, and explore burgeoning research aimed at understanding the molecular pathways regulating macrophage functions during intervertebral disc degeneration.

PURPOSE: To evaluate the feasibility of arterial spin labeling (ASL) imaging of epiphyseal bone marrow in the distal femoral condyle of the knee at 7T MRI. METHODS: The knees of 7 healthy volunteers were imaged with ASL using a 7T whole body MRI scanner and a 28-channel knee coil. ASL imaging used a flow-sensitive alternating inversion recovery method for labeling and a single-shot fast spin echo sequence for image readout. ASL imaging with a single oblique transverse slice was performed at 2 slice positions in the distal femoral condyle. Blood flow was measured in 2 regions of interest: the epiphyseal bone marrow and the overlying patellofemoral cartilage. To analyze perfusion SNR, 200 noise images were also acquired using the same ASL imaging protocol with RF pulses turned off. RESULTS: Knee bone marrow perfusion imaging was successfully performed with all volunteers. The overall mean of blood flow in the knee bone marrow was 32.90 ± 2.41 mL/100 g/min, and the blood flow was higher at the more distal slice position. We observed significant B(0) and [Formula: see text] inhomogeneities, which need to be addressed in the future to improve the quality of ASL imaging and increase the reliability of knee bone marrow perfusion measurements. CONCLUSION: Bone marrow perfusion imaging of the distal femoral condyle is feasible using ASL at 7T. Further technical development is needed to improve the ASL method to overcome existing challenges.

Juvenile osteochondritis dissecans (JOCD) is a developmental disease characterized by formation of intra-articular (osteo)chondral flaps or fragments. Evidence-based treatment guidelines for JOCD are currently lacking. An animal model would facilitate study of JOCD and evaluation of diagnostic and treatment approaches. The purpose of this study was to assess the suitability of miniature pigs as a model of JOCD at the distal femur. First, stifle (knee) joints harvested from three juvenile miniature pigs underwent magnetic resonance imaging (MRI) to establish the vascular architecture of the distal femoral epiphyseal cartilage. Second, vessels supplying the axial or abaxial aspects of the medial femoral condyle were surgically interrupted in four additional juvenile miniature pigs, and the developing epiphyseal cartilage lesions were monitored using three consecutive MRI examinations over nine weeks. The miniature pigs were then euthanized, and their distal femora were harvested for histological evaluation. Vascular architecture of the distal femoral epiphyseal cartilage in the miniature pigs was found to be nearly identical to that of juvenile human subjects, characterized by separate vascular beds supplying the axial and abaxial aspects of the condyles. Surgical interruption of the vascular supply to the abaxial aspect of the medial femoral condyle resulted in ischemic cartilage necrosis (a precursor lesion of JOCD) in 75% (3/4) of the miniature pigs. Cartilage lesions were identified during the first MRI performed 3 weeks post-operatively. No clinically apparent JOCD-like lesions developed. In conclusion, miniature pigs are suitable for modeling JOCD precursor lesions. Further investigation of the model is warranted to assess induction of clinically apparent JOCD lesions. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2130-2137, 2019.

Biplane 2D-3D registration approaches have been used for measuring 3D, in vivo glenohumeral (GH) joint kinematics. Computed tomography (CT) has become the gold standard for reconstructing 3D bone models, as it provides high geometric accuracy and similar tissue contrast to video-radiography. Alternatively, magnetic resonance imaging (MRI) would not expose subjects to radiation and provides the ability to add cartilage and other soft tissues to the models. However, the accuracy of MRI-based 2D-3D registration for quantifying glenohumeral kinematics is unknown. We developed an automatic 2D-3D registration program that works with both CT- and MRI-based image volumes for quantifying joint motions. The purpose of this study was to use the proposed 2D-3D auto-registration algorithm to describe the humerus and scapula tracking accuracy of CT- and MRI-based registration relative to radiostereometric analysis (RSA) during dynamic biplanar video-radiography. The GH kinematic accuracy (RMS error) was 0.6–1.0 mm and 0.6–2.2° for the CT-based registration and 1.4–2.2 mm and 1.2–2.6° for MRI-based registration. Higher kinematic accuracy of CT-based registration was expected as MRI provides lower spatial resolution and bone contrast as compared to CT and suffers from spatial distortions. However, the MRI-based registration is within an acceptable accuracy for many clinical research questions.

Background: We introduce a quantitative measure of epiphyseal cartilage vascularity and examine vessel networks during human skeletal maturation. Understanding early morphological changes in the distal femoral condyle is expected to provide information on the pathogenesis of developmental diseases such as juvenile osteochondritis dissecans. Methods: Twenty-two cadaveric knees from donors ranging from 1 month to 10 years of age were included in the study. Images of bone, cartilage, and vascularity were acquired simultaneously with a 3-dimensional gradient-recalled-echo magnetic resonance imaging (MRI) sequence. The secondary ossification center volume and total epiphysis cartilage volume ratio and articular-epiphyseal cartilage complex and epiphyseal cartilage widths were measured. Epiphyseal cartilage vascularity was visualized for 9 data sets with quantitative susceptibility mapping and vessel filtering, resulting in 3-dimensional data to inform vessel network segmentation and to calculate vascular density. Results: Three distinct, non-anastomosing vascular networks (2 peripheral and 1 central) supply the distal femoral epiphyseal cartilage. The central network begins regression as early as 3 months and is absent by 4 years. From 1 month to 3 years, the ratio of central to peripheral vascular area density decreased from 1.0 to 0.5, and the ratio of central to peripheral vascular skeletal density decreased from 0.9 to 0.6. A narrow, peripheral vascular rim was present at 8 years but had disappeared by 10 years. The secondary ossification center progressively acquires the shape of the articular-epiphyseal cartilage complex by 8 years of age, and the central areas of the medial and lateral femoral condyles are the last to ossify. Conclusions: Using cadaveric pediatric knees, we provide quantitative, 3-dimensional measures of epiphyseal cartilage vascular regression during skeletal development using vessel image features. Central areas with both early vascular regression and delayed ossification correspond to predilection sites of juvenile osteochondritis dissecans in this limited case series. Our findings highlight specific vascular vulnerabilities that may lead to improved understanding of the pathogenesis and better-informed clinical management decisions in developmental skeletal diseases. Clinical Relevance: This paradigm shift in understanding of juvenile osteochondritis dissecans etiology and disease progression may critically impact future patient management. Our findings highlight specific vascular vulnerabilities during skeletal maturation in a group of active young patients seen primarily by orthopaedic surgeons and sports medicine professionals.

A single dose of either 30 µg or 60 µg of nonadjuvanted respiratory syncytial virus prefusion F protein antigen boosts humoral immune responses in women of childbearing age. The investigational vaccine was well tolerated and had a safety profile similar to that of the widely used combined Tdap vaccine., Background Respiratory syncytial virus (RSV) causes bronchiolitis and pneumonia in neonates and infants. RSV vaccination during pregnancy could boost preexisting neutralizing antibody titers, providing passive protection to newborns. Methods Two observer-blinded, controlled studies (RSV F-020 [clinical trials registration NCT02360475] and RSV F-024 [NCT02753413]) evaluated immunogenicity and safety of an investigational RSV vaccine in healthy, nonpregnant 18–45-year-old women. Both studies used a licensed adult formulation of combined tetanus toxoid-diphtheria toxoid-acellular pertussis (Tdap) vaccine as a control. RSV F-020 evaluated immunogenicity and safety: participants were randomized (1:1:1:1) to receive 1 dose of RSV–prefusion F protein (PreF) vaccine containing 30 µg or 60 µg of nonadjuvanted RSV-PreF, 60 µg of aluminum-adjuvanted RSV-PreF, or Tdap. RSV F-024 evaluated safety: participants were randomized 1:1 to receive 1 dose of 60 µg of nonadjuvanted RSV-PreF or Tdap. Results Both studies showed similar reactogenicity profiles for RSV-PreF and Tdap. No serious adverse events were considered vaccine related. In RSV F-020, geometric mean ratios of RSV-A neutralizing antibody levels at day 30 versus prevaccination were 3.1–3.9 in RSV-PreF recipients and 0.9 in controls. Palivizumab-competing antibody concentrations increased >14-fold in RSV-PreF recipients on day 30. RSV antibody titers waned after day 30 but remained well above baseline through day 90. Conclusions All formulations of RSV-PreF boosted preexisting immune responses in 18–45-year old women with comparable immunogenicity. The RSV-PreF safety profile was similar to that of Tdap vaccine.

INTRODUCTION: Bipolar disorder is characterized by recurring episodes of depression and mania. Defining differences in brain function during these states is an important goal of bipolar disorder research. However, few imaging studies have directly compared brain activity between bipolar mood states. Herein, we compare functional magnetic resonance imaging (fMRI) responses during a flashing checkerboard stimulus between bipolar participants across mood states (euthymia, depression, and mania) in order to identify functional differences between these states. METHODS: 40 participants with bipolar I disorder and 33 healthy controls underwent fMRI during the presentation of the stimulus. A total of 23 euthymic-state, 16 manic-state, 15 depressed-state, and 32 healthy control imaging sessions were analyzed in order to compare functional activation during the stimulus between mood states and with healthy controls. RESULTS: A reduced response was identified in the visual cortex in both the depressed and manic groups compared to euthymic and healthy participants. Functional differences between bipolar mood states were also observed in the cerebellum, thalamus, striatum, and hippocampus. CONCLUSIONS: Functional differences between mood states occurred in several brain regions involved in visual and other sensory processing. These differences suggest that altered visual processing may be a feature of mood states in bipolar disorder. LIMITATIONS: The key limitations of this study are modest mood-state group size and the limited temporal resolution of fMRI which prevents the segregation of primary visual activity from regulatory feedback mechanisms.

Background Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis and pneumonia in childhood. Maternal immunization could help to protect infants from RSV-associated infections in their first months of life. We evaluated the safety, reactogenicity and immunogenicity of the RSV maternal (RSVPreF3) vaccine candidate in non-pregnant women, at different dose levels. Methods In this phase I/II, observer-blind, multicenter study (NCT03674177), healthy non-pregnant women aged 18–45 years were randomized (1:1:1:1) and received 1 dose of either 30, 60 or 120 µg of RSVPreF3 vaccine (30/60/120 RSVPreF3 group) or placebo. Solicited adverse events (AEs) (until day 7 [D7] post-vaccination), unsolicited AEs (until D30 post-vaccination), hematological and biochemical laboratory abnormalities (at D8 and D31 post-vaccination) were recorded. Serious AEs (SAEs) were collected until D181 and immune responses until D91 post-vaccination. Exploratory analysis was performed at D31 to compare immunogenicity of different dose levels. Results 502 women were included in the exposed set. The most frequently reported solicited AEs were pain and headache (Fig 1). Grade 3 solicited AEs were infrequently reported. 180 women experienced unsolicited AEs; 19 reported grade 3 unsolicited AEs, among which 1 was vaccination-related (60 RSVPreF3). 3 SAEs were reported (1 in 120 RSVPreF3; 2 in placebo); none was related to vaccination. No clinically significant changes in laboratory parameters occurred. Geometric mean titers of anti-RSV A neutralizing antibody (≥ 8-fold at D8 and ≥ 5-fold until D91 vs baseline) and geometric mean concentrations of anti-RSVPreF3 IgG antibody (≥ 12-fold at D8 and ≥ 6-fold until D91 vs baseline) were boosted in all RSVPreF3 groups (Fig 2, 3). The 60 and 120 µg dose levels of RSVPreF3 were significantly more immunogenic than the 30 µg one. Figure 1. Solicited adverse events until day 7 post-vaccination Figure 2. GMTs of anti-RSV A neutralizing antibody (ED60) until day 91 post-vaccination Figure 3. GMCs of RSVPreF3 IgG antibody (EU/mL) until day 91 post-vaccination Conclusion All RSVPreF3 vaccine dose levels were well tolerated and no safety concerns identified. All 3 dose levels were immunogenic, with higher immune response induced by the 60 and 120 µg dose levels than the 30 µg one. These data support the further investigation of the 60 and 120 µg RSVPreF3 dose levels in pregnant women. Funding GlaxoSmithKline Biologicals SA Acknowledgment N Bulik/Q Deraedt (Modis c/o GSK) provided writing/editorial support Disclosures Tino Schwarz, PhD, GSK group of companies (Scientific Research Study Investigator, Speaker’s Bureau) Christine Grigat, MD, GSK group of companies (Scientific Research Study Investigator) Dan Apter, MD, PhD, GSK group of companies (Research Grant or Support) Peter Csonka, MD, PhD, GSK group of companies (Scientific Research Study Investigator) Thi Lien-Anh Nguyen, PhD, GSK group of companies (Employee, Shareholder) Feng F. Gao, PhD, GSK group of companies (Employee) Jyoti Soni, MA, GSK group of companies (Employee) Antonella Nadia Tullio, Dr., GSK group of companies (Employee) Ilse Dieussaert, IR, GSK group of companies (Employee, Shareholder) Marta Picciolato, PharmD, MSc, GSK group of companies (Employee) Ouzama Henry, MD, GSK group of companies (Employee, Shareholder)

BACKGROUND: We evaluated the safety and immunogenicity of liquid and lyophilized formulations of an investigational trivalent group B streptococcus (GBS) vaccine in non-pregnant women and assessed the formulations' equivalence in terms of serotype-specific immune response. METHODS: This phase II, randomized, comparative, observer-blind trial enrolled healthy non-pregnant women 18-40 years of age. Women received a single dose of fully liquid (n = 529) or lyophilized (n = 521) trivalent GBS vaccine on day 1. Safety assessments were performed up to day 181 (study termination). Serotype Ia/Ib/III-specific immunoglobulin G (IgG) antibodies were measured in sera from women on day 1 (pre-vaccination) and day 31. Equivalence between the two formulations was demonstrated if the two-sided 95% confidence interval (CI) for the ratio (liquid/lyophilized) of the geometric mean concentrations (GMCs) on day 31 was contained in a (0.5, 2.0) interval for each serotype. RESULTS: Solicited and unsolicited adverse events were reported at similar rates for both formulations. Serious adverse events were reported for six (1.1%) liquid GBS and nine (1.7%) lyophilized GBS vaccinated women, none of which were considered related to vaccination or fatal. On day 31, serotype-specific IgG concentrations were 8-16-fold higher than on day 1 in both groups. Equivalence of the liquid to the lyophilized formulation 30 days post-vaccination was demonstrated as the 95% CIs of the GMC ratios were within the pre-specified interval for the three serotypes: GMC ratios were 1.02 (95% CI: 0.79, 1.32) for serotype Ia, 0.93 (0.71, 1.21) for serotype Ib and 0.99 (0.76, 1.30) for serotype III. CONCLUSIONS: Both formulations of the investigational trivalent GBS vaccine had favorable safety profiles and induced similar GBS serotype-specific antibody concentrations. This study demonstrated that the fully liquid formulation was equivalent to the lyophilized formulation in healthy non-pregnant women in terms of immunogenicity for all three serotypes. CLINICAL TRIALS REGISTRATION: NCT02270944. ispartof: VACCINE vol:38 issue:16 pages:3227-3234 ispartof: location:Netherlands status: published

STUDY DESIGN: Ex vivo porcine imaging study. OBJECTIVES: Quantitatively evaluate change in MRI signal at the discs caudal to spinal fusion instrumentation. SUMMARY OF BACKGROUND DATA: Individuals who receive posterior spinal instrumentation are at risk of developing accelerated disc degeneration at adjacent levels. Degeneration is associated with a loss of biochemical composition and mechanical integrity of the disc, which can be noninvasively assessed through quantitative T2* (qT2*) MRI techniques. However, qT2* is sensitive to magnetic susceptibility introduced by metal. METHODS: Nine ex vivo porcine lumbar specimens were imaged with 3T MRI. Fast spin-echo T2-weighted (T2w) images and gradient-echo qT2* maps were acquired, both without and with posterior spinal fusion instrumentation. Average T2* relaxation times of the nuclei pulposi (NP) were measured at the adjacent and sub-adjacent discs and measurements were compared using t-tests before and after instrumentation. The size of the signal void and metal artifact were determined (modified ASTM F2119–07) within the vertebral body and spinal cord for both MRI sequences. The relationship between T2* signal loss and distance from the instrumentation was evaluated using Pearson’s correlation. RESULTS: There was no significant difference between adjacent and sub-adjacent NP T2* relaxation time prior to instrumentation (p=0.86). Following instrumentation, there was a significant decrease in the T2* relaxation time at the adjacent NP (average=20%, p=0.02), and no significant difference at the sub-adjacent NP (average=−3%, p=0.30). Furthermore, there was a significant negative correlation between signal loss and distance to disc (r=−0.61, p

PURPOSE: To introduce a new approach called tailored variable flip-angle (VFA) scheduling for SNR-efficient 3D T(1ρ) mapping of the brain using a magnetization-prepared gradient-echo sequence. METHODS: Simulations were used to assess the relative SNR efficiency, quantitative accuracy, and spatial blurring of tailored VFA scheduling for T(1ρ) mapping of brain tissue compared with magnetization-prepared angle-modulated partitioned k-space spoiled gradient-echo snapshots (MAPSS), a state-of-the-art technique for accurate 3D gradient-echo T(1ρ) mapping. Simulations were also used to calculate optimal imaging parameters for tailored VFA scheduling versus MAPSS, without and with nulling of CSF. Four participants were imaged at 3T MRI to demonstrate the feasibility of tailored VFA scheduling for T(1ρ) mapping of the brain. Using MAPSS as a reference standard, in vivo data were used to validate the relative SNR efficiency and quantitative accuracy of the new approach. RESULTS: Tailored VFA scheduling can provide a 2-fold to 4-fold gain in the SNR of the resulting T(1ρ) map as compared with MAPSS when using identical sequence parameters while limiting T(1ρ) quantification errors to 2% or less. In vivo whole-brain 3D T(1ρ) maps acquired with tailored VFA scheduling had superior SNR efficiency than is achievable with MAPSS, and the SNR efficiency improved with a greater number of views per segment. CONCLUSIONS: Tailored VFA scheduling is an SNR-efficient GRE technique for 3D T(1ρ) mapping of the brain that provides increased flexibility in choice of imaging parameters compared with MAPSS, which may benefit a variety of applications.

Summary Objective Evaluate articular cartilage by magnetic resonance imaging (MRI) T2∗ mapping within the distal femur and proximal tibia in adolescents with juvenile osteochondritis dissecans (JOCD). Design JOCD imaging studies acquired between August 2011 and February 2019 with clinical and T2∗ mapping MRI knee images were retrospectively collected and analyzed for 31 participants (9F/22M, 15.0 ± 3.8 years old) with JOCD lesions in the medial femoral condyle (MFC). In total, N = 32 knees with JOCD lesions and N = 14 control knees were assessed. Mean T2∗ values in four articular cartilage regions-of-interest (MFC, lateral femoral condyle (LFC), medial tibia (MT), and lateral tibia (LT)) and lesion volume were measured and analyzed using Wilcoxon-rank-sum tests and Spearman correlation coefficients (R). Results Mean ± standard error T2∗ differences observed between the lesion-sided MFC and the LFC in JOCD-affected knees (28.5 ± 0.9 95% confidence interval [26.8, 30.3] vs 26.3 ± 0.7 [24.8, 27.7] ms, P = 0.088) and between the affected- and control-knee MFC (28.5 ± 0.9 [26.8, 30.3] vs 28.5 ± 0.6 [27.1, 29.9] ms, P = 0.719) were nonsignificant. T2∗ was significantly increased in the lesion-sided MT vs the LT for the JOCD-affected knees (21.5 ± 0.7 [20.1, 22.9] vs 18.0 ± 0.7 [16.5, 19.5] ms, P = 0.002), but this same difference was also observed between the MT and LT in control knees (21.0 ± 0.6 [19.7, 22.3] vs 18.1 ± 1.1 [15.8, 20.4] ms, P = 0.037). There was no significant T2∗ difference between the affected- and control-knee MT (21.5 ± 0.7 [20.1, 22.9] vs 21.0 ± 0.6 [19.7, 22.3] ms, P = 0.905). T2∗ within the lesion-sided MFC was not correlated with patient age (R = 0.20, P = 0.28) or lesion volume (R = 0.06, P = 0.75). T2∗ values were slightly increased near lesions in later-stage JOCD subjects but without statistical significance. Conclusions T2∗ relaxations times were not significantly different from control sites in the articular cartilage overlying JOCD lesions in the MFC or adjacent MT cartilage in early-stage JOCD.

Numerous human diseases involve abnormal metabolism, and proton exchange is an effective source of magnetic resonance imaging (MRI) contrast for assessing metabolism. One MRI technique that capitalizes on proton exchange is R1 relaxation in the rotating frame (R1ρ ). Here, we investigated the sensitivity of R1ρ to various proton-exchange mechanisms at spin-lock pulses within Food and Drug Administration (FDA) safety guidelines for radiofrequency-induced heating. We systematically varied pH known to change the rate of proton exchange as well as the glucose and lysine concentrations, thus changing the number of amide, hydroxyl and amine exchangeable sites in a series of egg-white albumin phantoms. The resulting effects on quantitative relaxation time measurements of R1ρ , R1 and R2 were observed at 3 T. Using spin-lock amplitudes available for human imaging (less than 23.5 μT) at near physiologic temperatures, we found R1ρ was more sensitive to physiologic changes in pH than to changes in glucose and lysine concentrations. In addition, R1ρ was more sensitive to pH changes than R1 and R2 . Models of proton exchange fitted to the relaxation measurements suggest that amide groups were the primary source of pH sensitivity. Together, these experiments suggest an optimal spin-lock amplitude for measuring pH changes while not exceeding FDA-subject heating limitations.

Purpose To use quantitative susceptibility mapping (QSM) to investigate changes in cartilage canals in the distal femur of juvenile goats after their surgical transection. Methods Chondronecrosis was surgically induced in the right medial femoral condyles of four 4-day-old goats. Both the operated and control knees were harvested at 2, 3, 5, and 10 weeks after the surgeries. Ex vivo MRI scans were conducted at 9.4 Tesla using TRAFF (relaxation time along a fictitious field)-weighted fast spin echo imaging and QSM to detect areas of chondronecrosis and investigate cartilage canal abnormalities. Histological sections from these same areas stained with hematoxylin and eosin and safranin O were evaluated to assess the affected tissues. Results Both the histological sections and the TRAFF -weighted images of the femoral condyles demonstrated focal areas of chondronecrosis, evidenced by pyknotic chondrocyte nuclei, loss of matrix staining, and altered MR image contrast. At increasing time points after surgery, progressive changes and eventual disappearance of abnormal cartilage canals were observed in areas of chondronecrosis by using QSM. Conclusion Abnormal cartilage canals were directly visualized in areas of surgically induced chondronecrosis. Quantitative susceptibility mapping enabled investigation of the vascular changes accompanying chondronecrosis in juvenile goats. Magn Reson Med 77:1276-1283, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose To introduce a blind compressed sensing (BCS) framework to accelerate multi-parameter MR mapping, and demonstrate its feasibility in high-resolution, whole-brain and T2 mapping. Methods BCS models the evolution of magnetization at every pixel as a sparse linear combination of bases in a dictionary. Unlike compressed sensing, the dictionary and the sparse coefficients are jointly estimated from undersampled data. Large number of non-orthogonal bases in BCS accounts for more complex signals than low rank representations. The low degree of freedom of BCS, attributed to sparse coefficients, translates to fewer artifacts at high acceleration factors (R). Results From 2D retrospective undersampling experiments, the mean square errors in and T2 maps were observed to be within 0.1% up to R = 10. BCS was observed to be more robust to patient-specific motion as compared to other compressed sensing schemes and resulted in minimal degradation of parameter maps in the presence of motion. Our results suggested that BCS can provide an acceleration factor of 8 in prospective 3D imaging with reasonable reconstructions. Conclusion BCS considerably reduces scan time for multiparameter mapping of the whole brain with minimal artifacts, and is more robust to motion-induced signal changes compared to current compressed sensing and principal component analysis-based techniques. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

The race for finding effective treatments for nonalcoholic fatty liver disease (NAFLD) has been slowed down by the high screen-failure rate for including patients in trials due to the lack of a noninvasive biomarker that can identify patients with significant disease. Recently, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP) has shown promise in predicting liver fibrosis. The aims of this study were to evaluate the utility of WFA+ -M2BP as a biomarker to sub-classify patients with NAFLD according to their disease severity and to assess its correlation with histologic features of NAFLD.Patients undergoing biopsy for clinical suspicion of NAFLD and healthy controls were included. Patients with NAFLD were classified into: NAFL, early NASH (F0-F1), fibrotic NASH (F2-F3), and NASH cirrhosis (F4). Levels of WFA+ -M2BP in sera was measured by a HISCL™ M2BPGi™ assay kit using an automated immunoanalyzer (HISCL™-800; Sysmex, Kobe, Japan). Analysis of covariance was used to assess difference in WFA+ -M2BP between the groups and Spearman's correlation coefficients were used to assess correlation with histological features.Our cohort consisted of 20 healthy controls and 198 patients with biopsy-proven NAFLD divided as follows: 52 with NAFL, 62 with early NASH, 52 with fibrotic NASH, and 32 with NASH cirrhosis. WFA+ -M2BP level was found to be significantly increased in the fibrotic NASH and NASH cirrhosis groups compared to healthy controls and those with early NAFLD after adjusting for age, gender and BMI. Furthermore, patients with NASH cirrhosis had significantly higher WFA+ -M2BP levels (2.4[1.5, 4.2] C.O.I (Cut-off Index)) than those with fibrotic NASH (1.2[0.79, 1.9]), p0.001. WFA+ -M2BP level had moderate correlation with inflammation, ballooning and NAFLD activity score and strong correlation with fibrosis stage. Additionally, ROC curve analysis demonstrated that WFA+ -M2BP accurately differentiated F2-4 from F0-F1.In a large cohort of patients with the full spectrum of NAFLD, WFA+ -M2BP levels predicted the presence of advanced disease and correlated strongly with fibrosis stage.

BACKGROUND Legg-Calve-Perthes disease (LCPD) is a childhood hip disorder thought to be caused by disruption of blood supply to the developing femoral head. There is potential for imaging to help assess revascularization of the femoral head. PURPOSE To investigate whether quantitative susceptibility mapping (QSM) can detect neovascularization in the epiphyseal cartilage following ischemic injury to the developing femoral head. STUDY TYPE Prospective. ANIMAL MODEL Right femoral head ischemia was surgically induced in 6-week-old male piglets. The animals were sacrificed 48 hours (n = 3) or 4 weeks (n = 7) following surgery, and the operated and contralateral control femoral heads were harvested for ex vivo MRI. FIELD STRENGTH/SEQUENCE Preclinical 9.4T MRI to acquire susceptibility-weighted 3D gradient echo (GRE) images with 0.1 mm isotropic spatial resolution. ASSESSMENT The 3D GRE images were used to manually segment the cartilage overlying the femoral head and were subsequently postprocessed using QSM. Vessel volume, cartilage volume, and vessel density were measured and compared between operated and control femoral heads at each timepoint. Maximum intensity projections of the QSM images were subjectively assessed to identity differences in cartilage canal appearance, location, and density. STATISTICAL TESTS Paired t-tests with Bonferroni correction were used (P

PURPOSE: To determine whether quantitative MRI relaxation time mapping techniques can help to detect ischemic injury to the developing femoral head. MATERIALS AND METHODS: For this prospective animal study conducted from November 2015 to February 2018, 10 male 6-week-old piglets underwent an operation to induce complete right femoral head ischemia. Animals were humanely killed at 48 hours (n = 2) or 4 weeks (n = 8) after the operation, and the operated and contralateral-control femoral heads were harvested and frozen. Thawed specimens were imaged at 9.4-T MRI by using T1, T2, T1 in the rotating frame (T1ρ), adiabatic T1ρ, relaxation along a fictitious field (RAFF), and T2* mapping and evaluated with histologic analysis. Paired relaxation time differences between the operated and control femoral heads were measured in the secondary ossification center (SOC), epiphyseal cartilage, articular cartilage, and metaphysis and were analyzed by using a paired t test. RESULTS: In the SOC, T1ρ and RAFF had the greatest percent increases in the operated versus control femoral heads at both 48 hours (112% and 72%, respectively) and 4 weeks (74% and 70%, respectively). In the epiphyseal and articular cartilage, T2, T1ρ, and RAFF were similarly increased at both points (range, 24%–49%). At 4 weeks, T2, T1ρ, adiabatic T1ρ, and RAFF were increased in the SOC (P = .004, .018, < .001, and .001, respectively), epiphyseal cartilage (P = .009, .008, .011, and .007, respectively), and articular cartilage (P = .005, .016, .033, and .018, respectively). Histologic assessment identified necrosis in SOC and deep layer of the epiphyseal cartilage at both points. CONCLUSION: T2, T1 in the rotating frame, adiabatic T1 in the rotating frame, and relaxation along a fictitious field maps are sensitive in helping to detect ischemic injury to the developing femoral head. © RSNA, 2018 Online supplemental material is available for this article.

Recent experiments suggest that T1 relaxation in the rotating frame ( T1ρ) is sensitive to metabolism and can detect localized activity-dependent changes in the human visual cortex. Current functional magnetic resonance imaging (fMRI) methods have poor temporal resolution due to delays in the hemodynamic response resulting from neurovascular coupling. Because T1ρ is sensitive to factors that can be derived from tissue metabolism, such as pH and glucose concentration via proton exchange, we hypothesized that activity-evoked T1ρ changes in visual cortex may occur before the hemodynamic response measured by blood oxygenation level-dependent (BOLD) and arterial spin labeling (ASL) contrast. To test this hypothesis, functional imaging was performed using BOLD, and ASL in human participants viewing an expanding ring stimulus. We calculated eccentricity phase maps across the occipital cortex for each functional signal and compared the temporal dynamics of T1ρ versus BOLD and ASL. The results suggest that T1ρ changes precede changes in the two blood flow-dependent measures. These observations indicate that T1ρ detects a signal distinct from traditional fMRI contrast methods. In addition, these findings support previous evidence that T1ρ is sensitive to factors other than blood flow, volume, or oxygenation. Furthermore, they suggest that tissue metabolism may be driving activity-evoked T1ρ changes.

Huntington’s disease (HD) is a progressive, fatal, autosomal-dominant, neurodegenerative disease with no disease-modifying treatment. The disease is caused by an abnormal trinucleotide cytosine-adenine-guanine (CAG) expansion in the huntingtin gene. Detecting pathophysiological processes underlying HD before a clinical motor diagnosis offers hope for assessment of treatments and allows for early intervention, which ultimately will result in improved outcomes.1 To evaluate treatments before a clinical motor diagnosis is given, biomarkers are needed that can be objectively measured, are an indicator of disease progression, and measure a pharmacological response. To date, there are no proven biomarkers in HD and continued evaluation of potential biomarkers is needed.2 MRI provides a number of modalities that have been studied as potential biomarkers for HD progression during the premanifest phase preceding motor diagnosis, including structural imaging, diffusion imaging, magnetization transfer imaging, spectroscopy, and functional imaging, as previously reviewed in Bohanna et al.3 Weir et al.4 and van Den Bogaard et al.5 The size of the caudate and putamen have been shown to be potential biomarkers for disease progression.6,7 Based on the PREDICT-HD study, decreased volume of the striatum and white matter (WM) are detectable years to decades before estimated motor diagnosis of HD8 and are significantly atrophied close to clinical manifestation.9 The change in volume has been found to be approximately linear during the premanifest phase of the illness. Changes in brain metabolism10,11 and function12–15 have also been reported. There has been growing interest in using quantitative parametric MRI as a biomarker for neurodegenerative disorders.16–22 Quantitative imaging has a number of advantages over existing MRI techniques, including the ability to study changes in the relaxation time without the need to normalize to a standard (e.g., volumetric normalized to intracranial volume). Quantitative measurements offer the possibility to relate these changes back to pathological processes given that they reflect tissue properties at the microscopic level, instead of the macroscopic level, such as striatal volume. Coupling of multiple quantitative parametric imaging techniques facilitates the identification of the underlying mechanisms that may be responsible for the relaxation time changes. Previous studies have employed quantitative T2 and T2* mapping to study how these relaxation times change in HD19,23–25 These studies were motivated by the findings that subjects with HD have an increased iron concentration in the striatum postmortem16,26 and the known sensitivity of these relaxation parameters to metal ion concentrations. These studies have largely found decreased T2* relaxation rates within the globus pallidus (GP) and nonsignificant changes in the striatum.19,23–25 WM T2* relaxation times have been found to increase only during the early manifest stage.23 T2 mapping has been shown to largely disassociate from iron concentrations in HD,19 suggesting that other microstructural changes are largely driving the changes in T2 relaxation times. Recently, another quantitative MR parameter, T1 relaxation in the rotating frame (T1ρ), has been used to study progressive changes in Parkinson’s and Alzheimer’s disease.21,27,28 T1ρ measures proton exchange, which is influenced by metabolism (pH and glucose)29–31 and protein concentrations.32 However, T1ρ relaxation is sensitive to a number of microscopic environmental factors, including water content, which can be measured using T2 measurements. Therefore, this study was designed to collect multiple quantitative imaging parameters to better understand the underlying microscopic changes that are occurring associated with disease progression. The aims of this study were to apply multiple quantitative MRI techniques to determine whether T1ρ can serve as a unique quantitative biomarker for disease progression and examine whether T1ρ changes occur in the absence of T2 changes in terms of regional specificity and proximity to disease onset.

OBJECTIVES Quantitative mapping of T1 relaxation in the rotating frame (T1ρ) is a magnetic resonance imaging technique sensitive to pH and other cellular and microstructural factors, and is a potentially valuable tool for identifying brain alterations in bipolar disorder. Recently, this technique identified differences in the cerebellum and cerebral white matter of euthymic patients vs healthy controls that were consistent with reduced pH in these regions, suggesting an underlying metabolic abnormality. The current study built upon this prior work to investigate brain T1ρ differences across euthymic, depressed, and manic mood states of bipolar disorder. METHODS Forty participants with bipolar I disorder and 29 healthy control participants matched for age and gender were enrolled. Participants with bipolar disorder were imaged in one or more mood states, yielding 27, 12, and 13 imaging sessions in euthymic, depressed, and manic mood states, respectively. Three-dimensional, whole-brain anatomical images and T1ρ maps were acquired for all participants, enabling voxel-wise evaluation of T1ρ differences between bipolar mood state and healthy control groups. RESULTS All three mood state groups had increased T1ρ relaxation times in the cerebellum compared to the healthy control group. Additionally, the depressed and manic groups had reduced T1ρ relaxation times in and around the basal ganglia compared to the control and euthymic groups. CONCLUSIONS The study implicated the cerebellum and basal ganglia in the pathophysiology of bipolar disorder and its mood states, the roles of which are relatively unexplored. These findings motivate further investigation of the underlying cause of the abnormalities, and the potential role of altered metabolic activity in these regions.

Abnormal metabolism has been reported in bipolar disorder, however, these studies have been limited to specific regions of the brain. To investigate whole-brain changes potentially associated with these processes, we applied a magnetic resonance imaging technique novel to psychiatric research, quantitative mapping of T1 relaxation in the rotating frame (T1ρ). This method is sensitive to proton chemical exchange, which is affected by pH, metabolite concentrations and cellular density with high spatial resolution relative to alternative techniques such as magnetic resonance spectroscopy and positron emission tomography. Study participants included 15 patients with bipolar I disorder in the euthymic state and 25 normal controls balanced for age and gender. T1ρ maps were generated and compared between the bipolar and control groups using voxel-wise and regional analyses. T1ρ values were found to be elevated in the cerebral white matter and cerebellum in the bipolar group. However, volumes of these areas were normal as measured by high-resolution T1- and T2-weighted magnetic resonance imaging. Interestingly, the cerebellar T1ρ abnormalities were normalized in participants receiving lithium treatment. These findings are consistent with metabolic or microstructural abnormalities in bipolar disorder and draw attention to roles of the cerebral white matter and cerebellum. This study highlights the potential utility of high-resolution T1ρ mapping in psychiatric research.

Intervertebral disc degeneration is a prevalent phenomenon associated with back pain. It is of critical clinical interest to discriminate disc health and identify early stages of degeneration. Traditional clinical T2-weighted magnetic resonance imaging (MRI), assessed using the Pfirrmann classification system, is subjective and fails to adequately capture initial degenerative changes. Emerging quantitative MRI techniques offer a solution. Specifically, T2* mapping images water mobility in the macromolecular network, and our preliminary ex vivo work shows high predictability of the disc's glycosaminoglycan content (s-GAG) and residual mechanics. The present study expands upon this work to predict the biochemical and biomechanical properties in vivo and assess their relationship with both age and Pfirrmann grade. Eleven asymptomatic subjects (range: 18–62 yrs) were enrolled and imaged using a 3T MRI scanner. T2-weighted images (Pfirrmann grade) and quantitative T2* maps (predict s-GAG and residual stress) were acquired. Surface maps based on the distribution of these properties were generated and integrated to quantify the surface volume. Correlational analyses were conducted to establish the relationship between each metric of disc health derived from the quantitative T2* maps with both age and Pfirrmann grade, where an inverse trend was observed. Furthermore, the nucleus pulposus (NP) signal in conjunction with volumetric surface maps provided the ability to discern differences during initial stages of disc degeneration. This study highlights the ability of T2* mapping to noninvasively assess the s-GAG content, residual stress, and distributions throughout the entire disc, which may provide a powerful diagnostic tool for disc health assessment.

Functional T1ρ mapping has been proposed as a method to assess pH and metabolism dynamics in the brain with high spatial and temporal resolution. The purpose of this work is to describe and evaluate a variant of the spin-locked echo-planar imaging sequence for functional T1ρ mapping at 3 T. The proposed sequence rapidly acquires a time series of T1ρ maps with 4.0 second temporal resolution and 10 slices of volumetric coverage. Simulation, phantom, and in vivo experiments are used to evaluate many aspects of the sequence and its implementation including fidelity of measured T1ρ dynamics, potential confounds to the T1ρ response, imaging parameter tradeoffs, time series analysis approaches, and differences compared to blood oxygen level dependent functional magnetic resonance imaging. It is shown that the high temporal resolution and volumetric coverage of the sequence are obtained with some expense including underestimation of the T1ρ response, sensitivity to T1 dynamics, and reduced signal-to-noise ratio. In vivo studies using a flashing checkerboard functional magnetic resonance imaging paradigm suggest differences between T1ρ and blood oxygen level dependent activation patterns. Possible sources of the functional T1ρ response and potential sequence improvements are discussed. The capability of T1ρ to map whole-brain pH and metabolism dynamics with high temporal and spatial resolution is potentially unique and warrants further investigation and development.

To determine the feasibility of using real-time fluoroscopic tracking for bolus-chase magnetic resonance (MR) angiography of peripheral vasculature to image three stations from the aortoiliac bifurcation to the pedal arteries.This prospective study was institutional review board approved and HIPAA compliant. Eight healthy volunteers (three men; mean age, 48 years; age range, 30-81 years) and 13 patients suspected of having peripheral arterial disease (five men; mean age, 67 years; age range, 47-81 years) were enrolled and provided informed consent. All subjects were imaged with the fluoroscopic tracking MR angiographic protocol. Ten patients also underwent a clinical computed tomographic (CT) angiographic runoff examination. Two readers scored the MR angiographic studies for vessel signal intensity and sharpness and presence of confounding artifacts and venous contamination at 35 arterial segments. Mean aggregate scores were assessed. The paired MR angiographic and CT angiographic studies also were scored for visualization of disease, reader confidence, and overall diagnostic quality and were compared by using a Wilcoxon signed rank test.Real-time fluoroscopic tracking performed well technically in all studies. Vessel segments were scored good to excellent in all but the following categories: For vessel signal intensity and sharpness, the abdominal aorta, iliac arteries, distal plantar arteries, and plantar arch were scored as fair to good; and for presence of confounding artifacts, the abdominal aorta and iliac arteries were scored as fair. The MR angiograms and CT angiograms did not differ significantly in any scoring category (reader 1: P = .50, .39, and .39; reader 2: P = .41, .61, and .33, respectively). CT scores were substantially better in 20% (four of 20) and 25% (five of 20) of the pooled evaluations for the visualization of disease and overall image quality categories, respectively, versus 5% (one of 20) for MR scores in both categories.Three-station bolus-chase MR angiography with real-time fluoroscopic tracking provided high-spatial-resolution arteriograms of the peripheral vasculature, enabled precise triggering of table motion, and compared well with CT angiograms.

Purpose To describe, assess, and implement a simple precision estimation framework for optimization of spin-lock time (TSL) sampling schedules for quantitative T1ρ mapping using a mono-exponential signal model. Materials and Methods A method is described for estimating T1ρ precision, and a cost function based on the precision estimates is evaluated to determine efficient TSL sampling schedules. The validity of the framework was tested by imaging a phantom with various sampling schedules and comparing theoretical and experimental precision values. The method utility was demonstrated with in vivo T1ρ mapping of brain tissue using a similar procedure as the phantom experiment. To assist investigators, optimal sampling schedules are tabulated for various tissue types and an online calculator is implemented. Results Theoretical and experimental precision values followed similar trends for both the phantom and in vivo experiments. The mean absolute percentage error (MAPE) of theoretical estimates of T1ρ map signal-to-noise ratio (SNR) was typically 5% in the phantom experiment and 33% in the in vivo demonstration. In both experiments, optimal TSL schedules yielded greater T1ρ map SNR efficiency than typical schedules. Conclusion The framework can be used to improve the imaging efficiency of T1ρ mapping protocols and to guide selection of imaging parameters. J. Magn. Reson. Imaging 2015;41:242–250. © 2014 Wiley Periodicals, Inc.

Purpose To describe and evaluate the method we refer to as “vascular masking” for improving signal-to-noise ratio (SNR) retention in sensitivity encoding (SENSE)-accelerated contrast-enhanced magnetic resonance angiography (CE-MRA). Materials and Methods Vascular masking is a technique that restricts the SENSE unfolding of an accelerated subtraction angiogram to the voxels within the field of view known to have enhancing signal. This is a more restricted voxel set than that identified with conventional masking, which excludes only voxels in the air around the object. Thus, improved retention of SNR is expected. Evaluation was done in phantom and in vivo studies by comparing SNR and the g-factor in results reconstructed using vascular versus conventional masking. A radiological evaluation was also performed comparing conventional and vascular masking in R = 8 accelerated CE-MRA studies of the thighs (n = 21) and calves (n = 13). Results Images reconstructed with vascular masking showed a significant reduction in g-factor and improved retention of SNR versus those reconstructed with conventional masking. In the radiological evaluation, vascular masking consistently provided reduced background noise, improved luminal signal smoothness, and better small vessel conspicuity. Conclusion Vascular masking provides improved SNR retention and improved depiction of the vasculature in accelerated, subtraction 3D CE-MRA of the thighs and calves. J. Magn. Reson. Imaging 2014;39:1161–1170. © 2013 Wiley Periodicals, Inc.

Parallel imaging using two-dimensional (2D) techniques was initially described a decade ago (1) and, in recent years, has been used in various applications of three-dimensional Fourier transformation acquisition, perhaps most notably in 3D contrast-enhanced MR angiography (CE-MRA) (2–8). Just as for one-dimensional (1D) acceleration, 2D acceleration is implemented by increasing the distance between samples in k-space, but in two phase-encode directions rather than one. Specific to SENSE acceleration, a model-based image-space-based parallel imaging framework, two other specific characteristics of the 1D implementation can be extended to the 2D case. First, regions within the field of view (FOV) which are known to have zero magnetization, typically the air outside the object under study, can be forced to have zero signal in the SENSE-unfolded image and thereby reduce signal-to-noise ratio (SNR) loss in the unfolding process (9). Second, because acceleration is implemented by simply adjusting the incremental spacings along the kY and kZ directions, the accelerations along these directions, defined here as RY and RZ, respectively, can assume non-integer values. The net SENSE acceleration R is the product: R = RY × RZ. The above aspects of SENSE acceleration provide more flexibility in selecting the desired acceleration factors for the 2D vs. the 1D case. The fraction of the volume of a 3D FOV actually filled by an object depends on the anatomy under study, but is often no more than about 60% and even considerably smaller for some anatomic regions. It is generally not obvious how the zero magnetization regions in such a case can be exploited by appropriate choice of RY and RZ. Also, for a given target overall acceleration R, there are many pairs (RY, RZ), or “R-pairs,” for which R ≈ RY × RZ, but again it is generally not clear beforehand which specific R-pair is best to use. This uncertainty in selecting (RY, RZ) is further compounded in applications such as contemporary accelerated 3D CEMRA where acceleration factors of R = 6–8 or higher are routinely used (10–14). That is to say, the region over RY−RZ “acceleration” space in which high quality images can be generated is much broader than if, say, practical overall acceleration factors were limited to R < 4. Previously, the Controlled Aliasing In Parallel Imaging Results IN Higher Acceleration (CAIPIRINHA) technique (15,16) has been presented as a means to improve acceleration performance for a given R by making aliasing more benign through adjustment of the 2D SENSE under-sampling kernel to shift the directions of aliasing. CAI-PIRINHA has been further generalized (17). In contrast, the purpose of this work is to develop Acceleration Apportionment in which the acceleration values (RY, RZ) themselves are altered rather than the undersampling lattice pattern. Specifically, we illustrate the potential gains available when RY and RZ are allowed to vary for a given R, show how the choice of an optimum R-pair depends upon the subject, and describe an algorithm for selecting patient-specific RY and RZ based on a quality metric calculated from the subject-specific 3D g-factor map. We also describe an implementation for determining the optimum R-pair within one minute after acquisition of the coil sensitivity images, allowing incorporation into the subsequent accelerated scan. The feasibility of the method is demonstrated in CE-MRA studies of the lower extremities.

In vivo cartilage imaging of the musculoskeletal system using clinical 3 T magnetic resonance imaging (MRI) systems is limited by low spatial resolution, low signal-to-noise ratio, and/or long acquisition times. Ultrahigh-field (≥7 T) whole-body MRI systems have great potential to overcome these limitations and become the new standard for clinical muskuloskeletal imaging of articular cartilage. However, a number of technical challenges must first be addressed, including transmit B1 field inhomogeneities, radiofrequency heating, errors due to B0 inhomogeneities, gradients, motion, and extended examination times. In this chapter, we provide an overview of technical solutions to address these challenges and their potential benefit for articular cartilage imaging with particular attention to joints within the torso (hip and shoulder). We also highlight a number of emerging applications for articular and epiphyseal cartilage imaging that may significantly benefit from ultrahigh-field systems and the latest technical developments. Given the rapid development of MRI technology at ultrahigh field strengths and the broad potential of these systems to improve musculoskeletal imaging capabilities of cartilage, ultrahigh-field whole-body MRI is certain to play a significant role in the advancement of our understanding of articular cartilage abnormalities and the investigation of therapeutic interventions.

Purpose To retrospectively determine if a modified clinical magnetic resonance (MR) imaging protocol provides information on the origin of juvenile osteochondritis dissecans (JOCD) lesions and allows for staging on the basis of the proposed natural history of JOCD to better guide clinical management of the disease. Materials and Methods This institutional review board-approved, HIPAA-compliant, retrospective study was performed in 13 consecutive patients (mean age, 14.9 years; age range, 10-22 years; nine male and four female patients) and one additional comparative patient (a 44-year-old man), in which 19 knees with 20 JOCD lesions were imaged. Seventeen lesions occurred in the medial femoral condyle, two occurred in the lateral femoral condyle, and one occurred in the medial trochlea. The clinical 3-T MR imaging protocol was supplemented with a routinely available multiecho gradient-recalled-echo sequence with the shortest attainable echo time of approximately 4 msec (T2* mapping). Results At the earliest manifestation, the lesion was entirely cartilaginous (n = 1). Subsequently, primary cartilaginous lesions within the epiphyseal cartilage developed a rim calcification that originated from normal subjacent bone, which defined a clear cleft between the lesion progeny and the parent bone (n = 9). Secondarily, progeny lesions became ossified (n = 7) while at the same time forming varying degrees of osseous bridging and/or clefting with the parent bone. Two healed lesions with a linear bony scar and one detached lesion were identified. Conclusion The modified MR imaging protocol allowed for identification of the epiphyseal cartilage origin and subsequent stages of ossification in JOCD. The approach allows further elucidation of the natural history of the disease and may better guide clinical management.

This paper examines the shape collapse problem that occurs when registering a pair of images or a population of images of the brain to a reference (target) image coordinate system using diffeomorphic image registration. Shape collapse occurs when a foreground or background structure in an image with non-zero volume is transformed into a set of zero or near zero volume as measured on a discrete voxel lattice in the target image coordinate system. Shape collapse may occur during image registration when the moving image has a structure that is either missing or does not sufficiently overlap the corresponding structure in the target image[4]. Such a problem is common in image registration algorithms with large degrees of freedom such as many diffeomorphic image registration algorithms. Shape collapse is a concern when mapping functional data. For example, loss of signal may occur when mapping functional data such as fMRI, PET, SPECT using a transformation with a shape collapse if the functional signal occurs at the collapse region. This paper proposes an novel shape collapse measurement algorithm to detect the regions of shape collapse after image registration in pairwise registration. We further compute the shape collapse for a population of pairwise transformations such as occurs when registering many images to a common atlas coordinate system. Experiments are presented using the SyN diffeomorphic image registration algorithm. We demonstrate how changing the input parameters to the SyN registration algorithm can mitigate some of the collapse image registration artifacts.

Background The ectodomain of matrix protein 2 (M2e) is a promising candidate for a broadly protective influenza A vaccine because it is highly conserved and antibodies to M2e are protective in animal models. STF2.4xM2e (VAX102) is a recombinant fusion protein that links four tandem copies of the M2e antigen to Salmonella typhimurium flagellin, a TLR5 ligand used as an adjuvant. The objectives of this first-in-human study were to assess the safety and immunogenicity of VAX102 given as a prime-boost regimen to healthy adults. Methods Sixty subjects 18–49 years old were enrolled in a multicenter, double-blind, randomized, placebo-controlled trial (Study 1). Based on pre-clincial data, initial design included doses starting at 10 μg, with an escalation plan. After reactogenicity was noted at the 10 μg dose, the trial was redesigned to evaluate 0.3, 1.0, and 3 μg doses. Following this study, 16 subjects were enrolled in Study 2, an open label, low dose study, to evaluate doses of 0.03 and 0.1 μg. In both trials, vaccine or placebo was given intramuscularly (i.m.) at 0 and 28 days. Clinical and laboratory safety assessments took place 1 and 7 days after immunization. Immune responses to M2e and flagellin were assessed by ELISA at 7, 14 and 28 days after each dose. Seroconversion was defined as a serum IgG anti-M2e antibody value ≥0.174 μg/ml and a fourfold rise in concentration. Results Doses of 0.03–1 μg were safe and well tolerated in all subjects. Doses of 0.03 and 0.1 μg produced limited immunogenicity (38% and 75% respectively), after the second dose of vaccine. Doses of 0.3 and 1.0 μg were immunogenic in 18 (75%) of 24 vaccinees after the first dose and 23 (96%) after the second dose. In the 1.0 μg group, the geometric mean M2e antibody concentration was 0.4 μg/ml after the first dose and 1.7 μg/ml after the booster dose. M2e antibody concentrations and seroconversion rates were not significantly different at higher doses ( p > 0.05). Immune response to flagellin was robust but did not appear to interfere with M2e antibody responses after the booster dose. Following the first injection of VAX102 at higher doses (3 and 10 μg), self-limited but severe symptoms were noted in some subjects and were associated with elevated levels of C-reactive protein. Although not directly measured, this reaction was believed to be mediated by cytokine release. Conclusions VAX102 was safe and induced high antibody levels to M2e at 0.3 and 1.0 μg doses. The TLR5 ligand, S. typhimurium flagellin, is a novel approach to adjuvant-like activity through activation of innate immunity, and when fused to multiple copies of the M2e protein, the vaccine was able to induce a fourfold rise in antibody in humans, to a previously non-immunogenic, highly-conserved portion of the influenza virus. Clinical correlates of protection that may be afforded by M2e antibody in humans are a future focus of investigation.

Time-resolved bolus-chase contrast-enhanced MR angiography (CE-MRA) with real-time station switching is demonstrated. The Cartesian acquisition with projection reconstruction-like sampling (CAPR) technique and high 2D sensitivity encoding (SENSE) (6x or 8x) and 2D homodyne (1.8x) accelerations were used to acquire 3D volumes with 1.0 mm isotropic spatial resolution and frame times as low as 2.5 seconds in two imaging stations covering the thighs and calves. A custom real-time system was developed to reconstruct and display CAPR frames for visually-guided triggering of table motion upon passage of contrast through the proximal station. The method was evaluated in seven volunteers. High spatial resolution arteriograms with minimal venous contamination were consistently acquired in both stations. Real-time stepping table CE-MRA is a method for providing time-resolved images with high spatial resolution over an extended field-of-view.

Control of seasonal and pandemic influenza represents a global public health challenge due to the virus's ability to circumvent protective immune responses through frequent mutation and subunit recombination. These characteristics, coupled with influenza's ability to spread rapidly during outbreaks, require continuous global surveillance, frequent vaccine reformulation, and tightly scheduled manufacturing. Egg- and cell-culture–based vaccine production methods are resource- and time-intensive, leaving little room for error in selection of vaccine components or timing of production. For example, in 2014–2015, long manufacturing lead times prevented the industry from addressing a discrepancy between the H3 virus predominantly circulating in the northern hemisphere and the H3 included in the licensed vaccine [1]. Furthermore, low vaccine effectiveness in the 2012–2013 season was attributed to mutations introduced as part of egg-based manufacturing [2]. Rapid response, high-yield methods that remain faithful to the circulating virus sequences are therefore needed to address the shortcomings of current approaches. Recombinant technologies have the potential to address such current shortcomings and include production of recombinant HA [3], virus-like particles consisting of hemagglutinin (HA), neuraminidase (NA), and matrix (M1) proteins [4, 5], vaccinia virus-based expression of HA and NA [6], the HA1 fragment of HA [7], or the HA2 stalk of HA [8], as well as DNA vector-based expression of multiple antigens [9]. To date, none has achieved a combination of rapid, high-yield production, potency, and ability to remain faithful to the circulating sequence that is sufficient to address the deficiencies associated with egg- and cell-based approaches. We have developed a recombinant influenza vaccine platform whereby the globular head domain of the major protective antigen, HA, is fused to the Toll-like receptor (TLR)5 agonist, flagellin (Salmonella typhimurium flagellin type 2 [STF2]) [10–12]. The binding of STF2 to TLR5 on the surface of sentinel immune cells activates the innate immune system and, in turn, enhances the adaptive immune response [10]. The flagellin moiety of the vaccine therefore serves as a built-in adjuvant. These relatively simple recombinant fusion proteins can be rapidly and inexpensively produced in standard Escherichia coli production systems at high yield. Specifically, current production yields range from 0.3 to 1 mg of purified bulk drug substance per liter of fermentation, with a cycle time of under 2 weeks (unpublished observations). In animal models and in humans, the individual HA-STF2 fusion proteins elicit HA-specific neutralizing antibodies at low microgram doses of vaccine [13]. We have reproduced these results using HA from a variety of influenza type A and B strains, and we have also determined the optimal, subtype or type-specific placement of each HA subunit within the STF2 protein sequence [12–17]. The low dose of antigen required, coupled with the rapidity and efficiency of production, further demonstrate that the platform has the capacity to address the shortcomings associated with current licensed vaccines. Extending on this work, we are developing a prototypic quadrivalent seasonal flu vaccine, VAX2012Q. We report results from a Phase I dose-ranging study designed to identify the total antigen dose and component ratio that provides optimal tolerability and immunogenicity profiles.

A new Age-Momentum Correlation apparatus has been built for the purpose of studying Positronium-Gas scattering. This apparatus uses a HPGe detector to perform time-resolved Doppler Broadening Studies on positronium in a gas environment. With this information, the thermalization process can be studied by observing the energy as a function of time. Modelling the rate of thermalization can then be used to extract a momentum transfer cross-section. Improved data rate and energy resolution over previous measurements that used Doppler broadening methods have been obtained. More importantly, the simultaneous acquisition of both time and energy spectra allow for systematic checks that were not available to previous experiments. Preliminary results are presented. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

To use quantitative susceptibility mapping (QSM) to investigate changes in cartilage canals in the distal femur of juvenile goats after their surgical transection.Chondronecrosis was surgically induced in the right medial femoral condyles of four 4-day-old goats. Both the operated and control knees were harvested at 2, 3, 5, and 10 weeks after the surgeries. Ex vivo MRI scans were conducted at 9.4 Tesla using TBoth the histological sections and the TAbnormal cartilage canals were directly visualized in areas of surgically induced chondronecrosis. Quantitative susceptibility mapping enabled investigation of the vascular changes accompanying chondronecrosis in juvenile goats. Magn Reson Med 77:1276-1283, 2017. © 2016 International Society for Magnetic Resonance in Medicine.