Adil Bashir

Nondestructive imaging of human cartilage glycosaminoglycan concentration by MRI

Despite the compelling need mandated by the prevalence and morbidity of degenerative cartilage diseases, it is extremely difficult to study disease progression and therapeutic efficacy, either in vitro or in vivo (clinically). This is partly because no techniques have been available for nondestructively visualizing the distribution of functionally important macromolecules in living cartilage. Here we describe and validate a technique to image the glycosaminoglycan concentration ([GAG]) of human cartilage nondestructively by magnetic resonance imaging (MRI). The technique is based on the premise that the negatively charged contrast agent gadolinium diethylene triamine pentaacetic acid (Gd(DTPA)2‐) will distribute in cartilage in inverse relation to the negatively charged GAG concentration. Nuclear magnetic resonance spectroscopy studies of cartilage explants demonstrated that there was an approximately linear relationship between T1 (in the presence of Gd(DTPA)2‐) and [GAG] over a large range of [GAG]. Furthermore, there was a strong agreement between the [GAG] calculated from [Gd(DTPA)2‐] and the actual [GAG] determined from the validated methods of calculations from [Na+] and the biochemical DMMB assay. Spatial distributions of GAG were easily observed in T1‐weighted and T1‐calculated MRI studies of intact human joints, with good histological correlation. Furthermore, in vivo clinical images of T1 in the presence of Gd(DTPA)2‐ (i.e., GAG distribution) correlated well with the validated ex vivo results after total knee replacement surgery, showing that it is feasible to monitor GAG distribution in vivo. This approach gives us the opportunity to image directly the concentration of GAG, a major and critically important macromolecule in human cartilage. Magn Reson Med 41:857–865, 1999.

MRI techniques in early stages of cartilage disease.

Burstein D, Bashir A, Gray ML. MRI techniques in early stages of cartilage disease. Invest Radiol 2000;35:622–638. ABSTRACT.Cartilage degenerative diseases affect millions of people. Our understanding of these diseases and our ability to establish efficacious treatment strategies have been confounded by the difficulty of nondestructively evaluating the state of cartilage. Imaging strategies that allow visualization of cartilage integrity would revolutionize the field by allowing us to visualize early stages of degeneration and thus to evaluate predisposing factors for cartilage disease and changes resulting from interventions (eg, therapies) in culture studies, tissue-engineered systems, animal models, and in vivo in humans. Here we briefly review current state-of-the-art MRI strategies relevant to understanding and following treatment in early cartilage degeneration. We review MRI as applied to the assessment of the whole joint, of cartilage as a whole (as an organ), of cartilage tissue, and of cartilage molecular composition and structure. Each of these levels is amenable to assessment by MRI and offers different information that, in the long run, will serve as an important element of cartilage imaging.

Magnetic resonance imaging of relative glycosaminoglycan distribution in patients with autologous chondrocyte transplants.

Gillis A, Bashir A, McKeon B, et al. Magnetic resonance imaging of relative glycosaminoglycan distribution in patients with autologous chondrocyte transplants. Invest Radiol 2001;36:743–748. rationale and objectives. Autologous chondrocyte transplantation (ACT) is a potential treatment for full-thickness chondral lesions in the knee. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) has recently been developed as a sensitive and specific measure of cartilage glycosaminoglycans (GAGs). Under the conditions of dGEMRIC, T1 is directly related to the GAG concentration. Our aim for this study was to demonstrate the potential of dGEMRIC to evaluate ACT implants. methods. Eleven ACT implants were studied 2 to 24 months postoperatively by dGEMRIC. T1 values from three regions of interest were obtained to examine GAG content (1) in the implant, (2) in native cartilage adjacent to the implant, and (3) in native cartilage further removed from the implant (as “control”). results. One implant failed and therefore was not included. Four of the implants were studied between 2 and 6 months postoperatively and showed low T1 (GAG), less than 80% of the control native cartilage. Five of the six implants studied between 12 and 24 months postoperativley showed T1 (GAG) comparable to (>80%) of control. One 18-month graft showed low T1 comparable to the surrounding native cartilage, with normal GAG seen in cartilage far from the graft site. The GAG index (T1 values of the graft normalized to control) from the group of implants 6 months or less was 59% ± 5% of control, whereas those at 12 to 24 months were 91% ± 18% of control. The two groups were statistically different with a P value of 0.005. conclusions. The GAG level in grafts that were implanted for less than 12 months appeared to be lower than that in the remote cartilage. At 12 months or greater, the grafts in this study had GAG levels that were comparable to both the adjacent and remote cartilage. This preliminary study of ACT implants has shown that it is feasible to apply the dGEMRIC technique in patients with ACT as a way to obtain information related to the composition of grafts. These results provide motivation and the pilot data with which to design further clinical studies.

Hyperpolarized 3He MR Imaging: Physiologic Monitoring Observations and Safety Considerations in 100 Consecutive Subjects

PURPOSEnTo evaluate the safety of hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging.nnnMATERIALS AND METHODSnLocal institutional review board approval and informed consent were obtained. Physiologic monitoring data were obtained before, during, and after hyperpolarized (3)He MR imaging in 100 consecutive subjects (57 men, 43 women; mean age, 52 years +/- 14 [standard deviation]). The subjects inhaled 1-3 L of a gas mixture containing 300-500 mL (3)He and 0-2700 mL N(2) and held their breath for up to 15 seconds during MR imaging. Heart rate and rhythm and oxygen saturation of hemoglobin as measured by pulse oximetry (Spo(2)) were monitored continuously throughout each study. The effects of (3)He MR imaging on vital signs and Spo(2) and the relationship between pulmonary function, number of doses, and clinical classification (healthy volunteers, patients with asthma, heavy smokers, patients undergoing lung volume reduction surgery for severe emphysema, and patients with lung cancer) and the lowest observed Spo(2) were assessed. Any subjective symptoms were noted.nnnRESULTSnExcept for a small postimaging decrease in mean heart rate (from 78 beats per minute +/- 13 to 73 beats per minute +/- 11, P < .001), there was no effect on vital signs. A mean transient decrease in Spo(2) of 4% +/- 3 was observed during the first minute after gas inhalation (P < .001) in 77 subjects who inhaled a dose of 1 L for 10 seconds or less, reaching a nadir of less than 90% at least once in 20 subjects and of less than 85% in four subjects. There was no correlation between the lowest Spo(2) and pulmonary function parameters other than baseline Spo(2) (r = 0.36, P = .001). The lowest mean Spo(2) varied by 1% between the first and second and second and third doses (P < .001) and was unrelated to clinical classification (P = .40). Minor subjective symptoms were noted by 10 subjects. No serious adverse events occurred.nnnCONCLUSIONnHyperpolarized (3)He MR imaging can be safely performed in healthy subjects, heavy smokers, and those with severe obstructive airflow limitation, although unpredictable transient desaturation suggests that potential subjects should be carefully screened for comorbidities.

Natural Linewidth Chemical Shift Imaging (NL-CSI)

The discrete Fourier transform (FT) is a conventional method for spatial reconstruction of chemical shifting imaging (CSI) data. Due to point spread function (PSF) effects, FT reconstruction leads to intervoxel signal leakage (Gibbs ringing). Spectral localization by imaging (SLIM) reconstruction was previously proposed to overcome this intervoxel signal contamination. However, the existence of magnetic field inhomogeneities creates an additional source of intervoxel signal leakage. It is demonstrated herein that even small field inhomogeneities substantially amplify intervoxel signal leakage in both FT and SLIM reconstruction approaches. A new CSI data acquisition strategy and reconstruction algorithm (natural linewidth (NL) CSI) is presented that eliminates effects of magnetic field inhomogeneity‐induced intervoxel signal leakage and intravoxel phase dispersion on acquired data. The approach is based on acquired CSI data, high‐resolution images, and magnetic field maps. The data are reconstructed based on the imaged object structure (as in the SLIM approach) and a reconstruction matrix that takes into account the inhomogeneous field distribution inside anatomically homogeneous compartments. Phantom and in vivo results show that the new method allows field inhomogeneity effects from the acquired MR signal to be removed so that the signal decay is determined only by the “natural” R2 relaxation rate constant (hence the term “natural linewidth” CSI). Magn Reson Med, 2006.

Calibration of RF transmitter voltages for hyperpolarized gas MRI.

MRI with hyperpolarized gases, 3He, 129Xe, 13C, and others, has the potential to become an important diagnostic technique for clinical imaging. Due to the nonreversible loss of magnetization in hyperpolarized gas imaging, the choice of the flip angle is a major factor that influences the signal intensity, and hence, the signal‐to‐noise ratio. Conventional automated radiofrequency (RF) calibration procedures for 1H imaging are not suitable for hyperpolarized gas imaging. Herein, we have demonstrated a simple procedure for RF calibration for magnetic resonance imaging (MRI) with hyperpolarized gases that is easily adaptable to clinical settings. We have demonstrated that there exists a linear relationship between the RF transmitter voltages required to obtain the same nutation angle for protons (V1H) and hyperpolarized gas nuclei (V3He). For our 1H and 3He coils we found that V3He = 1.937 · V1H with correlation coefficient r2 = 0.97. This calibration can be done as a one‐time procedure during the routine quality assurance (QA) protocol. The proposed procedure was found to be extremely robust in routine scanning and provided an efficient method to achieve a desired flip angle, thus allowing optimum image quality. Magn Reson Med 61:239–243, 2009.

Impaired cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with Barth syndrome

Barth syndrome (BTHS) is an X‐linked condition characterized by altered cardiolipin metabolism and cardioskeletal myopathy. We sought to compare cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardiac function and exercise capacity. Children/adolescents and young adults with BTHS (n = 20) and children/adolescent and young adult control participants (n = 23, total n = 43) underwent 31P magnetic resonance spectroscopy (31P‐MRS) of the lower extremity (calf) and heart for estimation of skeletal muscle and cardiac bioenergetics. Peak exercise testing (VO2peak) and resting echocardiography were also performed on all participants. Cardiac PCr/ATP ratio was significantly lower in children/adolescents (BTHS: 1.5 ± 0.2 vs. Control: 2.0 ± 0.3, P < 0.01) and adults (BTHS: 1.9 ± 0.2 vs. Control: 2.3 ± 0.2, P < 0.01) with BTHS compared to Control groups. Adults (BTHS: 76.4 ± 31.6 vs. Control: 35.0 ± 7.4 sec, P < 0.01) and children/adolescents (BTHS: 71.5 ± 21.3 vs. Control: 31.4 ± 7.4 sec, P < 0.01) with BTHS had significantly longer calf PCr recovery (τPCr) postexercise compared to controls. Maximal calf ATP production through oxidative phosphorylation (Qmax‐lin) was significantly lower in children/adolescents (BTHS: 0.5 ± 0.1 vs. Control: 1.1 ± 0.3 mmol/L per sec, P < 0.01) and adults (BTHS: 0.5 ± 0.2 vs. Control: 1.0 ± 0.2 mmol/L sec, P < 0.01) with BTHS compared to controls. Blunted cardiac and skeletal muscle bioenergetics were associated with lower VO2peak but not resting cardiac function. Cardiac and skeletal muscle bioenergetics are impaired and appear to contribute to exercise intolerance in BTHS.

1H-Magnetic Resonance Spectroscopy for Quantifying Myocardial Lipid Content in Humans With the Cardiometabolic Syndrome

Elevated serum free fatty acid (FFA) levels are common in people at risk for cardiometabolic syndrome. These FFA are transported, converted, and stored as monoglycerides, diglycerides, and triglycerides in nonadipose tissues including liver, skeletal muscle, and heart. For the heart, this lipid accumulation has been associated with insulin resistance, diabetes, systolic dysfunction, and in animal models, apoptosis.1–7 However, the relationship between FFA, cardiometabolic syndrome, and cardiovascular disease is unclear and the correlations imperfect. In contrast to FFA levels, a direct measure of cardiac intramyocellular lipid (IMCL) content provides a clear indicator of ectopic lipid accumulation and may provide a better risk predictor for disease. Here we describe and demonstrate a 1H magnetic resonance spectroscopy (MRS) technique for quantifying human myocardial lipid content.

Translation of Myocardial Metabolic Imaging Concepts into the Clinics

Flexibility in myocardial substrate metabolism for energy production is fundamental to cardiac health. This loss in plasticity or flexibility leads to overdependence on the metabolism of an individual category of substrates, with the predominance in fatty acid metabolism characteristic of diabetic heart disease and the accelerated glucose use associated with pressure-overload left ventricular hypertrophy being prime examples. There is a strong demand for accurate noninvasive imaging approaches of myocardial substrate metabolism that can facilitate the crosstalk between the bench and the bedside, leading to improved patient management paradigms. In this article potential future applications of metabolic imaging, particularly radionuclide approaches, for assessment of cardiovascular disease are discussed.

Peak oxygen uptake (VO2peak) across childhood, adolescence and young adulthood in Barth syndrome: Data from cross-sectional and longitudinal studies

Barth syndrome (BTHS) is an ultra-rare, X-linked recessive disorder characterized by cardio-skeletal myopathy, exercise intolerance, and growth delay. Oxygen uptake during peak exercise (VO2peak) has been shown to be severely limited in individuals with BTHS however; the trajectory of VO2peak from childhood to young adulthood is unknown. The objective of this study was to describe VO2peak from childhood through young adulthood in BTHS. Methods and Materials: VO2peak over time was presented through cross-sectional (n = 33 participants) and a longitudinal analyses (n = 12 participants). Retrospective data were obtained through maximal exercise testing on a cycle ergometer from individuals with BTHS who were or are currently enrolled in a research study during July 2006-September 2017. Participants included in the cross-sectional analysis were divided into 3 groups for analysis: 1) children (n = 13), 2) adolescents (n = 8), and 3) young adults (n = 12). Participants in the longitudinal analysis had at least two exercise tests over a span of 2–9 years. Results: VO2peak relative to body weight (ml/kgBW/min), fat-free mass (FFM) and by percent of predicted VO2peak obtained were not significantly different between children, adolescents and young adults. VO2peak did not longitudinally change over a mean time of ~5 years in late adolescent and young adult participants with repeated tests. A model including both cardiac and skeletal muscle variables best predicted VO2peak. Conclusions: In conclusion, VO2peak relative to body weight and fat-free mass demonstrates short- and long-term stability from childhood to young adulthood in BTHS with some variability among individuals.