Sarmad Siddiqui

Bone and cartilage demonstrate changes localized to bone marrow edema-like lesions within osteoarthritic knees

OBJECTIVE Our objective is to understand the biological and mechanical pathways linking cartilage, bone, and marrow changes in the progression of osteoarthritis (OA). The aim of the present study was to evaluate bone structure and composition within bone marrow edema-like lesion (BMEL) regions associated with knee OA. METHODS Tibial plateau specimens (n = 18) were collected from 10 subjects with knee OA during total knee arthroplasty (TKA). Magnetic resonance (MR) imaging was used to identify BMEL and quantify metrics of cartilage composition. Micro-computed tomography (μCT) and high-resolution peripheral quantitative computed tomography (HR-pQCT) were used to quantify density and microstructure of the subchondral trabecular bone. Fourier transform infrared (FTIR) spectroscopy was used to quantify tissue composition. RESULTS Trabecular bone within BMEL was higher in volume fraction, with more and thicker trabeculae that were more plate-like in structure compared to unaffected regions. BMEL trabecular tissue composition had decreased phosphate and carbonate content. Marrow infiltration by a fibrous collagen network and evidence of increased bone remodeling were present. Structural and compositional changes were specifically localized to regions underlying cartilage degradation. CONCLUSION These results support the paradigm of focal interactions among bone, marrow, and cartilage in the progression of knee OA. Quantitative evaluation of tissue changes and interactions may aid in the understanding of disease pathophysiology and provide imaging markers for disease progression.

Regional Fractional Ventilation by Using Multibreath Wash-in (3)He MR Imaging

Purpose To assess the feasibility and optimize the accuracy of the multibreath wash-in hyperpolarized helium 3 ((3)He) approach to ventilation measurement by using magnetic resonance (MR) imaging as well as to examine the physiologic differences that this approach reveals among nonsmokers, asymptomatic smokers, and patients with chronic obstructive pulmonary disease (COPD). Materials and Methods All experiments were approved by the local institutional review board and compliant with HIPAA. Informed consent was obtained from all subjects. To measure fractional ventilation, the authors administered a series of identical normoxic hyperpolarized gas breaths to the subject; after each inspiration, an image was acquired during a short breath hold. Signal intensity buildup was fit to a recursive model that regionally solves for fractional ventilation. This measurement was successfully performed in nine subjects: three healthy nonsmokers (one man, two women; mean age, 45 years ± 4), three asymptomatic smokers (three men; mean age, 51 years ± 5), and three patients with COPD (three men; mean age, 59 years ± 5). Repeated measures analysis of variance was performed, followed by post hoc tests with Bonferroni correction, to assess the differences among the three cohorts. Results Whole-lung fractional ventilation as measured with hyperpolarized (3)He in all subjects (mean, 0.24 ± 0.06) showed a strong correlation with global fractional ventilation as measured with a gas delivery device (R(2) = 0.96, P < .001). Significant differences between the means of whole-lung fractional ventilation (F2,10 = 7.144, P = .012) and fractional ventilation heterogeneity (F2,10 = 7.639, P = .010) were detected among cohorts. In patients with COPD, the protocol revealed regions wherein fractional ventilation varied substantially over multiple breaths. Conclusion Multibreath wash-in hyperpolarized (3)He MR imaging of fractional ventilation is feasible in human subjects and demonstrates very good global (whole-lung) precision. Fractional ventilation measurement with this physiologically realistic approach reveals significant differences between patients with COPD and healthy subjects. To minimize error, several sources of potential bias must be corrected when calculating fractional ventilation. (©) RSNA, 2016 Online supplemental material is available for this article.

Metabolic spectroscopy of inflammation in a bleomycin-induced lung injury model using hyperpolarized 1-13C pyruvate

Metabolic activity in the lung is known to change in response to external insults, inflammation, and cancer. We report measurements of metabolism in the isolated, perfused rat lung of healthy controls and in diseased lungs undergoing acute inflammation using hyperpolarized 1‐13C‐labeled pyruvate. The overall apparent activity of lactate dehydrogenase is shown to increase significantly (on average by a factor of 3.3) at the 7 day acute stage and to revert substantially to baseline at 21 days, while other markers indicating monocarboxylate uptake and transamination rate are unchanged. Elevated lung lactate signal levels correlate well with phosphodiester levels as determined with 31P spectroscopy and with the presence of neutrophils as determined by histology, consistent with a relationship between intracellular lactate pool labeling and the density and type of inflammatory cells present. We discuss several alternate hypotheses, and conclude that the most probable source of the observed signal increase is direct uptake and metabolism of pyruvate by inflammatory cells and primarily neutrophils. This signal is seen in high contrast to the low baseline activity of the lung. Copyright

The use of hyperpolarized carbon-13 magnetic resonance for molecular imaging.

&NA; Until recently, molecular imaging using magnetic resonance (MR) has been limited by the modalitys low sensitivity, especially with non‐proton nuclei. The advent of hyperpolarized (HP) MR overcomes this limitation by substantially enhancing the signal of certain biologically important probes through a process known as external nuclear polarization, enabling real‐time assessment of tissue function and metabolism. The metabolic information obtained by HP MR imaging holds significant promise in the clinic, where it could play a critical role in disease diagnosis and therapeutic monitoring. This review will provide a comprehensive overview of the developments made in the field of hyperpolarized MR, including advancements in polarization techniques and delivery, probe development, pulse sequence optimization, characterization of healthy and diseased tissues, and the steps made towards clinical translation.

High-resolution magic angle spinning NMR spectroscopy of human osteoarthritic cartilage.

Osteoarthritis (OA) is a degenerative disease of the joints and results in changes in the biochemical composition of cartilage. Previous studies have been undertaken that have used high‐resolution NMR spectroscopy to study the biochemical composition of porcine, canine and bovine cartilage. In the present study, high‐resolution magical angle spinning (HR‐MAS) NMR spectroscopy at 11.7 T has been used to characterize metabolites and detect differences in the spectral signature of human knee articular cartilage from non‐OA healthy cadaver knees and samples acquired from severe OA patients at the time of total knee replacement surgery. A statistically significant difference in the alanine (1.47 p.p.m.), N‐acetyl (2.04 p.p.m.), choline (3.25 p.p.m.) and glycine (3.55 p.p.m.) metabolite levels was observed between healthy and OA specimens. The results of the present study indicate that a decrease in the intensity of N‐acetyl resonance occurs in the later stages of OA. A positive correlation of the N‐acetyl levels as measured by 1H HR‐MAS NMR spectroscopy with the total proteoglycan content in the same cartilage specimens as measured by the glycosaminoglycan (GAG) assay was observed. This indicates that N‐acetyl can serve as an important bio‐marker of OA disease progression. A decrease in the alanine concentration in OA may be attributed to the degradation of the collagen framework with disease progression and eventual loss of the degradation products that are transported from cartilage into the synovial cavity. Copyright

Vertical gradients in regional alveolar oxygen tension in supine human lung imaged by hyperpolarized 3He MRI

The purpose of this study was to evaluate whether regional alveolar oxygen tension (PAO2) vertical gradients imaged with hyperpolarized 3He can identify smoking‐induced pulmonary alterations. These gradients are compared with common clinical measurements including pulmonary function tests (PFTs), the six minute walk test, and the St. Georges Respiratory Questionnaire.

A hybrid multibreath wash-in wash-out lung function quantification scheme in human subjects using hyperpolarized 3He MRI for simultaneous assessment of specific ventilation, alveolar oxygen tension, oxygen uptake, and air trapping

To present a method for simultaneous acquisition of alveolar oxygen tension (PAO2), specific ventilation (SV), and apparent diffusion coefficient (ADC) of hyperpolarized (HP) gas in the human lung, allowing reinterpretation of the PAO2 and SV maps to produce a map of oxygen uptake (R).

The effect of exogenous substrate concentrations on true and apparent metabolism of hyperpolarized pyruvate in the isolated perfused lung

Although relatively metabolically inactive, the lung has an important role in maintaining systemic glycolytic intermediate and cytosolic redox balance. Failure to perform this function appropriately may lead to lung disease progression, including systemic aspects of these disorders. In this study, we experimentally probe the response of the isolated, perfused organ to varying glycolytic intermediate (pyruvate and lactate) concentrations, and the effect on the apparent metabolism of hyperpolarized 1‐13C pyruvate. Twenty‐four separate conditions were studied, from sub‐physiological to super‐physiological concentrations of each metabolite. A three‐compartment model is developed, which accurately matches the full range of experiments and includes a full account of evolution of agent concentration and polarization. The model is then refined using a series of approximations which are shown to be applicable to cases of physiological relevance, and which facilitate an intuitive understanding of the saturation and scaling behavior. Perturbations of the model assumptions are used to determine the sensitivity to input parameter estimates, and finally the model is used to examine the relationship between measurements accessible by NMR and the underlying physiological parameters of interest. Based on the observed scaling of lactate labeling with lactate and pyruvate concentrations, we conclude that the level of hyperpolarized lactate signal in the lung is primarily determined by the rate at which NAD+ is reduced to NADH. Further, although weak dependences on other factors are predicted, the modeled NAD+ reduction rate is largely governed by the intracellular lactate pool size. Conditions affecting the lactate pool can therefore be expected to display the highest contrast in hyperpolarized 13C‐pyruvate imaging. The work is intended to serve as a basis both to interpret the signal dynamics of hyperpolarized measurements in the normal lung and to understand the cause of alterations seen in a variety of disease and exposure models. Copyright

Unstable Inflation Causing Injury. Insight from Prone Position and Paired Computed Tomography Scans

&NA; Rationale: It remains unclear how prone positioning improves survival in acute respiratory distress syndrome. Using serial computed tomography (CT), we previously reported that “unstable” inflation (i.e., partial aeration with large tidal density swings, indicating increased local strain) is associated with injury progression. Objectives: We prospectively tested whether prone position contains the early propagation of experimental lung injury by stabilizing inflation. Methods: Injury was induced by tracheal hydrochloric acid in rats; after randomization to supine or prone position, injurious ventilation was commenced using high tidal volume and low positive end‐expiratory pressure. Paired end‐inspiratory (EI) and end‐expiratory (EE) CT scans were acquired at baseline and hourly up to 3 hours. Each sequential pair (EI, EE) of CT images was superimposed in parametric response maps to analyze inflation. Unstable inflation was then measured in each voxel in both dependent and nondependent lung. In addition, five pigs were imaged (EI and EE) prone versus supine, before and (1 hour) after hydrochloric acid aspiration. Measurements and Main Results: In rats, prone position limited lung injury propagation and increased survival (11/12 vs. 7/12 supine; P = 0.01). EI‐EE densities, respiratory mechanics, and blood gases deteriorated more in supine versus prone rats. At baseline, more voxels with unstable inflation occurred in dependent versus nondependent regions when supine (41 ± 6% vs. 18 ± 7%; P < 0.01) but not when prone. In supine pigs, unstable inflation predominated in dorsal regions and was attenuated by prone positioning. Conclusions: Prone position limits the radiologic progression of early lung injury. Minimizing unstable inflation in this setting may alleviate the burden of acute respiratory distress syndrome.

In vivo imaging of the progression of acute lung injury using hyperpolarized [1-13C] pyruvate

To investigate pulmonary metabolic alterations during progression of acute lung injury.