Phillip Zhe Sun

Quantifying exchange rates in chemical exchange saturation transfer agents using the saturation time and saturation power dependencies of the magnetization transfer effect on the magnetic resonance imaging signal (QUEST and QUESP): pH calibration for poly-L-lysine and a starburst dendrimer

The ability to measure proton exchange rates in tissue using MRI would be very useful for quantitative assessment of magnetization transfer properties, both in conventional MT imaging and in the more recent chemical exchange saturation transfer (CEST) approach. CEST is a new MR contrast mechanism that depends on several factors, including the exchange rate of labile protons in the agent in a pH‐dependent manner. Two new methods to monitor local exchange rate based on CEST are introduced. The two MRI‐compatible approaches to measure exchange are quantifying exchange using saturation time (QUEST) dependence and quantifying exchange using saturation power (QUESP) dependence. These techniques were applied to poly‐L‐lysine (PLL) and a generation‐5 polyamidoamine dendrimer (SPD‐5) to measure the pH dependence of amide proton exchange rates in the physiologic range. Data were fit both to an analytical expression and to numerical solutions to the Bloch equations. Results were validated by comparison with exchange rates determined by two established spectroscopic methods. The exchange rates determined using the four methods were pooled for the pH‐calibration curve of the agents consisting of contributions from spontaneous (k0) acid catalyzed (ka), and base catalyzed (kb) exchange rate constants. These constants were k0 = 68.9 Hz, ka = 1.21 Hz, kb = 1.92 × 109 Hz, and k0 = 106.4 Hz, ka = 25.8 Hz, kb = 5.45 × 108 Hz for PLL and SPD‐5, respectively, showing the expected predominance of base‐catalyzed exchange for these amide protons. Magn Reson Med, 2006.

Quantitative description of proton exchange processes between water and endogenous and exogenous agents for WEX, CEST, and APT experiments.

The proton exchange processes between water and solutes containing exchangeable protons have recently become of interest for monitoring pH effects, detecting cellular mobile proteins and peptides, and enhancing the detection sensitivity of various low‐concentration endogenous and exogenous species. In this work, the analytic expressions for water exchange (WEX) filter spectroscopy, chemical exchange‐dependent saturation transfer (CEST), and amide proton transfer (APT) experiments are derived by the use of Bloch equations with exchange terms. The effects of the initial states for the system, the difference between a steady state and a saturation state, and the relative contributions of the forward and backward exchange processes are discussed. The theory, in combination with numerical calculations, provides a useful tool for designing experimental schemes and assessing magnetization transfer (MT) processes between water protons and solvent‐exchangeable protons. As an example, the case of endogenous amide proton exchange in the rat brain at 4.7 T is analyzed in detail. Magn Reson Med 51:945–952, 2004.

Detection of the Ischemic Penumbra Using pH-Weighted MRI

The classic definition of the ischemic penumbra is a hypoperfused region in which metabolism is impaired, but still sufficient to maintain cellular polarization. Perfusion- and diffusion-weighted MRI (PWI, DWI) can identify regions of reduced perfusion and cellular depolarization, respectively, but it often remains unclear whether a PWI—DWI mismatch corresponds to benign oligemia or a true penumbra. We hypothesized that pH-weighted MRI (pHWI) can subdivide the PWI—DWI mismatch into these regions. Twenty-one rats underwent permanent middle cerebral artery occlusion and ischemic evolution over the first 3.5 h post-occlusion was studied using multiparametric MRI. End point was the stroke area defined by T2-hyperintensity at 24 h. In the acute phase, areas of reduced pH were always larger than or equal to DWI deficits and smaller than or equal to PWI deficits. Group analysis showed that pHWI deficits during this phase coincided with the resulting infarct area at endpoint. Final infarcts were smaller than PWI deficits (range 65% to 90%, depending on the severity of the occlusion) and much larger than acute DWI deficits. These data suggest that the outer boundary of the hypoperfused area showing a decrease in pH without DWI abnormality may correspond to the outer boundary of the ischemic penumbra, while the hypoperfused region at normal pH may correspond to benign oligemia. These first results show that pHWI can provide information complementary to PWI and DWI in the delineation of ischemic tissue.

Investigation of optimizing and translating pH-sensitive pulsed-chemical exchange saturation transfer (CEST) imaging to a 3T clinical scanner.

Chemical exchange saturation transfer (CEST) MRI provides a sensitive detection mechanism that allows characterization of dilute labile protons usually undetectable by conventional MRI. Particularly, amide proton transfer (APT) imaging, a variant of CEST MRI, has been shown capable of detecting ischemic acidosis, and may serve as a surrogate metabolic imaging marker. For preclinical CEST imaging, continuous‐wave (CW) radiofrequency (RF) irradiation is often applied so that the steady state CEST contrast can be reached. On clinical scanners, however, specific absorption rate (SAR) limit and hardware preclude the use of CW irradiation, and instead require an irradiation scheme of repetitive RF pulses (pulsed‐CEST imaging). In this work, CW‐ and pulsed‐CEST MRI were systematically compared using a tissue‐like pH phantom on an imager capable of both CW and pulsed RF irradiation schemes. The results showed that the maximally obtainable pulsed‐CEST contrast is approximately 95% of CW‐CEST contrast, and their optimal RF irradiation powers are equal. Moreover, the pulsed‐CEST sequence was translated to a 3 Tesla clinical scanner and detected pH contrast from the labile creatine amine groups (1.9 ppm). Furthermore, pilot endogenous APT imaging of normal human volunteers was demonstrated, warranting future APT MRI of stroke patients to elucidate its diagnostic value. Magn Reson Med 60:834–841, 2008.

Correction for artifacts induced by B0 and B1 field inhomogeneities in pH-sensitive chemical exchange saturation transfer (CEST) imaging

Chemical exchange saturation transfer (CEST) imaging provides an indirect detection mechanism that allows quantification of certain labile groups unobservable using conventional MRI. Recently, amide proton transfer (APT) imaging, a variant form of CEST imaging, has been shown capable of detecting lactic acidosis during acute ischemia, providing information complementary to that of perfusion and diffusion MRI. However, CEST contrast is usually small, and therefore, it is important to optimize experimental conditions for reliable and quantitative CEST imaging. In particular, CEST imaging is sensitive to B0 and B1 field, while on the other hand; field inhomogeneities persist despite recent advances in magnet technologies, especially for in vivo imaging at high fields. Consequently, correction algorithms that can compensate for field inhomogeneity‐induced measurement errors in CEST imaging might be very useful. In this study, the dependence of CEST contrast on field distribution was solved and a correction algorithm was developed to compensate for field inhomogeneity‐induced CEST imaging artifacts. In addition, the proposed algorithm was verified with both numerical simulation and experimental measurements, and showed nearly complete correction of CEST imaging measurement errors caused by moderate field inhomogeneity. Magn Reson Med, 2007.

Imaging pH using the chemical exchange saturation transfer (CEST) MRI: Correction of concomitant RF irradiation effects to quantify CEST MRI for chemical exchange rate and pH.

Chemical exchange saturation transfer (CEST) MRI has been shown capable of detecting dilute labile protons and abnormal tissue glucose/oxygen metabolism, and thus, may serve as a complementary imaging technique to the conventional MRI methods. CEST imaging, however, is also dependent on experimental parameters such as the power, duration, and waveform of the irradiation RF pulse. As a result, its sensitivity and specificity for microenvironment properties such as pH is not optimal. In this study, the dependence of CEST contrast on experimental parameters was solved and an iterative compensation algorithm was proposed that corrects the experimentally measured CEST contrast from the concomitant RF irradiation effects. The proposed algorithm was verified with both numerical simulation and experimental measurements from a tissue‐like pH phantom, and showed that pH derived from the compensated CEST imaging agrees reasonably well with pH‐electrode measurements within 0.1 pH unit. In sum, our study validates the use of a correction algorithm to compensate CEST imaging from concomitant RF irradiation effects for accurate calibration of the chemical exchange rate, and demonstrates the feasibility of pH imaging with CEST MRI. Magn Reson Med 60:390–397, 2008.

MRI of insulitis in autoimmune diabetes

Development of imaging techniques that would allow the mapping of immune cells in vivo could greatly aid our understanding of a number of inflammatory and autoimmune diseases. The current study focused on imaging of autoimmune destruction of the insulin‐producing pancreatic beta‐cells by cytotoxic lymphocytes, the cause of insulin‐dependent diabetes mellitus (IDDM; Type 1 diabetes). Using high‐resolution MR microscopy and a conventional clinical MR imaging system, it was possible to visualize the infiltration of immune cells in the diabetic mouse pancreas. Mouse lymphocytes were visualized by magnetically labeling them with recently developed magnetic nanoparticles (CLIO‐Tat). The results from this study could potentially lead to detection of immune infiltration during diabetes formation in vivo, which would be one of the earliest parameters of disease development. Magn Reson Med 47:751–758, 2002.

Simplified quantitative description of amide proton transfer (APT) imaging during acute ischemia

Amide proton transfer (APT) imaging employs the chemical exchange saturation transfer (CEST) mechanism to detect mobile endogenous proteins and peptides. It can be used to detect pH reduction during acute ischemia and thus provide complementary information to perfusion‐weighted (PWI) and diffusion‐weighted (DWI) imaging. However, the APT contrast depends strongly on the choice of imaging parameters, especially the radiofrequency (RF) saturation time and strength, which need to be optimized. In this work it is shown that even though at least three proton pools are present, the description of the APT process during acute ischemia can be greatly simplified by means of a dual two‐pool model analysis. With this approach, the experimentally measured RF irradiation power dependence of the effect in the rat brain was well predicted. The results showed an optimal RF strength of 0.75 μT for our particular coil setup, and a maximally obtainable APT ratio difference of 2.9% ± 0.3% between ischemic and normal brain regions. Magn Reson Med 57:405–410, 2007.

Association between pH-weighted endogenous amide proton chemical exchange saturation transfer MRI and tissue lactic acidosis during acute ischemic stroke

The ischemic tissue becomes acidic after initiation of anaerobic respiration, which may result in impaired tissue metabolism and, ultimately, in severe tissue damage. Although changes in the major cerebral metabolites can be studied using magnetic resonance (MR) spectroscopy (MRS)-based techniques, their spatiotemporal resolution is often not sufficient for routine examination of fast-evolving and heterogeneous acute stroke lesions. Recently, pH-weighted MR imaging (MRI) has been proposed as a means to assess tissue acidosis by probing the pH-dependent chemical exchange of amide protons from endogenous proteins and peptides. In this study, we characterized acute ischemic tissue damage using localized proton MRS and multiparametric imaging techniques that included perfusion, diffusion, pH, and relaxation MRI. Our study showed that pH-weighted MRI can detect ischemic lesions and strongly correlates with tissue lactate content measured by 1H MRS, indicating lactic acidosis. Our results also confirmed the correlation between apparent diffusion coefficient and lactate; however, no significant relationship was found for perfusion, T1, and T2. In summary, our study showed that optimized endogenous pH-weighted MRI, by sensitizing to local tissue pH, remains a promising tool for providing a surrogate imaging marker of lactic acidosis and altered tissue metabolism, and augments conventional techniques for stroke diagnosis.

Background gradient suppression in pulsed gradient stimulated echo measurements.

Pulsed gradient spin echo (PGSE) experiments can be used to measure the probability distribution of molecular displacements. In homogeneous samples this reports on the molecular diffusion coefficient, and in heterogeneous samples, such as porous media and biological tissue, such measurements provide information about the samples morphology. In heterogeneous samples however background gradients are also present and prevent an accurate measurement of molecular displacements. The interference of time independent background gradients with the applied magnetic field gradients can be removed through the use of bipolar gradient pulses. However, when the background gradients are spatially non-uniform molecular diffusion introduces a temporal modulation of the background gradients. This defeats simple bipolar gradient suppression of background gradients in diffusion related measurements. Here we introduce a new method that requires the background gradients to be constant over coding intervals only. Since the coding intervals are typically at least an order of magnitude shorter than the storage time, this new method succeeds in suppressing cross-terms for a much wider range of heterogeneous samples.