Jean Philippe Galons

In vivo imaging of extracellular pH using 1H MRSI.

Tumor pH is physiologically important since it influences a number of processes relevant to tumorigenesis and therapy. Hence, knowledge of localized pH within tumors would contribute to understanding these processes. The destructiveness, poor spatial resolution, and poor signal‐to‐noise ratio (SNR) of current technologies (e.g., microelectrodes, 31P magnetic resonance spectroscopy) have limited such studies. An extrinsic chemical extracellular pH (pHe) probe is described that is used in combination with 1H magnetic resonance spectroscopic imaging to yield pHe maps with a spatial resolution of 1 × 1 × 4 mm3. The principle of the technique is demonstrated on a phantom. Further data are shown to demonstrate its application in vivo, and results agree with previously reported pH values. The accuracy of the reported pH measurements is <0.1 pH units, as derived from a detailed analysis of the errors associated with the technique, the description of which is included. Magn Reson Med 41:743–750, 1999.

Quantitative Volumetric Analyses of Brain Magnetic Resonance Imaging from Rat with Chronic Neuroinflammation

Brain inflammation may have a pathogenic role in many neurodegenerative diseases, including Alzheimers disease. In the present study, we investigated the effects of chronic neuroinflammation upon anatomical changes in two regions of interest in the temporal lobe using high-resolution magnetic resonance imaging techniques. We show that chronic infusion of lipopolysaccharide into the fourth ventricle for 4 consecutive weeks enlarged the lateral ventricles and significantly decreased the size of the hippocampal formation and the temporal lobe region. These changes are comparable to those observed in humans during the early stages of Alzheimers disease.

Redox-Sensitive Contrast Agents for MRI Based on Reversible Binding of Thiols to Serum Albumin

DOTA‐based complexes of gadolinium (Gd) bearing a thiol moiety on a propyl or hexyl arm were synthesized. It was hypothesized that these complexes would form reversible covalent linkages with human serum albumin (HSA), which contains a reactive thiol at cysteine‐34. The binding constant of the hexyl complex to HSA was measured to be 64 mM−1 and decreased to 17, 6.1, and 3.6 mM−1 in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The binding constant of the propyl complex to HSA was significantly lower (5.0 mM−1) and decreased to 2.0, 1.5, and 0.87 mM−1 in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The longitudinal water‐proton relaxivities of the hexyl and propyl complexes at 37°C and 4.7 T were 2.3 and 2.9 mM−1 s−1, respectively, in saline. The relaxivities of the HSA‐bound forms of the hexyl and propyl complexes were calculated to be 5.3 and 4.5 mM−1 s−1, respectively. The in vivo pharmacokinetics of both thiol complexes were altered by a chase of homocysteine but not saline, while the washout of GdDTPA was unaffected by either chase. Such redox‐sensitive reversible binding of Gd complexes to plasma albumin can be exploited for imaging tissue redox and the blood‐pool by MRI. Magn Reson Med, 2006.

Longitudinal diffusion tensor imaging in a rat brain glioma model

In order to investigate the properties of water motion within and around brain tumors as a function of tumor growth, longitudinal diffusion tensor imaging (DTI) was carried out in a rat brain glioma (C6) model. As tumors grew in size, significant anisotropy of water diffusion was seen both within and around the tumor. The tissue water surrounding the tumor exhibited high planar anisotropy, as opposed to the linear anisotropy normally seen in white matter, indicating that cells were experiencing stress in a direction normal to the tumor border. When tumors were sufficiently large, significant anisotropy was also seen within the tumor because of longer‐range organization of cancer cells within the tumor borders. These findings have important implications for diffusion‐weighted MRI experiments examining tumor growth and response to therapy. Copyright

Assessment of the effects of cellular tissue properties on ADC measurements by numerical simulation of water diffusion

The apparent diffusion coefficient (ADC), as measured by diffusion‐weighted MRI, has proven useful in the diagnosis and evaluation of ischemic stroke. The ADC of tissue water is reduced by 30‐50% following ischemia and provides excellent contrast between normal and affected tissue. Despite its clinical utility, there is no consensus on the biophysical mechanism underlying the reduction in ADC. In this work, a numerical simulation of water diffusion is used to predict the effects of cellular tissue properties on experimentally measured ADC. The model indicates that the biophysical mechanisms responsible for changes in ADC postischemia depend upon the time over which diffusion is measured. At short diffusion times, the ADC is dependent upon the intrinsic intracellular diffusivity, while at longer, clinically relevant diffusion times, the ADC is highly dependent upon the cell volume fraction. The model also predicts that at clinically relevant diffusion times, the 30‐50% drop in ADC after ischemia can be accounted for by cell swelling alone when intracellular T2 is allowed to be shorter than extracellular T2. Magn Reson Med, 2009.

Measurement of liver fat fraction and iron with MRI and MR spectroscopy techniques

Diffuse liver disease is a widespread global healthcare burden, and the abnormal accumulation of lipid and/or iron is common to important disease processes. Developing the improved methods for detecting and quantifying liver lipid and iron is an important clinical need. The inherent risk, invasiveness, and sampling error of liver biopsy have prompted the development of noninvasive imaging methods for lipid and iron assessment. Ultrasonography and computed tomography have the ability to detect diffuse liver disease, but with limited accuracy. The purpose of this review is to describe the current state-of-the-art methods for quantifying liver lipid and iron using magnetic resonance imaging and spectroscopy, including their implementation, benefits, and potential pitfalls. Imaging- and spectroscopy-based methods are naturally suited for lipid and iron quantification. Lipid can be detected and decomposed from the inherent chemical shift between lipid and water signals, whereas iron imparts significant paramagnetic susceptibility to tissue, which accelerates proton relaxation. However, measurements of these biomarkers are confounded by technical and biological effects. Current methods must address these factors to allow a precise correlation between the lipid fraction and iron concentration. Although this correlation becomes increasingly challenging in the presence of combined lipid and iron accumulation, advanced techniques show promise for delineating these quantities through multi-lipid peak analysis, T2 water mapping, and fast single-voxel water-lipid spectroscopy.

Imaging biomarkers to monitor response to the hypoxia-activated prodrug TH-302 in the MiaPaCa2 flank xenograft model

TH-302, a hypoxia-activated anticancer prodrug, was evaluated for antitumor activity and changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in a mouse model of pancreatic cancer. TH-302 monotherapy resulted in a significant delay in tumor growth compared to vehicle-treated controls. TH-302 treatment was also associated with a significant decrease in the volume transfer constant (K(trans)) compared to vehicle-treated controls 1 day following the first dose measured using DCE-MRI. This early decrease in K(trans) following the first dose as measured is consistent with selective killing of the hypoxic fraction of cells which are associated with enhanced expression of hypoxia inducible transcription factor-1 alpha that regulates expression of permeability and perfusion factors including vascular endothelial growth factor-A. No changes were observed in DW-MRI following treatment with TH-302, which may indicate that this technique is not sensitive enough to detect changes in small hypoxic fractions of the tumor targeted by TH-302. These results suggest that changes in tumor permeability and/or perfusion may be an early imaging biomarker for response to TH-302 therapy.

Magnetization transfer contrast imaging in Niemann pick type C mouse liver

To investigate livers of mice afflicted with Niemann Pick type C (NP‐C) disease using magnetization transfer contrast (MTC) imaging and to test the hypothesis that the MT ratio reproducibly changes during disease progression.

Uncovering of intracellular water in cultured cells

The complexity of biologic tissues, with multiple compartments each with its own diffusion and relaxation properties, requires complex formalisms to model water signal in most magnetic resonance imaging or magnetic resonance spectroscopy experiments. In this article, we describe a magnetic susceptibility‐induced shift in the resonance frequency of extracellular water by the introduction of a gadolinium contrast agent to medium perfusing a hollow fiber bioreactor. The frequency shift of the extracellular water (+185 Hz at 9.4 T) uncovers the intracellular water and allows direct measurement of motional and relaxation properties of the intracellular space. The proposed method provides a unique tool for understanding the mechanisms underlining diffusion and relaxation in the intracellular space. Magn Reson Med 54:79–86, 2005.

Diffusion‐Weighted MRI and Response to Anti‐Cancer Therapies

In oncology practice, longitudinal studies are routinely conducted to monitor the size and enhancement of tumors in cancer patients undergoing therapy. Imaging protocols typically use gadolinium-enhanced T 1 -weighted images or T 2 -weighted images from which tumor size is inferred and tumor response estimated. The past few years have also seen the emergence of diffusion-weighted magnetic resonance imaging (DWMRI) as a potential alternative to monitor therapeutic response (Kauppinen, R.A., NMR Biomed. 2002, 15, 6). The attractiveness of DWMRI resides in its ability to detect local microstructural changes associated with treatment long before their effects are translated into effective size changes. Damage to cell membrane integrity, changes in viscosity, and/or relative size of intra- vs. extracellular compartments all translate into changes in the apparent diffusion coefficient of tumor water measured by DWMRI. This dependence makes DWMRI a particularly sensitive method to detect response to a wide variety of chemotherapeutic agents. This review will focus on the emerging role of DWMRI to monitor the response of tumors to anti-cancer chemotherapies.