RESEARCH: HYPERPOLARIZED NOBLE GAS MR IMAGING
Dr. Mitchell S. Albert’s laboratory focuses on using hyperpolarized (HP) noble gas MRI, an innovative technology that provides spectacularly detailed images of structures and processes within the body. HP gas MRI has the potential to allow medical researchers and health care providers to significantly improve diagnosis and treatment of a variety of diseases, including lung diseases, stroke, and cancer. HP noble gas MRI uses a high-powered, diode laser to produce polarized light that aligns the nuclei of atoms of helium-3 (3He) or xenon-129 (129Xe). Polarized 3He or 129Xe can then be inhaled, permitting high-resolution imaging of the degree of ventilation of the airways and periphery of the lungs. In addition, 129Xe dissolves in the blood, permitting it to be used to trace the flow of blood (perfusion) in body tissues, including the brain. Our research program comprises of 3 parts:
Subsequently, the Albert group developed HP 129Xe for imaging cerebral blood flow (CBF) and cerebral function, creating a HP-xenon-based functional MRI technology that provides measurement of cerebral activity more directly and with higher signal enhancement than BOLD fMRI. Albert and colleagues used HP 129Xe fMRI to image ischemic areas of the brain following middle cerebral artery occlusion (Fig. 1)[Zhou et al. 2011]. Albert also used HP 129Xe MRI to provide functional images (Xe fMRI) of the rat brain following pain stimulation (Fig. 2)[Mazzanti et al. 2011].
Traditional proton-based MRI has revealed alterations in neural structure and function in AD patients. Conventional, BOLD brain fMRI offers a powerful tool to observe human brain activity, but it faces challenges, including the challenge of detecting relatively low signal enhancement changes amongst an inherently noisy background signal. This necessitates considerations in experimental design and analysis in order to best detect this signal. HP 129Xe fMRI, because it uses an exogenous signal source that directly demonstrates gas delivery and exchange to tissues in the body, and has no naturally occurring background signal in the body, has the potential to overcome these challenges. Signal changes detected with HP 129Xe fMRI in response to a task or stimulus are significantly larger (~50%) than with conventional, proton-based BOLD fMRI (~3%–4%); thus, HP 129Xe fMRI offers the promise of providing more sensitive measurement of cerebral function.
HP 129Xe fMRI of cerebral activity holds promise for applications in diagnosis, drug development, and treatment planning for AD, Parkinson’s disease, schizophrenia, autism, and traumatic brain injury (TBI). Dr. Albert’s group is undertaking a clinical trial to demonstrate how HP Xe fMRI can be used to localize brain function.
The advent of molecular imaging has the potential to revolutionize the diagnosis and management of disease. This promise is due to the inherently non-invasive nature of molecular imaging: an imaging biosensor (also referred to as a molecular probe) is injected into a patient. This imaging biosensor is designed to have a high affinity to a particular pathological molecule or cell within the body. By applying a variety of imaging modalities, molecular imaging techniques can detect the presence of pathological sites and even differentiate between different forms of a particular disease. For example, molecular imaging has the potential to differentiate between two similar cancerous tumours: one which warrants aggressive treatment and another subtype which is better treated in a more conservative way. These types of imaging studies have the potential to make invasive surgical biopsies a thing of the past. If molecular imaging biosensors can be detected, they have the potential to supplant histological investigation by a pathologist as the preferred definitive modality to detect and differentiate diseases. We propose to develop magnetic resonance imaging (MRI) based imaging biosensors which offer significant advantages over existing techniques.
The most common method of molecular imaging involves positron emission tomography (PET). In PET, a radioactive probe, which consists of a radioactive tracer label as part of a molecule which has a high affinity to a pathological molecule of interest in the body. The patient being investigated is injected with the label and a PET scan detects the presence of the radioactive tracer. However, PET has a number of limitations. Firstly, it uses ionizing radiation which makes its use unsuitable for high-frequency longitudinal studies. Secondly, PET has spatial resolution limits and relies on computed tomography (CT) or magnetic resonance imaging (MRI) for localization. Perhaps most importantly, PET scans are very expensive, both because of the capital expense of a PET scanner and the cost involved in producing radiotracers.
What if we could develop a non-radioactive molecular imaging modality that uses mostly existing common hospital imaging infrastructure while maintaining the sensitivity of PET? Hyperpolarized (HP) xenon gas magnetic resonance (MR) imaging biosensors have the potential to achieve these goals . In the short term, we intend to build on our recent success of detecting part of such a biosensor in vivo, to functionalize and optimize prototype imaging biosensors. Following the success of this project, we intend translate the knowledge gained from this project to develop a class of HP Xe MR imaging biosensors to detect and characterize diseases such as cancer or Alzheimer’s disease. This technique has the potential to have PET-like sensitivity with the superior resolution of MRI, without the use of ionizing radiation, all at a lower cost than existing PET studies. The fulfillment of our long-term goals have the potential to make invasive biopsies a thing of the past.
HP noble gas MRI can provide extraordinarily detailed information on structures within the body, but one of its largest advantages is that it can also provide information on physiological function. Imaging data on physiological function is invaluable for detecting and accurately characterizing diseases, and for guiding treatment strategies. Figure 1 shows an example of HP 3He MR images from my laboratory used to assess the effect of therapy on lung ventilation in a cystic fibrosis patient. The top row shows lung ventilation before treatment; the bottom row shows lung ventilation following treatment. Notice that the images in the bottom row are brighter, especially in the upper lobes, indicating improved ventilation function.
HP noble gas MRI uses no ionizing radiation (CT does use radiation), and it does not require exposing patients to the risks of chemical contrast agents that are sometimes used with conventional MRI. This allows HP gas MRI to be used to image patients repeatedly over time, allowing physicians to monitor how medical conditions progress, and to assess the effectiveness of specific treatments.
The advantages of HP noble gas MRI make it a powerful tool for medical research on a number of body systems. This laboratory uses HP noble gas MRI to investigate gas ventilation within the lungs, gas exchange in the alveoli of the lungs, and moment-to-moment functional activity in the brain. We are also developing the use of xenon biosensor probes to perform HP xenon MR molecular imaging, a technology that will be able to image physiological function in systems throughout the body. HP xenon biosensor MRI has powerful potential applications for the diagnosis of, and treatment guidance for, cancer. We pursue our investigations on HP gas MRI in collaborations with physicians, and with biomedical scientists, engineers, chemists, and physicists at TBRRI and a number of other universities and corporations. Currently, our investigations include work in the following areas:
- Studying ventilation defects in patients with asthma
- Assessing drugs for treatment of cystic fibrosis
- Testing the effects bronchodilator therapeutics have on regional lung ventilation function in patients with COPD
- Detecting and treating pulmonary embolism
- Applying HP 129Xe MR imaging to studies of stroke
- Using HP 129Xe MR imaging for functional MRI (fMRI) of the brain
- Developing xenon biosensor probes to detect vulnerable plaques in the arteries of people with atherosclerosis
- Designing xenon biosensor probes to image peripheral benzodiazepine receptors (PBR) in the brain
- Developing xenon biosensors to detect and stage cancer, including HER2-positive stage breast cancer