PET/MRI evaluation of white matter inflammation in a co-morbid rat model of ischemic stroke and Alzheimer’s disease (and others)

Jonathan Thiessen, Ph.D., Director, PET/MRI Program, Assistant Professor, Depts. of Medical Biophysics and Medical Imaging, Western University

Matthew S. Fox, Ph.D., Preclinical Imaging Physicist, Lawson Health Research Institute Research Associate, Dept. of Physics and Astronomy, Western University

By helping to advance hybrid PET/MRI and multi-parametric diagnostic imaging tools, we hope to give new insight into the early biomarkers of disease and improve diagnosis and therapy in patients.

Projects at a glance:

PET/MRI evaluation of white matter inflammation in a co-morbid rat model of ischemic stroke and Alzheimer’s disease

One in three individuals over 60 will either experience a stroke, develop dementia or experience both. In addition, the number of Alzheimer’s disease (AD) cases is expected to triple in the next 40 years. When AD and stroke exist together, cognitive impairment increases. White matter inflammation may be the mediator for this interaction. We are using a PET tracer sensitive to the presence of activated microglia ([18F]FEPPA) to measure neuroinflammation longitudinally together with MRI and CT perfusion in a co-morbid rat model of ischemic stroke and Alzheimer’s disease. We are also working to implement a new PET tracer sensitive to synaptic density ([11C]UCB-J). Changes in MRI and PET biomarkers following a stroke have been measured separately and by disparate research labs. Our study represents a unique and comprehensive assessment of brain structure and function using quantitative MRI, dual PET tracers sensitive to neuroinflammation and synaptic density, and behavioural studies assessing motor and executive function. Simultaneous PET/MRI will help us understand when and where white matter inflammation occurs, it’s impact on white matter integrity and synaptic density, and help predict its role in cognitive impairment following a stroke.

PET/MRI of altered glucose metabolism and its byproducts in a rat model of glioma

Gliomas are a type of brain tumour characterized, in part, by high energy demands. This increased tumour metabolism can be imaged with radiolabelled glucose ([18F]FDG) using positron emission tomography (PET). Although [18F]FDG-PET is a powerful tool for assessing the metabolic activity of tumour cells, it is less effective in the brain, where the surrounding brain tissue also exhibits increased metabolism. In order to better visualize brain tumours and predict their progression, we are investigating magnetic resonance imaging (MRI) methods that can measure brain tumour metabolism and its byproducts without the use of radioactive PET tracers. Specifically, we are using a brain tumour model to investigate two distinct aspects of brain tumour growth:

1. One byproduct of increased tumour metabolism is a change in acidity, known as tumour acidosis. We are investigating an MRI method known as chemical exchange saturation transfer (CEST) that is sensitive to changes in tumour acidosis. Our experiment will use both FDG-PET to measure the rate of glucose metabolism and MRI to measure the amount of tumour acidosis in a C6 rat model of glioma. Based on previous results, we expect to see an increase in tumour acidosis that corresponds to the metabolic activity of the tumour as well as changes outside of the main tumour that may help identify the spread of tumour cells (AKA tumour proliferation).

2. The body’s immune system responds to the presence of tumour cells by sending immune cells to the site of injury. This is known as the inflammatory response. In turn, inflammatory cells take up glucose and may conceal the true extent of metabolically active tumor cells measured with FDG-PET. Inflammation may also contribute to the proliferation of tumour cells in the brain. We are able to measure active inflammatory cells with another PET tracer, [18F]FEPPA. We are using CEST-MRI to measure chemicals related to the inflammatory response in conjunction with [18F]FEPPA-PET. MRI measurements sensitive to inflammation will allow us to create a more complete picture of the tumour and measure treatment response with simultaneous PET and MRI systems (PET/MRI).

This project is unique in its combination of information from two distinct and powerful imaging methods: PET and MRI. With the help of gold-standard PET measurements of glucose metabolism and inflammation, we are developing comparable MRI methods that will help classify the aggressiveness of brain tumours and guide the design of new therapies. Eventually, we aim to translate this work to our clinical PET/MRI located in the same research facility to help improve patient outcomes.

Carotid artery image derived input functions and kinetic modeling using simultaneous PET/MRI

Arterial input functions are often needed in order to perform kinetic modelling of dynamic PET data. Blood sampling in small animal models is challenging due to the availability of total blood volume and ethically permitted sampling volumes in longitudinal studies. Image derived input functions may eliminate the need for invasive blood sampling. Our goal here is to validate a carotid artery image-derived input function (cIDIF) compared to gold standard left ventricle image-derived input functions and arterial blood sampling. Utility of the cIDIF extends to imaging small animal models on PET and PET/MRI systems (e.g., Cubresa NuPET) having short axial FOVs and may extend to clinical imaging where a single bed position scan covers only a head-sized region.

Simultaneous x-nuclei PET/MRI

The power of multi-parametric and multi-modal imaging for the study and diagnosis of diseases has fueled research in combining modalities, resulting in imaging techniques with higher sensitivity for disease. Advancements in technology have already made possible the combination of simultaneous PET and MRI. Bringing multi-modal and multi-parametric imaging techniques together enables simultaneous imaging, natural co-localization and potential improvement in patient comfort. This arm of our program serves to incorporate several non-proton MRI techniques (e.g. 23Na, 19F and 129Xe) for pre-clinical and clinical simultaneous PET/MRI, enabling improved vision into human disease diagnosis and treatment management.