Development of metabolic and molecular imaging by simultaneous PET-MRI for studying dementia and neurodegeneration.

Keywords: Tissue disease and degeneration, Neurodegeneration
Positrom Emission Tomography, Imaging, Alzhemier's Disease

Recent MRC investment has established a network of PET-MRI scanners targeted for neuroimaging research in dementia under the umbrella of Dementias Platform UK (DPUK). This new technology combines positron emission tomography (PET) within the same scanner as the magnetic resonance imaging (MRI) system to allow simultaneous collection of molecular imaging (PET), structural, physiological and metabolic data (MRI). These scans can provide a comprehensive, non-invasive assessment of disease processes in a single examination. However, the true capabilities of this new generation of imaging technology have not been yet determined. We have extensive experience developing and applying quantitative MRI and PET tracer studies in dementia and this project will extend our previous research to explore the capabilities of PET-MRI technology.

The project will focus on developing MR spectroscopy (MRS) methods on the PET-MRI platform to allow important brain metabolites to be quantified alongside the molecular imaging measurement from PET. This work will shape the future use of both MRI and simultaneous PET-MRI in dementia research and clinical diagnosis and will be carried out in close collaboration with the scanner manufacturer.

The project will be divided into 2 specific phases:

1) An important target for dementia research is beta-amyloid deposition within the neurodegenerative processes. Amyloid levels can be assessed using PET imaging via appropriate radiotracers, but the need for local radiotracer production and the small nationally installed base of PET scanners will limit the use of PET as a routine diagnostic tool. Recent post-mortem studies have suggested that the glial and neuronal density changes which can be quantified by MRS measurements are sensitive to amyloid and tau respectively. As MRI is widely available, the use of MRS as a surrogate measure of amyloid could have a significant impact in dementia diagnosis. Post-mortem studies are however inherently limited to measuring pathological burden in end stage disease and so in vivo imaging research is essential to determine the relevance of post-mortem observations to living patients.

Phase 1 of this project will develop proton-MRS imaging methodology (MRSI) to create spatial maps of neuronal and glial density. Amyloid PET imaging is available for dementia research in Newcastle (18F-Amyvid is regularly used). By using these new MRSI methods as part of the simultaneous PET-MRI measurements, we will determine the strength of the relationship between the PET and MRS assessment of amyloid. This work will determine the applicability of the MRSI technique as a surrogate diagnostic marker for amyloid in dementia.

2) Alzheimer's disease (AD) is characterised by regional cortical hypometabolism assessed by PET 18F-deoxyglucose (FDG) scans to measure metabolic rate of glucose consumption. One hypothesised mechanism for this hypometabolism is mitochondrial dysfunction, but this has been difficult to assess in living patients. Phosphorus MRS (31P-MRS) quantifies tissue energetics by mapping phosphocreatine and ATP levels which, when combined with appropriate modulation of regional brain activity, can indirectly assess mitochondrial activity.

Phase 2 will use the specialised multi-nuclear capability of our PET-MRI scanner to develop 31P-MRS combined with FDG PET-MRI measurements to study the areas of posterior cortical hypo-metabolism seen in AD patients with a view to assessing the degree of mitochondrial dysfunction.