Molecular imaging of neurodegenerative pathology using deuterium MRI (MINDER)

Problem: Alzheimer's disease is the main cause of dementia, a disease that affects the memory of older people. Current clinical diagnosis of Alzheimer's disease is performed by a doctor, usually by asking the patient a set of questions about their day-to-day experiences and asking them to undertake a memory test. These expert clinical assessments are wrong 30% of the time. In a research environment, it is possible to make a more accurate diagnosis using a positron emission tomography (PET) scan. These scans use special dyes that highlight parts of the brain affected by the disease. Unfortunately, PET scans are not in routine clinical use because of their high cost and limited availability. When new drugs become available, it will be vital to have widely accessible tools that can accurately diagnose whether a patient has Alzheimer's disease or not and to monitor how well the drug is working.

Proposed solution: In the project we will adapt existing PET dyes so that they can be used within an magnetic resonance imaging (MRI) scan. MRI is far more widely available than PET. We will adapt the PET dye using a process called deuteration which involves using chemistry to replace hydrogen atoms within the dye with deuterium atoms. Since living tissue contains only very small amounts of deuterium, this will make it much easier for the MRI scanner to detect if the patient has Alzheimer's disease or not.
Approach: We will test our new 'MRI compatible' dye using a series of experiments, first in a highly controlled environment (test tubes containing the dye and other known ingredients), then in alive genetically modified mice that mimic Alzheimer's disease. We will spend time ensuring our MRI scans are as efficient as possible, and then compare our proposed approach to PET scanning.

Benefits: The approach, if successful, will provide doctors with the tools to accurately diagnose Alzheimer's disease in any hospital.

Problem: Alzheimer's disease (AD) accounts for 60-70% of dementia cases, and is characterised by insidious accumulation of beta-amyloid and tau proteins in cortical regions. Current diagnosis of AD is led by clinical assessment of cognition/history, however such expert clinical estimates are wrong 30% of the time. In research studies, the precise contribution of AD relative to e.g. coexisting vascular pathology can be established using positron emission tomography (PET) scanning or cerebrospinal fluid analysis, however these tests are not in routine clinical use because of their high cost and limited availability. New imaging approaches that can detect molecular targets using clinically ubiquitous technologies such as magnetic resonance imaging (MRI) are urgently needed. However MRI currently lacks routine capability to detect proteins such as beta-amyloid, which are present in AD brain at concentrations between 1-10 microMolar (~1-10 nmol/g tissue).

Proposed solution: Our objective is to make molecular imaging widely accessible by creating versatile 'MRI detectable' ligands. To demonstrate proof of concept, we will target beta-amyloid plaques by labelling existing beta-amyloid PET ligands with deuterium, then using deuterium-tuned MRI coils to detect the presence of the these ligands in the brain. We will optimise imaging protocols to maximise sensitivity to the ligand, including using ultra-short time-to-echo (UTE) spectroscopic imaging to capture rapidly decaying signal from bound ligand with short T2. Finally, we will obtain vital validatory data comparing detection of our deuterated ligand to florbetaben PET in 5xFAD mice, a commonly used mouse model of amyloidosis.

Impact: The approach, if successful, could fundamentally transform clinical imaging capabilities both nationally and internationally by providing a means to perform molecular imaging in any hospital.