Novel MRI Techniques for Brain Banking and Motor Neuron Disease Research

Neurodegenerative diseases are brain disorders in which neurons (brain cells) die prematurely, with devastating consequences. Parkinson's, Alzheimer's and motor neuron disease (MND) each affect different aspects of brain function, none with effective treatments to reverse neurodegeneration. There is an urgent need to develop "biomarkers": measurements that can be made in living patients with neurodegenerative disease to guide clinical decisions and assess treatment outcomes in drug trials. In this project, we will investigate a technique to validate potential imaging biomarkers for neurodegeneration in MND.

Brain scanning technologies like Magnetic Resonance Imaging (MRI) are known to have enormous potential as biomarkers by revealing subtle brain changes in disease. However, despite this exquisite sensitivity, MRI currently lacks specificity. A given change measured with MRI could come from several plausible changes to brain tissue. For example, neurons could be shrinking, losing outer membranes, or become more chaotically packed in disease. The "gold standard" for studying neurodegeneration is to look at the neurons directly under a microscope, providing a more interpretable picture of what aspects of the neurons are affected in disease. However, extracting brain (or spinal) tissue for microscopic examination cannot be done during life without causing irreparable damage.

Our research will bring together these two complementary areas of research, MRI scanning and tissue microscopy, to maximise the strengths of each. Brain banks, collections of brains donated by individuals after death, are a critically important resource in neurodegeneration research. They provide a crucial link between microscopic measurements that can be made in donated brain tissue and the MRI measurements that can be taken in living patients. Our project will explore this link via two strands of research: the first developing the necessary techniques and the second demonstrating the potential of this approach in MND.

The first research strand will build on proof-of-principle methods we have developed for scanning donated brains before they are sectioned for microscopy. We will translate these methods to make them suitable for studies of disease in a practical setting. This will require merging recently pioneered acquisition techniques with cutting-edge hardware. Equally exciting is the opportunity to obtain much better quality images on donated brains by scanning for extended periods, enabling unprecedented anatomical detail that has value on its own. Finally, we will explore technologies that may allow doctors to study neurons more directly than is currently possible by measuring properties that previously have only been detected in tissue samples under a microscope.

These techniques will be used to scan a unique set of brains donated to research by MND patients, in comparison with those from individuals with no known pathology. These MRI data will then be compared to histological measures of tissue properties that are expected to underpin the MRI signal, including microscopic geometry and molecular content. We will investigate regions of the brain that are known to be affected by MND, including the motor system and areas involved in MND-related dementia. Some of these patients will have previously taken part in a MRI study during life, which will provide a vital link to the post mortem imaging we propose to develop in this project. In reverse, the insights gained will allow us to improve and inform future MRI studies in living patients. This has the potential to improve the diagnostic process, and develop more sensitive tools to assess candidate drug therapies.

This research aims to provide neuroscientists with a general approach for directly comparing post-mortem MRI with histopathological measures, with the ultimate goal of improving the interpretation of MRI scans in living patients.

Magnetic resonance imaging (MRI) has enormous potential as a biomarker in neurodegenerative disease, in particular techniques that are sensitive to microstructure show great promise for phenotyping and monitoring disease progression. However, these measures currently lack specificity. We propose to combine post-mortem MRI with histopathology in the same tissue to aid in the interpretation of in-vivo MRI measures. We will focus on motor neuron disease (MND), an area of expertise in Oxford for which MRI has considerable potential as a biomarker.

MRI can provide various types of "contrast" (analogous to different tissue stains) with complementary information about anatomy and tissue composition. We will acquire images with a broad range of contrasts, with particular focus on diffusion MRI, a powerful method that presents particular challenges in post-mortem tissue. We will build on our recent advances in MRI software and cutting-edge hardware to improve signal strength by a factor of 5-6 and enable unprecedented spatial detail. We will also explore recent MRI techniques that aim to provide more biologically-meaningful information.

We will conduct a proof-of-concept study in MND, which provides an ideal testbed for these methods as a relatively "clean" pathology in which pre- and post-mortem MRI scans are available. A range of MRI scans will be acquired in MND and control brains, the latter being a crucial resource for future expansion into other diseases and conditions. We will demonstrate the potential of MRI-to-histology comparisons in neurodegenerative disease. Specifically, we will investigate whether histological staining supports the use of MRI as an early marker of MND and the related condition frontotemporal dementia. Finally, we will develop a basic prototype database for on-line data exploration and distribution, linked in to the Oxford Brain Bank and freely accessible to the neuroscience community.

Our proposal is expected to have impact in a range of spheres outside of academia. Although we aim to focus on motor neuron disease, the techniques considered in this grant are applicable to a broad range of disorders and organ systems, resulting in broader impact within healthcare and across society. The ultimate aims of this research direction have significant potential impact on health and well-being, economy, and knowledge, albeit beyond the duration of this project.

The MRI methods that we propose to validate through comparison with histopathology have enormous potential as a tool for early detection of neurodegeneration and other neurological disorders. Further, they have the potential to more effectively target and assess future therapeutics. The development of more sensitive markers would reduce costs of early-stage drug trials, enabling faster 'no-go' decisions, earlier exclusion of ineffective compounds and thus allowing more compounds to be explored than is currently cost effective. The ability to directly link MRI measures with human post-mortem tissue may also reduce dependence on animal models, which is an ethical consideration of importance to society.

Neurodegenerative disorders already have an enormous physical, emotional and socioeconomic burden, which is set to increase with the ageing population. Economic impact via improved diagnosis and treatment of disease can lead to tremendous financial savings in the healthcare sector. There is also economic impact associated with the techniques themselves within the global market in healthcare. For example, the world-wide market for MRI scanners was $4.4 billion in 2010, with just three vendors dominating the market (GE, Siemens and Philips). We have a history of working with these vendors to patent technical advances (Dr Miller holds 3 patents funded by GE and Siemens). Similarly, drug trials run by pharmaceutical companies cost millions of pounds, and several UK companies (e.g., Ixico) have been founded to analyze data (including images) for these studies.

Further impact to society will occur from our more general understanding of how the brain works, and in knowledge for broader use of imaging technologies. As discussed above, we will provide the neuroscience community with a unique resource of high-resolution brain scans for research. Further, the developed methods and experimental approaches will enable us to study how the brain develops after birth, how learning sculpts the brain's network at a microscopic level, even in adulthood, and how certain interventions such as transcranial direct current stimulation may improve our ability to learn. Our research will thus contribute broadly to our understanding of the brain, helping to answer fundamental scientific questions: how does the brain work, and how can we facilitate healthy function?