Novel MRI Biomarkers in Neuromuscular Disease

Lead Research Organisation: Newcastle University
Department Name: Biosciences Institute

Abstract

More than 2,000 people a year die of motor neuron disease (MND). In this relentlessly progressive condition, the motor nerve fibres that control the muscles die off, resulting in weakness and eventually paralysis. Early diagnosis allows patients to receive life-prolonging treatment, but current clinical tests are only sensitive to the later stages of the disease by which time it may be too late for these to work.

We have recently developed an entirely new way to detect early changes in the muscles of patients with MND. This uses a type of MRI scanning that can detect characteristic twitches in tiny regions of the muscles (called fasciculation) that occur before the nerve fibres have died. These regions are called motor units. We were able to show that our new technique, which we call Motor Unit MRI (MUMRI), detected hundreds of fasciculations in the leg muscles of patients with MND but not in healthy subjects. This is very exciting as it is the first time that fasciculation has been detected using MRI, and it potentially offers a sensitive, quick, and entirely pain-free way to diagnose and monitor patients with MND and other diseases.

The aims of this project are: to take these promising early results and develop them into a tool that can be used to study the same muscle region repeatedly; to then use the refined technique to answer fundamental questions about how the disease develops; and to produce a 'whole-body' version that can be used to study patients in the clinic.

We will ask patients with MND to undergo several scans over a two-year period. As well as taking the MUMRI images, we will also perform currently used tests such as muscle MRI, ultrasound, and electrical muscle tests. This will allow us to see when the changes seen on MUMRI first appear, whether these occur earlier in the disease than currently available tests, and how the changes develop as the disease progresses.

A great strength of MUMRI is that it detects activity at the level of individual motor nerve fibres. This has never before been possible in humans, and it allows us to answer some fundamental questions about how MND develops. For example, we do not know if motor units that start to show fasciculation are about to die, or whether in fact these are the healthy ones doing their best to compensate for the damage occuring around them. We also do not know if the disease starts throughout the muscle, or start in just a few motor units before spreading. Since we can repeatedly image the same motor units with MUMRI we can begin to answer these questions, and in turn learn more about the disease itself.

Finally, we will develop new ways to use MUMRI in muscles other than the legs. This is important since MND can affect anywhere in the body, and this is an essential step to MUMRI being used in the clinical setting. It will also allow us to study how fasciculation spreads throughout the body in MND, complimenting the earlier work on understanding how the disease originates.

Our team includes research physicists, neurophysiologists, radiologists and neurologists. This gives us the ability to bring together a broad range of techniques to study MND. It also helps us to engage with a wide range of stakeholders from people involved in basic science into new imaging techniques, clinicians who apply these to diagnose and treat patients, and patients themselves. This gives us the best opportunity to translate this promising new technique into the clinic, whilst ensuring that our results are relevant and acceptable.

Technical Summary

There is a pressing need to develop sensitive and reproducible biomarkers of motor unit loss in motor neuron disease (MND). We recently developed a novel diffusion-weighted MRI protocol (Motor Unit MRI or MUMRI) sensitive to the spontaneous or electrically-evoked contraction of individual skeletal motor units (Ann Neurol 2019 Mar;85(3):455-459).

In this fellowship I will a) validate this novel imaging technique against current clinical measures of motor unit fasciculation (ultrasound and surface electromyography), b) perform a longitudinal study of motor unit dysfunction and degeneration in the lower limbs of patients with MND, using a combination of MUMRI and conventional imaging modalities (T1, STIR, T2 mapping, and 3-point Dixon fat fraction) and c) develop a 'whole-body' MUMRI imaging system with which to investigate the spread of fasciculation both within and between skeletal muscles.

The outcomes of this project will be a validated and trial-ready MR-based skeletal muscle imaging system suitable for use in both clinical diagnosis and longitudinal studies of novel therapies. The pattern whereby fasciculation and structural changes develop in muscles within and between different body regions will also inform the ongoing debate as to whether or not MND develops by prion-like spread of aberrantly folded proteins between neighbouring populations of motor neurons or as an inherently diffuse process.

Planned Impact

Patients with motor neuron disease (MND), a progressive muscle wasting condition which is ultimately fatal, wait on average 12 months from symptom onset to definitive diagnosis. This delays the commencement of currently available life-prolonging therapies, and precludes the early recruitment of patients into clinical trials aimed at developing better ones.

We recently developed a novel MRI technique (motor unit MRI or MUMRI) that can image the activity of human muscles. This reveals florid microscopic muscle twitches known as fasciculation in patients with MND but not in healthy controls. Fasciculation is a promising biomarker for MND in that it occurs in regions of affected muscle but which have not yet died. This project aims to use this novel imaging technique to study how MND develops and spreads within the body, and to further develop MUMRI for use in the clinic.

The initial impact will be in improved diagnosis for patients. The current diagnostic gold standard is electromyography, which involves inserting a fine metal needle in to multiple muscles and recording their electrical activity. This is painful and time consuming, and critically has a low sensitivity due to the tiny volume of muscle sampled. Since MUMRI allows multiple muscles to be imaged simultaneously we hypothesise that it will provide a more sensitive and entirely pain-free diagnostic tool.

Further impact will be on clinical trial design for novel therapies in MND. The lack of trial-ready biomarkers has been identified as a barrier to progress in MND research (for which only a single drug of limited efficacy is approved in the UK). Due to the limitation of electromyography as a tool in clinical trials, there has been increasing focus on non-invasive imaging using for example T2 mapping. MUMRI offers a quantitative and repeatable biomarker which unlike previous imaging modalities provides information at the level of individual motor units rather than whole muscles. MUMRI also reveals early functional changes which are not visible on conventional imaging techniques, allowing recruitment of patients into trials early in the disease when therapies are more likely to be effective.

We will use MUMRI to study the spread of fasciculation within and between muscles. This will provide novel insights into the longstanding controversy as to whether MND develops through a mechanism of 'dying forward', 'dying back' or a combination of the two. In the longer term this mechanistic information will help identify targets for future therapies.

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