Going ‘haywire’ is bad news for MND sufferers

30 Apr 2018

New research at AIBN in collaboration with colleagues at the UQ Centre for Clinical Research (UQCCR) shows that increased energy use in patients with MND (motor neurone disease) is associated with faster disease progression and shorter disease survival.

The findings have been published in the Journal of Neurology, Neurosurgery and Psychiatry.

AIBN researcher Dr Shyuan Ngo and Dr Frederik Steyn (UQCCR) explain that their findings reveal important information as to how the body responds to MND.

“It brings us one step closer to understanding the disease,” says Steyn.

Motor Neurone Disease (MND), which comprises a group of neuromuscular diseases that include ALS (amyotrophic lateral sclerosis), is a fatal neurodegenerative condition that progresses rapidly. There is no cure, in part because the genetic and cellular mechanisms that lead to the disease are not yet fully understood.

Following diagnosis, patients have an average life expectancy of two to five years, but Ngo and Steyn say there is a great deal of variability from person to person. Some patients may die within weeks or months following diagnosis, while others may live for many years.

It has been extremely difficult for clinicians to identify which patients will progress rapidly and which won’t. Naturally, this means that the patients themselves don’t know if they have slow or fast progressing disease, and this uncertainty can have significant psychological and quality of life impacts for them.

“To treat this disease, we need to understand what makes people different,” says Steyn.

One of the hallmarks of MND is that cellular metabolism in muscle and nerve cells becomes dysregulated, and goes haywire. The result is heightened energy use, a phenomena that could impact whole body energy use. This, as Ngo and Steyn’s research now shows, can contribute to the progression of disease, and might manifest as fatigue, weakness and atrophy.

For over 20 years, it has been thought that changes in energy use in MND would affect disease outcomes, but this has proved difficult to measure in the clinic. The way in which energy use has been historically measured in people living with MND is based on a standard average of how much energy a typical person should be using. But this involves a great degree of guesswork. In essence, these standardised averages don’t work in MND because of the amount of muscle wasting that people experience.

Steyn and Ngo wanted to develop a more accurate, personalised measure of energy use, so they took 58 people with ALS and 58 healthy controls and assessed how much muscle each person actually has.

This was done by having the individual sit in an egg-shaped device called the BodPod, which can accurately determine how much fat mass and how much fat-free mass the person has. They used this measure to make more accurate predictions of how much energy each individual should use at rest. Then, for each participant, they measured energy use by monitoring respiration at rest.

“We coupled these measures with detailed clinical information for each patient,” says Ngo. This included their clinical history, as well as genetic information.

The result was a comprehensive analysis of each patient, with individualised knowledge of how much energy that individual should use, compared to how much energy they actually use.

The study revealed that patients who are hypermetabolic, meaning they use more energy at rest than was expected, were more than twice as likely to die within 12 months following the assessment. This is a grim revelation, however it provides critical information needed to help researchers, clinicians, as well as patients to understand the disease.

“We’ve identified the significance of hypermetabolism in this disease,” says Steyn. “We now know that how the body responds from a metabolic perspective can have a big impact on a person’s progression and survival.”

“It adds to the bigger picture of where this field is going,” says Ngo, explaining that, in addition to providing a way to identify patients with rapid disease progression, these findings provide extremely useful new information to help manage disease progression in the clinic, and opens up new avenues for targeting the metabolic nature of the disease to improve outcomes.

“We are now working towards a greater understanding of why these individuals use more energy, and by proxy, this will help us to identify ways to intervene and slow the progression of disease,” says Ngo.

To do this, Ngo and her research group are looking at how muscles and neurons from MND patients use energy. By comparing these measures to measures of whole body energy use in the individuals who donated these tissues, her team are aiming to develop treatments that are tailored for each individual patient.

In addition to work performed at AIBN and UQCCR, this research has involved input from multiple institutes and organisations:

Royal Brisbane and Women’s Hospital, Wesley Hospital, and Wesley Medical Research (for patients and research funding); Queensland Brain Institute (involved in funding Shyuan Ngo); Motor Neurone Disease Research Institute of Australia (research funding), MND and Me Foundation (funding for Shyuan Ngo).

Read the full article at UQ News