Approved Research

Motor system ageing and the pathogenesis of amyotrophic lateral sclerosis

Lay summary

Amyotrophic lateral sclerosis (ALS, also known as motor neurone disease) is a progressive and fatal neurodegenerative condition affecting adults of all ages, but with highest prevalence in the older population. Loss of nerves of the motor system originating in the brain leads to progressive muscle weakness of the limbs, speech and swallowing, eventually affecting the muscles of breathing. This results in death, on average, less than 3 years from the start of symptoms.

There is no cure. A major barrier to therapy development is the lack of objective markers of disease activity against which to test candidate drug therapies. Advanced brain imaging (MRI) has been particularly useful in revealing the part of the brain most involved in ALS. It is not known who is at risk of ALS, as most cases do not run through successive generations of families in a simple genetically-driven way. It has been noted from some large population studies that those individuals who develop ALS may have a particular type of metabolism before symptoms emerge, involving a generally lower body mass index, altered blood fat levels and insulin sensitivity, and increased physical activity.

This 2-year study will use the unique resource of UKBiobank to study how the pattern of MRI brain changes in participants who have gone on to develop a diagnosis of ALS, before and after symptoms emerged, relates to participants who did not develop ALS. We will also study the interaction of factors relating to metabolism and physical activity recorded for all participants in relation to MRI measures of motor system ageing.

The results are expected to provide a very powerful way to move the global research efforts towards preventing ALS, eventually to screen and target those who are at greatest risk before damage becomes too extensive to rescue. The results may also provide novel evidence around key pathways for better targeting of drugs.

Scope extension:

Current scope:

How does the cerebral structural and functional neurodegeneration associated with amyotrophic lateral sclerosis (ALS) relate to the natural patterns of cerebral senescence in the wider population and what is the influence of premorbid metabolic and physical activity factors?

Additional aims:

To understand the influence of premorbid genetic and wider systemic factors on brain ageing and risk of ALS.