Cognitive change in MND: what causes it, and why measure it?

Up to 50% of people with the adult-onset, ALS form of motor neurone disease will experience some degree of changes in thinking, learning and behaviour, which are collectively called cognitive changes.

Why assess cognitive changes?

Euan MacDonald Centre Investigator Professor Sharon Abrahams and her team have pioneered research into assessing cognitive changes in MND. They have developed a tool for healthcare professionals called the Edinburgh Cognitive ALS Screen (ECAS). The ECAS is like a quiz with lots of different types of questions. The scores people get on the quiz provide an assessment of cognition and behaviour. It can be done in written or spoken form, making it suitable for people with physical disability. The ECAS has been translated into many different languages and is widely used to assess the needs of people with MND across the world.

In order to assess the impact of the ECAS, the team have recently undertaken research to look at how widely it is used, and what effect it has on care. In a survey of 22 UK healthcare services, it was found that 95% conduct cognitive screening, and of those, all use the ECAS. Patients and carers reported that completing the ECAS was helpful to understand the complete clinical picture. Furthermore, those who did not have identified cognitive changes found it reassuring to be told, while those who did have cognitive changes found it validating, as they had usually noticed some changes themselves. People found it useful practically too, as it helped confirm whether they were fit for work, or to obtain healthcare funding.

Healthcare professionals reported that they found the ECAS useful to help them identify changes that might otherwise go unnoticed, and to help explain a patient's unexpected behaviour. The ECAS helped them assess capacity, which is very important when discussing topics like end-of-life care.

Insights from the brain bank

But what causes cognitive changes in MND? Another team of Euan MacDonald Centre researchers, led by Professor Colin Smith, has recently published findings based on their studies of post-mortem brain tissue from people with MND, which had been donated to a brain bank. They analysed the brain tissue from 27 people with MND who had completed the ECAS test before their death. The researchers found that everyone with cognitive changes showed accumulation of a protein called TDP-43 in brain regions associated with decision-making and language. The function of TDP-43 is not fully known, but it is thought that when clumps of it form in the brain, it becomes toxic to cells. The results suggest that the accumulation of TDP-43 might be involved in causing the cognitive changes.

However, puzzlingly, the researchers also found TDP-43 accumulation in the brains of some people who had not experienced cognitive changes, so-called mismatch cases. Investigating further, they looked at another protein, called clusterin. There was good evidence that clusterin might be involved, as other researchers had previously shown that it can stop TDP-43 forming the toxic clumps. Interestingly, the team found that in the mismatch cases, the clusterin was mainly found in the neurons themselves, but in the others, clusterin was mainly found in the supporting cells, the glia. This suggests that perhaps clusterin can protect against the toxic build-up of TDP-43, and reduce or delay cognitive changes. The teams will now be undertaking further work to investigate this in more detail.

Psychologists, pathologists & cell biologists working together

These important insights have only been made possible because in the Euan MacDonald Centre, researchers in different disciplines work together. Using different ways to study MND helps us make faster progress, and means that our findings are more relevant to people living with MND today.

Related content

Research case study: The Edinburgh Cognitive ALS Screen

Find out more about donating your brain for research on the University of Edinburgh website

Read the scientific articles:

1. The clinical impact of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and neuropsychological intervention in routine ALS care, by Hodgins et al. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019. doi.org/10.1080/21678421.2019.1674874
2. Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS, by Gregory et al. Journal of Neurology, Neurosurgery & Psychiatry, 2019. doi: 10.1136/jnnp-2019-320807
3. Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis, by Gregory et al. Neuropathology & Applied Neurobiology, 2019. doi.org/10.1111/nan.12575