Readable Research

A lay summary by Harry McDonough, reviewed by Ian Coldicot and by an MND lay panel.

Background

Motor neurone disease (MND) is a progressive and disabling condition of the nervous system with no current cure. Faced with this diagnosis and outlook, it might be expected that the mood and emotional wellbeing of people living with MND could be affected.

Whilst each individual will process and respond to their MND diagnosis in their own way, some may have more persistent psychological difficulty. Depression is a condition in which there is a persistent change in mood, where individuals may feel sad, anxious, worthless, or lose interest in things previously enjoyed.

Why is the study important?

It is currently uncertain how common depression is in MND. This would be useful and important information for:

• MND sufferers and their loved ones – to be aware of the signs of depression and discuss with healthcare professionals as needed

• Healthcare professionals – to know whether to routinely assess for depression and, if required, offer treatment

• Planning clinical services – to ensure psychological services are available and accessible for people with MND

What did the authors do and how did they do it?

This study aimed to determine how common depression is in MND. The study was part of a wider national study called TONiC (Trajectories of Outcome in Neurological Conditions). TONiC looks at the factors that influence quality of life for people with neurological conditions, including MND.

People living with MND were recruited to the TONiC study. To best determine how common depression was in the group studied, the authors identified cases of depression in multiple ways:

• Modified-Hospital Anxiety Depression scale (M-HADS-D): a questionnaire commonly used to assess individuals for depression

• Medications taken by people with MND: was the individual already prescribed an antidepressant medication?

• Questionnaire of past medical history: this asked individuals if they had already been diagnosed with depression in the past

The researchers also looked at how depression symptoms changed over a period of 2.5 years in the group recruited to the study. To do this, they used computer modelling techniques to identify groups of individuals that followed similar trajectories of depressive symptoms over time.

What are the results?

Depression was found in 23% of the 1120 people living with MND recruited into the study. On average, those with depression were more likely to be younger and have more advanced MND than those without depression. Females were more likely to have depression than males and those with depression reported a worse level of quality of life in comparison to those without depression. The presence of depression did not, however, seem related to how long an individual had had MND.

Depression was more common in people with MND if they

• Were young

• Were female

• Had more advanced MND

The authors looked at when people were diagnosed with depression in relation to their MND diagnosis. They found 23% were diagnosed with depression at the time of or following their MND diagnosis. 5% reported their depression began more than 3 years prior to their MND diagnosis, with the remaining 72% being affected in the 3 years leading up to their MND diagnosis.

The authors studied whether those identified as having depression were on antidepressant medication. They found that 82% of people with MND with depression were on antidepressant medication. Those not on medication were much more likely to be male and at an advanced stage of MND.

The study aimed to categorise people with MND into groups based on their trajectories of depressive symptoms over time. Doing this, the authors found that people fell into 3 different groups. As they studied the groups over time throughout the study, they saw that the level of depressive symptoms stayed stable in each group. The table above describes that depression was more common in people with MND if they were female, young, or had advanced MND.

What do the findings mean going forward for people with the disease?

The study estimates that 23% of people living with MND have depression. Given how common depression would appear to be, the authors suggest MND clinics should routinely and proactively assess people for depression, exploring treatment options, including ready access to psychology services.

Nearly three-quarters of depression cases in people with MND start less than 3 years before MND diagnosis. With this in mind, the authors suggest that depression may be an early feature of MND before the more widely recognised symptoms start. Indeed, depression has been recognised as an early symptom in other neurological conditions, such as multiple sclerosis. It is, however, worth remembering that more than 75% of people with MND in this study did not have depression. Therefore, if depression is an early symptom of MND, it does not appear to be the case for everyone.

Looking to areas for future research, the authors suggest it is important to consider undertaking a trial of treatments of depression symptoms in MND. This study shows that depression is common in people with MND, affects quality of life, yet the effects of treatments for depression in MND are not yet known.

This study can be found at:
https://www.tandfonline.com/doi/pdf/10.1080/21678421.2022.2096410?casa_token=SfHRxtDNXmQAAAAA:PyXfSYlAsuV8oe0Xghl4bTOrq5935CLRxIqwVQTrHKDc9TVzBpo-oaiEjqjr38ZFAI23ReHDOS582Q

Paper title
Prevalence of depression in amyotrophic lateral sclerosis / motor neuron disease: multi-attribute ascertainment and trajectories over 30 months

Author list
C. A. Young, J. Ealing, C. J. McDermott, T. L. Williams, A. Al-Chalabi, T. Majeed, K. Talbot, T. Harrower, C. Faull, A. Malaspina, J. Annadale, R. J. Mills, A. Tennant & On Behalf Of The Tonic Study Group

Publication details including date of publication

Journal: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Year: 2023

How common is depression in motor neurone disease? - Readable Research 

Lay summary by Louise Heywood, reviewed by Dr Tom Payne, and by a Parkinson’s Disease Lay Panel.

Background

Mitochondria act as the batteries of the cell, producing high amounts of energy for cells to function properly. In Parkinson’s, these batteries produce less energy, resulting in brain cells starving and dying. Therefore, one hope to slow down the progression of Parkinson’s is to use medication to keep mitochondria healthy. Ursodeoxycholic acid (UDCA) is commonly used as a treatment for liver disease, making it an ideal candidate for drug repurposing – using existing drugs to treat different conditions. This study was a Phase II clinical trial, where patients were randomly assigned to either UDCA treatment or a placebo drug, with neither participants nor doctors knowing which participants were taking UDCA. The study took place across two centres, one at Sheffield Teaching Hospitals (STH) and one at University College London (UCL) Hospitals. All participants had been diagnosed with Parkinson’s for less than three years.

Why is the study important?

There are currently no approved treatments for Parkinson’s that can prevent the loss of affected brain cells nor alter the progression of the condition – the available treatments can help reduce symptoms, but not the underlying causes. UDCA is a potential ‘neuroprotective’ drug that is hoped can prevent further loss of brain cells, and as such, represents an important step forward in the treatment of Parkinson’s. The first step to getting a new treatment to patients is to assess its safety and efficacy in clinical trials.

What did the authors do and how did they do it?

The trial consisted of 31 total participants randomly assigned to either UDCA treatment or placebo group with 20 taking UDCA and 10 taking a placebo. Participants remained on the treatments for 48 weeks, followed by an 8-week ‘wash-out’ period where treatment was stopped, to assess the longevity of UDCAs effects.

The main assessments were regarding safety and tolerability, but the study also looked at the effects of UDCA on the brain, and on Parkinson’s movement symptoms. To confirm that UDCA was having an effect on the brain a type of brain scan known as phosphorus-31 magnetic resonance spectroscopy was used. This is a specific brain scan that can measure the changes in levels of energy in the brain. Changes in movement symptoms were assessed using the standard clinical rating scale (MDP-UPDRS-III) and a digital, wearable, sensor-based system (Sheffield cohort only).

What are the results?

One participant completely withdrew from the study, due to problems swallowing, the high number of capsules, and was subsequently replaced. Another two participants stopped taking their tablets early, but still completed the study. This was due to the burden of taking so many capsules in addition to their existing medication. There were two serious adverse events during the trial, both of which affected the same patient in the placebo group, and in total 24 adverse reactions in 14/31 participants, affecting 10 UDCA participants and 4 placebo participants. The most frequently reported side effects of UDCA were mild diarrhoea and mild nausea, which required no treatment and was of short (24-72 hr) duration, therefore the authors felt that the 30 mg/kg dose of UDCA daily was well-tolerated and safe.

The brain scans of participants taking UDCA showed that there was a potentially increased efficiency of energy breakdown in the brains of UDCA participants, suggesting that UDCA is having a positive effect on Parkinson’s. The sensor-based movement analysis showed that participants taking UDCA had an increase in steps per minute when walking, and a reduction in time taken to make a full stride, and the time stood on both feet while walking when compared to those taking placebo. All of this would tentatively suggest an improvement in walking ability in the UDCA group, however the small number of participants means that the results must be approached with caution. However, the MDP-UPDRS-III clinical rating scale showed that both those taking UDCA and placebo experienced an improvement in their Parkinson’s symptoms during the study.

The study also looked at effects of UDCA on non-motor symptoms, such as depression; on a depression rating scale (MADRS), scores showed a small but important increase in the UDCA group, compared to the placebo group, though scores were overall still far below the cut off that indicates depression.

What do the findings mean going forward for people with the disease?

The study shows an improvement, or comparatively slower decline, in walking ability in the UDCA group, in addition to a slower progression of movement symptoms on the standard rating scale, suggesting UDCA has potential as a new Parkinson’s drug. Though the results of this study seem promising for the safety of UDCA, which was its primary aim, the study is limited by its small number of participants, and therefore a larger trial is needed to confirm whether UDCA can slow down the progression of Parkinson’s.

This study can be found at
Wiley Online Library DOI: 10.1002/mds.29450

Paper title
A Double-Blind, Randomised, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson’s Disease

Author list
Payne, T., Appleby, M., Buckley, E., van Gelder, L. M. A., Mullish, B. H., Sassani, M., Dunning, M. J., Hernandez, D., Scholz, S. W., McNeill, A., Libri, V., Moll, S., Marchesi, J. R., Taylor, R., Su, L., Mazza, C., Jenkins, T. M., Foltynie, T. and Bandmann, O.

Publication details including date of publication.
Movement Disorders, Published May 2023

Clinical trial results for UDCA as a new drug for Parkinson’s Disease - Readable Research 

Lay summary by Rhiannon Brown, reviewed by Dr Tom Payne & a Parkinson’s disease lay panel

Background

Parkinson’s Disease involves the progressive loss of brain cells that leads to symptoms such as muscle stiffness, tremors and difficulty walking. It is unclear why people with Parkinson’s lose these brain cells, but we know that two tiny cell components, called mitochondria and lysosomes, are commonly affected. Mitochondria act as batteries to provide the energy that cells need to survive; lysosomes recycle damaged parts of cells (including damaged mitochondria) so that they can stay healthy. Lots of previous research has shown that in Parkinson’s Disease, the mitochondria and the lysosomes are not working correctly, which may contribute to the development of Parkinson’s.

Why is the study important?

There are over 135,000 people with Parkinson’s in the UK (Parkinson’s UK, 2023) and each person with Parkinson’s is unique. This could be through the specific problem in the brain cells causing their Parkinson’s, the symptoms they experience, or how their condition progresses over time. This means that it is very hard to find a cure that works for everyone. Consequently, many researchers are looking for similarities between people so they can group those with similar versions of the disease into smaller and more treatable groups.

One possible way that people can be grouped is by the type and extent of damage to their mitochondria and lysosomes. However, it is difficult to investigate the condition of mitochondria and lysosomes as they are very small and located inside the body, therefore it is important to trial different methods to find the best approach.

What did the authors do and how did they do it?

The authors took 35 people with Parkinson’s and 25 healthy people without Parkinson’s and compared two methods for assessing the number and function of the mitochondria and lysosomes, in order to evaluate the potential use of these methods for grouping patients. The two methods are as follows:

1. A small amount of the person’s skin was taken from their forearm and grown in a lab for multiple weeks until lots of skin cells were present. The cells were then analysed using advanced microscopes.

2. Images of two areas of the brain affected in Parkinson’s were recorded using a specialised MRI scanning technique. Rather than using it to produce images of the brain (the most common use of MRI scanners in clinical practice) they used a different technique to measure how well the brain cells produced energy (which reflects how well the mitochondria are working: more energy = better mitochondria).

What are the results?

The results from both methods showed that the number and function of the mitochondria and lysosomes can be both greatly increased or decreased in people with Parkinson’s. This contrasts with the results for healthy people which are much more similar to each other. This agrees with previous research that different people with Parkinson’s have different amounts and type of damage to their mitochondria and lysosomes and therefore it is feasible to group them into smaller, more similar groups. This could be advantageous for finding specific and more personalised treatments. Both methods showed similar results, however the brain imaging approach (method two) is a lot easier and quicker and therefore more likely to be of use in situations when people need grouping quickly, such as in clinical trials.

What do the findings mean going forward for people with the disease?

The findings add further evidence that people with Parkinson’s can have varying and different problems in their cells which reinforces the need for grouping them when investigating new drugs. For example, some people with Parkinson’s possess a larger number of mitochondria and lysosomes, however they are damaged and do not work very well. These people would likely not benefit from a drug that increases the number of mitochondria or lysosomes but instead would need a drug that can improve their function. Testing a specific drug on a targeted group of people with Parkinson’s, could increase the likelihood of positive outcomes in clinical trials and new drugs being approved for use.

This study can be found at
https://doi.org/10.1093/brain/awad364

Paper title
Multimodal assessment of mitochondrial function in Parkinson’s disease

Lead Authors
Thomas Payne, Heather Mortiboys, Oliver Bandmann

Publication details including date of publication
Brain, Volume 147, Issue 1, January 2024.

Using two methods to investigate damaged mitochondria in Parkinson’s Disease - Readable Research 

Lay summary by David O’Brien, reviewed by Ian Coldicott and an MND lay panel

Background

Motor neuron disease (MND) causes damage to the nerves controlling muscles involved in movement, speech, swallowing and breathing. There is currently no cure, so the main focus is on treating the symptoms of MND and maintaining quality of life. MND affects both physical and mental wellbeing, and we know that depression, anxiety and fear are common in those who have MND. We also know that people with MND might benefit from psychological support to cope with such a devastating diagnosis, and adapt to their condition as it progresses over time.

Acceptance and Commitment Therapy (ACT) is a psychological therapy that involves acceptance of the condition, mindfulness, motivation, and behaviour change techniques. These allow the individual to live their life in a meaningful way despite their worries, fears and negative thoughts. ACT has already been shown to be beneficial for improving quality of life and mental wellbeing in other long-term health conditions, including muscle diseases and chronic pain. This large study involving 16 centres in the UK has found that ACT improves quality of life for people living with MND.

Why is the study important?

This is the first major clinical trial showing that a psychological therapy can be beneficial for improving quality of life and wellbeing in MND. The next steps will be to translate the benefit from this study into real-world quality of life benefits for people living with MND.

What did the authors do and how did they do it?

• This study was a type of clinical trial called a randomised controlled trial (RCT). This is considered the best way of working out if an intervention (like a drug, a device, or a psychological therapy, for instance) is really effective.

• Half the participants are randomly selected to receive the intervention (in this case Acceptance and Commitment Therapy) alongside their usual MND care, while half receive their usual MND care but do not receive the additional intervention. Sometimes a placebo, or dummy intervention, is used but this can be difficult when assessing interventions other than drugs.

• In this study, 97 participants received ACT in addition to their usual MND care and 94 received their usual care alone. 93 caregivers were also interviewed to assess the effect of ACT on carer burden, which is the physical and psychological strain on caregivers of someone with MND. Roughly half the caregivers involved were carers of a participant in the ACT group.

• The ACT group received up to 8 one-to-one sessions with a trained therapist, each lasting up to 1 hour, over 4 months. Around 1 in 10 of the included participants reported depression and 2 in 10 reported anxiety at the beginning of the study. The majority did not report any psychological problems.

• The study team assessed the participant’s change in overall quality of life, as well as changes in depression, anxiety and caregiver burden. These were assessed at 6 months and 9 months after entry into the study..

What are the results?

The participants who received ACT in addition to their usual care reported a better overall quality of life, when this was assessed using the McGill Quality of Life Questionnaire (a common quality of life questionnaire used in research that asks questions about physical, psychological, emotional and existential wellbeing) after 6 months and 9 months. They also had a significantly lower level of depression on average, and fewer participants in the ACT group developed depression compared with the usual care group. Statistical tests showed that this effect is likely to be meaningful for people with MND. There were no significant changes in the levels of carer burden between the two groups.

Around 8 in 10 participants in the ACT group were satisfied with this intervention, and around 7 in 10 attended all 8 sessions. There were no serious negative effects associated with ACT. The majority of ACT sessions were delivered by video call, which is more inclusive for many people with MND who live remotely or struggle to attend a face to face appointment.

What do the findings mean going forward for people with the disease?

Following the evidence that ACT can improve quality of life and mental wellbeing in people with MND, there will be a good case for providing this therapy as part of routine care. This will take some time, as it will require the necessary training and funding to be provided so that MND centres can deliver this. There are plans to develop an online self-help version of ACT to allow more people access to this intervention. It may be that some individuals benefit from ACT more than others, and this may be explored in future studies.

This study can be found at
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00533-6/fulltext  

Paper title
Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK 

Lead Authors
Rebecca L. Gould, Christopher J. McDermott,…, on behalf of the COMMEND Collaboration Group 

Publication details including date of publication
Lancet 2024; 403: 2381–94 Published Online May 9, 2024 https://doi.org/10.1016/ S0140-6736(24)00533-6 

Trial indicates psychological therapy can improve quality of life for people living with MND - Readable Research