Findings from the largest biomarker study of people with Kennedy’s Disease, published in the journal Neurology, found a predictive biomarker to help in differential diagnosis and tracking clinical progression. Led by Dr Pietro Fratta from University College London, the research team highlighted the importance of markers of muscle mass rather than neuronal damage in Kennedy’s Disease, differentiating it from the slightly more common motor neurone disease (MND).
Kennedy’s Disease, also known as Spinal and Bulbar Muscular Atrophy (SBMA), is a rare genetic condition that leads to progressive weakening and wasting of muscles, particularly affecting the limbs and bulbar region. Caused by a mistake on the AR (androgen receptor) gene (positioned on the X chromosome), this condition mainly affects males, with a 50% chance of receiving the affected gene from their mothers (women can only be carriers of the genetic mistake without developing the disease).
Some of its clinical features, including muscle wasting and muscle twitching, make it similar to MND, which might often be the primary diagnosis. Similarly to MND, there are no treatments for Kennedy’s Disease, and the lack of biomarkers that would help track the outcome of a treatment and measure disease progression makes it difficult to develop new clinical trials. In this new study, researchers collected blood samples from people with Kennedy’s Disease, MND and healthy controls to measure the levels of three different proteins and distinguish the two conditions from each other as well as from ‘the norm’.
What can blood tell us about our health?
It turns out a lot! Our blood is pumped throughout our bodies and so, in addition to its main role to carry oxygen to all of our cells, it is also handy to act as a way to remove waste materials from damaged tissues. This is a normal occurrence that happens in all of us. When excessive damage is done to some of our tissue however, more waste products are ‘dumped’ into the blood, allowing us to detect a significant change to the levels of the waste product.
It has already been showed that in MND the levels of the neurofilament light chain (NfL) protein, occurring due to breakdown of neurones, are significantly increased compared to healthy individuals, indicating a substantial degeneration of motor neurones. Similar increase in NfL levels is also however found in other neurodegenerative diseases, making it difficult to distinguish the different types of neurodegeneration based purely on this marker.
But NfL isn’t the only protein occurring in the blood in conditions similar to MND, and we should look beyond markers of neuronal degeneration to find out more about the disease. As both MND and Kennedy’s Disease are neuromuscular conditions, we also need to consider the importance of markers of muscle degeneration. Creatinine is a waste product of our muscles due to general wear and tear and is usually produced at a fairly constant rate by the body (depending on overall amount of muscle). Someone with an unusually high muscle mass (such as body builders) is therefore expected to have higher levels of creatinine in their blood as opposed to people with half their muscle mass. Another protein, called creatine kinase (CK) is a protein present in the muscles, and its abundance in the blood can mark various conditions indicating damage to the muscle tissue (ranging from non-serious strain injury, to serious skeletal muscle damage or a heart attack). It therefore depicts whether a muscle is healthy or whether it has been damaged.
Looking at biomarkers of Kennedy’s Disease
The study recruited 93 people with Kennedy’s Disease, 53 people with MND and 73 healthy participants across two sites (London, UK and Padova, Italy), and collected their blood to analyse it for the presence and levels of three proteins: neurofilament light chain (NfL), creatinine and creatine kinease (CK). Evaluation of the disease severity was assessed by validated measures; ALSFRS-R (ALS Functional Rating Scale) for people with MND, and its equivalent, SBMAFRS, together with Adult Myopathy Assessment Tool (AMAT), for people with Kennedy’s Disease. Blood samples were also collected after 1 and 2 years to observe change in protein levels. In brief, these were the main findings:
- Neuronal damage: NfL. Levels of NfL were unchanged in people with Kennedy’s Disease (19 and 25 pg/mL in the UK and Italian cohorts, respectively), which compared to those of healthy participants (29 and 28 pg/mL). In the majority of the people, the levels remained stable across the 2-year follow-up period. In people with MND however, NfL levels were significantly higher and also distinguished people classed as fast progressors from slow progressors (365 and 112 pg/mL), confirming previous findings.
- Muscle mass. Creatinine levels were profoundly decreased in people with Kennedy’s Disease (54 and 52 μmol/L in UK and Italian cohorts, respectively) compared to MND (76 and 82 μmol/L in fast and slow progressors, respectively) and healthy controls (88 μmol/L). These reduced levels were also associated with the two measures of outcome (AMAT and SBMAFRS), showing that creatinine is a reliable predictor of disease progression in Kennedy’s Disease. Other studies previously conducted in Japan (2012, 2016) also found that decrease in creatinine levels corresponds to reduction in grip strength and 6-minute walk distance, confirming the connection between creatinine and loss of muscle mass in Kennedy’s Disease.
- Muscle damage. CK levels were significantly higher (951 and 940 U/L in UK and Italian cohorts, respectively) than in people with MND (307 and 274U/L in fast and slow progressors, respectively) and the healthy participants (273 U/L). Unlike with creatinine however, CK levels were not associated with measures of disease progression, which was suggested to be due to the more immediate effect of muscle degeneration.
Relating these results to the clinic
The importance of these findings becomes clearer when we consider the use of NfL, creatinine and CK levels to directly inform diagnosis and measure disease progression when trialling a new treatment. Although loss of lower motor neurones has been confirmed in people with Kennedy’s Disease, this study, together with previous findings from mouse models, highlights loss of muscle tissue as the fundamental indicator of the disease. Using a panel of the three proteins, NfL, creatinine and CK could therefore be used to:
- Confirm diagnosis of Kennedy’s Disease in initial blood testing where MND is considered, by showing normal levels of NfL protein.
- Objectively inform progression of the disease by using CK and creatinine levels as markers of muscle damage and mass, rather than focusing on markers of neuronal damage.
- Monitor improvement when testing a new treatment by observing decrease in CK levels (representing slowing down of muscle tissue breakdown) and increase in creatinine (linked to increase in muscle mass).
Commenting on the study results and their importance, Dr Pietro Fratta said: “Biomarkers are crucial for carrying out clinical trials and identifying effective treatments. This work supports the use of a muscle biomarker (creatinine) for Kennedy’s disease trials.
“This work also tells us something very important about the disease process in Kennedy’s. Although traditionally Kennedy’s is thought to be caused mostly by motor neurons degenerating, many studies in animal models had suggested muscles to be an important site of disease too. This study supports this to be the case also in patients. The analyses of blood samples from a very large number of patients confirm a strong damage of muscles. This is very important as it does show that future therapies will also need to be targeted to muscles directly“.
This study was possible only thanks to the incredibly strong participation to research of patients attending the Kennedy’s Clinic at the National Hospital in London and the University of Padova, funding from KDUK, Motor Neurone Disease Association, MRC and UCLH-NIHR-BRC, and is part of the “ALS Biomarker Study” (a longstanding study running in UCLP by Dr Malaspina).
- Dr Pietro Fratta leads the only clinic specific to Kennedy’s Disease in the UK – find out more about it here.
- Find out more about Kennedy’s Disease on our website.
- Read the original paper here.