Sarcopenia as a biomarker for people with multiple long-term conditions: an epidemiological perspective

Supervisors:

• Dr Thomas Wilkinson tjw26@le.ac.uk
• Dr Safoora Gharibzadeh sgh18@leicester.ac.uk
• Professor Kamlesh Khunti kk22@le.ac.uk

Project Description:

Background 

The term ‘multiple long-term conditions’ (MLTCs) refers to the co-existence of two or more chronic conditions (physical or mental) in a person [Navickas et al. 2016]. There are ~14 million people in England living with MLTCs and this number is growing, in line with our ageing population. Early recognition, screening and treatment of MLTCs are vital to reduce morbidity and minimise the risks to individuals while reducing costs to the healthcare system.

One way to identify individuals at an earlier stage is through the use of biological and physiological markers (i.e., biomarkers) that predict the risk of developing MLTCs. A biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”.  The accumulation of MLTCs at older ages has been associated with various markers that may act as an early warning sign to better target interventions, aid the identification of preventive strategies and reduce the associated burden of MLTCs through better treatment.

Estimated to affect 10-30% of individuals [Petermann‐Rocha et al., 2022], sarcopenia is a syndrome characterised by a progressive decline in muscle mass and strength, with subsequent deterioration of functional performance and independence, and increased frailty, morbidity, and mortality. Partly driven by ageing, sarcopenia is accelerated and more prevalent in those with MLTCs [El-Sebaie and Elwakil, 2023]. Whether sarcopenia can act as an appropriate biomarker of MLTCs and whether it contributes to the development of MLTCs is unclear. Moreover, the emergence of long covid has also been thought to accelerate sarcopenia – in part through inflammation – although more work is needed in this area [Martone et al, 2022]. 

Our group recently identified that serum creatinine/cystatin C ratio – taken from two routine blood tests - was a valid and accurate biomarker of sarcopenia in UK Biobank [Wilkinson et al. data under review]; however, it is unknown how this biomarker may change over time and whether or not it offers any prognostic ability regarding the development of MLTCs or clinical outcomes (e.g., mortality, hospitalisation). Other promising biomarkers have been identified in the last few years and may represent useful parameters to explore sarcopenia and MLTCs (e.g., neurobiomarkers such as Neurofilament Light Chain Levels)) [Capo et a., 2023]. 

We hypothesise that sarcopenia may be a biomarker for the incidence and precursor in the development of MLTCs. This work has great potential to impact applied practice as identifying readily available biomarkers for MLTCs and long covid may support their diagnosis, facilitate the tracking of changes over time, and help clinical and therapeutic decision-making processes.

Aims and objectives 

The objectives for this studentship are:

1. To complete a systematic/scoping review of potential biomarkers of sarcopenia to inform possible variables in objective #2 (conducted per Cochrane and PRISMA methodology).

2. To complete an epidemiological analysis using UK Biobank to explore the following:
- What is the prevalence of sarcopenia (assessed using objective and blood biomarkers) across different pre-existing MLTCs and/or people with long covid?
- What is the association of sarcopenia with long-term clinical outcomes (e.g., mortality, hospitalisation) in people with pre-existing MLTCs and/or long covid?
- In those without pre-existing MLTCs, can sarcopenia be used as a prognostic ‘red flag’ / biomarker for the development of MLTCs and/or long covid?
- What are the validity and prognostic ability of other novel and promising biomarkers (from objective #1) with sarcopenia (e.g., neurobiomarkers such as Neurofilament Light Chain Levels)? 

This studentship will suit those with an interest in epidemiology, ‘big data’, biostatistics, ageing, and MLTCs. The student will be supported to disseminate their work through peer-reviewed journal publications and at appropriate medical conferences/meetings. 

The supervisory team consists of Dr Thomas Wilkinson (Research Fellow), Professor Kamlesh Khunti (Director of Leicester Real World Evidence Unit and NIHR Applied Research Collaboration East Midlands), and Dr Safoora Gharibzadeh (Research Fellow in Medical Statistics).

Potential impact/sustainability

This PhD studentship is linked to the NIHR Applied Research Collaboration East Midlands (https://arc-em.nihr.ac.uk/home) and Leicester Real World Evidence Unit (https://www.lrwe.org.uk/about) based at the Diabetes Research Centre. Successful completion by the right candidate is likely to lead to the submission of an NIHR (or similar) fellowship application. The student will be supported to apply for further grant funding through NIHR, MRC, Wellcome or similar. The proposed work has significant potential to impact future research in the area.

References 

Cesari M, Fielding RA, Pahor M, et al. Biomarkers of sarcopenia in clinical trials-recommendations from the International Working Group on Sarcopenia. J Cachexia Sarcopenia Muscle. 2012 Sep;3(3):181-90. doi: 10.1007/s13539-012-0078-2

El-Sebaie, M., Elwakil, W. Biomarkers of sarcopenia: an unmet need. Egypt Rheumatol Rehabil 50, 45 (2023). https://doi.org/10.1186/s43166-023-00213-w

Petermann‐Rocha, F., Balntzi, V., Gray, S. R., Lara, J., Ho, F. K., Pell, J. P., & Celis‐Morales, C. (2022). Global prevalence of sarcopenia and severe sarcopenia: a systematic review and meta‐analysis. Journal of cachexia, sarcopenia and muscle, 13(1), 86-99.

Capo X, Galmes-Panades AM, Navas-Enamorado C, et al. Circulating Neurofilament Light Chain Levels Increase with Age and Are Associated with Worse Physical Function and Body Composition in Men but Not in Women. Int J Mol Sci. 2023 Aug 13;24(16):12751. doi: 10.3390/ijms241612751.

Martone AM, Tosato M, Ciciarello F, et al. Sarcopenia as potential biological substrate of long COVID-19 syndrome: prevalence, clinical features, and risk factors. J Cachexia Sarcopenia Muscle. 2022 Aug;13(4):1974-1982. doi: 10.1002/jcsm.12931.

Navickas R, Petric VK, Feigl AB, Seychell M. Multimorbidity: What do we know? What should we do? J Comorb. 2016 Feb 17;6(1):4-11. doi: 10.15256/joc.2016.6.72. PMID: 29090166; PMCID: PMC5556462.