Circulating Biomarkers in Neuromuscular Disorders: What Is Known, What Is New

Abstract

The urgent need for new therapies for some devastating neuromuscular diseases (NMDs), such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis, has led to an intense search for new potential biomarkers. Biomarkers can be classified based on their clinical value into different categories: diagnostic biomarkers confirm the presence of a specific disease, prognostic biomarkers provide information about disease course, and therapeutic biomarkers are designed to predict or measure treatment response. Circulating biomarkers, as opposed to instrumental/invasive ones (e.g., muscle MRI or nerve ultrasound, muscle or nerve biopsy), are generally easier to access and less “time-consuming”. In addition to well-known creatine kinase, other promising molecules seem to be candidate biomarkers to improve the diagnosis, prognosis and prediction of therapeutic response, such as antibodies, neurofilaments, and microRNAs. However, there are some criticalities that can complicate their application: variability during the day, stability, and reliable performance metrics (e.g., accuracy, precision and reproducibility) across laboratories. In the present review, we discuss the application of biochemical biomarkers (both validated and emerging) in the most common NMDs with a focus on their diagnostic, prognostic/predictive and therapeutic application, and finally, we address the critical issues in the introduction of new biomarkers.

Patient-Reported Outcome Measures in Neuromuscular Diseases: A Scoping Review

“…In contrast, functional status, general health perceptions, and QoL are valuable because they provide a more holistic assessment of the impact of symptoms on a person’s overall functioning (Vand, [ 4 ]. The number of clinical trials and the use of PROMs in clinical practice and research in NMD is expected to continue to increase.…”

N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy

“…Further, biomarkers within circulation provide a snapshot of muscle health throughout the body. However, CK is known to have wide intra- and inter-subject variability [ 52 , 53 ], is thought to passively leak from the muscle, and decreases with age in DMD [ 53 ], limiting its usefulness as a PD biomarker of therapeutic efficacy, especially in older participants.…”

Longitudinal Assessment of Creatine Kinase, Creatine/Creatinineratio, and Myostatin as Monitoring Biomarkers in Becker Muscular Dystrophy

“…Markers related to muscle structure or integrity are of specific interest due to the replacement of muscle tissue by fat a prominent sign of pathology in a muscle wasting condition like BMD. Creatine kinase (CK), commonly used as a diagnostic biomarker in muscular dystrophies, may not be optimal to monitor the disease due to the fact that its serum levels change due to both the membrane pathology and the amount of remaining muscle mass, next to other factors like seasonal variation and dependence on physical activity 12 . Alternatively, creatine, derived from diet or synthesized in liver, is nonenzymatically converted to creatinine in muscle at a constate rate.…”

“…Creatine kinase (CK), commonly used as a diagnostic biomarker in muscular dystrophies, may not be optimal to monitor the disease due to the fact that its serum levels change because of both the membrane pathology and the amount of remaining muscle mass, next to other factors such as seasonal variation and dependence on physical activity. 12 Alternatively, creatine, derived from diet or synthesized in the liver, is nonenzymatically converted to creatinine in muscle at a constant rate. Therefore, the conversion of creatine to creatinine is more closely related to the amount of preserved muscle tissue where this conversion takes place.…”