High Creatinine Kinase Levels Predict Slower Progression in ALS, Study Finds

Levels of creatinine kinase — a marker of muscle damage — are elevated in most amyotrophic lateral sclerosis (ALS) patients and appear to be significantly higher among those whose disease progresses at a slower pace, a study in patients and mice shows.

These findings suggest that this protein, whose rise appears to be specific to ALS and not to other neurodegenerative diseases, may be used to predict the rate of disease progression among ALS patients.

The study, “Creatine Kinase and Progression Rate in Amyotrophic Lateral Sclerosis,” was published in the journal Cells.

Biomarkers that help to inform about disease progression are valuable tools for determining how a disease will change over time, and to objectively measure the effectiveness of treatments.

In ALS, patients normally experience an increase in their creatinine kinase levels, which has been associated with the loss of motor neurons (the nerve cells involved in voluntary movement), loss of connection between nerves and muscles, and muscle wasting.

But it is unclear if this rise in creatinine kinase is a compensatory mechanism to counter muscle damage, or if it is a feature of ALS that helps predict disease progression.

A team of researchers in Italy measured blood levels of creatinine kinase in 126 ALS patients, with an average age of 66, whose symptoms had appeared about 26 months before entering the study.

As a control group, the team examined 88 patients (mean age, 65) with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), an autoimmune disease in which the protective myelin sheath is lost and nerve cells die, causing motor symptoms in about 94% of these people.

The reasoning for this control group was that CIDP patients have distinct disease mechanisms, but the disease affects their motor neurons in ways similar to ALS patients. This helps researchers understand if increases in creatinine kinase are in fact a compensatory mechanism.

Results showed that ALS patients with spinal-onset disease (which begins with weakness in the arms and legs) had higher levels of both creatinine kinase and another protein involved in muscle function, myoglobin, than did patients with bulbar-onset ALS (which begins with weakness in the muscles for speech, chewing, and swallowing).

These two proteins were also significantly higher in patients with slow progressing disease — defined as a 0.5 point or lesser monthly reduction in ALS functional rating scale-revised (ALSFRS-R) scores since symptom onset — compared with fast progressing patients.

Researchers then measured creatinine kinase levels at four, eight, 12, and 16 months after enrollment in the study. Levels remained significantly higher in slow progressors until one year of follow-up, showing no differences among groups only at 16 months.

From study start to month 12 month, creatinine kinase levels were also significantly associated with ALSFRS scores, with higher protein levels predicting higher scores (or better function in patients).

But the association was logarithmic, meaning that “for low blood CK [creatinine kinase] levels, minor variations in CK levels are associated with great variations in ALSFRS-R score,” the researchers wrote.

A comparison of creatine kinase and myoglobin levels among ALS patients and controls demonstrated that both these proteins were significantly elevated in ALS, suggesting that a rise in these proteins was specific to this disease.

The researchers then confirmed their findings in ALS mouse models, demonstrating that a model with slow progressing disease had higher creatinine kinase levels than another model whose disease progressed at a faster pace. These animal findings also suggested that slow progressing mice do progress at slower rates because they have greater muscle mass, and are more able to counter disease mechanisms for longer periods.

Overall, “serum CK and Mb [myoglobin] can be a useful tool to predict and monitor ALS disease progression, as higher levels are linked to a slow progression of disease,” the researchers concluded.

They also suggest “a central role of the muscle as a possible therapeutic target in ALS,” since the two muscle proteins examined in this study are not at elevated levels in other diseases also involving motor neuron damage.