ALS Blood Inflammatory Markers Correlate with Disease Severity, Study Shows

An analysis of inflammatory marker levels in blood samples from amyotrophic lateral sclerosis (ALS) patients, improves patient categoration and may help design future ALS clinical trials, according to a new study.

The study “Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis,” was published in the journal Neurology: Neuroimmunology & Neuroinflammation.

ALS disease, in its early stages, triggers the innate immune system with the activation of different cell types including microglia, T-cells, dendritic, and antigen-presenting cells; and the release of inflammatory molecules such as cytokines, C-reactive protein (CRP), and ferritin.

Although not easily detected, previous studies reported ALS-induced changes at a systemic level included a decrease in the frequency of regulatory T cells in blood from individuals with a faster disease progression.

In the new study, researchers investigated how the expression of blood circulating markers of inflammation and neuromuscular disease changes in ALS individuals when compared to healthy controls.

The team recruited 95 patients with ALS and 88 neurologically healthy controls between 2009 and 2015.

From 59 of the 95 patients with ALS, they retrieved serial blood samples and clinical information, over a maximum follow-up period of 48 months.

Researchers analyzed blood samples for the levels of circulating biomarkers – creatine kinase (CK), ferritin; and 11 cytokines which are small proteins that are secreted by immune cells that act as chemical messengers, allowing immune cells to communicate with each other. The levels of circulating biomarkers were then correlated with disease progression and neurofilament light chain (NfL) levels. NfLs are the main byproducts of neuroaxonal breakdown, and are used as biomarkers of neurodegeneration in ALS.

Researchers found significantly higher levels of CK, ferritin, and several cytokines including  interleukins  such as  IL-1 beta, IL-2, IL-8, IL-12p70, IL-4, IL-5, IL-10, and IL-13; and lower levels of interferon (IFN)-gamma in blood samples from the study subjects with ALS.

After analyzing all the combined markers, researchers found that three cytokines, IL-6, TNF-alpha, and IFN-gamma, are the strongest and coherent disease signals. Additionally, researchers detected that high levels of ferritin and IL-2 are predictors of poor survival; TNF-alpha levels were positively correlated with NfL. Additionally,  IL-6 was the only marker showing increased expression at disease end-stages.

In conclusion, the neuromuscular features of ALS are linked to a systemic regulation of inflammatory markers, particularly those linked to immune responses mediated by T cells. The results suggest that stratification of ALS patients using the prognostic value of circulating IL-2/ferritin levels is a potential strategy for clinical trial design in ALS.

Researchers also concluded that further validation with larger and independent ALS cohorts is needed.