Researchers have found a unique immune molecular signature that can distinguish amyotrophic lateral sclerosis (ALS) patients with rapidly progressing disease and that may help identify new potential targets for the disease.
This signature is the simultaneous presence of low levels of leptin (a metabolism- and immune-related protein) and higher levels of two immune molecules, CCL16 and sTNF-RII.
Reduced leptin levels were found to be associated with overactivation of AMPK — a metabolic-sensing enzyme known to regulate leptin production — in fat cells, or adipocytes, of a mouse model of ALS.
As such, AMPK, which stands for adenosine 5′-monophosphate-activated protein kinase, may be a future target of ALS therapeutic approaches.
The results were presented by Vincent Picher-Martel, MD, PhD, of the CERVO Brain research center and Laval University, in Canada, in an oral presentation at the 2021 virtual American Academy of Neurology Annual Meeting, running April 17–22.
The presentation was titled “Changes in Leptin, CCL16 and sTNF-RII as a Distinctive Plasma Immune Profile in Patients with Fast Progressing ALS.”
ALS is a neurodegenerative disease caused by the progressive loss of motor neurons, the specialized nerve cells that control voluntary movement. ALS symptoms and progression can widely vary from patient to patient, and 10%–20% of patients develop a rapidly progressive form of the disease that leads to death in the first year.
“Therefore, there is an increasing need for an early detection of unique molecular signatures associated with more aggressive forms of disease,” the researchers wrote, as it may help predict how a disease will develop (prognosis) and identify potential therapeutic targets.
As abnormal immune responses are increasingly seen as key contributors in ALS, Picher-Martel and colleagues set out to identify a unique immune molecular signature of rapidly advancing ALS.
They analyzed the levels of 62 cytokines in blood samples from 45 sporadic ALS patients and 35 age-matched healthy volunteers (usually the patient’s spouse) recruited at two tertiary centers in Quebec, Canada. Cytokines are a family of secreted proteins involved in immune and inflammatory responses.
Patients had a mean age of 63 years and had been living with the disease for a mean of 34 months (about three years). A total of 10 (22%) patients had bulbar onset disease, and eight (18%) showed rapidly progressing disease, as assessed with a 4-point or greater loss in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale in 12 weeks.
Bulbar onset ALS first affects muscles involved in speaking, swallowing, and breathing, and is typically more common in fast-progressing patients.
There were no significant differences between patients and healthy volunteers in parameters such as age, weight, and body mass index.
Results showed that ALS patients had significantly lower levels of leptin (a 17% reduction) compared with healthy individuals.
While leptin is historically known for its role in regulating hunger, energy expenditure, and overall energy balance, it also works as a cytokine, promoting the production of pro-inflammatory molecules, such as tumor necrosis factor (TNF)-alpha.
The levels of eight other pro- and anti-inflammatory cytokines, such as TNF-alpha, were also significantly reduced, but to a lesser extent (between 5%–8%), in ALS patients.
No cytokines were found to be significantly increased in ALS patients relative to healthy individuals.
The researchers then assessed cytokine differences between patients with and without fast-progressing disease. The groups did not differ in any of the evaluated demographic and clinical features, except for rate of disease progression.
The team found that the aggressive ALS form was associated with a trend toward lower leptin levels, and significantly higher levels of immune markers CCL16 and sTNF-RII, compared with the non-aggressive form.
CCL16 is a pro-inflammatory cytokine, while sTNF-RII has anti-inflammatory effects since it captures the TNF-alpha in the bloodstream, preventing it from exerting its pro-inflammatory actions.
The levels of leptin, CCL16, and sTNF-RII were not affected by body mass index.
Further analysis revealed that the combination of all three markers allowed the correct identification of 87.5% of rapidly progressing ALS patients and the correct determination of 91.9% of cases with a normal disease progression, providing “a negative predictive value of 97.1%,” Picher-Martel said.
“This means that for one patient without a decrease in leptin and an increase in CC16L and sTNF-RII, the chance of being fast progressor is almost absent,” he said.
The researchers also found that leptin was similarly suppressed in a mouse model of ALS across disease stages, and even before disease onset, suggesting that this metabolic/immune molecule may have a key role in the development and progression of ALS.
Additional studies in this model also revealed that this leptin drop was linked to a significant increase in the activation of AMPK, a known regulator of leptin production, in adipocytes of male and female mice and across different disease stages.
This link was also confirmed in human adipocytes grown in the lab, which showed a significant increase in activated AMPK levels and a significant reduction in leptin when exposed to blood from people with fast-progressing, sporadic ALS. This leptin reduction was suppressed in the presence of an AMPK inhibitor.
These findings suggest that overactivation of AMPK may underlie the lower-than-normal levels of leptin found in the blood of ALS patients, including those with fast progressing disease.
“We propose that the combination of decreased plasma leptin levels and up-regulation in CCL16/sTNF-RII may be used as prognostic biomarker to identify fast progressing ALS patients,” the researchers wrote.
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