Changes in Leptin, CCL16 and sTNF-RII as a Distinctive Plasma Immune Profile in Patients with Fast Progressing ALS
Vincent Picher-Martel1, Hejer Boutej1, Pierre Cordeau1, Hannah Kaneb2, Jean-Pierre Julien1, Angela Genge2, Nicolas Dupre3, Jasna Kriz1
1CERVO Brain research centre, 2Mcgill University, 3CHU de Quebec - U Laval
Objective:

To establish a unique immune molecular signature in ALS patients and determine whether alterations in inflammatory cytokines may serve as predictors of the rate of disease progression in ALS.

Background:

Amyotrophic lateral sclerosis (ALS) is clinically highly heterogeneous disease with survival rate ranging from months to decades. Approximately 10-20% of patients develop a rapidly progressive disease and may die within the first year. Therefore, there is an increasing need for an early detection of unique molecular signatures associated with more aggressive forms of disease as it may help identify therapeutic targets. Growing evidence suggests that chronic deregulation of immune response may represent one key pathogenesis mechanism.

Design/Methods:

We measured 62 immune markers in plasma of sporadic ALS patients (sALS) using cytokines array. We recruited 45 sALS patients and 35 age-matched healthy controls. The immune profiles were then compared between normal (37) vs fast progressing ALS (8).

Results:

We found that leptin, an important metabolic sensor, was significantly downregulated in plasma of sALS patients and more importantly in fast progressing disease, while immune markers CCL16 and sTNF-RII were significantly increased in rapidly progressing disease as compared to normal ALS. Multiple logistic regression revealed that the combination of all three markers had 87.5% sensibility and 91.9% specificity for the diagnosis of rapidly progressing disease. We also found that leptin was significantly downregulated in plasma of SOD1G93A mice from pre-onset to late disease stage. The downregulation in leptin was caused by an increased in levels of phospho-AMPK in mice adipocytes and in adipocytes exposed to fast sALS patients' plasma.

Conclusions:

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. This unique immune/metabolic profile may cause dysfunction in metabolic homeostasis by hyperactivation of AMPK pathways in adipocytes.