By Lucy Piper, medwireNews Reporter
medwireNews: Circulating endocannabinoids (eCBs) are associated with amyotrophic lateral sclerosis (ALS) disease activity and progression, demonstrating potential prognostic value, report researchers in the European Journal of Neurology.
They also found that individuals with a specific clinical subtype of ALS, namely aggressive disease and loss of appetite, had a unique profile of eCBs and associated mediators, receptors, and enzymes (termed endocannabinoidome [eCBome]) that differed to that of other individuals with neurological diseases.
“Therefore, this study lays the grounds for the use of eCBs and eCB-like metabolites both as biomarkers of disease activity and, hopefully, for therapeutic purposes,” say Raffaele Dubbioso (University of Naples Federico II, Italy) and colleagues.
They explain that the eCB system is “a perfect candidate biomarker for patients with ALS,” as it plays a “crucial role in the regulation of metabolism and eating behaviour, with its receptors (CB1R and CB2R) expressed in the brain areas and peripheral organs regulating energy metabolism, immune reactions, inflammatory responses and many other cell functions.”
The team measured blood levels of the two major eCBs anandamide (AEA) and 2-arachidonoylglycerol (2-AG), as well as the AEA congeners palmitoylethanolamide (PEA), oleoylethanolamide (OEA), eicosapentaenoylethanolamide (EPEA), 2-docosaheaenoylglycerol (2-DHG), and docosahexaenoylethanolamide (DHEA) in 65 patients with ALS (63% men) who were aged a mean of 68 years and had a median disease duration of 27 months.
For comparison, serum levels of eCBs were also measured in 16 patients with other neurodegenerative diseases, such as hereditary motor neuropathy, Parkinson’s disease, and primary lateral sclerosis, and 32 healthy controls, all of whom were matched with the ALS patients according to age and sex.
Levels of AEA, 2-AG, PEA, OEA and EPEA were significantly higher in patients with ALS than in individuals with neurodegenerative diseases and healthy controls. Levels of 2-AG, OEA and EPEA were also significantly higher in patients with neurodegenerative diseases than in controls, suggesting that “the level of these mediators does not appear to be disease specific,” say the investigators.
Nevertheless, eCBome mediator levels differed significantly across ALS clinical stages, for AEA, 2-AG, PEA, OEA and EPEA, but not for 2-DHG and DHEA, and the researchers found that the greatest differences between healthy controls and ALS patients were seen in patients with more advanced disease and higher levels of circulating eCBome mediators.
Longitudinal analysis involving 46 of the ALS patients showed that AEA, PEA, OEA and EPEA all significantly increased over a median follow-up of 4.5 months, whereas 2-DHG levels significantly decreased and levels of DHEA remained unchanged.
Moreover, ALS patients who progressed to aggressive disease according to monthly decline on the ALS Functional Rating Scale Revised (ALSFRS-R) experienced significantly greater increases in OEA and EPEA levels than patients whose disease progressed more slowly.
The researchers highlight that the eCBome mediator levels showed prognostic ability in multivariate analysis of survival. Four were significantly associated with shorter survival, namely high levels of PEA (≥1.17 pmol/mg), OEA (≥1.23 pmol/mg), EPEA (≥0.04 pmol/mg) and 2-DHG (≥165 pmol/mg), with respective crude hazard ratios of 5.10, 7.49, 5.57, and 0.34, respectively. And after adjustment for confounding factors, PEA and OEA levels remained significantly associated with shorter survival alongside older age at onset and faster monthly decline on the ALSFRS-R.
When the team included these four eCBome mediators in a cluster analysis, two distinct clusters were identified. Cluster 1 included 47.7% of patients who appeared to have mild ALS, with few observed differences compared with individuals with other neurodegenerative diseases or controls.
Conversely, the 52.3% of patients in cluster 2 were characterised by higher levels of PEA, OEA and EPEA, and lower levels of 2-DHG than those seen in patients in cluster 1, and these were associated with more severe disease, rapid disease progression, significantly shorter survival time, and appetite loss.
While Dubbioso and colleagues acknowledge that further study is needed to “shed light on the molecular mechanism(s) causing the eCBome dysregulation and its role in ALS,” the researchers conclude that circulating eCB profiles could “[pave] the way to a personalized, rather than a ‘one-fits-all,’ therapeutic approach targeting the endocannabinoidome.”
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Eur J Neurol 2024; doi:10.1111/ene.16400