The levels of two types of fatty molecules — anandamide and glucocerebroside — are significantly altered in people with Parkinson’s disease, and associate with sensory nerve damage and chronic pain, a study reported.
These findings suggest that patients with sensory problems and pain may benefit from available treatments that help to normalize these types of molecules.
The study, “High Glucosylceramides and Low Anandamide Contribute to Sensory Loss and Pain in Parkinson’s Disease,” was published in the journal of Movements Disorders.
Two-thirds of Parkinson’s patients have chronic pain, the main non-motor symptom of the disease, which may or may not respond to antiparkinsonian medication.
Previous studies have suggested that Parkinson’s-associated pain is related to a dysfunction in the endocannabinoid system, poor inhibitory pain control, and damage to sensory nerves — those responsible for carrying sensory information, such as touch, pressure, pain, and temperature, to the brain.
The endocannabinoid system involves several cell surface receptors, mainly in the brain, that are activated by fatty molecules called cannabinoids. These include those naturally produced by the body, such as anandamide, and those derived from the cannabis plant.
A type of fatty molecule known to promote the toxicity of alpha-synuclein, called glucocerebroside or glucosylceramide, appears to also be dysregulated in Parkinson’s, potentially contributing to its development and progression.
Notably, low activity levels of beta-glucocerebrosidase, the enzyme responsible for breaking down glucocerebroside, were found among Parkinson’s patients with and without mutations in GBA, the enzyme’s coding gene.
While these findings suggest that fatty molecule dysregulation may contribute to Parkinson’s-associated sensory nerve damage and pain, supporting evidence is limited.
Researchers in Germany and Israel set out to describe sensory problems in Parkinson’s patients, and assess their potential association with unbalances in the levels of several fatty substances.
Their study involved two groups of participants. The first included 128 Israeli Parkinson’s patients (who typically have a higher frequency of GBA mutations) and 224 young and healthy people in Germany (used as controls), while the second had 50 German patients and 50 matched healthy German controls for deeper analyses.
Patients’ pain was analyzed using intensity ratings and questionnaires, and the main sensory impairments through quantitative sensory tests (QST). QST determined the perception and pain thresholds for cold and warm temperatures, mechanical stimuli, and vibration by stimulating the skin and comparing the results to normative values.
Blood levels of multiple fatty molecules were measured both in patients and controls.
Results showed no major differences between the two groups of Parkinson’s patients in terms of age, sex, disease duration and severity, medication, analgesics, and pain ratings.
Chronic pain was present in 74% of German and 66% of Israeli patients, and was reported by 40% of healthy participants. The main sensory impairments in Parkinson’s patients involved a loss of thermal (cold and warm) and vibration perception, mostly on the feet, along with an increased sensitivity to mechanical pain, particularly on the hands.
These data pointed to a Parkinson’s-associated damage of distinct sensory nerves, consistent with previous findings.
Patients from both groups also had significantly higher levels of glucocerebrosides and lower levels of anandamide, compared with healthy controls.
These changes appeared to be more pronounced in patients with higher pain intensity ratings and with sensory problems, independent of the presence of chronic pain, especially for glucocerebroside.
Those reporting nerve-associated pain or that related to involuntary movements also had higher glucocerebrosides levels and lower anandamide levels than those without pain or with pain affecting the muscles, tendons, and bones.
These findings highlighted that Parkinson’s patients both with or without chronic pain show sensory dysfunction, which is at least partly due to the loss of anandamide and the accumulation of glucocerebrosides.
Such changes are “theoretically amenable to available medication,” the researchers wrote.
They noted that anandamide deficiency may be treated with cannabis-based products, while glucocerebrosides levels may be lowered using current therapies for Gaucher disease, which is caused by a toxic buildup of glucocerebroside due to GBA mutations.
Gaucher treatments include enzyme replacement therapy, which involves the administration of a functional beta-glucocerebrosidase, and substrate reduction therapy, in which the metabolic step of generating glucocerebroside is suppressed.
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