Possible blood biomarkers of Parkinson’s fatigue identified

Research focuses on phosphorylated alpha-synuclein and TNF-a

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Blood levels of tumor necrosis factor alpha (TNF-a), an inflammatory molecule, and phosphorylated alpha-synuclein, a Parkinson’s disease biomarker, could be used to distinguish Parkinson’s patients with or without fatigue.

Those findings from a recent study suggest the two markers may be  “promising biomarkers in discriminating PD [Parkinson’s disease] with fatigue from PD without fatigue,” the researchers wrote.

The study, “Plasma TNF-α and phosphorylated α-syn are associated with fatigue in patients with Parkinson’s disease,” was published in the Journal of Neuroimmunology.

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Fatigue is a common nonmotor symptom of Parkinson’s disease, with reports indicating its presence in anywhere from 30%-70% of patients, according to researchers.

Yet, the mechanisms by which fatigue arises in the neurodegenerative disease are not completely known, and biomarkers for this troublesome symptom are lacking.

Inflammation plays a key role in Parkinson’s, contributing to its onset and progression. Inflammatory signaling molecules called cytokines are found at higher-than-normal levels in circulation among Parkinson’s patients.

It’s possible that cytokine levels also might be biomarkers of Parkinson’s fatigue. A few studies have linked various cytokines to the symptom, but the findings have not been consistent.

Blood levels of alpha-synuclein, the protein that toxically accumulates in the Parkinson’s brain, also are thought to be a general disease biomarker. Specifically, a form of the protein that’s undergone a modification called phosphorylation is thought to best distinguish Parkinson’s patients from healthy people.

It is not known whether phosphorylated alpha-synuclein might similarly serve as a biomarker for fatigue in Parkinson’s.

In this report, the scientists discussed findings from a study wherein they evaluated the relationship between fatigue, cytokines, and phosphorylated alpha-synuclein among 63 Parkinson’s patients seen at a hospital in China from 2021 to 2023.

Assessment with the Fatigue Severity Scale

Fatigue was assessed with the Fatigue Severity Scale (FSS). With scores ranging from 9-63, a score of 36 or more is considered clinically relevant fatigue. This was seen in 35 of the patients.

Fatigued patients were significantly older, had been living with Parkinson’s longer, had more severe motor symptoms, worse health-related life quality, and lower cognition, compared to people without fatigue.

Analyses indicated that these clinical features were correlated significantly with FSS scores. Higher FSS scores, indicating more fatigue, were associated with older age, longer disease duration, motor symptom severity, worse life quality, and worse cognition.

Fatigued patients had significantly higher levels of certain cytokines, namely interleukin-1-beta (IL-1B), interleukin-18 (IL-18), and TNF-alpha than non-fatigued patients. They also had higher levels of phosphorylated alpha-synuclein.

All of these markers correlated positively with FSS scores, where higher scores were linked to higher biomarker levels.

Risk factors classified as strong or significant

In final analyses, lower life quality — or a higher score on the Parkinson’s Disease Questionnaire (PDQ-39) — as well as higher TNF-alpha were considered strong risk factors for fatigue in Parkinson’s disease. Phosphorylated alpha-synuclein levels were considered a significant risk factor for fatigue in Parkinson’s disease.

Alone, phosphorylated alpha-synuclein had about a 66% ability to accurately detect the symptom, and TNF-alpha had a 79% ability.

When used together, the detection ability rose to about 80%, “suggesting that the combination may probably be a better predictive tool for the occurrence of fatigue in [Parkinson’s],” the researchers wrote.

The scientists emphasized that their findings do not establish a cause-effect relationship. That means it is not known whether TNF-alpha and phosphorylated alpha-synuclein directly contribute to fatigue or not, but only that their levels are linked to the symptom.

“Further large-scale prospective cohort studies warrant exploring the diagnostic biomarkers for fatigue in PD,” the researchers concluded.