Levels of 2 Key Proteins Not Seen to Be Altered by REM Sleep Disorder

Somi Igbene, PhD avatar

by Somi Igbene, PhD |

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People with Parkinson’s disease and rapid eye movement (REM) sleep behavior disorder — marked by acting out dreams, sometimes violently — showed no significant differences in their levels of tumor necrosis factor (TNF)-alpha, an inflammatory protein, and orexin, a protective protein, relative to patients without this sleep disorder or people with only the sleep disorder.

Further work in larger groups of Parkinson’s patients at differing disease stages are needed, its researchers suggested, as repeat studies show an association between REM sleep behavior disorder and synucleinopathies like Parkinson’s and Lewy body dementia.

The study, “Cerebrospinal fluid TNF-alpha and orexin in patients with Parkinson’s disease and rapid eye movement sleep behaviour disorder,” was published in Frontiers in Neurology.

REM sleep behavior disorder is characterized by muscle tension (“loss of muscle atonia”) during sleep that causes individuals to act out vivid dreams, risking injuries to themselves and others. It is known in people with synucleinopathies, or neurological disorders involving the alpha-synuclein protein, but can also affect those with no apparent neurological disease. In such cases, it is considered an idiopathic disorder, meaning of unknown cause.

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“Multicenter prospective cohort studies have shown that over 60% of iRBD [idiopathic REM sleep behavior disorder] developed overt [alpha]-synucleinopathies in a decade or more,” the research team in China wrote, and a “meta-analysis confirmed a risk of more than 90% at 14 years.”

Recent research shows that alpha-synuclein protein begins to accumulate in neurons regulating smell and digestion before a disorder’s movement symptoms become apparent. Identifying proteins that reflect signs of future problems could help in diagnosing diseases like Parkinson’s early.

Orexins are proteins that transmit messages between neurons (nerve cells) and play a protective role in Parkinson’s disease through “a variety of mechanisms,” the scientists noted. They also regulate sleep-wake cycles and may influence normal muscle relaxation during REM sleep. An animal study, moreover, supports a link between TNF-alpha, which has an established inflammatory role in Parkinson’s, sleep disorders, and orexin dysfunction.

That mouse study suggested that “repeated TNF challenge induces RBD-like behavior and sleep dysfunction in mice, as well as a decrease in learning, cognition, and memory,” the researchers wrote.

A team with Capital Medical University in Beijing explored whether TNF-alpha affects the orexin system in people with Parkinson’s and REM sleep behavior disorder.

In total, 145 adults diagnosed either with Parkinson’s and REM sleep behavior disorder (38 people; PD+RBD group), Parkinson’s without that disorder (55 people; PD-RBD group), or with idiopathic REM sleep behavior disorder but no neurological disease (52 people; iRBD group) were recruited to the study. All were being followed at the neurology department of the university’s hospital.

Their average ages were 64 for those with PD+RBD, 59 for the PD-RBD group, and 63 for those with iRBD. Men in the majority in both Parkinson’s groups, while more women than men were among patients with iRBD only.

Participants’ disease course, motor symptoms, sleep, cognition, anxiety, and depression levels were assessed through various scale tests; sleep behavior was evaluated using the REM Sleep Behaviour Disorder Questionnaire-Hong Kong (RBDQ-HK).

Researchers collected blood and cerebrospinal fluid — CSF, the liquid that surrounds the brain and spinal cord — samples from 20 patients (13 with Parkinson’s) to measure TNF-alpha and orexin levels. CSF samples from 10 healthy people were also collected and used as controls.

Unified Parkinson’s Disease Rating Scales part III (UPDDRS-III) scores, which reflect motor function, were significantly higher (worse) in Parkinson’s patients compared with those with idiopathic REM sleep disorder.  Among people with Parkinson’s, UPDDRS-III scores were also higher — although not significantly — in the PD+RBD group than the PD-RBD, “consistent with previous research that PD [Parkinson’s disease] patients with RBD have more severe motor impairment,” the researchers wrote.

Conversely, REM sleep disorder scores were significantly higher in the iRBD group than in either group of Parkinson’s patients.

People with Parkinson’s showed no significant difference in disease stage, sleep quality, depression, and sleepiness scores regardless of sleep disorder status. A trend toward lower cognition scores, as measured with the Montreal Cognitive Assessment or MoCA scale, was evident among  the PD+RBD group relative to patients without this sleep behavior disorder, but it did not reach statistical significance, meaning it could be due to chance.

“Many studies have found that PD patients with RBD [REM sleep behavior disorder] have a higher risk of cognitive impairment,” the researchers wrote.

Results also revealed that Parkinson’s patients with this sleep disorder were more anxious than those with iRBD but no neurological disease.

No significant differences in TNF-alpha protein levels in blood and CSF samples were seen among the three patient groups. Interestingly, orexin levels were abnormal (less than 200 picograms/milliliter or pg/ml) in all these patients, but not significantly lower than orexin levels in CSF samples from healthy controls (218 pg/ml).

Likewise, no significant association was found between TNF-alpha and orexin protein levels.

“Despite the fact that the differences were not statistically significant, our study found that orexin levels in the three groups decreased when compared to controls,” the researchers wrote. “We believe that the lower levels of orexin found in our study indicate that the orexinergic system dysfunction plays a role in the pathogenesis of Parkinson’s disease.”

Further, they added, “functional abnormalities may have occurred during the prodromal [early] stage of Parkinson’s disease.”

Limitations to this study include its small number of participants and not accounting for medication use. Its researchers advised that larger studies are needed into the effects of TNF-alpha and orexin in Parkinson’s disease.

“It is necessary to investigate the changes in TNF-alpha and orexin levels in different disease stages and to enlarge the sample sizes to determine whether TNF-alpha affects the function of the orexin system,” the scientists wrote.

Still, “our findings suggest that TNF-alpha may not have a significant effect on the orexinergic system in patients with Parkinson’s and iRBD,” they concluded.