Toxic protein levels higher with REM sleep disorder than Parkinson’s

Study into alpha-synuclein measures in stool to aid diagnosis, therapy discovery

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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An illustration of disturbed sleep, showing a person lying on a floor next to a bed stripped of its pillow and blanket.

People with REM sleep behavior disorder (RBD), a sleep disturbance that can precede Parkinson’s disease, have higher levels of toxic alpha-synuclein protein clumps in their stool than do Parkinson’s patients and healthy people, a study showed.

Alpha-synuclein aggregates, toxic to cells, are thought to contribute to Parkinson’s and other neurological diseases.

These findings suggest that measuring alpha-synuclein clumps in the stool may help in diagnosing Parkinson’s early, before symptoms are evident, the researchers noted.

“This could be of value for developing therapies targeting early disease stages, which may result in better efficacy,” they wrote.

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The study, “Patients with isolated REM-sleep behavior disorder have elevated levels of alpha-synuclein aggregates in stool,” was published in the journal npj Parkinson’s Disease.

During the rapid eye movement (REM) stage of sleep, people dream vividly and their muscles temporarily “freeze” — a mechanism thought to prevent potential injury from “acting out” dreams. People with RBD are able to move their muscles while in the REM stage, physically acting out vivid dreams.

Previous studies showed alpha-synuclein clumps also accumulate in the nervous system of RBD patients, who share some Parkinson’s symptoms, such as a diminished sense of smell and gastrointestinal problems.

Notably, many people with RBD go on to develop Parkinson’s or other neurological conditions related to alpha-synuclein within 10 to 20 years of a diagnosis.

While it is clear that alpha-synuclein clumps are a Parkinson’s biomarker, measuring their levels in bodily fluids can be challenging. This is in part due to the presence of high levels of alpha-synuclein as single molecules, which are not toxic.

To address this, a team of researchers in Germany used a technology called surface-based fluorescence intensity distribution analysis, or sFIDA, which is known to accurately measure alpha-synuclein aggregates despite the presence of single molecules. They hypothesized that alpha-synuclein clumps would be evident in patients’ stool.

They analyzed stool samples from 72 people with RBD, 94 people with Parkinson’s, and 51 healthy people without a past or current neurological disorder, used as controls.

RBD and Parkinson’s patients were similar in age (mean of 66.3 and 64.5 years), while healthy controls were on average eight to 10 years younger (56.4). Parkinson’s patients had been living with the disease for a mean of nine years, and RBD patients for a mean of 7.4 years.

People with RBD experienced significantly fewer motor and non-motor symptoms than those with Parkinson’s. They also were less constipated and their sense of smell was less diminished than that of people with Parkinson’s.

Toxic protein levels almost 2.5 higher in RBD patients’ stool than Parkinson’s

Alpha-synuclein aggregate levels in the stool of RBD patients (median of 9.2 fentomolars) were nearly 2.5 times higher than in Parkinson’s patients (3.8 fentomolars), and their concentration was about 1.8 times as high as those of healthy people (5.2 fentomolars). These differences were statistically significant, meaning they were not chance findings.

However, no significant differences were detected between Parkinson’s patients and healthy controls, which is in contrast to findings from previous studies measuring alpha-synuclein clumps in the cerebrospinal fluid surrounding the brain and spinal cord.

The team suggested that alpha-synuclein clumps might be shed into stool in greater concentrations during disease phases that precede the start of Parkinson’s-specific symptoms, rather than during more advanced stages.

The technology’s ability to tell RBD from Parkinson’s or healthy controls showed a high sensitivity, greater than 75%, the scientists noted. Sensitivity refers to the frequency with which a test can correctly identify a person with a certain disease, RBD in this case.

But its specificity, or the frequency with which a test comes back negative for people who do not have the disease and positive for those who do, was in the range of 49% to 52%.

“In contrast, the sFIDA assay was highly specific (96.1%) but much less sensitive (6.4%) in detecting [alpha-synuclein] aggregates in stool samples of [Parkinson’s disease] patients versus healthy controls,” the scientists wrote.

Greater discrimination might be possible if measures of alpha-synuclein aggregates in stool are combined with those of other biomarkers, they added.

Overall, findings show that alpha-synuclein aggregates “are excreted in stool and can be measured using the sFIDA assay,” the researchers wrote, making stool “an additional valuable and easily accessible resource with a potential for diagnostic purposes.”

Further studies are needed to determine whether RBD patients with high concentrations of alpha-synuclein aggregates in their stool are likely to convert more quickly to Parkinson’s or other alpha-synuclein-related disorders, the team noted.