Summary: Two landmark international studies show that brain biomarkers can predict whether people with REM sleep behaviour disorder (iRBD) will develop Parkinson’s disease or dementia with Lewy bodies (DLB). MRI scans revealed that reduced glymphatic system function signals higher risk for Parkinson’s, while increased free water in the basal nucleus of Meynert predicts progression to DLB.
These findings come from the largest imaging studies ever conducted in patients with confirmed iRBD. The results pave the way for earlier diagnosis, targeted monitoring, and preventive treatments before irreversible brain damage occurs.
Key Facts
- Parkinson’s Predictor: Reduced glymphatic fluid circulation doubled Parkinson’s risk.
- DLB Predictor: Higher free water in the basal nucleus of Meynert raised DLB risk 8-fold.
- Clinical Impact: First tools to differentiate disease outcomes years before symptoms.
Source: University of Montreal
An international research team led by Université de Montréal medical professor Shady Rahayel has made a major breakthrough in predicting neurodegenerative diseases.
Thanks to two complementary UdeM studies, scientists are now able to determine, years in advance, which individuals with a particular sleep disorder will develop Parkinson’s disease or dementia with Lewy bodies (DLB).
The studies focus on isolated REM sleep behaviour disorder (iRBD)—a condition in which people yell, thrash, or act out their dreams, sometimes violently enough to injure a bed partner.
“It’s not just restless sleep—it’s a neurological warning sign,” said Rahayel, a neuropsychologist and researcher at the Centre for Advanced Research in Sleep Medicine at Sacré-Cœur Hospital in Montreal.
Roughly 90 per cent of people with this sleep disorder will go on to eventually develop Parkinson’s disease or DLB. Until now, however, it was impossible to know which disease would occur—or when.
First biomarker: predicting Parkinson’s
The first study, led by UdeM doctoral student in neurosciences Violette Ayral and published in Neurology on September 16, involved 428 participants from five countries: Canada, the United States, France, the United Kingdom and Czechia.
It examined the brain’s glymphatic system—a network that clears metabolic waste during sleep, including proteins linked to neurodegeneration. When this system is impaired, waste accumulates, potentially triggering diseases like Parkinson’s.
Using an advanced MRI technique known as DTI-ALPS, researchers measured fluid circulation in specific brain regions in 250 patients with iRBD and 178 healthy control subjects, with an average follow-up of six years.
The key finding: patients with a lower DTI-ALPS index in the left hemisphere of the brain (indicating reduced fluid circulation) were 2.4 times more likely to develop Parkinson’s disease in the years that followed. No such link was found for dementia with Lewy bodies.
“This asymmetry mirrors what we see clinically in early Parkinson’s, where motor symptoms often start on one side of the body – it may mark the very earliest stage of the disease,” said Ayral.
This is the first evidence that glymphatic function, as measured by MRI, can predict progression to Parkinson’s—and the largest international study ever conducted on this topic among patients with polysomnography-confirmed REM sleep disorder.
Second biomarker: predicting DLB
The second study, led by UdeM doctoral student in neuropsychology Celine Haddad and published in Alzheimer’s & Dementia on September 19, focused on 438 participants from the same five countries as the first study.
It took a different approach to predict the onset of DLB —a condition combining Parkinsonian symptoms (tremors, rigidity) and Alzheimer-like symptoms (cognitive impairment, confusion, hallucinations). It’s the second most common degenerative dementia after Alzheimer’s.
Researchers measured the amount of “free water” — water not bound by brain cells and able to flow freely between them — in the basal nucleus of Meynert, a key region for thought and reasoning. This free water is a sign of early microscopic changes, such as inflammation or cell loss, and serves as an indirect marker of neuronal degeneration.
After a median follow-up of 8.4 years, the results were striking: individuals who developed DLB had significantly higher levels of free water in this brain region, making them eight times more likely to convert to this form of dementia. This method proved more sensitive than traditional approaches based on brain atrophy.
“What’s fascinating is that this marker picks up very early changes—even before symptoms emerge,” said Haddad.
Toward precision medicine
These studies represent the largest international imaging research ever done on patients with polysomnography-confirmed iRBD, and pave the way for personalized screening tests to predict which disease will develop before symptoms appear.
Clinicians will be able to tailor medical monitoring to each patient’s trajectory and better target clinical trials for preventive treatments, the researchers say, adding that their early intervention model could transform care for neurodegenerative diseases by addressing them before irreversible damage occurs.
“We already knew that isolated REM sleep behaviour disorder is a warning sign for these diseases,” said Rahayel.
“What we didn’t know was who would develop what. Thanks to these complementary studies, we now have tools to better predict and personalize care.”
About this sleep and Parkinson’s disease research news
Author: Julie Gazaille
Source: University of Montreal
Contact: Julie Gazaille – University of Montreal
Image: The image is credited to Neuroscience News
Original Research: Open access.
“DTI-ALPS associates with differential phenoconversion in patients with isolated REM sleep behaviour disorder: a multicenter MRI study” by Shady Rahayel et al. Neurology
Abstract
DTI-ALPS associates with differential phenoconversion in patients with isolated REM sleep behaviour disorder: a multicenter MRI study
Background and Objectives
Isolated REM sleep behavior disorder (iRBD) is the strongest prodromal marker of synucleinopathies, including Parkinson disease (PD) and dementia with Lewy bodies (DLB). Identifying brain biomarkers that predict progression and distinguish phenoconversion trajectories remains a challenge. The glymphatic system is involved in interstitial waste clearance, and its dysfunction has been associated with pathologic protein accumulation and neurodegeneration.
Diffusion tensor imaging along the perivascular space (DTI-ALPS) has been proposed as a noninvasive proxy for glymphatic function. The aim of this study was to determine whether patients with iRBD show a reduced DTI-ALPS index compared with controls and whether a lower DTI-ALPS index predicts future phenoconversion to PD or DLB.
Methods
We conducted a longitudinal, multicenter cohort study using brain MRI scans from patients with polysomnography-confirmed iRBD and healthy controls recruited across 5 international centers. All participants underwent T1-weighted and diffusion-weighted MRI. DTI-ALPS indices were computed from diffusivity along projection and associative fibers adjacent to the lateral ventricles.
The primary outcome was time to phenoconversion to synucleinopathy. Linear models assessed baseline group differences and clinical correlates, and Cox proportional hazard models assessed the predictive value of DTI-ALPS for time to phenoconversion.
Results
A total of 250 patients with iRBD (mean age: 66.5 ± 6.8 years; 87% male) and 178 controls (65.7 ± 6.8 years; 81% male) were included. Patients with iRBD showed a lower left DTI-ALPS index compared with controls (mean difference = −0.034, 95% CI −0.067 to −0.001; p = 0.043). Of 224 patients with iRBD followed for a mean of 6.1 ± 3.5 years, 65 phenoconverted to a synucleinopathy.
Converters had a lower left DTI-ALPS index than nonconverters (mean difference = −0.050, 95% CI −0.098 to −0.003; p = 0.038). Lower left DTI-ALPS index was associated with an increased risk of conversion to PD over time (hazard ratio = 2.43, 95% CI 1.13–5.25; p = 0.012). Other diffusion metrics inside periventricular masks, namely fractional anisotropy, diffusivity metrics, and free water, did not differ between groups.
Discussion
Patients with iRBD exhibit a reduced DTI-ALPS index, suggesting altered glymphatic function. This reduction was associated with future phenoconversion to PD, supporting the DTI-ALPS index as a potential prognostic MRI biomarker of progression in prodromal synucleinopathies.