Restless Sleep May Be an Early Sign of Serious Neurological Diseases

Researchers have discovered that people with a specific type of sleep disorder, REM sleep behavior disorder, in which the person "acts out dreams" during sleep, may be showing one of the first signs of neurological diseases such as Parkinson's and dementia with Lewy bodies. Using MRI scans, scientists found evidence that these people already have a less efficient "brain cleaning," meaning the brain is less able to remove accumulated toxic substances. These changes, observed years before symptoms appear, can help predict who is at higher risk of developing neurodegenerative diseases and allow for early interventions in the future.

Isolated REM sleep behavior disorder is a sleep condition in which a person loses the natural muscle paralysis that normally occurs during REM sleep, the phase in which we dream. As a result, the individual may move, speak, or even act as if they were in a dream, sometimes with intense or aggressive movements.

Although it may seem like a simple sleep disorder, this condition is now considered an important early sign of serious neurological diseases, such as Parkinson's disease and dementia with Lewy bodies. Studies show that about nine in ten people with this disorder will develop one of these diseases after about 15 years.

Despite this, we still don't fully understand why some people with this disorder develop neurodegenerative diseases and others do not. Scientists are seeking to understand the brain mechanisms that lead to this transformation and are looking for brain markers, signals visible on imaging tests, that indicate who is at higher risk of developing these diseases.

Both Parkinson's disease and dementia with Lewy bodies are called synucleinopathies because they involve the abnormal accumulation of a protein called alpha-synuclein. When this protein accumulates incorrectly, it forms clumps that impair brain cell function and ultimately cause their death.

The body has natural mechanisms to "clean" waste and toxic proteins from the brain. One of these is the glymphatic system, a network of microscopic channels that help remove this waste, especially while we sleep.

In this system, cerebrospinal fluid, a fluid that surrounds and protects the brain, enters through the arteries, circulates between brain cells, collects toxins, and exits through the veins, carrying waste away from the nervous system.

This cleanup depends on a protein called aquaporin-4, present in so-called glial cells (astrocytes), which help move fluid from inside to outside the brain. If the glymphatic system fails, toxins build up, which can contribute to diseases such as Parkinson's, Alzheimer's, and other degenerative conditions.

It's not possible to directly observe this system at work, so scientists use a special MRI technique called diffusion tensor imaging along the perivascular space, or DTI-ALPS.

This technique measures the movement of water within the brain. If water flow is reduced in certain areas near the ventricles (internal fluid-filled chambers), this may indicate that the glymphatic system is malfunctioning.

In other words, the DTI-ALPS index is an indirect, but non-invasive, way of measuring the efficiency of the "brain housekeeping." Previous studies have shown that this index is altered in people with Parkinson's and dementia with Lewy bodies, suggesting that impaired brain housekeeping may be an important factor in the progression of these diseases.

The researchers wanted to find out whether people with isolated REM sleep behavior disorder already show signs of glymphatic system malfunction before developing a more serious neurological disease, and whether this signal could predict who is more likely to develop Parkinson's or dementia with Lewy bodies.

To this end, they conducted a large, long-term, international study. Participants included 250 people with the disorder, diagnosed with detailed sleep exams, and 178 healthy individuals of the same age group for comparison. All underwent brain MRI scans using two techniques:

• One to view brain structure (called T1-weighted imaging),

• And another to measure water movement, used to calculate the DTI-ALPS index.

The scientists measured this index in regions near the cerebral ventricles, which are central cavities of the brain filled with fluid. They then followed the patients with the disorder for several years to see who would develop a neurological disease (Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy).

With this data, they used statistical models to compare the differences between the groups and see if the DTI-ALPS index could predict the time and likelihood of progression to a neurodegenerative disease.

The results were clear: people with the sleep disorder had a lower DTI-ALPS score on the left side of the brain compared to healthy individuals. This indicates that the glymphatic system in these individuals already functions less efficiently.

Among patients followed for approximately six years, those who developed Parkinson's disease had even lower scores at the beginning of the study compared to those who did not.

The risk of progression to Parkinson's was approximately two and a half times higher among those with a lower DTI-ALPS score.

Other parameters of the diffusion test, such as the velocity and general direction of the water, showed no significant differences between the groups, reinforcing the idea that the DTI-ALPS score may be a more sensitive and specific marker.

What does this mean?

These results indicate that people with isolated REM sleep behavior disorder already have an early sign of glymphatic system malfunction, even before they develop Parkinson's or dementia. This impairment in "brain cleanup" appears to be linked to a greater chance of developing one of these diseases over time.

Thus, the DTI-ALPS index may become a useful tool for identifying, through MRI scans, those at higher risk of neurodegeneration. This discovery is very important because, in the future, it will allow doctors to detect and monitor these changes long before symptoms appear, which is essential for early intervention and slowing the progression of neurodegenerative diseases.

READ MORE:

Association of DTI-ALPS Glymphatic Index With Differential Phenoconversion in Isolated REM Sleep Behavior DisorderA Multi-Cohort MRI Study

Violette Ayral, Alexandre Pastor-Bernier, Véronique Daneault, 

Christina Tremblay, Marie Filiatrault, Celine Haddad, 

Jean-François Gagnon, Ronald B. Postuma, Petr Dušek, Stanislav Marecek, 

Zsoka Varga, Johannes C. Klein, Michele, T. Hu, Stéphane Lehéricy, 

Isabelle Arnulf, Marie Vidailhet, Jean-Christophe Corvol, for the ICEBERG Study Group, and Shady Rahayel 

Neurology. October 7, 2025. Volume 105  number (7)

https://doi.org/10.1212/WNL.0000000000214042

Abstract: 

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. 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. 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. 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.