Research
Selective molecular and network architecture features underlie brain cortical atrophy in dementia with Lewy bodies
Journal of Biomedical Science, Volume 33, Issue 1, June 2026
Dementia with Lewy bodies is a common form of dementia that can cause memory and thinking problems, visual hallucinations, changes in attention, sleep-related dream enactment, and Parkinson-like movement symptoms. In this study, we used brain MRI scans from people with dementia with Lewy bodies and healthy participants to understand why some brain areas shrink more than others. We found that brain thinning was most pronounced in posterior brain regions, including areas involved in vision, attention, and thinking. By comparing these brain changes with maps of gene activity from healthy brains, we found that the most vulnerable regions were linked to genes involved in cell energy production and communication between brain cells. Some of these biological pathways overlapped with Parkinson’s disease and Alzheimer’s disease, but others appeared more specific to dementia with Lewy bodies, especially pathways related to GABA, an important brain chemical. These findings suggest that brain scans can reveal not only where damage occurs, but also why certain brain regions may be more vulnerable.
MRI-derived atrophy in multiple system atrophy aligns with mitochondrial and glial gene expression patterns
npj Parkinson's disease, Volume 12, Issue 1, December 2025
Multiple system atrophy is a rare brain disease that gets worse over time. It can affect movement, balance, coordination, and body functions that usually happen automatically, such as blood pressure control. In this study, we used brain scans to understand why certain parts of the brain are more affected than others. We found that the greatest brain shrinkage occurred in areas important for movement and coordination, including deep brain regions, the brainstem, and the cerebellum. These changes were linked to how severe the disease was. We also compared the affected brain regions with maps of gene activity from healthy brains. The most vulnerable regions were linked to genes involved in how brain cells produce energy and how support cells help protect nerve fibers. These findings suggest that brain scans can show more than where damage occurs: they may also give clues about the biological processes driving the disease and point toward future treatment targets.
Estrogen-related receptor gene expression associates with sex differences in cortical atrophy in isolated REM sleep behavior disorder
Nature Communications, Volume 10, Issue 1, October 2025
Isolated REM sleep behaviour disorder is a sleep condition in which people physically act out their dreams, and it is one of the strongest early signs of future Parkinson’s disease or dementia with Lewy bodies. This condition is more common in men, but it has been unclear whether men and women show the same brain changes at this early stage. In this study, we analyzed brain MRI scans from a large international group of people with isolated REM sleep behaviour disorder and healthy participants. We found that men with isolated REM sleep behaviour disorder showed more widespread thinning of the brain’s outer layer, while women showed less severe and more limited brain changes, even though men and women had similar age and clinical symptoms. We also found that brain regions relatively protected in women were linked to genes involved in estrogen-related biological pathways, especially genes connected to brain energy and mitochondrial function. These findings suggest that biological sex may influence how early neurodegeneration affects the brain and could help guide more personalized approaches to prevention and treatment.
Free water predicts dementia with Lewy bodies in isolated REM sleep behavior disorder
Alzheimer's & Dementia, Volume 21, Issue 9, September 2025
Isolated REM sleep behaviour disorder is a sleep condition in which people physically act out their dreams. It is also one of the strongest early warning signs of future Parkinson’s disease or dementia with Lewy bodies. In this study, we looked at whether a brain MRI measure called “free water” could help predict which disease people may later develop. Free water reflects subtle changes in brain tissue that may be related to inflammation, cell damage, or early neurodegeneration. We studied people with isolated REM sleep behaviour disorder and healthy participants from several international centers. Overall, free water did not clearly separate all patients from healthy people. However, among patients with long-term follow-up, those who later developed a neurodegenerative disease had higher free water in key brain regions. Most importantly, higher free water in a small brain region involved in memory and attention, called the nucleus basalis of Meynert, specifically predicted future dementia with Lewy bodies rather than Parkinson’s disease. These findings suggest that free water MRI may help identify people at higher risk for dementia earlier in the disease process.
Association of DTI-ALPS Glymphatic Index With Differential Phenoconversion in Isolated REM Sleep Behavior Disorder: A Multi-Cohort MRI Study
Neurology, Volume 105, Issue 7, October 2025
Isolated REM sleep behaviour disorder is a sleep condition in which people physically act out their dreams, and it is one of the strongest early warning signs of future Parkinson’s disease or dementia with Lewy bodies. In this study, we looked at whether a brain MRI measure related to the brain’s waste-clearing system could help predict who is more likely to develop one of these diseases. This waste-clearing system, called the glymphatic system, helps remove unwanted proteins from the brain. We studied 250 people with isolated REM sleep behaviour disorder and 178 healthy participants from five international centers. People with isolated REM sleep behaviour disorder showed signs of reduced waste-clearing function on MRI, especially on the left side of the brain. Among those followed over time, people who later developed a neurodegenerative disease had lower values on this MRI measure than those who did not. Lower values were especially linked to a higher risk of developing Parkinson’s disease. These findings suggest that MRI measures of brain waste clearance may help identify people at higher risk of disease progression.
Altered network efficiency in isolated REM sleep behavior disorder: A multicentric study
Alzheimer's & Dementia, Volume 21, Issue 8, August 2025
Isolated REM sleep behaviour disorder is a sleep condition in which people physically act out their dreams. It is also one of the strongest early warning signs of future Parkinson’s disease or dementia with Lewy bodies. In this study, we examined brain scans from 198 people with isolated REM sleep behaviour disorder and 174 healthy participants to understand whether the brain’s communication network is already changing before a diagnosis of Parkinson’s disease or dementia. We found that people with isolated REM sleep behaviour disorder already had less efficient brain connections, especially in regions involved in movement. Some brain areas also appeared to become more locally connected, possibly reflecting the brain trying to compensate for early damage. Importantly, changes in one brain region, the supramarginal gyrus, helped predict which individuals later developed dementia with Lewy bodies, but not Parkinson’s disease. These findings suggest that brain network measures may help detect early disease changes and identify people at higher risk for dementia.
Distinct brain atrophy progression subtypes underlie phenoconversion in isolated REM sleep behavior disorder
The Lancet eBioMedicine, Volume 117, July 2025
Certain brain diseases, including Parkinson’s disease and dementia with Lewy bodies, can begin many years before a person receives a diagnosis. One early warning sign is isolated REM sleep behaviour disorder, a condition in which people physically act out their dreams during sleep. In this study, we looked at brain scans and follow-up information from 1,276 people to better understand how brain shrinkage may begin and spread over time. We found two main patterns. In one pattern, brain changes started in the outer layer of the brain, which is important for thinking and memory, and this pattern was more strongly linked to later dementia with Lewy bodies. In the other pattern, changes started in deeper brain areas involved in movement, emotion, and automatic body functions. Both patterns were linked to worsening movement symptoms over time. These findings suggest that brain scans may help identify different disease pathways earlier and may help doctors monitor patients and choose participants for future clinical trials.
Lower estimated glomerular filtration rate relates to cognitive impairment and brain alterations
Alzheimer's & Dementia DADM, Volume 16, Issue 4, November 2024
Chronic kidney disease may be linked to brain aging and neurodegeneration, but we still do not fully understand why reduced kidney function can affect memory, thinking, and brain health. In this study, we looked at whether lower kidney function was related to cognitive abilities and brain structure in a large group of adults from the CARTaGENE cohort. We found that people with lower kidney function tended to perform worse on cognitive tests and showed thinning in specific areas of the brain. These links remained even after considering other factors such as age, sex, education, body weight, cardiovascular risk, and brain blood-vessel changes. We also found that the affected brain areas were related to genes involved in inflammation and the way cells produce energy. Overall, this study suggests that kidney health and brain health are closely connected and may share biological pathways involved in neurodegeneration.
99mTc-HMPAO SPECT perfusion signatures associated with clinical progression in patients with isolated REM sleep behavior disorder
Neurology, Volume 102, Issue 4, February 2024
In this study, we sought to find a brain blood flow pattern that could predict the onset of dementia with Lewy bodies. By analyzing brain scans with single-photon computed emission tomography and clinical features of individuals with isolated REM sleep behavior disorder compared to healthy controls and Parkinson's disease people, we identified two key patterns related to cognitive decline and the risk of developing neurodegenerative diseases. One pattern predicted a general risk for such diseases, while the other specifically indicated a transition to dementia with Lewy bodies. This suggests the potential of developing a new biomarker from individual scans to predict dementia in people at risk, offering a significant step forward in early diagnosis and treatment strategies for dementia with Lewy bodies.
Predicting longitudinal brain atrophy in Parkinson's disease using a Susceptible-Infected-Removed agent-based model
Network Neuroscience, Volume 7, Issue 3, October 2023, Pages 906–925
Parkinson's disease unfolds as brain cells deteriorate over time, a process linked to the buildup and spread of a misshapen protein known as alpha-synuclein. This protein is thought to behave similarly to prions, corrupting other normal proteins, spreading through the brain, and causing cell damage. This concept, while still under debate, was explored using a computer model called the Susceptible-Infected-Removed to simulate how alpha-synuclein propagates and inflicts damage within the brain. Through the analysis of over a thousand MRI scans from the Parkinson's Progression Markers Initiative, including scans from both Parkinson's people and healthy controls, we observed patterns of brain damage developing across specific regions over four years. The model accurately mirrored the observed patterns of brain shrinkage seen in Parkinson's disease, underscoring the significant roles of brain network connections and the activity of genes associated with alpha-synuclein. These findings lend support to the prion-like spread theory of Parkinson's and highlight the Susceptible-Infected-Removed model as a potential key tool for delving into the complex nature of neurodegenerative diseases and their progression over time.
Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies
Brain, Volume 146, Issue 8, August 2023, Pages 3301-3318
In this study, we investigated brain changes in patients predisposed to developing synucleinopathies like dementia with Lewy bodies and Parkinson’s disease. Using advanced MRI techniques on people with isolated REM sleep behavior disorder and healthy controls, the study identified specific gene expression patterns associated with cortical thinning in isolated REM sleep behavior disorder, highlighting the roles of mitochondrial function and macroautophagy. Furthermore, the research demonstrated that these brain changes are influenced by the brain's structural and functional networks, particularly affecting areas involved in motor and planning functions. Unlike Alzheimer's disease, the genetic and connectivity patterns in isolated REM sleep behavior disorder suggest unique pathways of disease progression, emphasizing the importance of specific genes and brain networks in the development of synucleinopathy-related brain atrophy.
Isolated REM sleep behavior disorder is a condition where people act out their dreams due to a brain disorder related to the same protein involved in Parkinson's disease and dementia with Lewy bodies. Researchers noticed that patients with isolated REM sleep behavior disorder have brain shrinkage similar to those with Parkinson's disease or dementia, but it's unclear how this shrinkage is connected to the protein causing the disorder. In this study, we used brain scans from people with isolated REM sleep behavior disorder and compared them to healthy people to look at brain shrinkage and how it relates to movement and thinking problems. We also used a computer model to simulate how the problematic protein spreads in the brain, considering brain structure and certain gene activity. Our findings showed that the brain shrinkage in isolated REM sleep behavior disorder patients was linked to how well they could move and think. The computer model, which considered how the brain is connected and the activity of specific genes, accurately mirrored the brain shrinkage seen in patients. This suggests that the way the problematic protein spreads and affects certain brain areas can explain the brain shrinkage seen in early stages of Parkinson's disease and dementia. This research supports the idea that the spread of this protein and vulnerability of certain brain regions are key to understanding these diseases, offering new ways to explore treatments to stop the disease from progressing.
Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression
Brain, Volume 145, Issue 9, September 2022, Pages 3162–3178
Differentially targeted seeding reveals unique pathological alpha-synuclein propagation patterns
Brain, Volume 145, Issue 5, June 2022, Pages 1743-1756
Parkinson's disease, a condition marked by the buildup of alpha-synuclein protein in the brain, progresses as this harmful protein spreads between cells, a process that's still not fully understood. In our study, we injected mice with a disease-causing form of alpha-synuclein and tracked how the disease spread across their brains over two years, using a detailed brain map and measurements at several time points. Additionally, we used a computer model to simulate this spread, considering both how brain regions are connected and the levels of alpha-synuclein produced by genes. Our findings revealed that the progression of the disease varied based on the injection site, yet most brain areas were susceptible to the disease, and our computer model accurately mirrored these patterns. This suggests that the brain's connectivity and alpha-synuclein levels play a crucial role in making regions more vulnerable to Parkinson's, hinting at a prion-like spread of the disease. This comprehensive dataset and model offer a new avenue for testing theories on halting the spread of Parkinson's disease within the brain.
We focused on studying isolated REM sleep behavior disorder, which is linked to the development of dementia with Lewy bodies and Parkinson's disease. Our goal was to find markers that could help us predict which individuals with isolated REM sleep behavior disorder would eventually develop these conditions, particularly dementia. By analyzing brain scans and clinical data from patients with confirmed isolated REM sleep behavior disorder, we discovered a specific brain-clinical pattern that indicated a higher likelihood of progressing to dementia with Lewy bodies. This pattern was then applied to a longer study involving more people with isolated REM sleep behavior disorder to see if it could predict their progression to diseases related to synucleinopathy, like dementia with Lewy bodies. Our findings showed that this pattern was effective in predicting the onset of dementia with Lewy bodies, but not Parkinson's disease, suggesting it could be a valuable tool for identifying people with isolated REM sleep behavior disorder at risk of developing dementia.
A prodromal brain-clinical pattern of cognition in synucleinopathies
Annals of Neurology, Volume 89, Issue 2, February 2021, Pages 341–357
Brain atrophy in Parkinson's disease with polysomnography-confirmed REM sleep behavior disorder
Sleep, Volume 42, Issue 6, June 2019
We studied brain changes in people with Parkinson's disease who also have REM sleep behavior disorder, confirmed by polysomnography. We compared people with Parkinson’s disease, half of whom had REM sleep behavior disorder, to healthy people, using advanced brain imaging to look at the thickness, shape, and volume of different brain regions. We found that those with REM sleep behavior disorder had thinner areas in certain parts of the brain and changes in the shape and size of brain structures related to movement control, compared to those without REM sleep behavior disorder and to healthy people. These changes were more pronounced in people with both Parkinson’s disease and REM sleep behavior disorder, indicating more severe brain damage. The study suggests that Parkinson’s patients with REM sleep behavior disorder experience more significant brain deterioration, which could explain why their symptoms are often more severe.
Cortical and subcortical gray matter bases of cognitive deficits in REM sleep behavior disorder
Neurology, Volume 90, Issue 20, May 2018, Pages e1759–1770
This study investigated brain changes in patients with REM sleep behavior disorder, some of whom also had mild cognitive impairment. Using advanced brain scans and cognitive tests, researchers found that patients with mild cognitive impairment showed significant brain thinning and changes in deep brain structures, while those without mild cognitive impairment mainly had thinning in the frontal part of the brain. These brain alterations were linked to declines in thinking abilities and other functions like smell and color vision. The findings suggest that brain changes in REM sleep behavior disorder patients are closely associated with their cognitive health, highlighting the importance of monitoring cognitive status in understanding neurodegenerative processes.
Abnormal Gray Matter Shape, Thickness, and Volume in the Motor Cortico-Subcortical Loop in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: Association with Clinical and Motor Features
Cerebral Cortex, Volume 28, Issue 2, February 2018, Pages 658–671
In this study, we studied people with idiopathic rapid eye movement sleep behavior disorder, which is known to increase the risk of Parkinson’s disease and dementia. We used advanced brain scans and motor skill tests on patients with this disorder and compared them to healthy people. Their findings showed that patients with isolated REM sleep behavior disorder had thinner brain areas and less brain volume in parts of the brain important for controlling movements and emotions. They also found changes in the shape of deep brain structures. These brain changes were linked to problems with movement and other symptoms of isolated REM sleep behavior disorder, indicating that the disorder affects certain brain areas involved in movement control.
Patterns of cortical thinning in idiopathic rapid eye movement sleep behavior disorder
Movement Disorders, Volume 30, Issue 5, April 2015, Pages 680–687
In this article, we studied people with a sleep disorder called isolated REM sleep behavior disorder, which can make someone more likely to develop dementia with Lewy bodies or Parkinson's disease. This disorder is linked to problems in how certain parts of the brain work, especially in the front and back areas, but it's unclear exactly why these problems happen. The study involved people with this sleep disorder and healthy people, all of whom had brain scans using advanced MRI techniques to look at the brain's structure and connections. They found that people with the disorder had thinner areas in some parts of the brain and less brain volume in one specific area, but there wasn't a significant difference in the brain's wiring between the two groups. These brain changes in people with the disorder were similar to those seen in dementia with Lewy bodies and Parkinson's disease, providing some clues about the physical changes in the brain associated with this disorder.