Comprehensive characterization of early-stage Parkinson's disease in patients with REM sleep behavior disorder
Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder worldwide, significantly affecting quality of life and causing substantial social and economic burdens. Currently, treatments for Parkinson's disease primarily manage symptoms through medication and lifestyle changes but cannot stop disease progression. By the time Parkinson's disease is diagnosed, substantial nerve-cell loss has already occurred in specific brain areas. Identifying early signs of PD before symptoms fully develop is essential for improving future treatment strategies.
This research project aims to deeply understand the earliest stages of Parkinson's disease by studying patients with REM sleep behavior disorder (RBD). RBD is a condition characterized by unusual movements or behaviors during dream sleep, caused by nerve-cell loss in the brainstem. Importantly, more than 80% of individuals with RBD eventually develop Parkinson's disease or related conditions, such as Dementia with Lewy Bodies or Multiple System Atrophy.
Study Goals:
Our study will examine multiple potential biomarkers (measurable indicators) that could help identify early stages of Parkinson's disease. These include:
1. Brain structure changes: The Investigators will use advanced imaging methods (7-Tesla MRI) to closely examine specific brain regions known to be affected early in Parkinson's disease, particularly the substantia nigra and the locus coeruleus (LC). The LC helps regulate sleep and wakefulness, and studies have shown it is damaged in patients with RBD and Parkinson's disease. Additionally, the investigators will use specialized imaging (Pe2i-PET and MIBG-scintigraphy) to measure dopamine availability and changes in heart nerve function. 2. Abnormal protein buildup (ɑ-synuclein): In Parkinson's disease, nerve-cell death is linked to abnormal clumping of a protein called ɑ-synuclein within cells. Detecting this abnormal protein buildup early might help identify who is at risk of developing Parkinson's disease. The investigators aim to explore how levels of ɑ-synuclein aggregation relate to other early signs of the disease. 3. Functional changes in brain and body: Polysomnography, an overnight sleep test recording brain (EEG) and heart (ECG) activity, is the best method for diagnosing RBD. The investigators will also measure brain activity during wakefulness to further understand early changes. 4. Symptoms and physical tests: Participants will undergo thorough clinical assessments, including motor and cognitive tests, as well as tests evaluating autonomic (automatic nervous system) function, such as cardiovascular responses using a tilt-table test.
Together, these extensive assessments will provide a detailed understanding of how Parkinson's disease begins and progresses. This knowledge can greatly improve early diagnosis, allowing earlier and potentially more effective treatments for individuals at high risk.
Study Design:
The investigators will recruit:
* 50 individuals diagnosed with REM sleep behavior disorder * 50 control participants without major psychiatric or neurological disease, matched by age and gender
THe investigation team have a complete, detailed plan and will begin collecting data as soon as ethical approval is granted.
Main Hypotheses:
Although our extensive data will allow many analyses, the investigation team specifically predict:
* Individuals with RBD will show more significant damage in the locus coeruleus compared to controls. * Greater damage in the locus coeruleus will correlate with more severe cognitive issues, sleep problems, and autonomic dysfunction. * Cognitive issues in RBD patients might correlate with specific patterns of damage in different parts of the locus coeruleus. For example, memory problems might be linked to more damage in the front (rostral) part of this region.
Impact:
This study will significantly enhance early detection of Parkinson's disease, paving the way for personalized medical approaches and potentially more effective treatments. Conducted by a multidisciplinary team of experts in brain imaging, sleep medicine, autonomic function, and protein aggregation, this research supports Denmark's leadership in precision clinical imaging and aligns closely with hospital research strategies aimed at understanding and treating chronic diseases. Ultimately, our goal is to improve personalized patient care for Parkinson's disease in the future.
Verified REM-sleep behaviour disorder via polysonography
No other significant neurological and psychiatric ilness
Ferrous objects in or around the body
Pacemaker or other implanted electronic devices
Drug abuse unrelated to medication or alcohol abuse over a period of 6 months prior to the experiment
Other major immunological, cardiac, neurological or neuropsychiatric disorders
We have 2 groups; Subjects diagnosed with REM-sleep behaviour disorder via polysomnography Healthy, age- and gendermatched controls. Our RBD-group will be recruited via an ongoing cohort at a different site (Danish center for sleep medicine), where subjects diagnosed with RBD via polysomnography will be asked to also participate in our cohort, should they fulfill our inclusion criteria. Controls will be recruited via our own institutions webpage, as well as advertisements on other danish websites such as trialtree.dk.
Case-control
Other
Not listed
Structural disintegraiton of the Locus Coeruleus
One of the main hypotheses is that there will be a strutural pattern of disintegration in the Locus Coeruleus (LC) in our RBD-cohort when compared to controls. This will be seen as a change in neuromelanin Contrast-to-Noise-Ratio (CNR) in the LC. We expect this pattern to have a caudo-rostral gradient, as other studies have shown in subjects with Parkinson's Disease.
Differences in neuromelanin-CNR in the Substantia Nigra pars Compacta in RBD-subjects compared to controls
As with the Locus Coeruleus, it is expected to see altered neuromelanin signal from the SNc in RBD subjects compared to controls
Motor-task performance
The investigators expect to see group-level differences in motor-task performance with an in-house designed motor-test battery, validated before being put into use.
Cognitive test performance
The investigators expect to see group-level differences in cognitive test performance, tested with particular tests from the CANTAB-battery, between RBD-subjects and controls, with controls performing better..
Resting-state EEG
Preliminary data from another study (Manuscript under review) at our site has shown that the aperiodic part of resting-state EEG is able to clearly separate subjects with clinically established Parkinson's Disease from controls. We will test whether this also holds true in the prodromal RBD-state using a short resting-state EEG recording.
Correlation between LC and autonomic dysfunction.
Loss of LC-CNR will positively correlate with increased burden of autonomic symptoms in RBD-subjects.
Longitudinal outcomes
At follow up, subjects with more progressive cognitive deficits measured via MOCA and CANTAB are hypothesized to show more pronounced change in rostral LC-CNR.
Longitudinal outcomes
Conversion rates to clinical ɑ-syn (PD, MSA, DLB) will be higher in subjects showing peripheral ɑ-synuclein pathology in blood and/or skin.
Longitudinal outcomes
Subjects converting to DLB will display more rostral change in LC-CNR than subjects converting to other ɑ-syn.
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Danish Research Centre for Magnetic Resonance
Lead sponsor
Danish Center for Sleep Medicine
Collaborator
University Hospital Bispebjerg and Frederiksberg
Collaborator
