Identification of Prodromal Neurodegeneration in Serotonergic-Induced REM Sleep Behavior Disorder

This project will test the hypotheses that people with 5-HT RBD have systemic alpha- synuclein pathology, prodromal DLB signs, and brainstem lesions in regions that control REM sleep. AIM 1 will seek to detect abnormally phosphorylated alpha- synuclein aggregates on targeted skin biopsy in a cohort of people with 5-HT RBD and matched controls (taking SSRIs but without RBD). Aim 2 will use ultra-high field MRI at 7T to examine the pontine region of the coeruleus/subcoeruleus complex for evidence of neurodegeneration as well as segment and parcellate REM sleep related neuronal structures. Aim 3 will test for speech deficits. While these aims are independent we suspect that the severity of autonomic, speech and cognitive deficits will correlate with loss of neuromelanin signal on MRI and pathology on skin biopsy.

The investigation is a longitudinal designed study to examine histopathology, neuroimaging changes and speech function from baseline (Time 1) to a follow-up after 30 months (Time 2). A total of 60 individuals, 30 with 5-HT RBD and 30 controls, will be recruited at Time 1, brought back at Time 2, and tested across all Aims at both study visits.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease; REM Sleep Behavior Disorder; Dementia With Lewy Bodies
• Intervention / Treatment: Diagnostic test: Skin biopsy; Diagnostic test: Speech testing; Diagnostic test: Ultra high field 7T MRI

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Joy Schmidt; Phone Number: (612) 624 -1456; Email: schmidtj@umn.edu

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • University of Minnesota
      • Contact: Joy Schmidt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Study Population

Candidates who meet inclusion/exclusion criteria will be considered for this research study. The patient will have been told about the study from their medical care provider and if the patient indicates willingness to be contacted, they will be contacted by a qualified, trained staff member who will explain the study and provide a copy of the informed consent form for review.

Description

Inclusion Criteria:

Serotonergic REM sleep behavior (5-HT RBD) participants

Inclusion Criteria:

• Diagnosis of polysomnogram-confirmed RBD with history of dream enactment or clear dream enactment visualized on video from polysomnogram.
• History of dream enactment began shortly after (less than 2 months) starting a serotonergic antidepressant medication. Control Participants

Inclusion Criteria:

• Age (±3 years) and sex matched to participants with 5-HT RBD
• On serotonergic medication for at least 6 months without history of dream enactment.

The following serotonergic medications will be included:

Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline

Exclusion Criteria:

Serotonergic REM sleep behavior (5-HT RBD) participants

Exclusion Criteria:

• Younger than 18
• Older than 75
• Meet criteria for Parkinson's disease, dementia with Lewy bodies, Multiple System Atrophy, Pure Autonomic Failure, Alzheimer's disease, other diagnosed neurodegenerative disorder, or other known cause of RBD (e.g. narcolepsy)
• Untreated obstructive sleep apnea, obesity hypoventilation, central sleep apnea or other sleep disordered breathing
• History of dysarthria, aphasia or other condition which could interfere with speech assessment
• Reduced capacity to consent
• MRI exclusion criteria for 7T scans: presence of any metallic clip(s) or implantable medical devices (e.g., heart valve, aneurysm clip, coils or surgery, renal or aortic clips, shunts, stents or stent grafts, metal mesh/coil implants, neurostimulator, insulin pump, IVC filter, etc.).
• History of allergic response to xylocaine or other local anesthesia
• Pregnant women will be excluded due to unknown risk of MRI on developing fetus Control Participants

Exclusion Criteria: same exclusion criteria as 5-HT RBD group, plus the following:

• History of dream enactment that may suggest RBD
• Increased REM motor tone (REM atonia index > 0.10) on PSG suggestive of RBD

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Research participants; Adults under the age of 75; who do not meet criteria for Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, other diagnosed neurodegenerative disorder, or other known cause of RBD; and have a history of or currently use the SSRIs of interest.	Diagnostic test: Skin biopsy; Skin biopsy to detect systemic alpha-synuclein pathology in 5-HT RBD; Diagnostic test: Speech testing; Speech Testing to quantify evolving signs of 5-HT RBD; Diagnostic test: Ultra high field 7T MRI; 7T MRI to examine 5-HT RBD for evidence of brainstem neurodegeneration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phosphorylated alpha synuclein deposits on skin biopsy	Incidence (positive or negative) of phosphorylated alpha synuclein deposits. Indicating direct histopathological confirmation of underlying alpha-synuclein degeneration in 5-HT RBD in a cohort of people with 5-HT RBD and matched controls (taking SSRIs but without RBD).	time point 1 (baseline) and time point 2 (24 months, +/- 3 months)
Neuromelanin signal intensity in the Subcoeruleus/Coeruleus Complex	Examination of the pontine region of the coeruleus/subcoeruleus complex for evidence of neurodegeneration as well as segment and parcellate REM sleep related neuronal structures.	time point 1 (baseline) and time point 2 (24 months, +/- 3 months)
Monopitch as measured by fundamental frequency variability.	Participants' voice and speech quality will be examined for synucleinopathy syndrome. The focus on speech function is designed to detect subtle brainstem deficits prior to more overt manifestations of cortical dementia.	time point 1 (baseline) and time point 2 (24 months, +/- 3 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subject-specific masks of all REM sleep-related pontine nuclei of interest, volume of Subcoeruleus/Coeruleus Complex.	Subject-specific masks of all REM sleep-related pontine nuclei of interest, volume of Subcoeruleus/Coeruleus Complex.	time point 1 (baseline) and time point 2 (24 months, +/- 3 months)
Speed of articulatory change as measured by F2 Transitions	Speed of articulatory change as measured by F2 Transitions, which are shown to be reduced in people with dysarthria	time point 1 (baseline) and time point 2 (24 months, +/- 3 months)

Collaborators and Investigators

• Sponsor: University of Minnesota
• Investigators: Principal Investigator: Michael Howell, MD, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: June 10, 2024
• First Submitted That Met QC Criteria: June 14, 2024
• First Posted (Actual): June 21, 2024

Study Record Updates

• Last Update Posted (Estimated): July 8, 2025
• Last Update Submitted That Met QC Criteria: July 6, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neurocognitive Disorders; Dementia; Neurodegenerative Diseases; Sleep Wake Disorders; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Parasomnias; REM Sleep Parasomnias; Mental Disorders; Parkinson Disease; Lewy Body Disease; REM Sleep Behavior Disorder; Nerve Degeneration
• Other Study ID Numbers: NEUR-2023-32484

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No