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

NCT06467461 | Recruiting

• 1 other identifier: NEUR-2023-32484
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Dementia With Lewy Bodies; Parkinson Disease; REM Sleep Behavior Disorder

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (2)

• 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

  time point 1 (baseline) and time point 2 (24 months, +/- 3 months)

Study Arms (1)

Research participants

OTHER

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; Diagnostic Test: Speech testing; Diagnostic Test: Ultra high field 7T MRI

Interventions

Skin biopsy DIAGNOSTIC_TEST

Skin biopsy to detect systemic alpha-synuclein pathology in 5-HT RBD

Research participants

Speech testing DIAGNOSTIC_TEST

Speech Testing to quantify evolving signs of 5-HT RBD

Research participants

Ultra high field 7T MRI DIAGNOSTIC_TEST

7T MRI to examine 5-HT RBD for evidence of brainstem neurodegeneration

Research participants

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Serotonergic REM sleep behavior (5-HT RBD) participants
• 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
• 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

You may not qualify if:

• Serotonergic REM sleep behavior (5-HT RBD) participants
• 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
• 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
• History of dream enactment that may suggest RBD
• Increased REM motor tone (REM atonia index \> 0.10) on PSG suggestive of RBD

Sponsors & Collaborators

• University of Minnesota: lead

Study Sites (1)

University of Minnesota

Minneapolis, Minnesota, 55455, United States

RECRUITING

MeSH Terms

Conditions

Lewy Body Disease; Parkinson Disease; REM Sleep Behavior Disorder

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; REM Sleep Parasomnias; Parasomnias; Sleep Wake Disorders

Study Officials

• Michael Howell, MD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Joy Schmidt

CONTACT

(612) 624 -1456; schmidtj@umn.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2024
• First Posted: June 21, 2024
• Study Start: February 8, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): September 1, 2028
• Last Updated: July 8, 2025

Record last verified: 2025-07

Locations

US (1)