Locus-coeruleus Function in Normal Elderly and AD Risk

NCT04403165 | Completed DMC

• 2 other identifiers: 20-000021R21AG067549-01
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

Growing evidence suggests that Alzheimer's disease (AD) pathological changes begin decades before clinical symptoms and tau abnormalities in the locus coeruleus (LC) can be observed since midlife. We have previously demonstrated functional vulnerability of the LC to aging and stress, as well as an association between higher cerebrospinal fluid (CSF) tau and impaired sleep phenomena influenced by the LC. We now aim to test whether LC dysfunction can be measured in preclinical AD stages by LC targeted imaging, and whether it objectively affects sleep architecture and attention. We will test this hypothesis in 30 cognitively normal older adults by performing a full clinical evaluation, one night of polysomnography, a lumbar puncture to obtain cerebrospinal fluid, \[11C\]MRB PET-MR, and attention testing. This study has the potential to identify a new mechanism by which tau pathology contributes to sleep and attention dysfunction and may provide a new therapeutic target for AD prevention.

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (8)

• Methylreboxetine (MRB)-LC Mean Standardized Uptake Value Ratio (SUVR) Values

  Visit 4 (1-4 weeks after LP)

• Total Rapid Eye Movement (REM) Duration (Min)

  REM sleep is derived from in-laboratory nocturnal polysomnography (NPSG) sleep study.

  Visit 3 (1-4 weeks after Visit 2)

• Percentage of Time Spent in REM Sleep

  REM sleep is derived from in-laboratory nocturnal polysomnography (NPSG) sleep study.

  Visit 3 (1-4 weeks after Visit 2)

• REM Sleep Continuity

  Reported as percentage of REM runs that are less than 5, greater than or equal to 5 and greater than or equal to 10 minutes.

  Visit 3 (1-4 weeks after Visit 2)

• Number of sleep spindles that occur per minute during the N2 stage of sleep (N2 Spindle Density)

  N2 Spindle Density is derived from in-laboratory nocturnal polysomnography (NPSG) sleep study.

  Visit 3 (1-4 weeks after Visit 2)

• Mean Psychomotor Vigilance Test (PVT) Reaction Time

  PVT measures the reaction speed to a randomly time-occuring visual stimuli, allowing the assessment of several aspects of attention including response times, attention lapses and false starts.

  Visit 3 (1-4 weeks after Visit 2)

• Mean picture test response time

  The "Picture" test is used to measure the strength of the participants' memory by using a series of images. Before sleep, participants identify whether or not the image was inside or outside and whether or not the picture was emotional or neutral to them. After sleep, the participant will be shown images where some are new and some are old and asked whether or not they saw them before sleep. The images are selected from The International Affective Picture System.

  Visit 3 (1-4 weeks after Visit 2)

• Percentage of Correct Responses on the picture test

  The "Picture" test is used to measure the strength of the participants' memory by using a series of images. Before sleep, participants identify whether or not the image was inside or outside and whether or not the picture was emotional or neutral to them. After sleep, the participant will be shown images where some are new and some are old and asked whether or not they saw them before sleep. The images are selected from The International Affective Picture System.

  Visit 3 (1-4 weeks after Visit 2)

Secondary Outcomes (1)

• Levels of Hyperphosphorylated Tau (P-Tau, T-Tau)

  Visit 4 (1-4 weeks after LP)

Other Outcomes (1)

• Aβ42/Aβ40 Ratio

  Visit 4 (1-4 weeks after LP)

Study Arms (1)

Cognitively Normal (CN) Older Adults

EXPERIMENTAL

Procedure: Nocturnal polysomnography (NPSG); Procedure: Lumbar Puncture (LP); Other: PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]Omethylreboxetine ([11C]MRB); Behavioral: Psychomotor Vigilance Task (PVT)

Interventions

Nocturnal polysomnography (NPSG) PROCEDURE

Nocturnal polysomnography (NPSG) to measure REM sleep and sleep spindles characteristics.

Cognitively Normal (CN) Older Adults

Lumbar Puncture (LP) PROCEDURE

Lumbar puncture (LP) to measure CSF P-Tau, T-Tau and Aβ42/40 ratio.

Cognitively Normal (CN) Older Adults

PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]Omethylreboxetine ([11C]MRB) OTHER

PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-\[11C\]O-methylreboxetine (\[11C\]MRB) to measure NET availability.

Cognitively Normal (CN) Older Adults

Psychomotor Vigilance Task (PVT) BEHAVIORAL

Psychomotor vigilance task (PVT) and the OddBall to measure test taskattention performance.

Cognitively Normal (CN) Older Adults

Eligibility Criteria

• Age: 55 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female subjects with normal cognition and 55-75 years of age will be enrolled.
• Subjects will be within normal limits on neurological and psychiatric examinations.
• All subjects enrolled will have a CDR of 0. This will be evaluated through a clinical interview administered by a study physician (informant interview will not be required).
• All subjects will have had a minimum of 12 years of education.

You may not qualify if:

• History of brain tumor, MRI evidence of brain damage or brain disease including significant trauma, hydrocephalus, seizures, stroke, mental retardation or other serious neurological disorder (e.g. Parkinson's disease or other movement disorders).
• Significant history of alcoholism or drug abuse.
• Significant history of psychiatric illness (e.g., schizophrenia, bipolar, PTSD, or life-long history of major depression).
• Geriatric Depression Scale (short form)\>6.
• Insulin dependent diabetes.
• Evidence of clinically relevant cardiac, pulmonary, endocrine or hematological conditions.
• Physical impairment of such severity as to adversely affect the validity of psychological testing.
• Any prosthetic devices (e.g., pacemaker or surgical clips) that constitutes a hazard for MRI imaging.
• History of a first-degree family member with early onset (age \<60 years) dementia.
• Irregular sleep-wake rhythms (based on the actigraphy recordings) or significant OSA (AHI4%≥15).
• Taking Coumadin/warfarin and/or medications affecting cognition or sleep.
• Failure to complete all study visit within 4 months

Sponsors & Collaborators

• NYU Langone Health: lead
• National Institute on Aging (NIA): collaborator

Study Sites (2)

NYU Grossman School of Medicine

New York, New York, 10016, United States

Location

Icahn School of Medicine Mount Sinai

New York, New York, 10029, United States

Location

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Spinal Puncture

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Biopsy; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Neurological; Punctures; Therapeutics; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Ricardo Osorio

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

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: May 21, 2020
• First Posted: May 27, 2020
• Study Start: August 6, 2020
• Primary Completion: March 26, 2024
• Study Completion: March 26, 2024
• Last Updated: December 2, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Immediately following publication. No end date.
• Access Criteria: The investigator who proposed to use the ricardo.osorio@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.

Locations

US (2)