Locus-coeruleus Function in Normal Elderly and AD Risk (LEAD)

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: 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)

Detailed Description

The purpose of this study is three-fold: to test whether lower NET availability in the LC is associated with: first, CSF tau levels typical of preclinical stages of AD (Aim 1); second, reduced REM and spindle density (Aim 2); and third, impaired performance on attention tasks (Aim 3). The goal is to test the overarching hypothesis that LC dysfunction occurs in preclinical AD stages, can be measured with MRB-PET, and translates into impairment of sleep architecture (LC tonic dysfunction) and attention (LC phasic dysfunction).

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine Mount Sinai
    • New York, New York, United States, 10016
      • NYU Grossman School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

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

Experimental: Cognitively Normal (CN) Older Adults

Procedure: Nocturnal polysomnography (NPSG); Nocturnal polysomnography (NPSG) to measure REM sleep and sleep spindles characteristics.; Procedure: Lumbar Puncture (LP); Lumbar puncture (LP) to measure CSF P-Tau, T-Tau and Aβ42/40 ratio.; Other: PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]Omethylreboxetine ([11C]MRB); PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]O-methylreboxetine ([11C]MRB) to measure NET availability.; Behavioral: Psychomotor Vigilance Task (PVT); Psychomotor vigilance task (PVT) and the OddBall to measure test taskattention performance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Methylreboxetine (MRB)-LC Mean Standardized Uptake Value Ratio (SUVR) Values		Visit 4 (1-4 weeks after LP)
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)
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 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of Hyperphosphorylated Tau (P-Tau, T-Tau)	Levels will be derived from the CSF and reported in pg/mL	Visit 4 (1-4 weeks after LP)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aβ42/Aβ40 Ratio	The presence of amyloid plaques will be represented as the binary indicator of a CSF Aβ42/Aβ40 ratio	Visit 4 (1-4 weeks after LP)

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Ricardo Osorio, NYU Langone Health

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2020
• Primary Completion (Actual): March 26, 2024
• Study Completion (Actual): March 26, 2024

Study Registration Dates

• First Submitted: May 21, 2020
• First Submitted That Met QC Criteria: May 21, 2020
• First Posted (Actual): May 27, 2020

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Investigative Techniques; Therapeutics; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Biopsy; Diagnostic Techniques, Neurological; Spinal Puncture
• Other Study ID Numbers: 20-00002; 1R21AG067549-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial, after deidentification.
• IPD Sharing Time Frame: Immediately following publication. No end date.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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