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

Primary Purpose

Alzheimer Disease

Status

Recruiting

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Nocturnal polysomnography (NPSG)

Lumbar Puncture (LP)

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

Psychomotor Vigilance Task (PVT)

About this trial

This is an interventional basic science trial for Alzheimer Disease

Eligibility Criteria

60 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Male and female subjects with normal cognition and 60-75 years of age will be enrolled.
Subjects will be within normal limits on neurological and psychiatric examinations. All subjects enrolled will have both a Clinical Dementia Rating (CDR)=0 and a MMSE>27.
All subjects will have had a minimum of 12 years of education. Among underrepresented group (URG) subjects, >80% of the elderly individuals coming to the NYU-ADRC meet this criterion. (The education restriction reduces performance variance on cognitive test measures and improves the sensitivity for detecting pathology and disease progression using the robust norms available at the NYU ADRC. Given the majority of subjects will meet this criterion we do not consider this a major selection bias or generalization limitation for this study).
An informed family member or life-partner (preferably bed-partner) will be interviewed to confirm the reliability of the subject interview.

Exclusion Criteria:

History of brain tumor, MRI evidence of brain damage or brain disease including significant trauma, hydrocephalus, seizures, mental retardation or other serious neurological disorder (e.g. Parkinson's disease or other movement disorders). Subjects with a Fazekas scale >2 will be excluded.
Significant history of alcoholism or drug abuse.
History of psychiatric illness (e.g., schizophrenia, bipolar, PTSD, or life-long history of major depression).
Geriatric Depression Scale (short form)>5.
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 (AHI3a%>/=15).
Medications affecting cognition or sleep.

Sites / Locations

NYU Grossman School of MedicineRecruiting
Icahn School of Medicine Mount Sinai

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cognitively Normal (CN) Older Adults

Arm Description

Outcomes

Primary Outcome Measures

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

Total REM Duration (Min)

Percentage of Time Spent in REM Sleep

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).

N2 Spindle Density

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.

Mean Oddball Test Response Time

The OddBall test measures task-related attention. Two different visual stimuli (frequent and infrequent) are presented in random succession as the subject presses a button only when the infrequent stimuli appears.

Percentage of Correct Responses

Secondary Outcome Measures

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

Levels will be derived from the CSF and reported in pg/mL

Full Information

NCT ID

NCT04403165

First Posted

May 21, 2020

Last Updated

May 10, 2023

Sponsor

NYU Langone Health

Collaborators

National Institute on Aging (NIA)

1. Study Identification

Unique Protocol Identification Number

NCT04403165

Brief Title

Locus-coeruleus Function in Normal Elderly and AD Risk

Acronym

LEAD

Official Title

Locus-coeruleus Function in Normal Elderly and AD Risk

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Recruiting

Study Start Date

August 6, 2020 (Actual)

Primary Completion Date

August 31, 2024 (Anticipated)

Study Completion Date

August 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

NYU Langone Health

Collaborators

National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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 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.

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer Disease

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Cognitively Normal (CN) Older Adults

Arm Type

Experimental

Intervention Type

Procedure

Intervention Name(s)

Nocturnal polysomnography (NPSG)

Intervention Description

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

Intervention Type

Procedure

Intervention Name(s)

Lumbar Puncture (LP)

Intervention Description

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

Intervention Type

Other

Intervention Name(s)

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

Intervention Description

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

Intervention Type

Behavioral

Intervention Name(s)

Psychomotor Vigilance Task (PVT)

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Time Frame

Visit 4 (1-4 weeks after LP)

Title

Total REM Duration (Min)

Time Frame