Locus-coeruleus Function in Normal Elderly and AD Risk

Alzheimer Disease Clinical Trial

— LEAD  

Official title:

Locus-coeruleus Function in Normal Elderly and AD Risk

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04403165
• Other study ID #: 20-00002
• Secondary ID: 1R21AG067549-01
• Status: Completed
• Phase: N/A
• Start date: August 6, 2020
• Est. completion date: March 26, 2024

Study information

• Verified date: April 2024
• Source: NYU Langone Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: March 26, 2024
• Est. primary completion date: March 26, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 55 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Procedure:
• Nocturnal polysomnography (NPSG)
Nocturnal polysomnography (NPSG) to measure REM sleep and sleep spindles characteristics.
• Lumbar Puncture (LP)
Lumbar puncture (LP) to measure CSF P-Tau, T-Tau and Aß42/40 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.

Locations

Country	Name	City	State
United States	Icahn School of Medicine Mount Sinai	New York	New York
United States	NYU Grossman School of Medicine	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
NYU Langone Health	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Aß42/Aß40 Ratio	The presence of amyloid plaques will be represented as the binary indicator of a CSF Aß42/Aß40 ratio	Visit 4 (1-4 weeks after LP)
Primary	Methylreboxetine (MRB)-LC Mean Standardized Uptake Value Ratio (SUVR) Values		Visit 4 (1-4 weeks after LP)
Primary	Total REM Duration (Min)		Visit 3 (1-4 weeks after Visit 2)
Primary	Percentage of Time Spent in REM Sleep		Visit 3 (1-4 weeks after Visit 2)
Primary	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)
Primary	N2 Spindle Density		Visit 3 (1-4 weeks after Visit 2)
Primary	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)
Primary	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.	Visit 3 (1-4 weeks after Visit 2)
Primary	Percentage of Correct Responses		Visit 3 (1-4 weeks after Visit 2)
Secondary	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)