Locus-coeruleus Function in Normal Elderly and AD Risk

Study Overview
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Brief Summary
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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
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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).

Official Title
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Locus-coeruleus Function in Normal Elderly and AD Risk

Conditions
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Alzheimer Disease

Intervention / Treatment
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* 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)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cognitively Normal (CN) Older Adults<br> | Procedure: Nocturnal polysomnography (NPSG)<br>* Nocturnal polysomnography (NPSG) to measure REM sleep and sleep spindles characteristics.<br>Procedure: Lumbar Puncture (LP)<br>* Lumbar puncture (LP) to measure CSF P-Tau, T-Tau and Aβ42/40 ratio.<br>Other: PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]Omethylreboxetine ([11C]MRB)<br>* PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]O-methylreboxetine ([11C]MRB) to measure NET availability.<br>Behavioral: Psychomotor Vigilance Task (PVT)<br>* Psychomotor vigilance task (PVT) and the OddBall to measure test taskattention performance.<br>|

What is the study measuring?
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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) | 
| Total REM Duration (Min) |  | Visit 3 (1-4 weeks after Visit 2) | 
| Percentage of Time Spent in REM Sleep |  | 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) | 
| N2 Spindle Density |  | 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 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) | 
| Percentage of Correct Responses |  | 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) |