Locus-coeruleus Function in Normal Elderly and AD Risk

Not Applicable

Completed

Interventions: 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)

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).

Recruitment & 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

Arm && Interventions

Group	Intervention	Description
Cognitively Normal (CN) Older Adults	Lumbar Puncture (LP)	-
Cognitively Normal (CN) Older Adults	Psychomotor Vigilance Task (PVT)	-
Cognitively Normal (CN) Older Adults	Nocturnal polysomnography (NPSG)	-
Cognitively Normal (CN) Older Adults	PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]Omethylreboxetine ([11C]MRB)	-

Primary Outcome Measures

Name	Time	Method
Total REM Duration (Min)	Visit 3 (1-4 weeks after Visit 2)
REM Sleep Continuity	Visit 3 (1-4 weeks after Visit 2)	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).
Methylreboxetine (MRB)-LC Mean Standardized Uptake Value Ratio (SUVR) Values	Visit 4 (1-4 weeks after LP)
Percentage of Time Spent in REM Sleep	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	Visit 3 (1-4 weeks after Visit 2)	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	Visit 3 (1-4 weeks after Visit 2)	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	Visit 3 (1-4 weeks after Visit 2)

Secondary Outcome Measures

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

Locations (2): NYU Grossman School of Medicine
🇺🇸
New York, New York, United States
Icahn School of Medicine Mount Sinai
🇺🇸
New York, New York, United States