Locus-coeruleus Function in Normal Elderly and AD Risk

NYU Langone Health30 enrolled

Overview

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.

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

Allocation

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Interventions

Nocturnal polysomnography (NPSG)PROCEDURE

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

Lumbar Puncture (LP)PROCEDURE

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

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

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

Psychomotor Vigilance Task (PVT)BEHAVIORAL

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

Eligibility

Sex: ALLMin age: 55 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

Time frame: Visit 4 (1-4 weeks after LP)

Total Rapid Eye Movement (REM) Duration (Min)

REM sleep is derived from in-laboratory nocturnal polysomnography (NPSG) sleep study.