Clinical trial NCT04403165: Locus-coeruleus Function in Normal Elderly and AD Risk
Official title: Locus-coeruleus Function in Normal Elderly and AD Risk
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Alzheimer Disease
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2020-05-27
Enrollment: 30
Sex: ALL
Minimum age (years): 55
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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).

Eligibility criteria: 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

Primary outcomes:
measure: Methylreboxetine (MRB)-LC Mean Standardized Uptake Value Ratio (SUVR) Values
timeFrame: Visit 4 (1-4 weeks after LP)
measure: Total REM Duration (Min)
timeFrame: Visit 3 (1-4 weeks after Visit 2)
measure: Percentage of Time Spent in REM Sleep
timeFrame: Visit 3 (1-4 weeks after Visit 2)
measure: REM Sleep Continuity
timeFrame: Visit 3 (1-4 weeks after Visit 2)
measure: N2 Spindle Density
timeFrame: Visit 3 (1-4 weeks after Visit 2)
measure: Mean Psychomotor Vigilance Test (PVT) Reaction Time
timeFrame: Visit 3 (1-4 weeks after Visit 2)
measure: Mean Oddball Test Response Time
timeFrame: Visit 3 (1-4 weeks after Visit 2)
measure: Percentage of Correct Responses
timeFrame: Visit 3 (1-4 weeks after Visit 2)
Secondary outcomes:
measure: Levels of Hyperphosphorylated Tau (P-Tau, T-Tau)
timeFrame: Visit 4 (1-4 weeks after LP)
Other outcomes:
measure: Aβ42/Aβ40 Ratio
timeFrame: Visit 4 (1-4 weeks after LP)
Locations:
city: New York
country: United States
facility: NYU Grossman School of Medicine
state: New York
city: New York
country: United States
facility: Icahn School of Medicine Mount Sinai
state: New York
Study officials:
affiliation: NYU Langone Health
name: Ricardo Osorio
role: PRINCIPAL_INVESTIGATOR
References: