Noradrenergic Dysregulation, Sleep and Cognition in Older Adults with Insomnia

Not Applicable

Recruiting

• Conditions: Insomnia

• Registration Number: NCT06694441
• Lead Sponsor: Northwestern University

Brief Summary

This study investigates the relationship between the noradrenergic (NA) system, sleep quality, and cognitive function in older adults with insomnia - a population at elevated risk for Alzheimer's disease-related dementias (ADRD) - compared to age and sex matched controls with normal sleep. The study characterizes NA function through multiple approaches: measuring 24-hour plasma levels of norepinephrine (NE) and its brain metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); evaluating central NA system response using the clonidine suppression test (a presynaptic α2 adrenoreceptor agonist that reduces locus coeruleus NA activity; and employing pupillometry as a non-invasive marker of autonomic function. To explore NA function's mechanistic role in insomnia, the study uses an intervention with bright light exposure to enhance daytime NA activity, with the goal of improving both sleep quality and cognitive performance.

Detailed Description

Not available

Study Timeline

• Status Verified: 2024-09
• Study Start: 2024-09-30
• Study First Submitted: 2024-11-13
• Study First Submitted QC: 2024-11-15
• Last Update Submitted: 2024-11-18
• Study First Posted: 2024-11-19
• Last Update Posted: 2024-11-21
• Primary Completion: 2029-07-31
• Study Completion: 2029-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

1. Age ≥ 55 years;
2. Independent in activities of daily living and without clinically significant cognitive impairment as determined by a mini-mental status examination (MMSE) score ≥ 26;
3. Due to the effect of reproductive hormones on autonomic regulation, sleep and cognition, women will be postmenopausal;
4. time spent in bed not greater than 8.5 hours;
5. Sedentary, defined as participation in exercise of moderate intensity for less than 30 minutes per day and less than two times per week on a regular basis.
6. average daily light exposure indicative of indoor environments (from questionnaire).

Inclusion criteria for the insomnia group:

1. Meet criteria for chronic insomnia disorder according to the International Classification of Sleep Disorders (3rd Ed.);
2. Subjective sleep efficiency less than 80% and/or awakening earlier than desired if before 6 AM for ≥3 nights/week in the previous 4 weeks;
3. Subjective WASO (sWASO) ≥ 60 minutes for ≥3 nights/week in previous 4 weeks. sWASO will include time spent awake after sleep onset before final awakening + time spent awake in bed attempting to sleep after the final awakening;
4. global PSQI score greater than 5;
5. average daily light exposure indicative of indoor environments (from questionnaire).

Inclusion criteria for the control group:

1. No history of chronic or short-term insomnia disorder according to the International Classification of Sleep Disorders (3rd Ed.);
2. Subjective sleep efficiency greater than 80%;
3. Subjective mean total sleep time of 6.5 hours to 8 hours;
4. Habitual bedtime of 9PM-midnight;
5. PSQI score ≤ 5. Participants in the control group will be matched with the insomnia group on sex and age (±3 years).

Exclusion Criteria

1. Sleep disorders other than insomnia (restless legs syndrome, parasomnias, REM behavior disorder, circadian rhythm sleep-wake disorder, sleep apnea by STOP questionnaire and apnea hypopnea index (AHI) ≥ 15 by home sleep apnea test;
2. habitual bedtime before 9pm or morning awakening before 5am;
3. History of neurological disorders;
4. History of psychiatric disorders;
5. A Beck depression inventory ((BDI-II) score greater than 16);
6. Unstable or serious medical conditions;
7. Diabetes;
8. Current, or use within the past month, of psychoactive, hypnotic, stimulant or analgesic medications (except occasionally);
9. Use of medications that interfere with NA system activity including B-blockers, selective serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective norepinephrine-dopamine reuptake inhibitors (NDRIs);
10. Hormone replacement therapy;
11. Use of medications that affects pupil diameter and responses to light (i.e. antihistamines, anticholinergics, benzodiazepines, narcotics for pain;
12. History of visual abnormalities that may interfere with pupillary responses to light exposure such as significant cataracts, narrow-angle glaucoma or blindness;
13. History of heart conditions (i.e. arrhythmia, coronary artery disease, angina, heart failure);
14. Shift work or other types of self-imposed irregular sleep schedules;
15. BMI > 30 kg/m2;
16. History of habitual smoking (6 or more cigarettes/week) or caffeine consumption > 400 mg/day.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
24h plasma norepinephrine	Enrollment to the end of treatment at 10 weeks.	24-h plasma norepinephrine (pg/mL) collected every two hours
Clonidine suppression test	Enrollment	Plasma norepinephrine levels (pg/mL) and 3- plasma 3-methoxy-4-hydroxyphenylglycol (MHPG, ng/mL) levels in response to clonidine suppression test. Collected at baseline and every 30 minutes for 2 hours after clonidine ingestion.
Wake after sleep onset (WASO)	Enrollment to the end of treatment at 10 weeks.	Duration in minutes obtained from polysomnography and actigraphy
Slow oscillatory activity during sleep	Enrollment to the end of treatment at 10 weeks.	SO activity (0.5 - 1Hz) is measured from EEG during in laboratory stay
Pittsburg Sleep Quality Index	Enrollment to the end of treatment at 10 weeks.	Self administered questionnaire to evaluate subjective sleep quality
NIH tool box	Enrollment to the end of treatment at 10 weeks.	Cognitive battery to assess executive functions, attention, episodic and working memory

Secondary Outcome Measures

Name	Time	Method
24-h plasma 3-methoxy-4-hydroxyphenylglycol (MHPG)	Enrollment to the end of treatment at 10 weeks.	MHPG (ng/mL) is the main metabolite of Norepinephrine from the brain measured in plasma.
24-h plasma cortisol levels	Enrollment to the end of treatment at 10 weeks.	24-h plasma cortisol levels (nmol/L) collected every two hours as a measure of autonomic activation
24h plasma melatonin	Enrollment to the end of treatment at 10 weeks.	24-h plasma melatonin (pg/mL) collected every two hour as a circadian measure
Pupillometry	Enrollment to the end of treatment at 10 weeks.	Pupil size (measure of autonomic activation)
Psychomotor Vigilance Test	Enrollment to the end of treatment at 10 weeks.	To assess reaction time (ms)
Wake EEG	Enrollment to the end of treatment at 10 weeks.	EEG power in alpha band during wake to measure vigilance levels
Heart Rate and Heart Rate Variability	Enrollment to the end of treatment at 10 weeks.	HR (bpm) and measures of HRV variability (high frequency (HF) component and low frequency to high frequency ratio LF/HF to assess autonomic function and sympatho-vagal balnce
Insomnia Severity Index	Enrollment to the end of treatment at 10 weeks.	Questionnaire to measure insomnia severity
Visual Analogue Scale	Enrollment to the end of treatment at 10 weeks.	Scale to measure global vigor ( score 0 to 100) and global alertness (0 to 100). Higher scores indicate greater levels of both vigor and positive affect.

Trial Locations

Locations (1)

Northwestern University Feinberg School of Medicine, Center for Circadian and Sleep Medicine; 🇺🇸 Chicago, Illinois, United States