Noradrenergic Dysregulation, Sleep and Cognition in Older Adults With Insomnia (NASC)

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.

Study Overview

• Status: Recruiting
• Conditions: Insomnia
• Intervention / Treatment: Other: Placebo; Other: Light Exposure

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marguerite McGuire; Phone Number: 844-707-5337; Email: marguerite.mcguire@northwestern.edu
• Study Contact Backup: Name: Daniela Grimaldi, MD, PhD; Phone Number: 844-707-5337; Email: daniela.grimaldi@northwestern.edu

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University Feinberg School of Medicine, Center for Circadian and Sleep Medicine
      • Principal Investigator: Phyllis C. Zee, MD, PhD
      • Contact: Daniela Grimaldi, MD, PhD; Phone Number: 844-707-5337; Email: daniela.grimaldi@northwestern.edu
      • Contact: Marguerite McGuire; Phone Number: 844-707-5337 844-707-5337; Email: marguerite.mcguire@northwestern.edu
      • Principal Investigator: Daniela Grimaldi, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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 85% 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 85%;
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 19);
6. Unstable or serious medical conditions;
7. Prediabetes and diabetes (HbA1C ≥ 5.7)
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 > 35 kg/m2;
16. History of habitual smoking (6 or more cigarettes/week) or caffeine consumption > 400 mg/day.

17.Use of weight-loss medications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dim Red Light; Participants randomized to the control group will wear for two 60-minute sessions (morning and afternoon) customized dim-red light (RL) control Re-Timer® light glasses (wavelength peak at 632nm, light intensity < 3 lux). Participants will be instructed to wear the light glasses in habitual indoor environments, without engaging in strenuous activities. Throughout the intervention, participants will keep a diary to monitor daily use of the glasses. Participants will have weekly phone calls with the research team to encourage compliance and monitor potential side effects.	Other: Placebo; Participants randomized to the control group will wear for two 60-minute sessions (morning and afternoon) customized dim-red light (RL) control Re-Timer® light glasses (wavelength peak at 632nm, light intensity < 3 lux).
Experimental: Intervention on Subjects with Insomnia; The intervention in this study will involve 28 (+10) days of daily exposure to bright light (BL) for two 60-minute sessions (morning and afternoon). For the intervention, we will use Re-Timer® light glasses emitting light with an intensity of 230μW/cm2 (~500lux) with a green blue 500nm dominant wavelength (between 480-520nm). Light with these characteristics has been shown effective in suppressing melatonin levels supporting their potential to exert effects on other biological non-visual functions associated with exposure to light relevant for this study. Throughout the intervention, participants will keep a diary to monitor daily use of the glasses. Participants will have weekly phone calls with the research team to encourage compliance and monitor potential side effects.	Other: Light Exposure; The intervention in this study will involve 28 (+10) days of daily exposure to bright light (BL) for two 60-minute sessions (morning and afternoon). For the intervention, we will use Re-Timer® light glasses emitting light with an intensity of 230μW/cm2 (~500lux) with a green blue 500nm dominant wavelength (between 480-520nm). Light with these characteristics has been shown effective in suppressing melatonin levels supporting their potential to exert effects on other biological non-visual functions associated with exposure to light relevant for this study. Throughout the intervention, participants will keep a diary to monitor daily use of the glasses. Participants will have weekly phone calls with the research team to encourage compliance and monitor potential side effects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24h plasma norepinephrine	24-h plasma norepinephrine (pg/mL) collected every two hours	Enrollment to the end of treatment at 10 weeks.
Clonidine suppression test	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.	Enrollment
Wake after sleep onset (WASO)	Duration in minutes obtained from polysomnography and actigraphy	Enrollment to the end of treatment at 10 weeks.
Slow oscillatory activity during sleep	SO activity (0.5 - 1Hz) is measured from EEG during in laboratory stay	Enrollment to the end of treatment at 10 weeks.
Pittsburg Sleep Quality Index	Self administered questionnaire to evaluate subjective sleep quality	Enrollment to the end of treatment at 10 weeks.
NIH tool box	Cognitive battery to assess executive functions, attention, episodic and working memory	Enrollment to the end of treatment at 10 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-h plasma 3-methoxy-4-hydroxyphenylglycol (MHPG)	MHPG (ng/mL) is the main metabolite of Norepinephrine from the brain measured in plasma.	Enrollment to the end of treatment at 10 weeks.
24-h plasma cortisol levels	24-h plasma cortisol levels (nmol/L) collected every two hours as a measure of autonomic activation	Enrollment to the end of treatment at 10 weeks.
24h plasma melatonin	24-h plasma melatonin (pg/mL) collected every two hour as a circadian measure	Enrollment to the end of treatment at 10 weeks.
Pupillometry	Pupil size (measure of autonomic activation)	Enrollment to the end of treatment at 10 weeks.
Psychomotor Vigilance Test	To assess reaction time (ms)	Enrollment to the end of treatment at 10 weeks.
Heart Rate and Heart Rate Variability	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	Enrollment to the end of treatment at 10 weeks.
Insomnia Severity Index	Questionnaire to measure insomnia severity	Enrollment to the end of treatment at 10 weeks.
Wake EEG	EEG power in alpha band during wake to measure vigilance levels	Enrollment to the end of treatment at 10 weeks.
Visual Analogue Scale	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.	Enrollment to the end of treatment at 10 weeks.

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Phyllis C Zee, MD, PhD, Northwestern University; Principal Investigator: Daniela Grimaldi, MD, PhD, Northwestern University

Publications and helpful links

General Publications

• Lim AS, Kowgier M, Yu L, Buchman AS, Bennett DA. Sleep Fragmentation and the Risk of Incident Alzheimer's Disease and Cognitive Decline in Older Persons. Sleep. 2013 Jul 1;36(7):1027-1032. doi: 10.5665/sleep.2802.
• Shi L, Chen SJ, Ma MY, Bao YP, Han Y, Wang YM, Shi J, Vitiello MV, Lu L. Sleep disturbances increase the risk of dementia: A systematic review and meta-analysis. Sleep Med Rev. 2018 Aug;40:4-16. doi: 10.1016/j.smrv.2017.06.010. Epub 2017 Jul 6.
• Van Egroo M, Koshmanova E, Vandewalle G, Jacobs HIL. Importance of the locus coeruleus-norepinephrine system in sleep-wake regulation: Implications for aging and Alzheimer's disease. Sleep Med Rev. 2022 Apr;62:101592. doi: 10.1016/j.smrv.2022.101592. Epub 2022 Jan 21.
• Mann DM. The locus coeruleus and its possible role in ageing and degenerative disease of the human central nervous system. Mech Ageing Dev. 1983 Sep;23(1):73-94. doi: 10.1016/0047-6374(83)90100-8.
• Cirelli C, Huber R, Gopalakrishnan A, Southard TL, Tononi G. Locus ceruleus control of slow-wave homeostasis. J Neurosci. 2005 May 4;25(18):4503-11. doi: 10.1523/JNEUROSCI.4845-04.2005.
• McCrae CS, Rowe MA, Tierney CG, Dautovich ND, Definis AL, McNamara JP. Sleep complaints, subjective and objective sleep patterns, health, psychological adjustment, and daytime functioning in community-dwelling older adults. J Gerontol B Psychol Sci Soc Sci. 2005 Jul;60(4):P182-9. doi: 10.1093/geronb/60.4.p182.

Helpful Links

• Center for Circadian and Sleep Medicine Website
• REDCap Initial Screening Eligibility Form

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2024
• Primary Completion (Estimated): July 31, 2029
• Study Completion (Estimated): August 31, 2029

Study Registration Dates

• First Submitted: November 13, 2024
• First Submitted That Met QC Criteria: November 15, 2024
• First Posted (Actual): November 19, 2024

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: sleep; cognitive function; cognition; Older Adults; Insomnia; Noradrenergic dysregulation
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Initiation and Maintenance Disorders
• Other Study ID Numbers: STU00219832; R01AG081520-01A1 (U.S. NIH Grant/Contract); 4RF1AG081520-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Study Data/Documents

1. Study Overview and Intial Screening Eligibility Form
   Information comments: Full protocol available via email request: CCSMresearch@northwestern.edu

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No