Noradrenergic Dysregulation, Sleep and Cognition in Older Adults With Insomnia

NCT06694441 | Recruiting

• 3 other identifiers: STU00219832R01AG081520-01A14RF1AG081520-02
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Insomnia

Keywords

Insomnia; Older Adults; Noradrenergic dysregulation; sleep; cognition; cognitive function

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (9)

• 24-h plasma 3-methoxy-4-hydroxyphenylglycol (MHPG)

  Enrollment to the end of treatment at 10 weeks.

• 24-h plasma cortisol levels

  Enrollment to the end of treatment at 10 weeks.

• 24h plasma melatonin

  Enrollment to the end of treatment at 10 weeks.

• Pupillometry

  Enrollment to the end of treatment at 10 weeks.

• Psychomotor Vigilance Test

  Enrollment to the end of treatment at 10 weeks.

Study Arms (2)

Intervention on Subjects with Insomnia

EXPERIMENTAL

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

Dim Red Light

ACTIVE COMPARATOR

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

Interventions

Light Exposure OTHER

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.

Intervention on Subjects with Insomnia

Placebo OTHER

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).

Dim Red Light

Eligibility Criteria

• Age: 55 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 55 years;
• Independent in activities of daily living and without clinically significant cognitive impairment as determined by a mini-mental status examination (MMSE) score ≥ 26;
• Due to the effect of reproductive hormones on autonomic regulation, sleep and cognition, women will be postmenopausal;
• time spent in bed not greater than 8.5 hours;
• 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.
• average daily light exposure indicative of indoor environments (from questionnaire).
• Meet criteria for chronic insomnia disorder according to the International Classification of Sleep Disorders (3rd Ed.);
• 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;
• 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;
• global PSQI score greater than 5;
• average daily light exposure indicative of indoor environments (from questionnaire).
• No history of chronic or short-term insomnia disorder according to the International Classification of Sleep Disorders (3rd Ed.);
• Subjective sleep efficiency greater than 85%;
• Subjective mean total sleep time of 6.5 hours to 8 hours;
• Habitual bedtime of 9PM-midnight;

You may not qualify if:

• 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;
• habitual bedtime before 9pm or morning awakening before 5am;
• History of neurological disorders;
• History of psychiatric disorders;
• A Beck depression inventory ((BDI-II) score greater than 19);
• Unstable or serious medical conditions;
• Prediabetes and diabetes (HbA1C ≥ 5.7)
• Current, or use within the past month, of psychoactive, hypnotic, stimulant or analgesic medications (except occasionally);
• 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);
• Hormone replacement therapy;
• Use of medications that affects pupil diameter and responses to light (i.e. antihistamines, anticholinergics, benzodiazepines, narcotics for pain;
• History of visual abnormalities that may interfere with pupillary responses to light exposure such as significant cataracts, narrow-angle glaucoma or blindness;
• History of heart conditions (i.e. arrhythmia, coronary artery disease, angina, heart failure);
• Shift work or other types of self-imposed irregular sleep schedules;
• BMI \> 35 kg/m2;

Sponsors & Collaborators

• Northwestern University: lead
• National Institute on Aging (NIA): collaborator

Study Sites (1)

Northwestern University Feinberg School of Medicine, Center for Circadian and Sleep Medicine

Chicago, Illinois, 60611, United States

RECRUITING

Related Publications (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.

  PMID: 35124476 BACKGROUND

• 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.

  PMID: 6228698 BACKGROUND

• 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.

  PMID: 15872097 BACKGROUND

• 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.

  PMID: 15980285 BACKGROUND

• 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.

  PMID: 23814339 BACKGROUND

• 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.

  PMID: 28890168 BACKGROUND

Related Links

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

MeSH Terms

Conditions

Sleep Initiation and Maintenance Disorders

Condition Hierarchy (Ancestors)

Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Mental Disorders

Study Officials

• Daniela Grimaldi, MD, PhD

  Northwestern University

  PRINCIPAL INVESTIGATOR

• Phyllis C Zee, MD, PhD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Marguerite McGuire

CONTACT

844-707-5337; marguerite.mcguire@northwestern.edu

Daniela Grimaldi, MD, PhD

CONTACT

844-707-5337; daniela.grimaldi@northwestern.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Neurology

Study Record Dates

• First Submitted: November 13, 2024
• First Posted: November 19, 2024
• Study Start: September 30, 2024
• Primary Completion (Estimated): July 31, 2029
• Study Completion (Estimated): August 31, 2029
• Last Updated: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)