Noradrenergic Dysregulation, Sleep and Cognition in Older Adults with Insomnia

NCT ID: NCT06694441

Last Updated: 2024-11-21

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-09-30
• Study Completion Date: 2029-08-31

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Intervention on Subjects with Insomnia

The intervention in this study will involve 28 (+4) 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.

Group Type: EXPERIMENTAL

Light Exposure

Intervention Type: OTHER

The intervention in this study will involve 28 (+4) 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.

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.

Group Type: ACTIVE_COMPARATOR

Placebo

Intervention Type: 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).

Interventions

Light Exposure

The intervention in this study will involve 28 (+4) 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 Type: 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).

Intervention Type: OTHER

Eligibility Criteria

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).

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).

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.

• Minimum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Northwestern University

OTHER

Sponsor Role: lead

Responsible Party

Daniela Grimaldi

Associate Professor of Neurology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Daniela Grimaldi, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Phyllis C Zee, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Locations

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

Chicago, Illinois, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Marguerite McGuire

Role: CONTACT

marguerite.mcguire@northwestern.edu

844-707-5337

Daniela Grimaldi, MD, PhD

Role: CONTACT

daniela.grimaldi@northwestern.edu

844-707-5337

Facility Contacts

Marguerite McGuire

Role: primary

marguerite.mcguire@northwestern.edu

844-707-5337 ext. 844-707-5337

Daniela Grimaldi, MD, PhD

Role: backup

daniela.grimaldi@northwestern.edu

844-707-5337

Daniela Grimaldi, MD, PhD

Role: backup

Phyllis C. Zee, MD, PhD

Role: backup

References

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.

Reference Type: BACKGROUND

PMID: 35124476 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 6228698 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15872097 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15980285 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23814339 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28890168 (View on PubMed)

Study Documents

Document Type: Study Overview and Intial Screening Eligibility Form

Full protocol available via email request: CCSMresearch@northwestern.edu

View Document

Related Links

https://www.feinberg.northwestern.edu/sleep

Center for Circadian and Sleep Medicine Website

https://redcap.nubic.northwestern.edu/redcap/surveys/?s=WK7CDXRNNTLCWEEK

REDCap Initial Screening Eligibility Form

Other Identifiers

R01AG081520-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STU00219832

Identifier Type: -

Identifier Source: org_study_id