Noradrenergic Dysregulation, Sleep and Cognition in Older Adults With Insomnia

Overview

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.

Interventions

• 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 functi
• 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).

Primary outcome measures

• 24h plasma norepinephrine [Time frame: Enrollment to the end of treatment at 10 weeks.]
• Clonidine suppression test [Time frame: Enrollment]
• Wake after sleep onset (WASO) [Time frame: Enrollment to the end of treatment at 10 weeks.]
• Slow oscillatory activity during sleep [Time frame: Enrollment to the end of treatment at 10 weeks.]
• Pittsburg Sleep Quality Index [Time frame: Enrollment to the end of treatment at 10 weeks.]
• NIH tool box [Time frame: Enrollment to the end of treatment at 10 weeks.]

Secondary outcome measures (9)

• 24-h plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) [Time frame: Enrollment to the end of treatment at 10 weeks.]
• 24-h plasma cortisol levels [Time frame: Enrollment to the end of treatment at 10 weeks.]
• 24h plasma melatonin [Time frame: Enrollment to the end of treatment at 10 weeks.]
• Pupillometry [Time frame: Enrollment to the end of treatment at 10 weeks.]
• Psychomotor Vigilance Test [Time frame: Enrollment to the end of treatment at 10 weeks.]
• Wake EEG [Time frame: Enrollment to the end of treatment at 10 weeks.]
• Heart Rate and Heart Rate Variability [Time frame: Enrollment to the end of treatment at 10 weeks.]
• Insomnia Severity Index [Time frame: Enrollment to the end of treatment at 10 weeks.]
• Visual Analogue Scale [Time frame: Enrollment to the end of treatment at 10 weeks.]

Eligibility criteria

Inclusion criteria

• 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).

Inclusion criteria for the insomnia group:

• 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).

Inclusion criteria for the control group:

• 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;
• PSQI score ≤ 5. Participants in the control group will be matched with the insomnia group on sex and age (±3 years).

Exclusion criteria

• 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;
• History of habitual smoking (6 or more cigarettes/week) or caffeine consumption > 400 mg/day.

17.Use of weight-loss medications

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Northwestern University Feinberg School of Medicine, Center for Circadian and Sleep Medici — Chicago

Publications

• 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
• 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
• 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
• 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
• 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
• 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

Identifiers

NCT: NCT06694441 · STU00219832 · R01AG081520-01A1 · 4RF1AG081520-02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗