Noradrenergic Dysregulation, Sleep and Cognition in Older Adults with Insomnia
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Sponsor
- Northwestern University
- Enrollment
- 60
- Locations
- 1
- Primary Endpoint
- 24h plasma norepinephrine
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Single (Participant)
Eligibility Criteria
- Ages
- 55 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
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 80% 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 80%;
- •Subjective mean total sleep time of 6.5 hours to 8 hours;
- •Habitual bedtime of 9PM-midnight;
- •PSQI score ≤
- •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 16);
- •Unstable or serious medical conditions;
- •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 > 30 kg/m2;
- •History of habitual smoking (6 or more cigarettes/week) or caffeine consumption > 400 mg/day.
Arms & Interventions
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.
Intervention: Light Exposure (Other)
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.
Intervention: Placebo (Other)
Outcomes
Primary Outcomes
24h plasma norepinephrine
Time Frame: Enrollment to the end of treatment at 10 weeks.
24-h plasma norepinephrine (pg/mL) collected every two hours
Clonidine suppression test
Time Frame: 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)
Time Frame: Enrollment to the end of treatment at 10 weeks.
Duration in minutes obtained from polysomnography and actigraphy
Slow oscillatory activity during sleep
Time Frame: 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
Time Frame: Enrollment to the end of treatment at 10 weeks.
Self administered questionnaire to evaluate subjective sleep quality
NIH tool box
Time Frame: Enrollment to the end of treatment at 10 weeks.
Cognitive battery to assess executive functions, attention, episodic and working memory
Secondary Outcomes
- 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.)
- Wake EEG(Enrollment to the end of treatment at 10 weeks.)
- Heart Rate and Heart Rate Variability(Enrollment to the end of treatment at 10 weeks.)
- Insomnia Severity Index(Enrollment to the end of treatment at 10 weeks.)
- Visual Analogue Scale(Enrollment to the end of treatment at 10 weeks.)
Investigators
Daniela Grimaldi
Associate Professor of Neurology
Northwestern University