Clinical trial NCT06694441: Noradrenergic Dysregulation, Sleep and Cognition in Older Adults with Insomnia
Official title: Noradrenergic Dysregulation, Sleep and Cognition in Older Adults with Insomnia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Insomnia
Keywords: Insomnia
Older Adults
Noradrenergic dysregulation
sleep
cognition
cognitive function
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2024-11-19
Enrollment: 60
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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).

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 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).

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 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.

Primary outcomes:
measure: 24h plasma norepinephrine
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: Clonidine suppression test
timeFrame: Enrollment
measure: Wake after sleep onset (WASO)
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: Slow oscillatory activity during sleep
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: Pittsburg Sleep Quality Index
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: NIH tool box
timeFrame: Enrollment to the end of treatment at 10 weeks.
Secondary outcomes:
measure: 24-h plasma 3-methoxy-4-hydroxyphenylglycol (MHPG)
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: 24-h plasma cortisol levels
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: 24h plasma melatonin
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: Pupillometry
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: Psychomotor Vigilance Test
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: Wake EEG
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: Heart Rate and Heart Rate Variability
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: Insomnia Severity Index
timeFrame: Enrollment to the end of treatment at 10 weeks.
measure: Visual Analogue Scale
timeFrame: Enrollment to the end of treatment at 10 weeks.
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine, Center for Circadian and Sleep Medicine
state: Illinois
Study officials:
affiliation: Northwestern University
name: Daniela Grimaldi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Northwestern University
name: Phyllis C Zee, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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