Time-in-bed Restriction in Older Adults With Sleep Difficulties With and Without Risk for Alzheimer's Disease (ALPS)
Primary Purpose
Alzheimer Disease, Late Onset, Mild Cognitive Impairment, Sleep
Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Time in Bed Restriction
Sleep Schedule
Sponsored by
About this trial
This is an interventional treatment trial for Alzheimer Disease, Late Onset
Eligibility Criteria
Inclusion Criteria:
- Age 65-85.
- Self-report mean sleep efficiency (the time in bed spent asleep within the time of lights out to final awakening) < 90% based on diary and actigraphy estimates and wake time after sleep onset > 20 minutes based on diary and actigraphy estimates.
- Self-reported normal or corrected-to-normal visual and auditory acuity.
Exclusion Criteria:
- Shift work involving night shift or regular work within the hours of 12am and 6am.
- Presence of a chronic condition that significantly affects sleep.
- Severe psychiatric condition including major depressive disorder, panic disorder, substance use disorders, and alcohol abuse/dependence within the past 6 months, or a lifetime history of a psychotic disorder or bipolar I disorder, based on initial online/phone self-report diagnoses, and subsequently based on the M.I.N.I International Neuropsychiatric Interview.
- Current use of medications affecting sleep such as antidepressants, antipsychotic medications, anticonvulsants, and steroids.
- Current use of sedating drugs used at bedtime.
- Consumption of > 14 alcohol drinks per week or > 6 drinks at a single sitting.
- Consumption of > 3 caffeine drinks per day.
- Prior diagnosis of a Central nervous system (CNS) disease, such as multiple sclerosis, stroke, Parkinson's disease, Alzheimer's disease, seizure disorder, delirium or dementia, a loss of consciousness > 24 hours, or traumatic brain injury as identified by the Cumulative Illness Rating Scale for Geriatrics (CIRS). Participants who are diagnosed with Alzheimer's disease based on neuropsychological testing will be excluded.
- Sleep efficiency > 90% and wake time after sleep onset < 20 minutes consistent with the rationale of the inclusion criteria described above.
- Apnea/hypopnea index greater than 15 as determined by one night of Apnea Link Plus screening.
- Metal in the body. Rationale: Due to the nature of magnetic resonance imaging (MRI), participants cannot have any metal implants in their bodies, cannot have worked in a metal shop or been exposed to metal fragments during combat. Metal dental work (e.g. fillings crowns) may be allowed if compatible with the fMRI scanner.
- Claustrophobia. Rationale: Could prevent the participant from completing the MRI scans.
- Severe obesity. BMI > 40. Rationale: Could prevent the participant from completing the MRI scan.
- Near-miss or prior automobile accident "due to sleepiness" within the past 12 months. Rationale: reduces the risk of sleepiness-related accidents.
- Employed as a commercial driver during the study (for example, bus drivers, train engineers, airplane pilots). Rationale: reduces the risk of sleepiness-related accidents.
- A score below 23 on the Telephone Interview for Cognitive Status. Rationale: This cut-off has been demonstrated to differentiate well between individuals with mild cognitive impairment from individuals with dementia who would have decision making impairments (Seo et al. 2011, Archives of Gerontology and Geriatrics). This ensures that decision making abilities are intact.
- An Epworth sleepiness score greater than 10. Rationale: ensures that sleepiness is not excessive before starting the intervention that could further increase sleepiness. (Mazzotti, Diego R., et al. "Is the Epworth Sleepiness Scale sufficient to identify the excessively sleepy subtype of OSA?." Chest 161.2 (2022): 557-561; Aurora, R. Nisha, et al. "Correlating subjective and objective sleepiness: revisiting the association using survival analysis." Sleep 34.12 (2011): 1707-1714.)
Sites / Locations
- UPMC Western Psychiatric HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Time in Bed Restriction
Control
Arm Description
Time in Bed (TIB) restriction of 85% of habitual TIB.
Participants will follow their typical sleep schedule consistent with measured average sleep and wake times.
Outcomes
Primary Outcome Measures
Mean change in slow-oscillation activity assessed with electroencephalography
Slow oscillation electroencephalographic power (0.5-1 Hz) during non-rapid eye movement sleep
Mean change in Hippocampal Activation
Change in mean percent signal change of the hippocampus during memory encoding assessed with functional magnetic resonance imaging
Medial prefrontal-Hippocampal Connectivity
Change in the correlation between medial prefrontal activity and hippocampal activity during memory encoding assessed with functional magnetic resonance imaging during awake rest
Change in mean Plasma amyloid-beta 1-42
Change in mean amyloid-beta detected in the plasma in the morning
Overnight memory retention on the AB paired associate task, preclinical Alzheimer's cognitive composite score
Mean change in percent correct memory and cognitive performance and cognitive composite score
Amyloid positivity status
Amyloid positivity above or below established cutoffs assessed with Pittsburgh Compound B positron emission tomography
Secondary Outcome Measures
Mean change in delta activity during sleep
Mean change in delta electroencephalographic power (1-4 Hz) during non-rapid eye movement sleep
Mean change in Sleep Efficiency
Mean change in the proportion of time in bed spent sleeping
Mean percent signal change in medial prefrontal activation
Mean percent signal change in medial prefrontal cortex activation during a memory encoding task
Mean change in medial temporal-Hippocampal Connectivity
Mean change in
mean change in plasma amyloid-beta composite score
mean change in amyloid-beta levels in plasma
Mean change in response time on executive function tasks
Computerized executive function task mean response time in milliseconds
Mean change in accuracy on executive function tasks
Computerized executive function task mean percent accuracy
Apolipoprotein (ApoE) e4 allele carrier status
presence of the e4 apolipoprotein based on genetic testing
Cognitive status based on neuropsychological adjudication
Cognitive status of healthy control or mild cognitive impairment
Clinical insomnia status
Diagnosis of insomnia based on clinical cutoffs with self-reported sleep questionnaires
Full Information
NCT ID
NCT05138848
First Posted
November 7, 2021
Last Updated
October 25, 2022
Sponsor
University of Pittsburgh
Collaborators
National Institute on Aging (NIA)
1. Study Identification
Unique Protocol Identification Number
NCT05138848
Brief Title
Time-in-bed Restriction in Older Adults With Sleep Difficulties With and Without Risk for Alzheimer's Disease
Acronym
ALPS
Official Title
Slow-wave Sleep Enhancement in Those at Risk for Alzheimer's Disease: Links With Memory, Excitotoxicity, and Plasma A-beta
Study Type
Interventional
2. Study Status
Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
January 3, 2022 (Actual)
Primary Completion Date
May 31, 2026 (Anticipated)
Study Completion Date
May 31, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Pittsburgh
Collaborators
National Institute on Aging (NIA)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Dementia caused by Alzheimer's disease affects approximately 5.6 million adults over age 65, with costs expected to rise from $307 billion to $1.5 trillion over the next 30 years. Behavioral interventions have shown promise for mitigating neurodegeneration and cognitive impairments. Sleep is a modifiable health behavior that is critical for cognition and deteriorates with advancing age and Alzheimer's disease. Thus, it is a priority to examine whether improving sleep modifies Alzheimer's disease pathophysiology and cognitive function. Extant research suggests that deeper, more consolidated sleep is positively associated with memory and executive functions and networks that underlie these processes. Preliminary studies confirm that time-in-bed restriction interventions increase sleep efficiency and non-rapid eye movement slow-wave activity (SWA) and suggest that increases in SWA are associated with improved cognitive function. SWA reflects synaptic downscaling predominantly among prefrontal connections. Downscaling of prefrontal connections with the hippocampus during sleep may help to preserve the long-range connections that support memory and cognitive function. In pre-clinical Alzheimer's disease, hyperactivation of the hippocampus is thought to be excitotoxic and is shown to leave neurons vulnerable to further amyloid deposition. Synaptic downscaling through SWA may mitigate the progression of Alzheimer's disease through these pathways. The proposed study will behaviorally increase sleep depth (SWA) through four weeks of time-in-bed restriction in older adults characterized on amyloid deposition and multiple factors associated with Alzheimer's disease risk. This study will examine whether behaviorally enhanced SWA reduces hippocampal hyperactivation, leading to improved task-related prefrontal-hippocampal connectivity, plasma amyloid levels, and cognitive function. This research addresses whether a simple, feasible, and scalable behavioral sleep intervention improves functional neuroimaging indices of excitotoxicity, Alzheimer's pathophysiology, and cognitive performance.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer Disease, Late Onset, Mild Cognitive Impairment, Sleep, Cognitive Change, Amyloid
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Participants will be randomized to one of two intervention groups. The active group will limit their time in bed for 4 weeks by following a consistent sleep schedule with 85% time in bed compared to their baseline time in bed. The control group will not limit their time in bed, but will be asked to maintain their typical sleep schedule consistent with their baseline time in bed.
Masking
Outcomes Assessor
Masking Description
Data collection and data reduction will be performed by sleep technicians and staff who are blind to study hypotheses and the randomization assignment.
Allocation
Randomized
Enrollment
116 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Time in Bed Restriction
Arm Type
Experimental
Arm Description
Time in Bed (TIB) restriction of 85% of habitual TIB.
Arm Title
Control
Arm Type
Active Comparator
Arm Description
Participants will follow their typical sleep schedule consistent with measured average sleep and wake times.
Intervention Type
Behavioral
Intervention Name(s)
Time in Bed Restriction
Intervention Description
Participants will undergo a 4-week sleep intervention that includes specified in- and out-of-bed times as well as a restriction to their habitual time in bed (average sleep opportunity including naps). This will be truncated equally at the beginning and end of the night.
Intervention Type
Behavioral
Intervention Name(s)
Sleep Schedule
Intervention Description
Participants will maintain their typical sleep schedule for 4-weeks.
Primary Outcome Measure Information:
Title
Mean change in slow-oscillation activity assessed with electroencephalography
Description
Slow oscillation electroencephalographic power (0.5-1 Hz) during non-rapid eye movement sleep
Time Frame
Baseline and 4 weeks
Title
Mean change in Hippocampal Activation
Description
Change in mean percent signal change of the hippocampus during memory encoding assessed with functional magnetic resonance imaging
Time Frame
Baseline and 4 weeks
Title
Medial prefrontal-Hippocampal Connectivity
Description
Change in the correlation between medial prefrontal activity and hippocampal activity during memory encoding assessed with functional magnetic resonance imaging during awake rest
Time Frame
Baseline and 4 weeks
Title
Change in mean Plasma amyloid-beta 1-42
Description
Change in mean amyloid-beta detected in the plasma in the morning
Time Frame
Baseline and 4 weeks
Title
Overnight memory retention on the AB paired associate task, preclinical Alzheimer's cognitive composite score
Description
Mean change in percent correct memory and cognitive performance and cognitive composite score
Time Frame
Baseline and 4 weeks
Title
Amyloid positivity status
Description
Amyloid positivity above or below established cutoffs assessed with Pittsburgh Compound B positron emission tomography
Time Frame
Baseline
Secondary Outcome Measure Information:
Title
Mean change in delta activity during sleep
Description
Mean change in delta electroencephalographic power (1-4 Hz) during non-rapid eye movement sleep
Time Frame
Baseline and 4 weeks
Title
Mean change in Sleep Efficiency
Description
Mean change in the proportion of time in bed spent sleeping
Time Frame
Baseline and 4 weeks
Title
Mean percent signal change in medial prefrontal activation
Description
Mean percent signal change in medial prefrontal cortex activation during a memory encoding task
Time Frame
Baseline and 4 weeks
Title
Mean change in medial temporal-Hippocampal Connectivity
Description
Mean change in
Time Frame
Baseline and 4 weeks
Title
mean change in plasma amyloid-beta composite score
Description
mean change in amyloid-beta levels in plasma
Time Frame
Baseline and 4 weeks
Title
Mean change in response time on executive function tasks
Description
Computerized executive function task mean response time in milliseconds
Time Frame
Baseline and 4 weeks
Title
Mean change in accuracy on executive function tasks
Description
Computerized executive function task mean percent accuracy
Time Frame
Baseline and 4 weeks
Title
Apolipoprotein (ApoE) e4 allele carrier status
Description
presence of the e4 apolipoprotein based on genetic testing
Time Frame
Baseline
Title
Cognitive status based on neuropsychological adjudication
Description
Cognitive status of healthy control or mild cognitive impairment
Time Frame
Baseline
Title
Clinical insomnia status
Description
Diagnosis of insomnia based on clinical cutoffs with self-reported sleep questionnaires
Time Frame
Baseline
10. Eligibility
Sex
All
Minimum Age & Unit of Time
65 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Age 65-85.
Self-report mean sleep efficiency (the time in bed spent asleep within the time of lights out to final awakening) < 90% based on diary and actigraphy estimates and wake time after sleep onset > 20 minutes based on diary and actigraphy estimates.
Self-reported normal or corrected-to-normal visual and auditory acuity.
Exclusion Criteria:
Shift work involving night shift or regular work within the hours of 12am and 6am.
Presence of a chronic condition that significantly affects sleep.
Severe psychiatric condition including major depressive disorder, panic disorder, substance use disorders, and alcohol abuse/dependence within the past 6 months, or a lifetime history of a psychotic disorder or bipolar I disorder, based on initial online/phone self-report diagnoses, and subsequently based on the M.I.N.I International Neuropsychiatric Interview.
Current use of medications affecting sleep such as antidepressants, antipsychotic medications, anticonvulsants, and steroids.
Current use of sedating drugs used at bedtime.
Consumption of > 14 alcohol drinks per week or > 6 drinks at a single sitting.
Consumption of > 3 caffeine drinks per day.
Prior diagnosis of a Central nervous system (CNS) disease, such as multiple sclerosis, stroke, Parkinson's disease, Alzheimer's disease, seizure disorder, delirium or dementia, a loss of consciousness > 24 hours, or traumatic brain injury as identified by the Cumulative Illness Rating Scale for Geriatrics (CIRS). Participants who are diagnosed with Alzheimer's disease based on neuropsychological testing will be excluded.
Sleep efficiency > 90% and wake time after sleep onset < 20 minutes consistent with the rationale of the inclusion criteria described above.
Apnea/hypopnea index greater than 15 as determined by one night of Apnea Link Plus screening.
Metal in the body. Rationale: Due to the nature of magnetic resonance imaging (MRI), participants cannot have any metal implants in their bodies, cannot have worked in a metal shop or been exposed to metal fragments during combat. Metal dental work (e.g. fillings crowns) may be allowed if compatible with the fMRI scanner.
Claustrophobia. Rationale: Could prevent the participant from completing the MRI scans.
Severe obesity. BMI > 40. Rationale: Could prevent the participant from completing the MRI scan.
Near-miss or prior automobile accident "due to sleepiness" within the past 12 months. Rationale: reduces the risk of sleepiness-related accidents.
Employed as a commercial driver during the study (for example, bus drivers, train engineers, airplane pilots). Rationale: reduces the risk of sleepiness-related accidents.
A score below 23 on the Telephone Interview for Cognitive Status. Rationale: This cut-off has been demonstrated to differentiate well between individuals with mild cognitive impairment from individuals with dementia who would have decision making impairments (Seo et al. 2011, Archives of Gerontology and Geriatrics). This ensures that decision making abilities are intact.
An Epworth sleepiness score greater than 10. Rationale: ensures that sleepiness is not excessive before starting the intervention that could further increase sleepiness. (Mazzotti, Diego R., et al. "Is the Epworth Sleepiness Scale sufficient to identify the excessively sleepy subtype of OSA?." Chest 161.2 (2022): 557-561; Aurora, R. Nisha, et al. "Correlating subjective and objective sleepiness: revisiting the association using survival analysis." Sleep 34.12 (2011): 1707-1714.)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kristine Wilckens, PhD.
Phone
(412) 586-9434
Email
wilckenska@upmc.edu
Facility Information:
Facility Name
UPMC Western Psychiatric Hospital
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristine Wilckens, PhD.
Phone
412-586-9434
Email
wilckenska@upmc.edu
First Name & Middle Initial & Last Name & Degree
Daniel Buysse, M.D.
First Name & Middle Initial & Last Name & Degree
Howard Aizenstein, M.D.
First Name & Middle Initial & Last Name & Degree
Meryl Butters, PhD.
First Name & Middle Initial & Last Name & Degree
Ann Cohen, PhD.
First Name & Middle Initial & Last Name & Degree
Marie Anne Gebara, M.D.
First Name & Middle Initial & Last Name & Degree
Brian Lopresti, M.C.
First Name & Middle Initial & Last Name & Degree
James Mountz, M.D./PhD.
First Name & Middle Initial & Last Name & Degree
M. Ilyas Kamboh, PhD.
First Name & Middle Initial & Last Name & Degree
Meredith Wallace, PhD.
First Name & Middle Initial & Last Name & Degree
Nathan Yates, PhD.
First Name & Middle Initial & Last Name & Degree
Kristine Wilckens, PhD.
First Name & Middle Initial & Last Name & Degree
Andrea Weinstein, PhD.
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
The investigators will prepare de-identified data sets comprising all of the data collected for this project and make those available to other investigators through NIH data repositories
IPD Sharing Time Frame
Data will be made available upon publication of the primary aims within 2 years of study completion.
Learn more about this trial
Time-in-bed Restriction in Older Adults With Sleep Difficulties With and Without Risk for Alzheimer's Disease
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