Sleep Disturbance and Emotion Regulation Brain Dysfunction as Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Dementia

Recent findings suggest that sleep disruption may contribute to the generation and maintenance of neuropsychiatric symptoms including anxiety, depression, agitation, irritation, and apathy while treating sleep disruption reduces these symptoms. Impairments in the neural systems that support emotion regulation may represent one causal mechanism mediating the relationship between sleep and emotional distress. However, this model has not yet been formally tested within a sample of individuals with or at risk for developing Alzheimer's Disease (AD)

This proposal aims to test a mechanistic model in which sleep disturbance contributes to neuropsychiatric symptoms through impairments in fronto-limbic emotion regulation function in a sample of individuals at risk for developing, or at an early stage of AD.

This study seeks to delineate the causal association between sleep disruption, fronto-limbic emotion regulation brain function, and neuropsychiatric symptoms. These aims will be achieved through a mechanistic, randomized 2-arm controlled trial design. 150 adults experiencing sleep disturbances and who also have cognitive impairment with the presence of at least mild neuropsychiatric symptoms will be randomized to receive either a sleep manipulation (Cognitive Behavioral Therapy for Insomnia CBT-I; n=75) or an active control (n=75). CBT-I improves sleep patterns through a combination of sleep restriction, stimulus control, mindfulness training, cognitive therapy targeting dysfunctional beliefs about sleep, and sleep hygiene education. Neuropsychiatric symptoms, fronto-limbic functioning, and sleep disruption will be assessed at baseline and at the end of the sleep manipulation through functional Magnetic Resonance Imaging (fMRI), clinical interviews, PSG recordings, and self-report questionnaires. Neuropsychiatric symptoms (anxiety and depression) and sleep disturbance (actigraphy, Insomnia Severity Index, and sleep diaries) will be assayed at baseline and each week throughout the sleep manipulation to assess week-to-week changes following an increasing number of CBT-I sessions. Wristwatch actigraphy will be acquired from baseline to the end of the sleep manipulation at week 11. Neuropsychiatric symptoms and sleep will be assessed again at six months post-manipulation.


Eligibility Criteria:
Inclusion Criteria:

* Males and females of any racial or ethnic group, aged 50-90 (inclusive)
* Subjective complaint of insomnia associated with daytime impairment or distress (ISI ≥ 10)
* Subjective complaint of sleep disturbance ≥ 3 months in duration
* Subjective complaint of Neuropsychiatric symptoms (Self-Report NPI distress total score ≥ 4 on any measure other than the sleep domain OR current symptoms from Study Partner NPI ≥ 1
* Able to verbalize understanding of involvement in the research and provide written informed consent or provide assent co-signed by a LAR
* Fluent and literate in English
* Written, informed consent
* Medications (including any dementia-related meds) stable for at least 4 weeks prior to study baseline
* Research diagnosis of memory impairment based on the following:

  i) Global Clinical Dementia Rating (CDR) of 0.5 or 1.0. OR a diagnosis of memory impairment from the Stanford/VA AD Center
* MRI safety screen passed , as assessed by the attached MRI safety screening form from the Stanford CNI, excluding mild claustrophobia that will be further screened at the in-person screening session per the screening protocol
* Have a caregiver or study partner willing to aid in facilitating the protocol and ratings
* Reside within approximately 60 miles of Stanford University

Exclusion Criteria:

* less than 20 on the Mini-Mental State Examination (MMSE)
* Acute or unstable chronic illness: including but not limited to: uncontrolled thyroid disease, kidney, prostate or bladder conditions causing excessively frequent urination (\> 3 times per night); medically unstable congestive heart failure, angina, other severe cardiac illness as defined by treatment regimen changes in the prior 3 months; stroke with serious sequelae; cancer if \< 1 year since end of treatment; asthma, emphysema, or other severe respiratory diseases uncontrolled with medications; and neurological disorders (with the exception of mild AD) such as Parkinson's disease and unstable epilepsy as defined by treatment regimen changes in the prior 3 months; unstable adult onset diabetes as defined by treatment regimen changes in the prior 3 months.
* Use of medication specifically prescribed for sleep disturbance or nighttime-only, low dose anti-depressants (e.g., doxepin, amitriptyline, trazodone used only at sub-therapeutic anti-depressant doses and taken only at bedtime) specifically prescribed for sleep disturbance and unwilling or unable to discontinue \> two weeks (anti-depressants) or \>1 week (sleep medications) prior to baseline data collection.
* Current or lifetime history of bipolar disorder
* History of psychosis preceding onset of memory impairments
* Substance abuse or dependence
* Excessive alcohol consumption (\>14 drinks per week or \> 4 drinks per occasion)
* Current exposure to trauma, or exposure to trauma within the past 3 months
* Presence of suicidal ideations representing high risk as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS). Individuals are considered high risk if they have endorsement of either of the following:

  1. A score of 4 or more for the past month on the C-SSRS
  2. ) A positive endorsement, relative to the past 90 days, in the "Suicide Behavior" section of item #6 (Have you ever done anything, started to do anything, or prepared to do anything to end your life?)
* History of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities OR traumatic brain injury in the past two months
* Severe impediment to vision, hearing and/or hand movement, likely to interfere with the ability to complete the assessments, or are unable and/or unlikely to follow the study protocols
* Current or expected cognitive behavior therapy or other evidence based psychotherapies; therapy for another condition (e.g. Depression)
* History of falling and/or severe mobility impairment
* Individuals who are not CPAP adherent or have untreated severe OSA (AHI \>= 30).CPAP adherence being defined as using the CPAP machine 70% of nights for a minimum of 4 hours per night.
* Received Cognitive Behavior Therapy for Insomnia (CBT-I) or Desensitization Therapy for Insomnia (DTI) within the past year
* Are not fully vaccinated for COVID-19 (e.g. 2 doses of Moderna or BioNTech, Pfizer vaccines; or 1 for Johnson and Johnson) and unwilling, if asked, to provide proof (e.g., CDC COVID-19 Vaccination Card, e-Health record, etc.)