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.
• 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