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

 -  Males and females of any racial or ethnic group, aged 50-90 (inclusive)

 -  Diagnosis of amnestic mild cognitive impairment (aMCI; single or multi domain) or mild
 AD

 -  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 (NPI total score ≥ 4)

 -  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

 -  Medications (including any dementia-related meds) stable for at least 4 weeks prior to
 study baseline

 -  Wechsler Memory Scale-Revised Logical Memory II subtest using the following rubric: ≤
 8 for subjects with 16 or more years of education, ≤ 4 for 8-15 years of education, 2
 ≤ for 0-7 years of education

 -  Global Clinical Dementia Rating (CDR) of 0.5 or 1.0.

 -  MRI safety screen passed

 -  Have a caregiver or study partner willing to aid in facilitating the protocol and
 ratings

 -  Caffeine consumption to ≤ 3 8 ounce cups prior to lunch every day for ≥ 3 weeks prior
 to treatment

 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 and unwilling or
 unable to discontinue > one week 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
 Sheehan-Suicide Tracking Scale (S-STS). Individuals are considered high risk if they
 endorse a 3 or 4 on questions 2 or 13, or endorse levels 2 or higher on any Question
 1a, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 14.

 -  Mild traumatic brain injury (history of physical brain injury or blow to the head
 resulting in loss of consciousness >5 minutes)

 -  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 behavioral therapy for another condition (e.g.
 depression)