Circadian rhythm disturbance, impaired sleep, and agitation in Alzheimer's disease Neuropsychiatric symptoms (NPS) in AD are a major cause of burden to patients, caregivers, and society. One of the most troubling of these symptoms is agitation (which we will term Agit-AD), typified by a variety of problem behaviors including irritability, emotional distress, combativeness, yelling, pacing, lack of cooperation with care, insomnia, and restlessness. Agit-AD is associated with significant caregiver stress. There is a consensus in the field that we need better treatments for Agit-AD and that to do so we need better understanding of the brain mechanisms underlying Agit-AD. Families and clinicians frequently note that Agit-AD occurs cyclically, with patients often becoming more agitated later in the day or in the middle of the night. These clinical observations have led to the hypothesis that Agit-AD is associated with impaired circadian rhythms (i.e., a disordered ?internal clock?). Indeed, there are data suggesting that the severity of Agit-AD is associated with greater circadian phase delay and reduced rhythm amplitude and is a potential target for treatment. Thus, improvement of the strength and phase of circadian rhythms may be a potential approach for treating Agit-AD but medication trials to date have been of little to no benefit. These failures may reflect an incomplete understanding of the precise relationship between circadian rhythms and agitation and the potential need for finer grained analysis of Agit-AD. We propose to examine the association of circadian rhythm and sleep disturbance with Agit-AD in a cross-sectional design comparing 50 subjects with Agit-AD vs. 50 control subjects with AD and minimal NPS.
SPECIFIC AIMS Aim 1: Compare phase and amplitude of circadian rhythms in 50 Agit-AD (+) subjects vs. 50 AD subjects with minimal NPS.
Aim 2 : Compare phase and amplitude of circadian rhythms in affective vs. executive subtypes in 50 Agit-AD (+).
Aim 3 : Compare sleep amount/quality and presence of SDB in 50 Agit-AD (+) subjects vs. 50 AD subjects with minimal NPS PUBLIC HEALTH SIGNIFICANCE: These data could be essential for the development of chronobiotic or sleep interventions for Agit-AD. If circadian rhythm disturbance (CRD) or poor sleep is associated with Agit-AD then these results would allow investigators to use actigraphy, core body temperature, or sleep measures as a surrogate biomarker in proof-of-concept studies of interventions targeting CRD for treatment of Agit-AD. If CRD or poor sleep is associated with a subgroup of patients with Agit-AD then actigraphy, core body temperature, or sleep measures could help investigators target that subgroup for intervention research.

Public Health Relevance

Agitation in Alzheimer's Disease is a major problem for patients and families and adds greatly to the public health burden of the disease. There is evidence suggesting that agitated Alzheimer's patients have disordered circadian rhythms and sleep; in other words, their ?internal clocks? may function abnormally, and we hypothesize that these disordered rhythms and sleep contribute to their agitation. We propose to study circadian rhythms and sleep in 50 Alzheimer's patients with agitation, comparing to 50 Alzheimer's patients with minimal neuropsychiatric symptoms, with the hope that a better understanding of these rhythms will lead to development of effective treatments for agitation in Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Mackiewicz, Miroslaw
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Johns Hopkins University
Schools of Medicine
United States
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Spira, Adam P (2018) Sleep and Health in Older Adulthood: Recent Advances and the Path Forward. J Gerontol A Biol Sci Med Sci 73:357-359