Potential Pathways for Circadian Dysfunction and Sundowning-Related Behavioral Aggression in Alzheimer’s Disease and Related Dementias

Abstract

Patients with Alzheimer's disease (AD) and related dementias are commonly reported to exhibit aggressive behavior and other emotional behavioral disturbances, which create a tremendous caretaker burden. There has been an abundance of work highlighting the importance of circadian function on mood and emotional behavioral regulation, and recent evidence demonstrates that a specific hypothalamic pathway links the circadian system to neurons that modulate aggressive behavior, regulating the propensity for aggression across the day. Such shared circuitry may have important ramifications for clarifying the complex interactions underlying "sundowning syndrome," a poorly understood (and even controversial) clinical phenomenon in AD and dementia patients that is characterized by agitation, aggression, and delirium during the late afternoon and early evening hours. The goal of this review is to highlight the potential output and input pathways of the circadian system that may underlie circadian dysfunction and behavioral aggression associated with sundowning syndrome, and to discuss possible ways these pathways might inform specific interventions for treatment. Moreover, the apparent bidirectional relationship between chronic disruptions of circadian and sleepwake regulation and the pathology and symptoms of AD suggest that understanding the role of these circuits in such neurobehavioral pathologies could lead to better diagnostic or even preventive measures.

Circadian Rhythms of the Hypothalamus: From Function to Physiology

“…The most studied and clinically used therapy is light therapy for sundowning patients, although, in some cases, the SCN may be too degenerated for light therapy to be effective [308]. One study reported that a non-invasive 40 HZ light flicker was sufficient to ameliorate the AD-associated rhythmic disruption in mice [309]. Sundowning severity increases as AD progresses, and light is sometimes recommended during the evening hours to reduce associated agitation.…”

Peripheral Leukocytosis Predicts Cognitive Decline but Not Behavioral Disturbances: A Nationwide Study of Alzheimer’s and Parkinson’s Disease Patients

“…Loss of cognitive functions in the early stage of dementia is highly associated with neuronal death boosted by the crosstalk between peripheral and CNS inflammation [44, 45], which includes different mechanisms such as vagal reflex-induced inflammation from the periphery to the brain [46, 47], blood-brain barrier disruption [13], and direct entry of peripheral immune cells into the brain parenchyma [12]. Decline of noncognitive functions has been related to changes in anatomic structures [48], circadian rhythm dysfunction [49], metabolic changes [50], and imbalance in the production of neurotransmitters [51, 52], but less is known about how much systemic inflammation aggravates noncognitive symptoms. Hence, our results open a debate on whether there is an underlying mechanism that produces a negative feedback in leukocytes, especially in late stages of dementia with BPSD, making leukocytosis values a reliable biomarker to identify CNS inflammation and damage at the time of BPSD onset.…”

MicroRNAs as Potential Orchestrators of Alzheimer's Disease-Related Pathologies: Insights on Current Status and Future Possibilities

“…However, circadian rhythms are markedly disturbed in AD all through the disease course. Day-time agitation, night insomnia, restlessness and sun-downing are among the (Todd, 2020). AD is often associated with changes in the physiological parameters of sleep that include decrease in total sleep time and efficiency, prolonged sleep time stage 1 and stage 2 sleep, lesser time in deeper sleep, increased REM sleep latency and decreased REM sleep, together with decreased density of eye movement activity (Weldemichael and Grossberg, 2010).…”

“…Day-time agitation, night insomnia, restlessness and sun-downing are among the characteristic changes observed in AD and they worsen with AD progression to affect around 42–52% of AD patients. Such sleep changes are majorly attributed to disruptions in the precise cascade of circadian rhythm (Todd, 2020 ).…”