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 sleep-wake 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.

Keywords: Alzheimer’s disease; aggression; agitation; circadian; dementia; sundowning.

FIGURE 1

Output and input pathways of the central circadian timing system in the mammalian brain that may be involved sundowning–related behavioral aggression and circadian dysfunction in Alzheimer’s disease and related dementias. The master circadian pacemaker, is the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN releases the fast neurotransmitter GABA, as well as several peptides including vasoactive intestinal peptide (VIP) and argine vasopressin (AVP) from its major axonal output pathway to the nearby subparaventricular zone (SPZ). The GABAergic SPZ regulates rhythms of locomotor activity, sleep-wake, and feeding via pathway to the dorsomedial hypothalamus (DMH), and regulates rhythms of aggression propensity via a pathway to the ventromedial hypothalamus (VMH). The SCN is entrained to the daily light-dark cycle by input from intrinsically photosensitive retinal ganglion cells, which release pituitary adenylate cyclase activating polypeptide (PACAP) and glutamate (GLU) via the retinohypothalamic tract (RHT). The RHT also densely innervates the SPZ in most nocturnal mammals, but provides little or no innervation of the SPZ in many diurnal mammals, including humans (indicated by dashed line). A cholinergic (ACh) input to the SCN from the basal forebrain has been suggested in rats, but is absent in mice (indicated by dashed line). Cholinergic input to the SCN has also been reported from the laterodorsal tegmentum (LDT), pedunculopontine tegmentum (PPT) complex, which also releases GABA and GLU. Serotonergic (5HT) inputs to both the SCN and SPZ have been reported from the midbrain raphe complex. Finally, the geniculo-hypothalamic tract (GHT), originating from the retinoreceipient (not shown here) ventral lateral geniculate nucleus (LGN) and intergeniculate leaflet (IGL) of the thalamus, provides an input of GABA and neuropeptide Y (NPY) to both the SCN and SPZ. Structures are not drawn to scale.