As Nox, Roman goddess of the night, sweeps the sky, some elderly people and those who have Alzheimer’s disease often become hyperactive, agitated, even delirious. A similar thing happens in mice, according to a paper published in the June 27 Proceedings of the National Academy of Sciences USA online. Given that mice are nocturnal, it is the incipient arrival of Aurora, the goddess of dawn, which makes them jumpy.
Aging and dementia are typically associated with off-kilter circadian rhythms, with more than 80 percent of the 65-plus age bracket suffering sleep problems (Foley et al., 1995). Behavioral symptoms such as insomnia and agitation are two of the main reasons caregivers cite when they place their loved ones in institutions (Pollak et al., 1990; Pollak et al., 1991).
But the existence of “sundowning syndrome,” as the late-day anxiety is called, has been controversial. It could be that people who have trouble communicating release a day’s worth of pent-up frustration as night approaches. Or, caretakers and nurses might perceive their charges as more disruptive when the carers themselves are tired and cranky at the end of the day. Finding evidence of “sunupping” in mice nearing night’s end suggests sundowning is a real, biological phenomenon, said first author Tracy Bedrosian, who led the study with senior author Randy Nelson at the Ohio State University Medical Center in Columbus.
To examine sunupping in mice, Bedrosian had to become somewhat nocturnal herself, observing the mice as their lights-on time—2:00 a.m.—approached. She used two tests to measure activity and anxiety. For activity, the animals’ cages were equipped with light beams; the machinery counted every time a mouse crossed a beam. For anxiety, Bedrosian put the mice in a maze with covered and open sections; mice that did not mind being out in the open were, presumably, less anxious than those hiding.
In one group of experiments, the researchers compared seven-month-old, middle-aged mice with 29-month-old seniors (comparable to an 80-year-old person). Early in their nighttime, between 5:00 and 6:00 p.m., the different age groups were similarly active in their cages and equivalently anxious in the maze. But as the end of darkness neared, between 11:00 p.m. and midnight, the older animals moved about more, and spent less time in the open areas of the maze, than their younger counterparts.
Next, the scientists looked for a biological basis for the altered activity. Disruption of the cholinergic system is associated with dementia and circadian changes, and blocking acetylcholine receptors causes anxiety in rodents (Smythe et al., 1998). Bedrosian fixed brain samples and compared acetylcholinesterase staining in the nucleus basis of Meynert, the site of maximal cholinergic neuron degeneration in people with AD. In the middle-aged mice, the amount of staining was similar between the early and late time points. In the older animals, acetylcholinesterase staining nearly doubled between the early and late times. Since acetylcholinesterases degrade acetylcholine, this would result in less of the transmitter, leading to amped-up anxiety.
Finally, Bedrosian repeated her experiments with nine-month-old AD model mice expressing mutant human amyloid precursor protein. These mice were more active throughout the night, and more anxious late, than wild-type nine-month-olds.
There are no standard treatments for sundowning, Bedrosian said, because scientists do not comprehend what happens in the brain as bedtime nears. “This paper provides a mechanistic insight,” said Phyllis Zee of the Northwestern University Feinberg School of Medicine in Chicago, Illinois. “Work like this could lead to more targeted strategies.” Zee added that circadian alterations might contribute not only to sundowning, but also to cognitive and memory problems.
Cholinesterase inhibitors are already approved as a treatment for Alzheimer’s. “Our data suggest it might have an effect on sundowning as well,” Bedrosian said. The researchers also tried melatonin treatment in the mice, with little effect. The addition of light and dark therapy might be more effective, Zee suggested. In people with AD, melatonin and light therapy seem to work best in tandem (see ARF related news story on Riemersma-van der Lek et al., 2008; Dowling et al., 2008).—Amber Dance
- Foley DJ, Monjan AA, Brown SL, Simonsick EM, Wallace RB, Blazer DG. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep. 1995 Jul;18(6):425-32. PubMed.
- Pollak CP, Perlick D, Linsner JP, Wenston J, Hsieh F. Sleep problems in the community elderly as predictors of death and nursing home placement. J Community Health. 1990 Apr;15(2):123-35. PubMed.
- Pollak CP, Perlick D. Sleep problems and institutionalization of the elderly. J Geriatr Psychiatry Neurol. 1991 Oct-Dec;4(4):204-10. PubMed.
- Smythe JW, Bhatnagar S, Murphy D, Timothy C, Costall B. The effects of intrahippocampal scopolamine infusions on anxiety in rats as measured by the black-white box test. Brain Res Bull. 1998;45(1):89-93. PubMed.
- Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA. 2008 Jun 11;299(22):2642-55. PubMed.
- Dowling GA, Burr RL, Van Someren EJ, Hubbard EM, Luxenberg JS, Mastick J, Cooper BA. Melatonin and bright-light treatment for rest-activity disruption in institutionalized patients with Alzheimer's disease. J Am Geriatr Soc. 2008 Feb;56(2):239-46. PubMed.
- Gabelle A, Dauvilliers Y. Editorial: sleep and dementia. J Nutr Health Aging. 2010 Mar;14(3):201-2. PubMed.
- Sharer J. Tackling sundowning in a patient with Alzheimer's disease. Medsurg Nurs. 2008 Feb;17(1):27-9. PubMed.
- Klaffke S, Staedt J. Sundowning and circadian rhythm disorders in dementia. Acta Neurol Belg. 2006 Dec;106(4):168-75. PubMed.
- Bachman D, Rabins P. "Sundowning" and other temporally associated agitation states in dementia patients. Annu Rev Med. 2006;57:499-511. PubMed.
- Bachman D, Rabins P. "Sundowning" and Other Temporally Associated Agitation States in Dementia Patients. Annu Rev Med. 2005 Aug 25; PubMed.
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- Bedrosian TA, Herring KL, Weil ZM, Nelson RJ. Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11686-91. PubMed.