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  • Print publication year: 2009
  • Online publication date: August 2010

12 - Circadian rhythm dysregulation in the elderly: advanced sleep phase syndrome

from Part 3 - Sleepdisorders in the elderly


The current evidence that aging is associated with a significant increase in sleep-wake cycle complaints has individual, social, and economic consequences. These age-related changes occur as early as the middle years of life, with over 35% of the population in their forties to sixties reporting sleep difficulties. Age effects on non-rapid eye movement (NREM) sleep electroencephalogram (EEG) differ between brain topographical sites in parallel with age-related changes in gray matter density of the brain. A precise interaction between the homeostatic and circadian processes is required for optimal sleep and vigilance. Age-related increase in wakefulness during sleep may be associated with a phase angle change between the signal from the circadian clock and sleep-wake cycles. Age-related changes in the neural correlates of NREM sleep oscillations may also underlie changes in memory and brain plasticity. There is need to determine the consequences of age-dependent changes to the sleep-wake cycle in middle-aged individuals.

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1. CarrierJ, MonkTH, BuysseDJ, KupferDJ. Sleep and morningness-eveningness in the ‘middle’ years of life (20–59 y). J Sleep Res 1997;6:230–7.
2. DuffyJF, DijkDJ, KlermanEB, CzeislerCA. Later endogenous circadian temperature nadir relative to an earlier wake time in older people. Am J Physiol 1998;275:R1478–87.
3. HorneJA, OstbergO. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol 1976;4:97–110.
4. FoleyDJ, MonjanAA, BrownSL, et al. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 1995;18:425–32.
5. CampbellSS, MurphyPJ, van den HeuvelCJ, RobertsML, StaubleTN. Etiology and treatment of intrinsic circadian rhythm disorders. Sleep Med Rev 1999;3(3):179–200.
6. ReidKJ, ZeePC. Circadian rhythm disorders. Semin Neurol 2004;24(3):315–25.
7. American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic & Coding Manual, 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.
8. CampbellSS. Duration and placement of sleep in a “disentrained” environment. Psychophysiology 1984;21(1):106–13.
9. JacobsD, Ancoli-IsraelS, ParkerL, KripkeDF. Twenty-four-hour sleep-wake patterns in a nursing home population. Psychol Aging 1989;4:352–6.
10. BuysseDJ, ReynoldsCF 3rd, KupferDJ, et al. Clinical diagnoses in 216 insomnia patients using the International Classification of Sleep Disorders (ICSD), DSM-IV and ICD-10 categories: a report from the APA/NIMH DSM-IV Field Trial. Sleep 1994;17:630–7.
11. KameiR, HughesL, MilesL, DementW. Advanced sleep phase syndrome studied in a time isolation facility. Chronobiologia 1979;6:115.
12. MoldofskyH, MusisiS, PhillipsonEA. Treatment of a case of advanced sleep phase syndrome by phase advance chronotherapy. Sleep 1986;9:61–5.
13. SchraderH, BovimG, SandT. The prevalence of delayed and advanced sleep phase syndromes. J Sleep Res 1993;2:51–5.
14. DaganY, EisensteinM. Circadian rhythm sleep disorders: toward a more precise definition and diagnosis. Chronobiol Int 1999;16:213–22.
15. LowreyPL, TakahashiJS. Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu Rev Genomics Hum Gen 2004;5:407–41.
16. GachonF, NagoshiE, BrownSA, RippergerJ, SchiblerU. The mammalian circadian timing system: from gene expression to physiology. Chromosoma 2004;113(3):103–12.
17. CzeislerCA, DuffyJF, ShanahanTL, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 1999;284(5423):2177–81.
18. PittendrighCS, DaanS. A functional analysis of circadian pacemakers in nocturnal rodents: IV. Entrainment: pacemaker as clock. J Comp Physiol [A] 1976;106:291–331.
19. VirshupDM, ForgerDB. After hours keeps clock researchers CRYing Overtime. Cell 2007;129:857–9.
20. DijkDJ, LockleySW. Integration of human sleep-wake regulation and circadian rhythmicity. J Appl Physiol 2002;92(2):852–62.
21. TohKL, JonesCR, HeY, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 2001;291(5506):1040–3.
22. DijkDJ, DuffyJF, CzeislerCA. Contribution of circadian physiology and sleep homeostasis to age-related changes in human sleep. Chronobiol Int 2000;17:285–311.
23. ZavadaA, GordijnMC, BeersmaDG, DaanS, RoennebergT. Comparison of the Munich Chronotype Questionnaire with the Horne-Ostberg’s Morningness-Eveningness Score. Chronobiol Int 2005;22:267–78.
24. LewyAJ, EmensJ, JackmanA, YuhasK. Circadian uses of melatonin in humans. Chronobiol Int 2006;23:403–12.
25. BenloucifS, BurgessHJ, KlermanEB, et al. Measuring melatonin in humans. J Clin Sleep Med 2008;4:66–9.
26. DuffyJF, DijkDJ. Getting through to circadian oscillators: why use constant routines?J Biol Rhythms 2002;17:4–13.
27. KlermanEB, DijkDJ, KronauerRE, CzeislerCA. Simulations of light effects on the human circadian pacemaker: implications for assessment of intrinsic period. Am J Physiol 1996;270:R271–82.
28. RalphMR, MenakerM. A mutation of the circadian system in golden hamsters. Science 1988;241:1225–7.
29. LowreyPL, ShimomuraK, AntochMP, et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 2000;288(5465):483–91.
30. GallegoM, EideEJ, WoolfMF, VirshupDM, ForgerDB. An opposite role for tau in circadian rhythms revealed by mathematical modeling. Proc Natl Acad Sci USA 2006;103:10618–23.
31. MengQJ, LogunovaL, MaywoodES, et al. Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 2008;58:78–88.
32. DrennanMD, SelbyJ, KripkeDF, KelsoeJ, GillinJC. Morningness/eveningness is heritable. Soc Neurosci Abstr 1992;18:196.
33. VinkJM, GrootAS, KerkhofGA, BoomsmaDI. Genetic analysis of morningness and eveningness. Chronobiol Int 2001;18(5):809–22.
34. EbisawaT. Circadian rhythms in the CNS and peripheral clock disorders: human sleep disorders and clock genes. J Pharmacol Sci 2007;103:150–4.
35. JonesCR, CampbellSS, ZoneSE, et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med 1999;5(9):1062–5.
36. VanselowK, VanselowJT, WestermarkPO, et al. Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes Dev 2006;20:2660–72.
37. XuY, TohKL, JonesCR, et al. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell 2007;128:59–70.
38. ReidKJ, ChangAM, DubocovichML, et al. Familial advanced sleep phase syndrome. Arch Neurol 2001;58(7):1089–94.
39. SatohK, MishimaK, InoueY, EbisawaT, ShimizuT. Two pedigrees of familial advanced sleep phase syndrome in Japan. Sleep 2003;26(4):416–7.
40. XuY, PadiathQS, ShapiroRE, et al. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 2005;434(7033):640–4.
41. WeinertD. Age-dependent changes of the circadian system. Chronobiol Int 2000;17:261–83.
42. DijkDJ, von SchantzM. Timing and consolidation of human sleep, wakefulness, and performance by a symphony of oscillators. J Biol Rhythms 2005;20:279–90.
43. PittendrighCS, DaanS. Circadian oscillations in rodents: a systematic increase of their frequency with age. Science 1974;186:548–50.
44. MorinLP. Age-related changes in hamster circadian period, entrainment, and rhythm splitting. J Biol Rhythms 1988;3:237–48.
45. DavisFC, ViswanathanN. Stability of circadian timing with age in Syrian hamsters. Am J Physiol 1998;44:R960–R8.
46. DuffyJF, ViswanathanN, DavisFC. Free-running circadian period does not shorten with age in female Syrian hamsters. Neurosci Lett 1999;271:77–80.
47. KendallAR, LewyAJ, SackRL. Effects of aging on the intrinsic circadian period of totally blind humans. J Biol Rhythms 2001;16:87–95.
48. DuffyJF, CzeislerCA. Age-related change in the relationship between circadian period, circadian phase, and diurnal preference in humans. Neurosci Lett 2002;318:117–20.
49. Van CoevordenA, MockelJ, LaurentE, et al. Neuroendocrine rhythms and sleep in aging men. Am J Physiol Endocrinol Metab 1991;260:E651–E61.
50. Van CauterE, LeproultR, KupferDJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996;81:2468–73.
51. DuffyJF, DijkDJ, HallEF, CzeislerCA. Relationship of endogenous circadian melatonin and temperature rhythms to self-reported preference for morning or evening activity in young and older people. J Investig Med 1999;47(3):141–50.
52. DuffyJF, ZeitzerJM, RimmerDW, et al. Peak of circadian melatonin rhythm occurs later within the sleep of older subjects. Am J Physiol Endocrinol Metab 2002;282(2):E297–E303.
53. DijkDJ, DuffyJF, CzeislerCA. Age-related increase in awakenings: impaired consolidation of nonREM sleep at all circadian phases. Sleep 2001;24:565–77.
54. KlermanEB, DavisJB, DuffyJF, DijkDJ, KronauerRE. Older people awaken more frequently but fall back asleep at the same rate as younger people. Sleep 2004;27:793–8.
55. DijkDJ, DuffyJF, RielE, ShanahanTL, CzeislerCA. Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms. J Physiol 1999;516(Pt 2):611–27.
56. SwaabDF, FliersE, PartimanTS. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res 1985;342(1):37–44.
57. HofmanMA, SwaabDF. Living by the clock: the circadian pacemaker in older people. Ageing Res Rev 2006;5:33–51.
58. CampbellSS, KripkeDF, GillinJC, HrubovcakJC. Exposure to light in healthy elderly subjects and Alzheimer’s patients. Physiol Behav 1988;42:141–4.
59. KawinskaA, DumontM, SelmaouiB, PaquetJ, CarrierJ. Are modifications of melatonin circadian rhythm in the middle years of life related to habitual patterns of light exposure?J Biol Rhythms 2005;20:451–60.
60. YoungstedtSD, KripkeDF, ElliottJA, BaehrW, SepulvedaRS. Light exposure, sleep quality, and depression in older adults. In JungEG, Holick MF, eds. Biological Effects of Light. Boston: Kluwer Academic; 1998. pp. 427–35.
61. YoonIY, KripkeDF, YoungstedtSD, ElliottJA. Actigraphy suggests age-related differences in napping and nocturnal sleep. J Sleep Res 2003;12:87–93.
62. BuxtonOM, L’Hermite-BaleriauxM, TurekFW, van CauterE. Daytime naps in darkness phase shift the human circadian rhythms of melatonin and thyrotropin secretion. Am J Physiol Regul Integr Comp Physiol 2000;278:R373–82.
63. KlermanEB, DuffyJF, DijkDJ, CzeislerCA. Circadian phase resetting in older people by ocular bright light exposure. J Investig Med 2001;49:30–40.
64. BenloucifS, GreenK, L’Hermite-BaleriauxM, et al. Responsiveness of the aging circadian clock to light. Neurobiol Aging 2006;27:1870–9.
65. KripkeDF, ElliottJA, YoungstedtSD, RexKM. Circadian phase response curves to light in older and young women and men. J Circadian Rhythms 2007;5:4.
66. BoivinDB, DuffyJF, KronauerRE, CzeislerCA. Dose-response relationships for resetting of human circadian clock by light. Nature 1996;379:540–2.
67. DuffyJF, ZeitzerJM, CzeislerCA. Decreased sensitivity to phase-delaying effects of moderate intensity light in older subjects. Neurobiol Aging 2007;28:799–807.
68. SackRL, AuckleyD, AugerRR, et al. Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. Sleep 2007;30:1484–501.
69. MorgenthalerTI, KapurVK, BrownT, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007;30:1705–11.
70. LewyAJ, AhmedS, JacksonJM, SackRL. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int 1992;9:380–92.
71. BersonDM. Strange vision: ganglion cells as circadian photoreceptors. Trends Neurosci 2003;26(6):314–20.
72. SuhnerAG, MurphyPJ, CampbellSS. Failure of timed bright light exposure to alleviate age-related sleep maintenance insomnia. J Am Geriatr Soc 2002;50:617–23.
73. LackL, WrightH. The effect of evening bright light in delaying the circadian rhythms and lengthening the sleep of early morning awakening insomniacs. Sleep 1993;16:436–43.
74. CampbellS, DawsonD, AndersonM. Alleviation of sleep maintenance insomnia with timed exposure to bright light. J Am Geriatric Soc 1993;41:829–36.
75. PalmerCR, KripkeDF, SavageHC Jr., et al. Efficacy of enhanced evening light for advanced sleep phase syndrome. Behav Sleep Med 2003;1:213–26.
76. PallesenS, NordhusIH, SkeltonSH, BjorvatnB, SkjerveA. Bright light treatment has limited effect in subjects over 55 years with mild early morning awakening. Percept Mot Skills 2005;101:759–70.
77. LackL, WrightH, KempK, GibbonS. The treatment of early-morning awakening insomnia with 2 evenings of bright light. Sleep 2005;28:616–23.