NeuroMolecular Medicine

, Volume 14, Issue 3, pp 194–204 | Cite as

Sleep Disturbances in Alzheimer’s and Parkinson’s Diseases

Review Paper


Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative disorders and exact a burden on our society greater than cardiovascular disease and cancer combined. While cognitive and motor symptoms are used to define AD and PD, respectively, patients with both disorders exhibit sleep disturbances including insomnia, hypersomnia and excessive daytime napping. The molecular basis of perturbed sleep in AD and PD may involve damage to hypothalamic and brainstem nuclei that control sleep–wake cycles. Perturbations in neurotransmitter and hormone signaling (e.g., serotonin, norepinephrine and melatonin) and the neurotrophic factor BDNF likely contribute to the disease process. Abnormal accumulations of neurotoxic forms of amyloid β-peptide, tau and α-synuclein occur in brain regions involved in the regulation of sleep in AD and PD patients, and are sufficient to cause sleep disturbances in animal models of these neurodegenerative disorders. Disturbed regulation of sleep often occurs early in the course of AD and PD, and may contribute to the cognitive and motor symptoms. Treatments that target signaling pathways that control sleep have been shown to retard the disease process in animal models of AD and PD, suggesting a potential for such interventions in humans at risk for or in the early stages of these disorders.


Alzheimer’s disease Parkinson’s disease Sleep Circadian 



This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging.


  1. Adlard, P. A., Perreau, V. M., Pop, V., & Cotman, C. W. (2005). Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. Journal of Neuroscience, 25, 4217–4221.PubMedCrossRefGoogle Scholar
  2. Ahlskog, J. E. (2011). Does vigorous exercise have a neuroprotective effect in Parkinson disease? Neurology, 77, 288–294.PubMedCrossRefGoogle Scholar
  3. Andretic, R., van Swinderen, B., & Greenspan, R. J. (2005). Dopaminergic modulation of arousal in Drosophila. Current Biology, 15, 1165–1175.PubMedCrossRefGoogle Scholar
  4. Arumugam, T. V., Phillips, T. M., Cheng, A., Morrell, C. H., Mattson, M. P., & Wan, R. (2010). Age and energy intake interact to modify cell stress pathways and stroke outcome. Annals of Neurology, 67, 41–52.PubMedCrossRefGoogle Scholar
  5. Baddeley, A. D., Baddeley, H. A., Bucks, R. S., & Wilcock, G. K. (2001). Attentional control in Alzheimer’s disease. Brain, 124, 1492–1508.PubMedCrossRefGoogle Scholar
  6. Baker, L. D., Frank, L. L., Foster-Schubert, K., Green, P. S., Wilkinson, C. W., McTiernan, A., et al. (2010). Aerobic exercise improves cognition for older adults with glucose intolerance, a risk factor for Alzheimer’s disease. Journal of Alzheimer’s Disease, 22, 569–579.PubMedGoogle Scholar
  7. Barraud, Q., Lambrecq, V., Forni, C., McGuire, S., Hill, M., Bioulac, B., et al. (2009). Sleep disorders in Parkinson’s disease: The contribution of the MPTP non-human primate model. Experimental Neurology, 2, 574–582.CrossRefGoogle Scholar
  8. Bedrosian, T. A., Herring, K. L., Weil, Z. M., & Nelson, R. J. (2011). Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice. Proceedings of the National Academy of Sciences of the USA, 108, 11686–11691.PubMedCrossRefGoogle Scholar
  9. Berkowitz, A., Sutton, L., Janowsky, D. S., & Gillin, J. C. (1990). Pilocarpine, an orally active muscarinic cholinergic agonist, induces REM sleep and reduces delta sleep in normal volunteers. Psychiatry Research, 33, 113–119.PubMedCrossRefGoogle Scholar
  10. Bliwise, D. L., Tinklenberg, J., Yesavage, J. A., Davies, H., Pursley, A. M., Petta, D. E., et al. (1989). REM latency in Alzheimer’s disease. Biol Psychiat., 25, 320–328.PubMedCrossRefGoogle Scholar
  11. Boeve, B. F., Silber, M. H., Saper, C. B., Ferman, T. J., Dickson, D. W., Parisi, J. E., et al. (2007). Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain, 130, 2770–2788.PubMedCrossRefGoogle Scholar
  12. Boldrini, M., Underwood, M. D., Hen, R., Rosoklija, G. B., Dwork, A. J., John Mann, J., et al. (2009). Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology, 34, 2376–2389.PubMedCrossRefGoogle Scholar
  13. Braak, H., Del Tredici, K., Rüb, U., de Vos, R. A., Jansen Steur, E. N., & Braak, E. (2003). Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging, 24, 197–211.PubMedCrossRefGoogle Scholar
  14. Brown, S. A., Schmitt, K., & Eckert, A. (2011). Aging and circadian disruption: Causes and effects. Aging, 3, 813–817.PubMedGoogle Scholar
  15. Burns, R. S., Chiueh, C. C., Markey, S. P., Ebert, M. H., Jacobowitz, D. M., & Kopin, I. J. (1983). A primate model of parkinsonism—selective destruction of dopaminergic-neurons in the pars compacta of the substantia nigra by n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. PNAS, 80, 4546–4550.PubMedCrossRefGoogle Scholar
  16. Cai, J. X., & Arnsten, A. F. T. (1997). Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. Journal of Pharmacology and Experimental Therapeutics, 283, 183–189.PubMedGoogle Scholar
  17. Chen, M. J., & Russo-Neustadt, A. A. (2007). Running exercise- and antidepressant-induced increases in growth and survival-associated signaling molecules are IGF-dependent. Growth Factors, 25, 118–131.PubMedCrossRefGoogle Scholar
  18. Chow, T. W., Pollock, B. G., & Milgram, N. W. (2007). Potential cognitive enhancing and disease modification effects of SSRIs for Alzheimer’s disease. Journal of Neuropsychiatric Disease and Treatment, 3, 627–636.Google Scholar
  19. Cirrito, J. R., Disabato, B. M., Restivo, J. L., Verges, D. K., Goebel, W. D., Sathyan, A., et al. (2011). Serotonin signaling is associated with lower amyloid-{beta} levels and plaques in transgenic mice and humans. Proceedings of the National Academy of Sciences of the USA, 108, 14968–14973.PubMedCrossRefGoogle Scholar
  20. Claassen, D. O., Josephs, K. A., Ahlskog, J. E., Silber, M. H., Tippmann-Peikert, M., & Boeve, B. F. (2010). REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology, 75, 494–499.PubMedCrossRefGoogle Scholar
  21. Comella, C. L. (2003). Sleep disturbances in Parkinson’s disease. Current Neurology and Neuroscienece Reports, 2, 173–180.CrossRefGoogle Scholar
  22. Comella, C. L. (2007). Sleep disorders in Parkinson’s disease: An overview. Movement Disorders, 17, S367–S373.CrossRefGoogle Scholar
  23. Craig, D., Hart, D. J., & Passmore, A. P. (2006). Genetically increased risk of sleep disruption in Alzheimer’s disease. Sleep, 29, 1003–1007.PubMedGoogle Scholar
  24. Crowley, K. (2011). Sleep and sleep disorders in older adults. Neuropsychology Review, 21, 41–53.PubMedCrossRefGoogle Scholar
  25. Dahan, L., Astier, B., Vautrelle, N., Urbain, N., Kocsis, B., & Chouvet, G. (2007). Prominent burst firing of dopaminergic neurons in the ventral tegmental area during paradoxical sleep. Neuropsychopharmacology, 32, 1232–1241.PubMedCrossRefGoogle Scholar
  26. Dauvilliers, Y. (2007). Insomnia in patients with neurodegenerative conditions. Sleep Medicine, 4, S27–S34.CrossRefGoogle Scholar
  27. Dong, H., Goico, B., Martin, M., Csernansky, C. A., Bertchume, A., & Csernansky, J. G. (2004). Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience, 127, 601–609.PubMedCrossRefGoogle Scholar
  28. Duan, W., & Mattson, M. P. (1999). Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. Journal of Neuroscience Research, 57, 195–206.PubMedCrossRefGoogle Scholar
  29. Eisensehr, I., Linke, R., Noachtar, S., Schwarz, J., Gildehaus, F. J., & Tatsch, K. (2000). Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson’s disease and controls. Brain, 123, 1155–1160.PubMedCrossRefGoogle Scholar
  30. Factor, S. A., McAlarney, T., Sanchez-Ramos, J. R., & Weiner, W. J. (1990). Sleep disorders and sleep effect in Parkinson’s disease. Movement Disorders, 5, 280–285.PubMedCrossRefGoogle Scholar
  31. Feng, Z., Qin, C., Chang, Y., & Zhang, J. T. (2006). Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer’s disease. Free Radical Biology & Medicine, 40, 101–109.CrossRefGoogle Scholar
  32. Franzen, P. L., & Buysse, D. J. (2008). Sleep disturbances and depression: Risk relationships for subsequent depression and therapeutic implications. Dialogues in Clinical Neuroscience, 10, 473–481.PubMedGoogle Scholar
  33. Friedman, L. F., Zeitzer, J. M., Lin, L., Hoff, D., Mignot, E., Peskind, E. R., et al. (2007). In Alzheimer disease, increased wake fragmentation found in those with lower hypocretin-1. Neurology, 68, 793–794.PubMedCrossRefGoogle Scholar
  34. Fronczek, R., Overeem, S., Lee, S. Y., Hegeman, I. M., van Pelt, J., van Duinen, S. G., et al. (2007). Hypocretin (orexin) loss in Parkinson’s disease. Brain, 130, 1577–1585.PubMedCrossRefGoogle Scholar
  35. Fronczek, R., van Geest, S., Frölich, M., Overeem, S., Roelandse, F. W., Lammers, G. J. et al. (2011) Hypocretin (orexin) loss in Alzheimer’s disease. Neurobiological Aging (Epub).Google Scholar
  36. Gagnon, J. F., Bédard, M. A., Fantini, M. L., Petit, D., Panisset, M., Rompré, S., et al. (2002). REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease. Neurology, 59, 585–589.PubMedCrossRefGoogle Scholar
  37. Gaig, C., & Tolosa, E. (2009). When does Parkinson’s disease begin? Movement Disorders, 24(Suppl 2), S656–S664.PubMedCrossRefGoogle Scholar
  38. German, D. C., Yazdani, U., Speciale, S. G., Pasbakhsh, P., Games, D., & Liang, C. L. (2003). Cholinergic neuropathology in a mouse model of Alzheimer’s disease. The Journal of Comparative Neurology, 462, 371–381.PubMedCrossRefGoogle Scholar
  39. Giacobini, E. (2003). Cholinergic function and Alzheimer’s disease. International Journal of Geriatric Psychiatry, 18, S1–S5.PubMedCrossRefGoogle Scholar
  40. Gingrich, J. A. (2002). Mutational analysis of the serotonergic system: Recent findings using knockout mice. Current Drug Targets: CNS & Neurological Disorders, 1, 449–465.CrossRefGoogle Scholar
  41. Grinberg, L. T., Rueb, U., Alho, A. T., & Heinsen, H. (2010). Brainstem pathology and non-motor symptoms in PD. Journal of the Neurological Sciences, 289, 81–88.PubMedCrossRefGoogle Scholar
  42. Grothe, M., Heinsen, H., & Teipel, S. J. (2011) Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer’s Disease. Biological Psychiatry (Epub).Google Scholar
  43. Halagappa, V. K., Guo, Z., Pearson, M., Matsuoka, Y., Cutler, R. G., Laferla, F. M., et al. (2007). Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer’s disease. Neurobiology of Diseases, 26, 212–220.CrossRefGoogle Scholar
  44. Hardeland, R., Cardinali, D. P., Srinivasan, V., Spence, D. W., Brown, G. M., & Pandi-Perumal, S. R. (2011). Melatonin—a pleiotropic, orchestrating regulator molecule. Progress in Neurobiology, 93, 350–384.PubMedCrossRefGoogle Scholar
  45. Harkany, T., O’Mahony, S., Keijser, J., Kelly, J. P., Kónya, C., Borostyánkoi, Z. A., et al. (2001). Beta-amyloid(1-42)-induced cholinergic lesions in rat nucleus basalis bidirectionally modulate serotonergic innervation of the basal forebrain and cerebral cortex. Neurobiology of Diseases, 8, 667–678.CrossRefGoogle Scholar
  46. Harkany, T., Penke, B., & Luiten, P. G. (2000). beta-Amyloid excitotoxicity in rat magnocellular nucleus basalis. Effect of cortical deafferentation on cerebral blood flow regulation and implications for Alzheimer’s disease. Annals of the New York Academy of Sciences, 903, 374–386.PubMedCrossRefGoogle Scholar
  47. Harley, C. (1991). Noradrenergic and locus coeruleus modulation of the perforant path-evoked potential in rat dentate gyrus supports a role for the locus coeruleus in attentional and memorial processes. Progress in Brain Research, 88, 307–321.PubMedCrossRefGoogle Scholar
  48. Heneka, M. T., Galea, E., Gavriluyk, V., Dumitrescu-Ozimek, L., Daeschner, J., O’Banion, M. K., et al. (2002). Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: Implications for Alzheimer’s disease. Journal of Neuroscience, 22, 2434–2442.PubMedGoogle Scholar
  49. Hirsch, E. C., Graybiel, A. M., Duyckaerts, C., & Javoy-Agid, F. (1987). Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. PNAS, 84, 5976–5980.PubMedCrossRefGoogle Scholar
  50. Hobson, J. A., & Pace-Schott, E. F. (2002). The cognitive neuroscience of sleep: Neuronal systems, consciousness and learning. Nature Reviews Neuroscience, 3, 679–693.PubMedCrossRefGoogle Scholar
  51. Insua, D., Suárez, M. L., Santamarina, G., Sarasa, M., & Pesini, P. (2010). Dogs with canine counterpart of Alzheimer’s disease lose noradrenergic neurons. Neurobiology of Aging, 31, 625–635.PubMedCrossRefGoogle Scholar
  52. Irvine, G. B., El-Agnaf, O. M., Shankar, G. M., & Walsh, D. M. (2008). Protein aggregation in the brain: The molecular basis for Alzheimer’s and Parkinson’s diseases. Molecular Medicine, 14, 451–464.PubMedCrossRefGoogle Scholar
  53. Isaac, S. O., & Berridge, C. W. (2003). Wake-promoting actions of dopamine D1 and D2 receptor stimulation. Journal of Pharmacology and Experimental Therapeutics, 307, 386–394.PubMedCrossRefGoogle Scholar
  54. Kalinin, S., Gavrilyuk, V., Polak, P. E., Vasser, R., Zhao, J., Heneka, M. T., et al. (2007). Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer’s disease. Neurobiology of Aging, 28, 1206–1214.PubMedCrossRefGoogle Scholar
  55. Kang, J. E., Lim, M. M., Bateman, R. J., Lee, J. J., Smyth, L. P., Cirrito, J. R., et al. (2009). Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science, 326, 1005–1007.PubMedCrossRefGoogle Scholar
  56. Kim, E. J., Lee, B. H., Seo, S. W., Moon, S. Y., Jung, D. S., Park, K. H., et al. (2007). Attentional distractibility by optokinetic stimulation in Alzheimer disease. Neurology, 69, 1105–1112.PubMedCrossRefGoogle Scholar
  57. Kremer, H. P., & Bots, G. T. (1993). Lewy bodies in the lateral hypothalamus: Do they imply neuronal loss? Movement Disorders, 8, 315–320.PubMedCrossRefGoogle Scholar
  58. Kroeger, D., & de Lecea, L. (2009). The hypocretins and their role in narcolepsy. CNS & Neurological Disorders: Drug Targets, 8, 271–280.CrossRefGoogle Scholar
  59. Kudo, T., Loh, D. H., Truong, D., Wu, Y., Colwell, C. S. (2011) Circadian dysfunction in a mouse model of Parkinson’s disease. Experimental Neurology. (Epub).Google Scholar
  60. Laloux, C., Derambure, P., Houdayer, E., Jacquesson, J. M., Bordet, R., Destée, A., et al. (2008). Effect of dopaminergic substances on sleep/wakefulness in saline- and MPTP-treated mice. Journal of Sleep Research, 17, 101–110.PubMedCrossRefGoogle Scholar
  61. Lange-Asschenfeldt, C., & Kojda, G. (2008). Alzheimer’s disease, cerebrovascular dysfunction and the benefits of exercise: From vessels to neurons. Experimental Gerontology, 43, 499–504.PubMedCrossRefGoogle Scholar
  62. Lau, Y. S., Patki, G., Das-Panja, K., Le, W. D., & Ahmad, S. O. (2011). Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration. European Journal of Neuroscience, 33, 1264–1274.PubMedCrossRefGoogle Scholar
  63. Lees, A. J., Blackburn, N. A., & Campbell, V. L. (1988). The nighttime problems of Parkinson’s disease. Clinical Neuropharmacology, 11, 512–519.PubMedCrossRefGoogle Scholar
  64. Léna, I., Parrot, S., Deschaux, O., Muffat-Joly, S., Sauvinet, V., Renaud, B., et al. (2005). Variations in extracellular levels of dopamine, noradrenaline, glutamate, and aspartate across the sleep–wake cycle in the medial prefrontal cortex and nucleus accumbens of freely moving rats. Journal of Neuroscience Research, 81, 891–899.PubMedCrossRefGoogle Scholar
  65. Lessig, S., Ubhi, K., Galasko, D., Adame, A., Pham, E., Remidios, K., et al. (2010). Reduced hypocretin (orexin) levels in dementia with Lewy bodies. NeuroReport, 21, 756–760.PubMedCrossRefGoogle Scholar
  66. Lima, M. M., Andersen, M. L., Reksidler, A. B., Vital, M. A., & Tufik, S. (2007). The role of the substantia nigra pars compacta in regulating sleep patterns in rats. PLoS ONE, 2, e513.PubMedCrossRefGoogle Scholar
  67. Luchsinger, J. A., Tang, M. X., Shea, S., & Mayeux, R. (2002). Caloric intake and the risk of Alzheimer disease. Archives of Neurology, 59, 1258–1263.PubMedCrossRefGoogle Scholar
  68. Maloney, K. J., Mainville, L., & Jones, B. E. (2002). c-Fos expression in dopaminergic and GABAergic neurons of the ventral mesencephalic tegmentum after paradoxical sleep deprivation and recovery. European Journal of Neuroscience, 15, 774–778.PubMedCrossRefGoogle Scholar
  69. Maria, B., Sophia, S., Michalis, M., Charalampos, L., Andreas, P., John, M. E., et al. (2003). Sleep breathing disorders in patients with idiopathic Parkinson’s disease. Respiratory Medicine, 10, 1151–1157.CrossRefGoogle Scholar
  70. Martin, B., Ji, S., Maudsley, S., & Mattson, M. P. (2010). “Control” laboratory rodents are metabolically morbid: Why it matters. Proceedings of the National Academy of Sciences of the USA, 107, 6127–6133.PubMedCrossRefGoogle Scholar
  71. Maswood, N., Young, J., Tilmont, E., Zhang, Z., Gash, D. M., Gerhardt, G. A., et al. (2004). Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease. Proceedings of the National Academy of Sciences of the USA, 101, 18171–18176.PubMedCrossRefGoogle Scholar
  72. Matsubara, E., Bryant-Thomas, T., Pacheco Quinto, J., Henry, T. L., Poeggeler, B., Herbert, D., et al. (2003). Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. Journal of Neurochemistry, 85, 1101–1108.PubMedCrossRefGoogle Scholar
  73. Mattson, M. P., Maudsley, S., & Martin, B. (2004). BDNF and 5-HT: A dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends in Neurosciences, 27, 589–594.PubMedCrossRefGoogle Scholar
  74. McCurry, S. M., Logsdon, R. G., Teri, L., Gibbons, L. E., Kukull, W. A., Bowen, J. D., et al. (1999). Characteristics of sleep disturbance in community-dwelling Alzheimer’s disease patients. Journal of Geriatric Psychiatry and Neurology, 12, 53–59.PubMedCrossRefGoogle Scholar
  75. McDowell, K. A., Hadjimarkou, M. M., Viechweg, S., Rose, A. E., Clark, S. M., Yarowsky, P. J., et al. (2010). Sleep alterations in an environmental neurotoxin-induced model of parkinsonism. Experimental Neurology, 226, 84–89.PubMedCrossRefGoogle Scholar
  76. McGeer, P. L., McGeer, E. G., Suzuki, J., Dolman, C. E., & Nagai, T. (1984). Aging, Alzheimer’s disease, and the cholinergic system of the basal forebrain. Neurology, 34, 741–745.PubMedCrossRefGoogle Scholar
  77. McMorris, T., Harris, R. C., Swain, J., Corbett, J., Collard, K., Dyson, R. J., et al. (2006). Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology (Berl), 185, 93–103.CrossRefGoogle Scholar
  78. Michelsen, K. A., Prickaerts, J., & Steinbusch, H. W. (2008). The dorsal raphe nucleus and serotonin: Implications for neuroplasticity linked to major depression and Alzheimer’s disease. Progress in Brain Research, 172, 233–264.PubMedCrossRefGoogle Scholar
  79. Mishima, K., Tozawa, T., Satoh, K., Matsumoto, Y., Hishikawa, Y., & Okawa, M. (1999). Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer’s type with disturbed sleep-waking. Biological Psychiatry, 45, 417–421.PubMedCrossRefGoogle Scholar
  80. Mitra, T., & Chaudhuri, K. R. (2009). Sleep dysfunction and role of dysautonomia in Parkinson’s disease. Parkinsonism and Related Disorders, 15, S93–S95.PubMedCrossRefGoogle Scholar
  81. Miyamoto, T., Miyamoto, M., Inoue, Y., Usui, Y., Suzuki, K., & Hirata, K. (2006). Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder. Neurology, 67, 2236–2238.PubMedCrossRefGoogle Scholar
  82. Monte-Silva, K., Kuo, M. F., Thirugnanasambandam, N., Liebetanz, D., Paulus, W., & Nitsche, M. A. (2009). Dose-dependent inverted U-shaped effect of dopamine (D2-Like) receptor activation on focal and nonfocal plasticity in humans. Journal of Neuroscience, 29, 6124–6131.PubMedCrossRefGoogle Scholar
  83. Monti, J. M., & Monti, D. (2007). The involvement of dopamine in the modulation of sleep and waking. Sleep Medicine Reviews, 11, 113–133.PubMedCrossRefGoogle Scholar
  84. Moore, R. Y. (1993). Principles of synaptic transmission. Annals of the New York Academy of Sciences, 695, 1–9.PubMedCrossRefGoogle Scholar
  85. Moraes Wdos, S., Poyares, D. R., Guilleminault, C., Ramos, L. R., Bertolucci, P. H., & Tufik, S. (2006). The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: A double-blind placebo-controlled study. Sleep, 29, 199–205.PubMedGoogle Scholar
  86. Moran, M., Lynch, C. A., Walsh, C., Coen, R., Coakley, D., & Lawlor, B. A. (2005). Sleep disturbance in mild to moderate Alzheimer’s disease. Sleep Medicine, 6, 347–352.PubMedCrossRefGoogle Scholar
  87. Muijsers, R. B., Plosker, G. L., & Noble, S. (2002). Sertraline: A review of its use in the management of major depressive disorder in elderly patients. Drugs and Aging, 19, 377–392.PubMedCrossRefGoogle Scholar
  88. Myhrer, T. (2003). Neurotransmitter systems involved in learning and memory in the rat: A meta-analysis based on studies of four behavioral tasks. Brain Research Reviews, 41, 268–287.PubMedCrossRefGoogle Scholar
  89. Naidoo, N., Zhu, J., Zhu, Y., Fenik, P., Lian, J., Galante, R., et al. (2011). Endoplasmic reticulum stress in wake-active neurons progresses with aging. Aging Cell, 10, 640–649.PubMedCrossRefGoogle Scholar
  90. Nelson, R. L., Guo, Z., Halagappa, V. M., Pearson, M., Gray, A. J., Matsuoka, Y., et al. (2007). Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice. Experimental Neurology, 205, 166–176.PubMedCrossRefGoogle Scholar
  91. Niu, S. F., Chung, M. H., Chen, C. H., Hegney, D., O’Brien, A., & Chou, K. R. (2011). The effect of shift rotation on employee cortisol profile, sleep quality, fatigue, and attention level: A systematic review. Journal of Nursing Research, 19, 68–81.PubMedCrossRefGoogle Scholar
  92. Olcese, J. M., Cao, C., Mori, T., Mamcarz, M. B., Maxwell, A., Runfeldt, M. J., et al. (2009). Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease. Journal of Pineal Research, 47, 82–96.PubMedCrossRefGoogle Scholar
  93. Pace-Schott, E. F., & Hobson, J. A. (2002). The neurobiology of sleep: Genetics, cellular physiology and subcortical networks. Nature Reviews Neuroscience, 3, 591–605.PubMedGoogle Scholar
  94. Palmer, A. M., & DeKosky, S. T. (1993). Monoamine neurons in aging and Alzheimer’s disease. Journal of Neural Transmission. General Section, 91, 135–159.PubMedCrossRefGoogle Scholar
  95. Parachikova, A., Nichol, K. E., & Cotman, C. W. (2008). Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiology of Diseases, 30, 121–129.CrossRefGoogle Scholar
  96. Postuma, R. B., Gagnon, J. F., Vendette, M., & Montplaisir, J. Y. (2009). Idiopathic REM sleep behavior disorder in the transition to degenerative disease. Movement Disorders, 24, 2225–2232.PubMedCrossRefGoogle Scholar
  97. Postuma, R. B., Lanfranchi, P. A., Blais, H., Gagnon, J. F., & Montplaisir, J. Y. (2010). Cardiac autonomic dysfunction in idiopathic REM sleep behavior disorder. Movement Disorders, 25, 2304–2310.PubMedCrossRefGoogle Scholar
  98. Powers, R. E., Struble, R. G., Casanova, M. F., O’Connor, D. T., Kitt, C. A., & Price, D. L. (1988). Innervation of human hippocampus by noradrenergic systems: Normal anatomy and structural abnormalities in aging and in Alzheimer’s disease. Neuroscience, 25, 401–417.PubMedCrossRefGoogle Scholar
  99. Pungor, K., Papp, M., Kékesi, K., & Juhász, G. (1990). A novel effect of MPTP: The selective suppression of paradoxical sleep in cats. Brain Research, 525, 310–314.PubMedCrossRefGoogle Scholar
  100. Qu, W. M., Xu, X. H., Yan, M. M., Wang, Y. Q., Urade, Y., & Huang, Z. L. (2010). Essential role of dopamine D2 receptor in the maintenance of wakefulness, but not in homeostatic regulation of sleep, in mice. Journal of Neuroscience, 30, 4382–4389.PubMedCrossRefGoogle Scholar
  101. Riederer, P., Bartl, J., Laux, G., & Grünblatt, E. (2011). Diabetes type II: A risk factor for depression-Parkinson-Alzheimer? Neurotoxicity Research, 19, 253–265.PubMedCrossRefGoogle Scholar
  102. Robbins, T. W. (1997). Arousal systems and attentional processes. Biological Psychology, 45, 57–71.PubMedCrossRefGoogle Scholar
  103. Romberg, C., Mattson, M. P., Mughal, M. R., Bussey, T. J., & Saksida, L. M. (2011). Impaired attention in the 3xTgAD mouse model of Alzheimer’s disease: Rescue by donepezil (Aricept). Journal of Neuroscience, 31, 3500–3507.PubMedCrossRefGoogle Scholar
  104. Santos, R. V., Tufik, S., & De Mello, M. T. (2007). Exercise, sleep and cytokines: Is there a relation? Sleep Medicine Reviews, 11, 231–239.PubMedCrossRefGoogle Scholar
  105. Sarkar, S., Katshu, M. Z., Nizamie, S. H., & Praharaj, S. K. (2010). Slow wave sleep deficits as a trait marker in patients with schizophrenia. Schizophrenia Research, 124, 127–133.PubMedCrossRefGoogle Scholar
  106. Saunders, N. L., & Summers, M. J. (2010). Attention and working memory deficits in mild cognitive impairment. Journal of Clinical and Experimental Neuropsychology, 32, 350–357.PubMedCrossRefGoogle Scholar
  107. Schenck, C. H., & Mahowald, M. W. (2003). REM behavior disorder (RBD): Delayed emergence of parkinsonism and/or dementia in 65 % of older men initially diagnosed with idiopathic RBD, and an analysis of the minimum and maximum tonic and/or phasic electromyographic abnormalities found during REM sleep. Sleep, 26, A316Abs.Google Scholar
  108. Seamans, J. K., & Yang, C. R. (2004). The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Progress in Neurobiology, 74, 1–58.PubMedCrossRefGoogle Scholar
  109. Sherrill, D. L., Kotchou, K., & Quan, S. F. (1998). Association of physical activity and human sleep disorders. Archives of Internal Medicine, 158, 1894–1898.PubMedCrossRefGoogle Scholar
  110. Siderowf, A., & Jennings, D. (2010). Cardiac denervation in rapid eye movement sleep behavior disorder and Parkinson’s disease: Getting to the heart of the matter. Movement Disorders, 25, 2269–2271.PubMedCrossRefGoogle Scholar
  111. Skene, D. J., & Swaab, D. F. (2003). Melatonin rhythmicity: Effect of age and Alzheimer’s disease. Experimental Gerontology, 38, 199–206.PubMedCrossRefGoogle Scholar
  112. Sterniczuk, R., Antle, M. C., Laferla, F. M., & Dyck, R. H. (2010). Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: Part 2. Behavioral and cognitive changes. Brain Research, 1348, 149–155.PubMedCrossRefGoogle Scholar
  113. Stranahan, A. M., Lee, K., Martin, B., Maudsley, S., Golden, E., Cutler, R. G., et al. (2009). Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice. Hippocampus, 19, 951–961.PubMedCrossRefGoogle Scholar
  114. Tandberg, E., Larsen, J. P., & Karlsen, K. A. (1998). Community-based study of sleep disorders in patients with Parkinson’s disease. Movement Disorders, 13, 895–899.PubMedCrossRefGoogle Scholar
  115. Tasali, E., Leproult, R., & Spiegel, K. (2009). Reduced sleep duration or quality: Relationships with insulin resistance and type 2 diabetes. Progress in Cardiovascular Diseases, 51, 381–391.PubMedCrossRefGoogle Scholar
  116. Taylor, T. N., Caudle, W. M., Shepherd, K. R., Noorian, A., Jackson, C. R., Iuvone, P. M., et al. (2009). Nonmotor symptoms of Parkinson’s disease revealed in an animal model with reduced monoamine storage capacity. Journal of Neuroscience, 29, 8103–8113.PubMedCrossRefGoogle Scholar
  117. Thal, D. R., Del Tredici, K., & Braak, H. (2004). Neurodegeneration in normal brain aging and disease. Science of Aging Knowledge Environment, 23, pe26.CrossRefGoogle Scholar
  118. Thannickal, T. C., Lai, Y. Y., & Siegel, J. M. (2007). Hypocretin (orexin) cell loss in Parkinson’s disease. Brain, 130, 1586–1595.PubMedCrossRefGoogle Scholar
  119. Tsunematsu, T., Kilduff, T. S., Boyden, E. S., Takahashi, S., Tominaga, M., & Yamanaka, A. (2011). Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice. Journal of Neuroscience, 31, 10529–10539.PubMedCrossRefGoogle Scholar
  120. Tucker, S., Ahl, M., Cho, H. H., Bandyopadhyay, S., Cuny, G. D., Bush, A. I., et al. (2006). RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine. Current Alzheimer Research, 3, 221–227.PubMedCrossRefGoogle Scholar
  121. Turner, R. S. (2002). Idiopathic rapid eye movement sleep behavior disorder is a harbinger of dementia with Lewy bodies. Journal of Geriatric Psychiatry and Neurology, 15, 195–199.PubMedGoogle Scholar
  122. van Someren, E. J., Hagebeuk, E. E., Lijzenga, C., Scheltens, P., de Rooij, S. E., Jonker, C., et al. (1996). Circadian rest-activity rhythm disturbances in Alzheimer’s disease. Biological Psychiatry, 40, 259–270.PubMedCrossRefGoogle Scholar
  123. Verhave, P. S., Jongsma, M. J., Van den Berg, R. M., Vis, J. C., Vanwersch, R. A., Smit, A. B., et al. (2011). REM sleep behavior disorder in the marmoset MPTP model of early Parkinson disease. Sleep, 34, 1119–1125.PubMedGoogle Scholar
  124. Vitiello, M. V., Prinz, P. N., Williams, D. E., Frommlet, M. S., & Ries, R. K. (1990). Sleep disturbances in patients with mild-stage Alzheimer’s disease. The Journals of Gerontology, 45, M131–M138.Google Scholar
  125. Volicer, L., Harper, D. G., Manning, B. C., Goldstein, R., & Satlin, A. (2001). Sundowning and circadian rhythms in Alzheimer’s disease. American Journal of Psychiatry, 158, 704–711.PubMedCrossRefGoogle Scholar
  126. Walker, L. C., Levine, H., 3rd, Mattson, M. P., & Jucker, M. (2006). Inducible proteopathies. Trends in Neurosciences, 29, 438–443.PubMedCrossRefGoogle Scholar
  127. Wang, J., Ho, L., Qin, W., Rocher, A. B., Seror, I., Humala, N., et al. (2005). Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer’s disease. FASEB Journal., 19, 659–661.PubMedCrossRefGoogle Scholar
  128. Weinshenker, D. (2008). Functional consequences of locus coeruleus degeneration in Alzheimer’s disease. Current Alzheimer Research, 5, 342–345.PubMedCrossRefGoogle Scholar
  129. Wisor, J. P., Edgar, D. M., Yesavage, J., Ryan, H. S., McCormick, C. M., Lapustea, N., et al. (2005). Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer’s disease: A role for cholinergic transmission. Neuroscience, 131, 375–385.PubMedCrossRefGoogle Scholar
  130. Wu, Y. H., Zhou, J. N., Van Heerikhuize, J., Jockers, R., & Swaab, D. F. (2007). Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer’s disease. Neurobiology of Aging, 28, 1239–1247.PubMedCrossRefGoogle Scholar
  131. Yanovsky, Y., Li, S., Klyuch, B. P., Yao, Q., Blandina, P., Passani, M. B., et al. (2011). L-Dopa activates histaminergic neurons. Journal of Physiology, 589, 1349–1366.PubMedCrossRefGoogle Scholar
  132. Zant, J. C., Leenaars, C. H., Kostin, A., Van Someren, E. J., & Porkka-Heiskanen, T. (2011). Increases in extracellular serotonin and dopamine metabolite levels in the basal forebrain during sleep deprivation. Brain Research, 1399, 40–48.PubMedCrossRefGoogle Scholar
  133. Zhang, B., Veasey, S. C., Wood, M. A., Leng, L. Z., Kaminski, C., Leight, S., et al. (2005). Impaired rapid eye movement sleep in the Tg2576 APP murine model of Alzheimer’s disease with injury to pedunculopontine cholinergic neurons. American Journal of Pathology, 167, 1361–1369.PubMedCrossRefGoogle Scholar
  134. Zigmond, M. J., Cameron, J. L., Leak, R. K., Mirnics, K., Russell, V. A., Smeyne, R. J., et al. (2009). Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency. Parkinsonism & Related Disorders, 15(Suppl 3), S42–S45.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2012

Authors and Affiliations

  1. 1.Laboratory of NeurosciencesNational Institute On Aging Intramural Research ProgramBaltimoreUSA

Personalised recommendations