E-ISSN: 2458-9101
Melatonin and Major Neurocognitive Disorders: Beyond the Management of Sleep and Circadian Rhythm Dysfunction
Olakunle James Onaolapo, Adejoke Yetunde Onaolapo
Sleep and Hypnosis: A Journal of Clinical Neuroscience and Psychopathology 2019; Online Ahead of Print
Major neurocognitive disorders (dementias) are characterised by impairments in memory, cognition, and several aspects of behaviour. Sleep disorders arising from circadian rhythm and sleep-wake cycle dysfunctions are among the most-troubling challenges encountered in individuals with dementia, and for which administration of melatonergic agents is an important management option. However, in addition to this, melatonin and melatonin receptor agonists appear unique in their potential for modulating symptoms known to be associated with major neurocognitive disorders, or altering the course of the underlying pathology. Hence, they are being continuously investigated for their ability to prevent or reverse cognitive decline, as well as for their antioxidant/neuroprotective properties. In this review, we examine the roles of melatonin and melatonergic agents in the management of major neurocognitive disorders, by looking beyond their classic roles in the management of dementia-related sleep disorders, to other potential roles in the overall management of symptoms and improvement of the quality of life of individuals with dementia.
Keywords: Alzheimer disease, Cognition, Dementia, Sleep, Melatonin receptors, Parkinson’s disease”
REFERENCES
AASM: American Academy of Sleep Medicine (2014). International classification of sleep disorders. 3rd ed. Darien (IL): American Academy of Sleep Medicine,

Adi N, Mash DC, Ali Y, Singer C, Shehadeh L, Papapetropoulos S (2010) Melatonin MT1 and MT2 receptor expression in Parkinson’s disease Med Sci Monit. 16:BR61-7.

Ambresin G, Gunn J (2014) Does agomelatine have a place in the treatment of depression? BMJ. 348:g2157. doi: 10.1136/bmj.g2157.

American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington: American Psychiatric Publishing. 101–05.

Amihaesei IC, Mungiu OC (2012) Main neuroendocrine features and therapy in primary sleep troubles. Rev Med Chir Soc Med Nat Iasi116:862–6.

Ancoli-Israel S, Klauber MR, Butters N, Parker L, Kripke DF (1991) Dementia in institutionalized elderly: relation to sleep apnea. J Am Geriatr Soc. 39:258-63

Ancoli-Israel S, Palmer BW, Cooke JR, Corey-Bloom J, Fiorentino L, Natarajan L, Liu L, Ayalon L, He F, Loredo JS (2008) Cognitive effects of treating obstructive sleep apnea in Alzheimer’s disease: a randomized controlled study. J Am Geriatr Soc56:2076–81.

Anderson KN, Jamieson S, Graham AJ, Shneerson JM (2008) REM sleep behaviour disorder treated with melatonin in a patient with Alzheimer’s disease. Clin. Neurol. Neurosurg. 110:492–495. doi: 10.1016/j.clineuro.2008.01.004.

Antolin I, Mayo JC, Sainz RM, del Brio Mde L, Herrera F, Martin V, Rodriguez C (2002) Protective effect of melatonin in a chronic experimental model of Parkinson’s disease. Brain Res. 943:163–173.

Arendt J (1988) Melatonin. Clin Endocrinol (Oxford). 29:205-29.

Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S (2003) Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J. Nippon Med. Sch. 70:334–341. doi: 10.1272/jnms.70.334.

Aziz NA, Pijl H, Frölich M, Schröder-van der Elst JP, van der Bent C, Roelfsema F, Roos RA (2009) Delayed onset of the diurnal melatonin rise in patients with Huntington’s disease J Neurol. 256:1961-5.

Badrakalimuthu VR, Tarbuck AF (2012) Anxiety: a hidden element in dementia. Adv. Psychiatric Treatment (18:119–128 doi: 10.1192/apt.bp.110.008458

Ballard C, Neill D, O’Brien J, McKeith IG, Ince P, Perry R (2000) Anxiety, depression and psychosis in vascular dementia: prevalence and associations. J Affective. Dis. 59:97–106

Bartlett DJ, Biggs SN, Armstrong SM (2013) Circadian rhythm disorders among adolescents: assessment and treatment options. Med J Aust. 199:S16–20

Bassani TB, Gradowski RW, Zaminelli T, Barbiero JK, Santiago RM, Boschen SL, da Cunha C, Lima MM, Andreatini R, Vital MA (2014) Neuroprotective and antidepressant-like effects of melatonin in a rotenone-induced Parkinson’s disease model in rats. Brain Res. 1593:95-105.

Bauer B (2017) Melatonin side effects: What are the risks? Mayo Clinic. Oct. 10,

Beekman AT, Bremmer MA, Deeg DJH, van Balkom AJ, Smit JH, de Beurs E, van Dyck R, van Tilburg W (1998) Anxiety disorders in later life: a report from the longitudinal aging study Amsterdam. Intl J Ger Psychiatry 13:717–26.

Binfaré RW, Mantovani M, Budni J, Santos AR, Rodrigues AL (2010) Involvement of dopamine receptors in the antidepressant-like effect of melatonin in the tail suspension test. Eur J Pharmacol. 638:78-83.

Blask DE, Sauer LA, Dauchy RT (2002) Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem. 2:113-32.

Bliwise DL (2005) “Normal aging,” in Roth T, Kryger MH, Dement WC (eds) Principles and Practice of Sleep Medicine, Philadelphia: Elsevier Saunders, pg 24–38

Borbély AA (1982) A two process model of sleep regulation Hum Neurobiol. 1:195-204

Bordet R, Devos D, Brique S, Touitou Y, Guieu JD, Libersa C, Destée A (2003) Study of circadian melatonin secretion pattern at different stages of Parkinson’s disease. Clin Neuropharmacol. 26:65-72.

Borja NL, Daniel KL (2006) Ramelteon for the treatment of insomnia. Clin Ther. 28:1540–1555.

Born J, Rasch B, Gais S (2006) Sleep to remember. Neuroscientist12:410–24.

Brillante R, Cossa G, Liu PY, Laks L (2012) Rapid eye movement and slow-wave sleep rebound after one night of continuous positive airway pressure for obstructive sleep apnoea. Respirology 17:547–53.

Brown RC, Lockwood AH, Sonawane BR (2005) Neurodegenerative diseases: an overview of environmental risk factors. Environ Health Perspect. 113:1250-6.

Brunner P, Sözer-Topcular N, Jockers R Ravid R, Angeloni D, Fraschini F, Eckert A, Müller-Spahn F, Savaskan E (2006) Pineal and cortical melatonin receptors MT1 and MT2 are decreased in Alzheimer’s disease. Eur J Histochem. 50:311-6.

Brusco L.I, Marquez M, Cardinali DP (1998) Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer’s disease. Neuro Endocrinol. Lett. 19:111–115.

Brusco LI, Marquez M, Cardinali DP (1998) Melatonin Treatment Stabilizes Chronobiologic and Cognitive Symptoms in Alzheimer’s Disease. Neuro. Endocrinol. Lett.19:111–115.

Brusco LI, Marquez M, Cardinali DP (1998) Monozygotic twins with Alzheimer’s disease treated with melatonin: Case report. J. Pineal Res. 25:260–263. doi: 10.1111/j.1600-079X.1998.tb00396.x

Buffington ALH,.Lipski DM, Westfall E (2013) Dementia: An Evidence-Based Review of Common Presentations and Family-Based Interventions Evid-Based Clin Rev.113:768-775

Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy Z (2013) Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc Nephrol. 24:353-63. doi: 10.1681/ASN.2012050536.

Buscemi N, Vandermeer B, Hooton N, Pandya N, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S (2005) The Efficacy and Safety of Exogenous Melatonin for Primary Sleep Disorders: A Meta-Analysis J Gen Intern Med.20: 1151–1158. doi: 10.1111/j.1525-1497.2005.0243.x

Cacabelos R, Goldgaber D, Roses AD, Vostrov A, Matsuki H, Torellas C, Cacabelos P Corzo D, Carril JC, Novoa LF, Carrera I (2015) Gene Interactions in the Pharmacogenomics of Alzheimer’s Disease. Int J Mol Genet Gene Ther 1. doi http://dx.doi.org/10.16966/2471-4968.10

Cajochen C, Knoblauch V, Wirz-Justice A, Kräuchi K, Graw P, Wallach D (2004) Circadian modulation of sequence learning under high and low sleep pressure conditions Behav Brain Res. 151:167-76.

Cajochen C, Krauchi K, Wirz-Justice A (1997) The acute soporific action of daytime melatonin administration: effects on the EEG during wakefulness and subjective alertness. J Biol Rhythms 12: 636–43.

Cajochen C, Krauchi K, Wirz-Justice A (2003) Role of Melatonin in the Regulation of Human CircadianRhythms and Sleep J. Neuroendocrinol, 15:432–437.

Cajochen C. (2005) TAK-375 Takeda. Current Opinion in Investigational Drugs.6:114–121.

Cappuccio FP, D’Elia L, Strazzullo P, Miller MA (2010) Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep. 33:585–92.

Cardinali DP, Vigo DE, Olivar N, Vidal MF, Furio AM, Brusco LI (2012) Therapeutic application of melatonin in mild cognitive impairment. Am J Neurodegener Dis. 1: 280–291.

Cardinali DP, Cano P, Jimenez-Ortega V. Esquifino AI (2011) Melatonin and the metabolic syndrome: Physiopathologic and therapeutical implications. Neuroendocrinol. 93:133–142.

Cardinali DP, Furio AM, Brusco LI (2010) Clinical Aspects of Melatonin Intervention in Alzheimer’s Disease Progression Curr Neuropharmacol. 8: 218–227.

Cardinali DP, Srinivasan V, Brzezinski A, Brown GM (2012) Melatonin and its analogs in insomnia and depression Journal of Pineal Research 52(4):365-375

Cardinali DP, Vigo DE, Olivar N, Vidal MF, Furio AM, Brusco LI (2012) Therapeutic application of melatonin in mild cognitive impairment. Am J Neurodegener Disease. 1:280–91.

Carney RM, Shelton RC (2011) Agomelatine for the treatment of major depressive disorder. Expert Opin. Pharmacother. 12:2411–2419.

Chan KH, Wong YH (2013) A molecular and chemical perspective in defining melatonin receptor subtype selectivity. Int J Mol Sci. 14:18385–406.

Chaudhuri KR, Schapira AH (2009) Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 8:464-74.

Chaudhury D, Colwell CS (2002) Circadian modulation of learning and memory in fear-conditioned mice. Behav Brain Res. 133:95-108.

Chi S, Yu JT, Tan MS, Tan L (2014) Depression in Alzheimer’s disease: epidemiology, mechanisms, and management. J Alzheimer’s Dis. 42:739–55.

Cipriani G, Lucetti C, Danti S, Nuti A (2015) Sleep disturbances and dementia Psychogeriatrics. 15:65-74.

Clemens Z, Fabo D, Halasz P (2005) Overnight verbal memory retention correlates with the number of sleep spindles. Neurosci.132:529–35

Collins DR, Davies SN (1997) Melatonin blocks the induction of long-term potentiation in an N-methyl-D-aspartate independent manner Brain Res. 767:162-5.

Comai S, Gobbi G, (2014) CCNP Award Paper: Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology. J Psychiatry Neurosci. 39: 6–21. doi: 10.1503/jpn.130009

Combs B, Kneynsberg A,. Kanaan NM (2016) Gene Therapy Models of Alzheimer’s Disease and Other Dementias. Methods Mol Biol. 1382: 339–366. doi: 10.1007/978-1-4939-3271-9_25

Coogan AN, Schutova B, Husung S, Furczyk K, Baune BT, Kropp P, Häßler F, Thome J (2013) The circadian system in Alzheimer’s disease: disturbances, mechanisms, and opportunities. Biol Psychiatry. 74:333–339.

Dabbeni-Sala F, di Santo S, Franceschini D, Skaper SD, Giusti P (2001). Melatonin protects against 6-OHDA-induced neurotoxicity in rats: A role for mitochondrial complex I activity. FASEB J. 15:164–170.

Dauvilliers Y (2007) Insomnia in patients with neurodegenerative conditions. Sleep Med. 4:S27–S34.

Deacon S, Arendt J (1995) Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans. Brain Res 688: 77–85.

Deng YQ, Xu GG, Duan P, Zhang Q, Wang JZ (2005) Effects of melatonin on wortmannin-induced tau hyperphosphorylation. Acta Pharmacol Sin. 26:519-26

Detanico BC, Piato AL, Freitas JJ Lhullier FL, Hidalgo MP, Caumo W, Elisabetsky E (2009) Antidepressant-like effects of melatonin in the mouse chronic mild stress model. Eur J Pharmacol. 607:121-5.

Dhillon S., Clarke M (2014) Tasimelteon: First global approval. Drugs. 74:505–511.

Diekelmann S, Born J (2010) The memory function of sleep. Nat Rev Neurosci11:114–26.10.1038/nrn2762

Dijk DJ, Cajochen C (1997) Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG. J Biol Rhythms 12:627–35.

Dijk DJ, Czeisler CA (1994) Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci Lett. 166: 63–68.

Dijk DJ, Duffy JF (1999) Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics. Ann Med. 31:130-40.

Dijk DJ, Duffy JF, Riel E, Shanahan TL, Czeisler CA (1999) Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms. J Physiol. 516:611-27.

Dillon C, Serrano CM, Castro D, Leguizamón PP, Heisecke SL, Taragano FE (2013) Behavioral symptoms related to cognitive impairment. Neuropsychiatr Dis Treat. 9:1443–55. doi: 10.2147/NDT.S47133.

Dolder CR, Nelson M, Snider M (2008) Agomelatine treatment of major depressive disorder. Ann. Pharmacother. 42:1822–1831.

Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI (2003) Molecular pharmacology, regulation and function of mammalian melatonin receptors. Front Biosci. 8: d1093–d1108

Ekmekcioglu C (2006) Melatonin receptors in humans: biological role and clinical relevance. Biomed Pharmacother. 60:97–108.

El Mrabet FZ, Ouakki S, Mesoui A, El Hessni A, Ouichou A (2012) Pinealectomy and exogenous melatonin regulate anxiety-like and depressive-like behaviors in male and female Wistar rats. Neurosci Med. 3:394–403.

El-Sherif Y, Hogan MV, Tesoriero J, Wieraszko A. (2002) Factors regulating the influence of melatonin on hippocampal evoked potentials: comparative studies on different strains of mice. Brain Res. 945:191-201.

El-Sherif Y, Tesoriero J, Hogan MV, Wieraszko A (2003) Melatonin regulates neuronal plasticity in the hippocampus. J Neurosci Res. 72:454-60.

Etindele Sosso FA (2016) Brain Disorders: Correlation between Cognitive Impairment and Complex Combination Mental Health in Family Medicine, 12:215-222

Etindele Sosso FA (2017a) Neurocognitive Game between Risk Factors, Sleep and Suicidal Behaviour Sleep Sci. 10(1): 41–46. doi: 10.5935/1984-0063.20170007

Etindele Sosso FA (2017b) Visual dot interaction with short-term memory. Neurodegener Dis Manag. 7:183-190. doi: 10.2217/nmt-2017-0012.

Fainstein I, Bonetto A, Brusco LI, Cardinali DP (1997) Effects of melatonin in elderly patients with sleep disturbance. A Pilot Study. Curr. Ther. Res.58:990–1000.

Fainstein I, Bonetto A, Brusco LI, Cardinali DP (1997) Effects of melatonin in elderly patients with sleep disturbance. A pilot study. Curr. Ther. Res. 58:990–1000. doi: 10.1016/S0011-393X(97)80066-5.

Feldman H, Scheltens P, Scarpini E, Hermann N, Mesenbrink P, Mancione L, Tekin S, Lane R, Ferris S (2004) Behavioral symptoms in mild cognitive impairment. Neurology. 62:1199–201.

Fertl E, Auff E, Doppelbauer A, Waldhauser F (1991) Circadian secretion pattern of melatonin in Parkinson’s disease. J Neural Transm Park Dis Dement Sect. 3:41-7.

Fischer W, Wictorin K, Bjorklund A, Williams LR, Varon S, Gage FH (1987) Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature. 329:65–68.

Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A (2003) Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on, a partial replication. J Neurol Neurosurg Psychiatry. 74:857-62.

Foley D, Monjan A, Masaki K, Ross W, Havlik R, White L, Launer L (2001) Daytime sleepiness is associated with 3-year incident dementia and cognitive decline in older Japanese-American men. J Am Geriatr Soc 49(12):1628–32. 10.1111/j.1532-5415.2001.49271.x

Ford AH, Almeida OP (2017) Management of Depression in Patients with Dementia: Is Pharmacological Treatment Justified? Drugs Aging. 34(2):89-95. doi: 10.1007/s40266-016-0434-6.

Franco R, Li S, Rodriguez-Rocha H, Burns M, Panayiotidis MI (2010) Molecular mechanisms of pesticide-induced neurotoxicity: Relevance to Parkinson’s disease. Chem Biol Interact. 188:289-300.

Fraschini F, Cesarani A, Alpini D, Esposti D, Stankov BM (1999) Melatonin influences human balance. Biol Signals Recept. 8:111–119.

Fuller PM, Gooley JJ, Saper CB (2006) Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms. 21:482–493.

Furio AM, Brusco LI, Cardinali DP. (2007) Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study. J Pineal Res43:404–9.

Gais S, Albouy G, Boly M, Dang-Vu TT, Darsaud A, Desseilles M, Rauchs G, Schabus M, Sterpenich V, Vandewalle G, Maquet P, Peigneux P (2007) Sleep transforms the cerebral trace of declarative memories. Proc Natl Acad Sci U S A104:18778–83.10.1073/pnas.0705454104

Gehrman PR, Connor DJ, Martin JLShochat T, Corey-Bloom J, Ancoli-Israel S (2009). Melatonin fails to improve sleep agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. Am J Geriatr Psychiatry 17: 166–169.

Genovese T, Mazzon E, Muià C, Bramanti P, De Sarro A, Cuzzocrea S (2005) Attenuation in the evolution of experimental spinal cord trauma by treatment with melatonin. J Pineal Res. 38:198-208.

Gerstner JR, Yin JC (2010) Circadian rhythms and memory formation. Nat Rev Neurosci. 11:577-88. doi: 10.1038/nrn2881.

Goel N, Basner M, Rao H, Dinges DF. (2013) Circadian rhythms, sleep deprivation, and human performance. Prog Mol Biol Transl Sci. 119:155-90. doi: 10.1016/B978-0-12-396971-2.00007-5.

Goldman SE, Adkins KW, Calcutt MW Carter MD, Goodpaster RL, Wang L, Shi Y, Burgess HJ, Hachey DL, Malow BA (2014) Melatonin in children with autism spectrum disorders: endogenous and pharmacokinetic profiles in relation to sleep. J Autism Dev Disord. 44:2525–2535.10.1007/s10803-014-2123-9.

Gong CX, Liu F, Grundke-Iqbal I, Iqbal K (2005) Post-translational modifications of tau protein in Alzheimer’s disease. J Neural Transm (Vienna). 112:813-38

Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ, Young T (2004) APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the sleep heart health study. Neurol. 63:664–8.

Grandy JK (2013) Melatonin: Therapeutic Intervention in Mild Cognitive Impairment and Alzheimer Disease. J Neurol Neurophysiol 4:148. doi:10.4172/2155-9562.1000148

Guarnieri B, Sorbi S (2015) Sleep and cognitive decline: a strong bidirectional relationship. It is time for specific recommendations on routine assessment and the management of sleep disorders in patients with mild cognitive impairment and dementia. Eur Neurol. 74:43–48.

Hallett PJ, Deleidi M, Astradsson A, Smith GA, Cooper O, Osborn TM, Sundberg M, Moore MA, Perez-Torres E, Brownell AL, Schumacher JM, Spealman RD, Isacson O (2015) Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson’s disease. Cell Stem Cell. 16:269–74.

Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR (2011) Melatonin--a pleiotropic, orchestrating regulator molecule. Prog Neurobiol. 93:350-84.

He H, Dong W, Huang F (2010) Anti-amyloidogenic and anti-apoptotic role of melatonin in Alzheimer disease. Curr Neuropharmacol 8: 211-217.

He P, Ouyang X, Zhou S, Yin W, Tang C, Laudon M, Tian S (2013) A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer’s disease. Horm Behav. 64:1–7.

Hita-Yanez E, Atienza M, Cantero JL (2013) Polysomnographic and subjective sleep markers of mild cognitive impairment. Sleep. 36:1327–1334.

Hogan MV, El-Sherif Y, Wieraszko A (2001) The modulation of neuronal activity by melatonin: in vitro studies on mouse hippocampal slices. J Pineal Res. 30:87-96.

Holvoet E, Gabriels L (2013) Disturbed sleep in children with ADHD: is there a place for melatonin as a treatment option? Tijdschr Psychiatr. 55:349–57.

Hoppe JB, Frozza RL, Horn AP, Comiran RA, Bernardi A, Campos MM, Battastini AM, Salbego C (2010) Amyloid-ß neurotoxicity in organotypic culture is attenuated by melatonin: Involvement of GSK-3ß, tau and neuroinflammation. J. Pineal Res. 48:230–238.

Huang Y, Potter R, Sigurdson W, Santacruz A, Shih S, Ju YE, Kasten T, Morris JC, Mintun M, Duntley S, Bateman RJ (2012) Effects of age and amyloid deposition on Abeta dynamics in the human central nervous system. Arch Neurol. 69:51–8.10.1001/archneurol.2011.235

Hugo J, Ganuli M (2014) Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. Clin Geriatr Med. 30:421-42. doi: 10.1016/j.cger.2014.04.001.

Imbesi M, Uz T, Dzitoyeva S, Manev H (2008) Stimulatory effects of a melatonin receptor agonist, ramelteon, on BDNF in mouse cerebellar granule cells. Neurosci Lett. 439:34–6.

IPA: International Psychogeriatric Association (2012) www.ipaonline.org/ipaonlinev3/publications

Iranzo A (2016) Sleep in Neurodegenerative Diseases. Sleep Med Clin. 11:1-18.

Jaussent I, Bouyer J, Ancelin ML, Berr C, Foubert-Samier A, Ritchie K, Ohayon MM, Besset A, Dauvilliers Y (2012) Excessive sleepiness is predictive of cognitive decline in the elderly. Sleep35(9):1201–7.10.5665/sleep.2070

Jean-Louis G, von Gizycki H, Zizi F (1998) Melatonin effects on sleep, mood, and cognition in elderly with mild cognitive impairment. J Pineal Res 25: 177-183.

Jean-Louis G, von Gizycki H, Zizi F (1998) Melatonin effects on sleep, mood, and cognition in elderly with mild cognitive impairment. J. Pineal Res. 25:177–183. doi: 10.1111/j.1600-079X.1998.tb00557.x.

Jockers R, Maurice P, Boutin JA, Delagrange P (2008) Melatonin receptors, heterodimerization, signal transduction and binding sites: what’s new? Br J Pharmacol. 154:1182–1195.

Jorm AF, Jolley D (1998) The incidence of dementia: a meta-analysis. Neurol. 51:728-33.

Ju YE, Lucey BP, Holtzman DM (2014) Sleep and Alzheimer disease pathology – a bidirectional relationship. Nat Rev Neurol. 10:115–119.

Karni A, Tanne D, Rubenstein BS, Askenasy JJ, Sagi D (1994) Dependence on REM sleep of overnight improvement of a perceptual skill. Science. 265:679–82.10.1126/science.8036518

Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M (2005) Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology.48:301–310.

Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro CM (2001) A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med63: 40–48

Kim H, Yun CH, Thomas RJ, (2013) Obstructive sleep apnea as a risk factor for cerebral white matter change in a middle-aged and older general population. Sleep. 36:709-715B.

Kim HJ, Seo SW, Chang JW, Lee JI, Kim CH, Chin J, Choi SJ, Kwon H, Yun HJ, Lee JM (2015) Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase 1 clinical trial. Alzheimers Dement. 1:95–102.

Kim SJ, Lee JH, Lee DY, Jhoo JH, Woo JI. (2011) Neurocognitive dysfunction associated with sleep quality and sleep apnea in patients with mild cognitive impairment. Am J Geriatr Psychiatry19:374–81.

Klein RL, Lin WL, Dickson DW Lewis J, Hutton M, Duff K, Meyer EM, King MA (2004) Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau. Am J Pathol. 164:347–353.

Kondoh T, Uneyama H, Nishino H, Torii K (2002) Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats. Life Sci. 72:583-90.

Kong X, Li X, Cai Z, Yang N, Liu Y, Shu J Pan L, Zuo P (2008). Melatonin regulates the viability and differentiation of rat midbrain neural stem cells. Cell Mol Neurobiol. 28: 569–579.

Krauchi K, Cajochen C, Werth E, Wirz-Justice A (1991) Warm feet promote the rapid onset of sleep. Nature 401: 36–37.

Krauchi K, Cajochen C, Werth E, Wirz-Justice A (2000) Functional linkbetween distal vasodilation and sleep-onset latency? Am J Physiol 278: R741–8

Krauchi K, Cajochen C, Wirz-Justice A (1997) A relationship between heat loss and sleepiness: effects of postural change and melatonin administration. J Appl Physiol. 83: 134–9.

Krishnan HC, Lyons LC (2015) Synchrony and desynchrony in circadian clocks: impacts on learning and memory Learn. Mem. 22: 426-437.

Lahiri DK (1999) Melatonin affects the metabolism of the beta-amyloid precursor protein in different cell types. J Pineal Res. 26:137-46

Lahiri DK, Chen D, Ge YW, Bondy SC, Sharman EH (2004) Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex. J Pineal Res. 36:224-31.

Larson J, Jessen RE, Uz T, Arslan AD, Kurtuncu M, Imbesi M, Manev H (2006) Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice. Neurosci Lett 393: 23–26.

LaudonM Frydman-Marom A (2014) Therapeutic Effects of Melatonin Receptor Agonists on Sleep and Comorbid Disorders. Int J Mol Sci. 15: 15924–15950. doi: 10.3390/ijms150915924

Lauterbach EC, Victoroff J, Coburn KL, Shillcutt SD, Doonan SM, Mendez MF (2010) Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data. J Neuropsychi. Clin Neurosci. 22:8–18.

Leger D, Laudon M, Zisapel N (2004) Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Am J Med. 116:91–95.10.1016/j.amjmed.2003.07.017

Lemoine P., Nir T., Laudon M., Zisapel N (2007) Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J. Sleep Res. 16:372–380.

Lemoine P., Zisapel N (2012) Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia. Expert Opin. Pharmacother. 13:895–905.

Levenson RW, Sturm VE, Haase CM (2014) Emotional and behavioral symptoms in neurodegenerative disease: a model for studying the neural bases of psychopathology. Annu Rev Clin Psychol. 28:581–606.

Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet. 25:402–405.

Lezak MD, Howieson DB, Loring DW (2004) Neuropsychological Assessment. 4th ed. New York, NY: Oxford University Press.

Li XC, Wang ZF, Zhang JX, Wang Q, Wang JZ (2005) Effect of melatonin on calyculin A-induced tau hyperphosphorylation Eur J Pharmacol. 510:25-30.

Lin L, Huang QX, Yang SS, Chu J, Wang JZ, Tian Q (2013) Melatonin in Alzheimer’s disease. Int J Mol Sci. 14:14575–93.

Ling ZQ, Tian Q, Wang L, Fu ZQ, Wang XC, Wang Q, Wang JZ (2009) Constant illumination induces Alzheimer-like damages with endoplasmic reticulum involvement and the protection of melatonin. J Alzheimer’s Dis. 16:287-300.

Liu C, Weaver DR, Jin X, Shearman LP, Pieschl RL, Gribkoff VK, Reppert SM (1997) Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron. 19:91–102

Liu J, Somera-Molina KC,Hudson RL, Dubocovich L (2013) Melatonin potentiates running wheel-induced neurogenesis in the dentate gyrus of adult C3H/HeN mice hippocampus. J Pineal Res. 54: 222–231.

Liu R, Fu A, Hoffman AE, Zheng T, Zhu Y (2013) Melatonin enhances DNA repair capacity possibly by affecting genes involved in DNA damage responsive pathways. BMC Cell Biol 14: 1.

Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF (1999) Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer’s disease, and apolipoprotein E-epsilon4/4 genotype. J Clin Endocrinol Metab. 84:323–327.

Liu SJ, Wang JZ (2002) Alzheimer-like tau phosphorylation induced by wortmannin in vivo and its attenuation by melatonin. Acta Pharmacol Sin. 23:183-7

Lockley SW, Skene DJ, Tabandeh H, Bird AC, Defrance R, Arendt J (1997) Relationship between napping and melatonin in the blind. J Biol Rhythms 12: 657–665.

Lucey BP, Bateman RJ (2014) Amyloid-beta diurnal pattern: possible role of sleep in Alzheimer’s disease pathogenesis. Neurobiol Aging.35:S29-34.

Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S (2002) Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA. 288:1475–83. doi: 10.1001/jama.288.12.1475.

Macchi MM, Bruce JA, Boulos Z, Cooper TB, Terman JS, Terman M (2002) Sleep, chronotype and seasonality after pineal resection in humans: initial findings. Eighth Meeting of the Society for Research on Biological Rhythms. Amelia Island, FL: SRBR. 103.

Mack JM, Schamne MG, Sampaio TB, Pértile RA, Fernandes PA, Markus RP, Prediger RD (2016) Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms. Oxid Med Cell Longev. 2016:3472032.

Mandel RJ, Gage FH, Clevenger DG, Spratt SK, Snyder RO, Leff SE (1999) Nerve growth factor expressed in the medial septum following in vivo gene delivery using a recombinant adeno-associated viral vector protects cholinergic neurons from fimbria-fornix lesion-induced degeneration. Exp Neurol. 155:59–64.

Mander BA, Rao V, Lu B, Saletin JM, Lindquist JR, Ancoli-Israel S, Jagust W, Walker MP (2013) Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging. Nat Neurosci. 16:357–64.10.1038/nn.3324

Mantovani M, Pértile R, Calixto JB, Santos AR, Rodrigues AL (2003) Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evidence for involvement of N-methyl-D-aspartate receptors and the L-arginine-nitric oxide pathway. .Neurosci Lett. 343:1-4.

Martínez-Morales PL, Revilla A, Ocaña I, González C, Sainz P, McGuire D, Liste I (2013) Progress in stem cell therapy for major human neurological disorders. Stem Cell Rev. 9:685-99.

Mathes AM, Kubulus D, Waibel L, Weiler J, Heymann P, Wolf B, Rensing H (2008) Selective activation of melatonin receptors with ramelteon improves liver function and hepatic perfusion after hemorrhagic shock in rat. Critical Care Medicine. 36:2863–70.

Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M (2009) Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep.32:351–360.

McArthur AJ, Gillette MU, Prosser RA (1991) Melatonin directly resets the rat suprachiasmatic circadian clock in vitro. Brain Res. 565:158–61.

McArthur AJ, Lewy AJ, Sack RJ (1996) Non-24-hour sleep–wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment. Sleep 19:544–53.

McCurry SM, Reynolds CF, Ancoli-Israel S, Teri L, Vitiello MV (2000) Treatment of sleep disturbance in Alzheimer’s disease. Sleep Med Rev. 4:603–608.

McGaugh JL (2000) Memory--a century of consolidation. Science. 287:248-51.

Miller M (2015) The role of sleep and sleep disorders in the development, diagnosis, and management of neurocognitive disorders. Front Neurol.6:224. 10.3389/fneur.2015.00224

Miller MA, Wright H, Hough J, Cappuccio FP. (2014) Sleep and cognition In: Idzikowski C, (ed) Sleep and its Disorders Affect Society. InTech Open. 3–28.10.5772/58735

Mishima K, Okawa M, Hozumi S, Hishikawa Y (2000) Supplementary Administration of Artificial Bright Light and Melatonin As Potent Treatment for Disorganized Circadian Rest-Activity and Dysfunctional Autonomic and Neuroendocrine Systems in Institutionalized Demented Elderly Persons. Chronobiol. Int 17:419–432.

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. Biol Psychiatry. 45:417–21.

Moran M, Lynch CA, Walsh C, Coen R, Coakley D, Lawlor BA (2005) Sleep disturbance in mild to moderate Alzheimer’s disease. Sleep Med. 6:347-52.

Münch M, Knoblauch V, Blatter K (2005) Age-related attenuation of the evening circadian arousal signal in humans. Neurobiol Aging. 26:1307-19.

Musiek ES (2015) Circadian clock disruption in neurodegenerative diseases: cause and effect? Front. Pharmacol., doi.org/10.3389/fphar.2015.00029

Musshoff U, Riewenherm D, Berger E, Fauteck JD, Speckmann EJ (2002) Melatonin receptors in rat hippocampus: molecular and functional investigations. Hippocampus. 12:165-73.

Nadel L, Moscovitch M (1997) Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol7:217–27.10.1016/S0959-4388(97)80010-4

Nakagawa H, Sack RL, Lewy AJ (1992) Sleep propensity free-runs with the temperature, melatonin, and cortisol rhythms in a totally blind person. Sleep 15:330–6.

Naskar A, Manivasagam T, Chakraborty J, Singh R, Thomas B, Dhanasekaran M, Mohanakumar KP (2013) Melatonin synergizes with low doses of L-DOPA to improve dendritic spine density in the mouse striatum in experimental Parkinsonism. J. Pineal Res. 55:304–312.

Nigam G, Camacho M, Riaz M (2017) Rapid Eye Movement (REM) rebound on initial exposure to CPAP therapy: a systematic review and meta-analysis Sleep Science and Practice 1:13 DOI 10.1186/s41606-017-0014-7

Nigam G, Pathak C, Riaz M (2016) A systematic review of central sleep apnea in adult patients with chronic kidney disease 2016 Sleep and Breathing 20: 957-964 doi: 10.1007/s11325-016-1317-0.

Ochoa-Sanchez R, Comai S, Spadoni G, Bedini A, Tarzia G, Gobbi G (2014) Melatonin, selective and non-selective MT1/MT2 receptors agonists: differential effects on the 24-h vigilance states. Neurosci Lett. 561:156–161.

Onaolapo AY, Adebayo AN, Onaolapo OJ. (2017b) Exogenous daytime melatonin modulates response of adolescent mice in a repeated unpredictable stress paradigm Naunyn-Schmiedeberg’s Arch. Pharmacol. 390:149–61.

Onaolapo AY, Aina OA, Onaolapo OJ. (2017a) Melatonin attenuates behavioural deficits and reduces brain oxidative stress in a rodent model of schizophrenia. Biomed. Pharmacother. 92: 373-83.

Onaolapo OJ, Onaolapo AY, Akanni AA, Eniafe AL (2014) Central depressant and nootropic effects of daytime melatonin in mice. Annal Neurosci 21:90-96.

O’Neal-Moffitt G, Pilli J, Kumar SS, Olcese J (2014) Genetic deletion of MT1/MT2 melatonin receptors enhances murine cognitive and motor performance. Neurosci. 277: 506–521.

Osinde M, Clavaguera F, May-Nass R, Tolnay M, Dev KK (2008) Lentivirus Tau (P301S) expression in adult amyloid precursor protein (APP)-transgenic mice leads to tangle formation. Neuropathol Appl Neurobiol. 34:523–531.

Osuna S, Siddiqui F, Vanegas MA, Walters AS, Chokroverty S (2008) Prevalence and factors affecting REM and slow wave sleep rebound on CPAP titration study in patients with obstructive sleep apnea. Revista de la Facultad de Medicina. 56:4–10.

Pace-Schott EF, Spencer RM (2011) Age-related changes in the cognitive function of sleep. Prog Brain Res. 191:75–89.10.1016/B978-0-444-53752-2.00012-6

Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, Cardinali DP (2008) Physiological effects of melatonin: Role of melatonin receptors and signal transduction pathways. Prog. Neurobiol.85:335–353/

Panza F, Frisardi V, Capurso C, D’Introno A, Colacicco AM, Imbimbo BP, Santamato A, Vendemiale G, Seripa D, Pilotto A, Capurso A, Solfrizzi V (2010) Late-life depression, mild cognitive impairment, and dementia: possible continuum? Am J Geriatr Psychiatry. 18:98-116.

Peck JS, LeGoff DB, Ahmed I, Goebert D (2004) Cognitive effects of exogenous melatonin administration in elderly persons: A pilot study. Am. J. Geriatr. Psychiatry. 12:432–436.

Peter-Derex L, Yammine P, Bastuji H, Croisile B (2015) Sleep and Alzheimer’s disease. Sleep Med Rev. 19:29–38.

Petit D, Gagnon JF, Fantini ML, Ferini-Strambi L, Montplaisir J (2004) Sleep and quantitative EEG in neurodegenerative disorders. J Psychosom Res. 56:487–496.

Pinquart M, Duberstein PR (2007) Treatment of anxiety disorders in older adults: a meta-analytic comparison of behavioral and pharmacological interventions. Am J Geriatr Psychiatry. 15:639–51.

Pistacchi M, Gioulis M, Contin F, Sanson F, Marsala SZ (2014) Sleep disturbance and cognitive disorder: epidemiological analysis in a cohort of 263 patients. Neurol Sci. 35:1955-62.

Plesničar BK (2014) Efficacy and tolerability of agomelatine in the treatment of depression Patient Prefer Adherence. 8: 603–612.

Pongsa-Asawapaiboon A, Asavaritikrai P, Withyachumnarnkul B, Sumridthong A (1998) Melatonin increases nerve growth factor in mouse submandibular gland. J. Pineal Res. 24:73–77.

Prince M, Guerchet M, Prina M (2013) The Global Impact of Dementia 2013–2050.London: Alzheimer’s Disease International.

Prince M, Wimo A, Guerchet M (2015) World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. London: Alzheimer’s disease International.

Prinz PN, Peskind ER, Vitaliano PP, Raskind MA, Eisdorfer C, Zemcuznikov N, Gerber CJ (1982) Changes in the sleep and waking EEGs of non demented and demented elderly subjects. J Am Geriatr Soc. 30:86–93.

Pushpanathan ME, Loftus AM, Thomas MG, Gasson N, Bucks RS (2016) The relationship between sleep and cognition in Parkinson’s disease: A meta-analysis Sleep Med Rev. 26:21-32.

Qiu C, Winblad B, Marengoni A, Klarin I, Fastbom J, Fratiglioni L (2006) Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med. 166:1003-8.

Quinn J, Kulhanek D, Nowlin J, Jones R, Praticò D, Rokach J, Stackman R (2005) Brain Res. 1037:209-13.

Rafii MS, Baumann TL, Bakay RA, Ostrove JM, Siffert J, Fleisher AS, Herzog CD, Barba D, Pay M, Salmon DP, Chu Y, Kordower JH, Bishop K, Keator D, Potkin S, Bartus RT (2014) A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimer’s Dement. 10:571–581.

Rajaratnam SM, Polymeropoulos MH, Fisher DM, Roth T, Scott C, Birznieks G, Klerman EB (2009) Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: Two randomized controlled multicenter trials. Lancet. 373:482–491.

Ramírez-Rodríguez G, Klempin F, Babu H, Benítez-King G, Kemperman G (2009) Melatonin Modulates Cell Survival of New Neurons in the Hippocampus of Adult Mice. Neuropsychopharmacol. 34:2180–2191,

Rawashdeh O, de Borsetti NH, Roman G, Cahill GM (2007) Melatonin suppresses nighttime memory formation in zebrafish. Science. 318:1144-6.

Rawashdeh O, Maronde E (2012) The hormonal Zeitgeber melatonin: role as a circadian modulator in memory processing. Front Mol Neurosci 5: 27. 10.3389/fnmol.2012.00027

Redman J, Armstrong S, Ng KT (1983) Free-running activity rhythms in the rat: entrainment by melatonin. Science. 219:1089–91.

Reiter RJ (2003) Melatonin: clinical relevance. Best Pract Res Clin Endocrinol Metab. 17:273-85.

Reiter RJ, Manchester LC, Tan DX (2010) Neurotoxins: free radical mechanisms and melatonin protection. Curr Neuropharmacol 8: 194-210.

Reppert SM, Weaver DR, Ebisawa T (1994) Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. 13:1177-8

Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ (2008) Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA. 299:2642–2655.

Roth T, Seiden D, Sainati S, Wang-Weigand S, Zhang J, Zee P (2006) Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Medicine.7:312–318.

Roth T, Seiden D, Wang-Weigand S, Zhang J (2007) A 2-night, 3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr. Med. Res. Opinion. 23:1005–1014.

Rowe JW, Kahn RL (1987) Human aging: usual and successful. Science. 237:143-9.

Rudy JW, Pugh CR (1998) Time of conditioning selectively influences contextual fear conditioning: further support for a multiple-memory systems view of fear conditioning J Exp Psychol Anim Behav Process. 24:316-24.

Santangeli P, Di Biase L, Bai R, Mohanty S, Pump A, Cereceda Brantes M, Horton R, Burkhardt JD, Lakkireddy D, Reddy YM, Casella M, Dello Russo A, Tondo C, Natale A (2012) Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm. 9:1761-8.

Savaskan E (2015) Sleep disorders in dementia patients. Z Gerontol Geriatr. 48:312-7. doi: 10.1007/s00391-015-0890-3.

Scheer FA, Morris CJ, Garcia JI, Smales C, Kelly EE, Marks J, Malhotra A, Shea SA (2012) Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: a randomized controlled trial. Sleep. 35:1395–1402.

Schott JM, Revesz T (2013) Inflammation in Alzheimer’s disease: insights from immunotherapy. Brain. 136:2654-6.

Serfaty M, Kennell-Webb S, Warner J, Blizard R, Raven P (2002) Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia. Int J Geriatr Psychiatry. 17:1120–1127.

Shechter A, Lesperance P, Ng Ying Kin NM, Boivin DB (2012) Nocturnal polysomnographic sleep across the menstrual cycle in premenstrual dysphoric disorder. Sleep Med. 13:1071–1078.

Shin HY, Han HJ, Shin DJ, Park HM, Lee YB, and Park KH (2014) Sleep problems associated with behavioural and psychological symptoms as well as cognitive functions in Alzheimer’s disease. J Clin Neurol. 10:203–9.

Sofic E, Rimpapa Z, Kundurovic Z, Sapcanin A, Tahirovic I, Rustembegovic A, Cao G (2005) Antioxidant capacity of the neurohormone melatonin. J Neural Transm (Vienna). 112:349-58.

Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW (2003) Mapping cortical change across the human life span. Nat Neurosci. 6:309–15.10.1038/nn1008 9.

Spiegel R, Herzog A, Koberle S (1999) Polygraphic sleep criteria as predictors of successful aging: an exploratory longitudinal study. Biol Psychiatry45:435–42.

Spira AP, Chen-Edinboro LP, Wu MN, Yaffe K. (2014) Impact of sleep on the risk of cognitive decline and dementia. Curr Opin Psychiatry. 27:478–83.

Spruyt K, Gozal D (2010) Sleep in children: the evolving challenge of catching enough and quality Zzz’s. In. Cappuccio FP, Miller MA, Lockley SW (ed). Sleep, Health, and Society from Aetiology to Public Health. Oxford: Oxford University Press, p. 215–38.

Srinivasan R, Davidson Y, Gibbons L, Payton A, Richardson AM, Varma A, Julien C, Stopford C, Thompson J, Horan MA, Pendleton N, Pickering-Brown SM, Neary D, Snowden JS, Mann DM. (2006) The apolipoprotein E epsilon4 allele selectively increases the risk of frontotemporal lobar degeneration in males. J Neurol Neurosurg Psychiatry. 77:154-8.

Srinivasan V, Kaur C, Pandi-Perumal S, Brown GM, Cardinali DP (2011) Melatonin and Its Agonist Ramelteon in Alzheimer’s Disease: Possible Therapeutic Value Int J Alzheimers Dis. 2011,doi: 10.4061/2011/741974

Takaesu Y, Futenma K, Kobayashi M, Komada Y, Tanaka N, Yamashina A, Inoue Y (2015) A preliminary study on the relationships between diurnal melatonin secretion profile and sleep variables in patients emergently admitted to the coronary care unit. Chronobiol Int. 32:875–879

Takahashi Y, Sawa K, Okada T (2013) The diurnal variation of performance of the novel location recognition task in male rats. Behav Brain Res. 256:488–493.

Tamarkin L, Baird CJ, Almeida OF (1985) Melatonin: a co-ordinating signal for mammalian reproduction? Science 227:714–20.

Tan D, Reiter RJ, Chen L, Poeggeler B, Manchester LC, Barlow-Walden LR (1994) Both physiological and pharmacological levels of melatonin reduce DNA adduct formation induced by the carcinogen safrole. Carcinogenesis.15:215–8.

Tang J, Xu H, Fan X, Li D, Rancourt D, Zhou G, Li Z, Yang L (2008) Embryonic stem cell-derived neural precursor cells improve memory dysfunction in Abeta (1-40) injured rats. Neurosci Res. 62:86-96.

Tang Y, Cai B, Yuan F, He X, Lin X, Wang J, Wang Y, Yang GY (2014) Melatonin pretreatment improves the survival and function of transplanted mesenchymal stem cells after focal cerebral ischemia. Cell Transplant. 23:1279-91. doi: 10.3727/096368913X667510.

Taragano FE, Allegri RF (2003) Mild behavioral impairment: the early diagnosis. Int Psychogeriatr. 15:12. doi: 10.1016/j.jalz.2012.01.003

Tilvis RS, Kähönen-Väre MH, Jolkkonen J, Valvanne J, Pitkala KH, Strandberg TE (2004) Predictors of cognitive decline and mortality of aged people over a 10-year period. J Gerontol A Biol Sci Med Sci. 59:268-74.

Tohgi H, Abe T, Takahashi S, Kimura M, Takahashi J, Kikuchi T (1992) Concentrations of serotonin and its related substances in the cerebrospinal fluid in patients with Alzheimer type dementia. Neurosci Lett. 141:9–12.

Tong LM, Fong H, Huang Y (2015) Stem cell therapy for Alzheimer’s disease and related disorders: current status and future perspectives. Exp Mol Med. 47:e151.

Turek FW, McMillan JP, Menaker M (1976) Melatonin: effects on the circadian locomotor rhythm of sparrows. Science 194:1441–3.

Uchida K, Okamoto N, Ohara K, Morita Y (1996) Daily rhythm of serum melatonin in patients with dementia of the degenerate type Brain Res. 22: 717:154-9.

Uchiyama M, Okawa M, Shibui K, Kim K, Tagaya H, Kudo Y, Kamei Y, Hayakawa T, Urata J, Takahashi K (2000) Altered phase relation between sleeptiming and core body temperature rhythm in delayed sleep phase syndrome and non-24-hour sleep–wake syndrome in humans. Neurosci Lett. 294:101–104.

Urrestarazu R, Iriarte J (2016) Clinical management of sleep disturbances in Alzheimer’s disease: current and emerging strategies. Nat Sci Sleep. 8: 21–33. doi: 10.2147/NSS.S76706

Valentinuzzi VS, Menna-Barreto L, Xavier GF (2004) Effect of circadian phase on performance of rats in the Morris water maze task. J Biol Rhythms. 19:312-24.

Van Cauter E, Copinschi G, Turek FW (2001) Endocrine and other biologic rhythms. In: DeGroot LJ, Jameson JL, (eds) Endocrinology. New York: WB Saunders, p. 235–56.

Van Cauter E, Leproult R, Plat L. (2000) Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA. 284:861–8.10.1001/jama.284.7.861

Van Dongen HPA, Dinges DF (2003) Investigating the interaction between the homeostatic and circadian processes of sleep-wake regulation for the prediction of waking neurobehavioural performance. J Sleep Res. 12:181–7.

Videnovic A, Noble C, Reid KJ, Peng J, Turek FW, Marconi A, Rademaker AW, Simuni T, Zadikoff C, Zee PC (2014) Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol. 71:463-9.

Villa C, Ferini-Strambi L, Combi R (2015) The synergistic relationship between Alzheimer’s disease and sleep disorders: an update. J Alzheimers Dis. 46:571–580.

Vitiello MV, Borson S (2001) Sleep disturbances in patients with Alzheimer’s disease: epidemiology, pathophysiology and treatment.CNS Drugs. 15:777-96.

Wade A.G., Crawford G., Ford I., McConnachie A, Nir T, Laudon M, Zisapel N (2011) Prolonged release melatonin in the treatment of primary insomnia: Evaluation of the age cut-off for short- and long-term response. Curr. Med. Res. Opin. 27:87–98.

Wade A.G., Ford I., Crawford G., McConnachie A, Nir T, Laudon M, Zisapel N (2010) Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: A randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Med. 8:51.

Wade AG, Farmer M, Harari G, Fund N, Laudon M, Nir T, Frydman-Marom A, Zisapel N (2014) Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer’s disease: a 6-month,randomized, placebo-controlled, multicenter trial. Clin Interv Aging 9: 947–961.

Walker MP (2009) The role of sleep in cognition and emotion. Ann N Y Acad Sci1156:168–97.10.1111/j.1749-6632.2009.04416.x

Wan Q, Man HY, Liu F, Braunton J, Niznik HB, Pang SF, Brown GM, Wang YT (1999) Differential modulation of GABAA receptor function by Mel1a and Mel1b receptors. Nat Neurosci. 2:401-3.

Wang LM, Suthana NA, Chaudhury D, Weaver DR, Colwell CS (2005) Melatonin inhibits hippocampal long-term potentiation. Eur J Neurosci. 22:2231-7.

Wang XC, Zhang J, Yu X, Han L, Zhou ZT, Zhang Y, Wang JZ (2005) Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat. Sheng Li Xue Bao. 57(:7-12.

World Health Organization (2012) Dementia: a public health priority. Geneva, Switzerland

Wright KP Jr, Hull JT, Hughes RJ, Ronda JM, Czeisler CA (2006) Sleep and wakefulness out of phase with internal biological time impairs learning in humans. J Cogn Neurosci. 18:508-21.

Wu YH, Feenstra MG, Zhou JN, Liu RY, Toranõ JS, Van Kan HJ, Fischer DF, Ravid R, Swaab DF (2003) Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab. 88:5898-906.

Wu YH, Fischer DF, Kalsbeek A, Garidou-Boof ML, van der Vliet J, van Heijningen C, Liu RY, Zhou JN, Swaab DF (2006) Pineal clock gene oscillation is disturbed in Alzheimer’s disease, due to functional disconnection from the “master clock.” FASEB J. 20:1874–1876.

Wu YH, Swaab DF (2007) Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer’s disease. Sleep Med. 8:623–636.

Wu YH, Zhou JN, Van Heerikhuize J, Jockers R, Swaab DF (2007) Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer’s disease Neurobiol Aging. 28:1239-47.

Xie Z, Chen F, Li WA, Geng X, Li C, Meng X, Feng Y, Liu W, Yu F (2017) A review of sleep disorders and melatonin. Neurol Res. 39:559-565. doi: 10.1080/01616412.2017.1315864.

Xu J, Wang LL, Dammer EB, Li CB, Xu G, Chen SD, Wang G (2015) Melatonin for sleep disorders and cognition in dementia: a meta-analysis of randomized controlled trials. Am J Alzheimers Dis Other Demen. 30:439-47. doi: 10.1177/1533317514568005.

Xuan AG, Long DH, Gu HG, Yang DD, Hong LP, Leng SL (2008) BDNF improves the effects of neural stem cells on the rat model of Alzheimer’s disease with unilateral lesion of fimbria-fornix. Neurosci Lett. 440:331-5.

Yamanishi T, Tachibana H, Oguru M, Matsui K, Toda K, Okuda B, Oka N (2013) Anxiety and depression in patients with Parkinson’s disease. Intern Med. 52:539-45.

Yang X, Yang Y, Fu Z, Li Y, Feng J, Luo J, Zhang Q, Wang Q, Tian Q (2011) Melatonin ameliorates Alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A. J Psychopharmacol. 25:1118-25.

Youngstedt SD, Kripke DF, Elliott JA (1998) Melatonin excretion is not related to sleep in the elderly. J Pineal Res. 24:142–145.

Yun HM, Kim HS, Park KR, Shin JM, Kang AR, il Lee K, Song S, Kim YB, Han SB, Chung HM, Hong JT (2013) Placenta-derived mesenchymal stem cells improve memory dysfunction in an Aß1-42-infused mouse model of Alzheimer’s disease. Cell Death Dis. 4:e958.

Zammit G, Schwartz H, Roth T, Wang-Weigand S, Sainati S, Zhang J (2009) The effects of ramelteon in a first-night model of transient insomnia. Sleep Medicine. 10:55–59.

Zeise ML, Semm P (1985) Melatonin lowers excitability of guinea pig hippocampal neurons in vitro. J Comp Physiol A. 157:23-9.

Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU (2001) Melatonin treatment for age-related insomnia. J. Clin. Endocrinol. Metab. 86: 4727–30. doi:10.1210/jc.86.10.4727.)

Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF (2003) Early neuropathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J. Pineal Res. 35:125–130.

Zhu LQ, Wang SH, Ling ZQ, Wang DL, Wang JZ (2004) Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rat. J Pineal Res. 37:71-7.
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