Melatonin Treatment of Day-Night Rhythm Disturbances and Sundowning in Alzheimer Disease

Mahlberg, Richard; Kunz, Dieter; Sutej, Igor; Kühl, Klaus-Peter; Hellweg, Rainer

doi:10.1097/01.jcp.0000132443.12607.fd

Cited by 89 publications

(56 citation statements)

References 11 publications

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“…Because of the importance of melatonin in regulating the sleep-wake cycle, it has been one major target of clinical studies for the treatment of sundowning. Results, however, have been mixed; some studies find substantial improvements in sundowning symptoms, whereas others do not (16,22,33,34). Because melatonin receptors are substantially reduced in the suprachiasmatic nucleus of elderly and AD individuals, there may be too little substrate for melatonin supplementation to have an effect (35).…”

Section: Discussionmentioning

confidence: 94%

“…Thus, critics have argued that the perception of increased afternoon/evening behavioral disruptions may well arise from the caretakers' own fatigue and not any change on the part of patients themselves (20). However, studies quantifying temporal patterns in disruptive behavior have, for the most part, ruled out this hypothesis (21)(22)(23). Moreover, our data support sundowning syndrome as a legitimate condition by demonstrating its central symptoms in a mouse model and documenting circadian and cholinergic dysregulation that occur in parallel to the behavioral changes.…”

Section: Discussionmentioning

confidence: 99%

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Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice

Bedrosian

Herring

Weil

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Both normal aging and dementia are associated with dysregulation of the biological clock, which contributes to disrupted circadian organization of physiology and behavior. Diminished circadian organization in conjunction with the loss of cholinergic input to the cortex likely contributes to impaired cognition and behavior. One especially notable and relatively common circadian disturbance among the aged is "sundowning syndrome," which is characterized by exacerbated anxiety, agitation, locomotor activity, and delirium during the hours before bedtime. Sundowning has been reported in both dementia patients and cognitively intact elderly individuals living in institutions; however, little is known about temporal patterns in anxiety and agitation, and the neurobiological basis of these rhythms remains unspecified. In the present study, we explored the diurnal pattern of anxiety-like behavior in aged and amyloid precursor protein (APP) transgenic mice. We then attempted to treat the observed behavioral disturbances in the aged mice using chronic nightly melatonin treatment. Finally, we tested the hypothesis that time-of-day differences in acetylcholinesterase and choline acetyltransferase expression and general neuronal activation (i.e., c-Fos expression) coincide with the behavioral symptoms. Our results show a temporal pattern of anxiety-like behavior that emerges in elderly mice. This behavioral pattern coincides with elevated locomotor activity relative to adult mice near the end of the dark phase, and with time-dependent changes in basal forebrain acetylcholinesterase expression. Transgenic APP mice show a similar behavioral phenomenon that is not observed among agematched wild-type mice. These results may have useful applications to the study and treatment of age-and dementia-related circadian behavioral disturbances, namely, sundowning syndrome.Alzheimer's disease | cholinesterase | nucleus basalis of Meynert | behavioral and psychological signs and symptoms of dementia B oth normal aging and dementia are associated with disturbances in the biological clock that contribute to dramatic circadian disorganization, including the sleep-wake cycle, body temperature rhythm, and daily patterns of hormone release (1). Generally, aging is associated with reduced amplitudes among these daily rhythms; the most severe changes are associated with Alzheimer's disease (AD) (2). Circadian disorders affect more than 80% of individuals over age 65 (3) because of several converging factors; loss of neurons in the suprachiasmatic nucleus, decreased melatonin and melatonin receptor sensitivity, and minimal zeitgebers because of lifestyle all contribute to circadian dysfunction (1, 4).Normal aging and dementia are also associated with impairments in cognition and behavior, in part caused by loss of cholinergic input to the cortex (5). In particular, parts of the basal forebrain, most notably the nucleus basalis of Meynert (NBM), undergo degenerative changes, such as down-regulation of choline acetyltransferase (ChAT) activity (the r...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice

Bedrosian

Herring

Weil

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…There is published information indicating that melatonin, as a chronobiotic agent, is effective in treating irregular sleep-wake cycles and sundowning symptoms in AD patients (Fainstein et al 1997 ;Jean-Louis et al 1998a ;Mishima et al 2000 ;Cohen-Mansfi eld et al 2000 ;Mahlberg et al 2004 ;Brusco et al 1998a ;Cardinali et al 2002 ;Asayama et al 2003 ;Singer et al 2003 ;Pappolla et al 2000 ) ( Table 9.1 ). In an initial study on 14 AD patients with 6-9 mg of melatonin given for a 2-3-year period, it was noted that melatonin improved sleep quality (Brusco et al 1998a ).…”

Section: Clinical Aspects Of Melatonin Application In Admentioning

confidence: 94%

“…The administration of melatonin (6 mg/day) for 4 weeks to AD patients reduced nighttime activity as compared to placebo (Mishima et al 2000 ). An improvement of sleep and alleviation of sundowning were reported in 11 AD patients treated with melatonin (3 mg/day at bedtime) and evaluated by using actigraphy (Mahlberg et al 2004 ). Improvement in behavioral signs was reported with the use of 6-9 mg/day of melatonin for 4 months in AD patients with sleep disturbances (Cardinali et al 2002 ).…”

Section: Clinical Aspects Of Melatonin Application In Admentioning

confidence: 97%

Therapeutical Implications of Melatonin in Alzheimer’s and Parkinson’s Diseases

Cardinali

Vigo

Olivar

et al. 2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

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Neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) are major health problems, and a growing recognition exists that efforts to prevent them must be undertaken by both governmental and nongovernmental organizations. In this context, the pineal product melatonin has a promising signifi cance because of its chronobiotic/cytoprotective properties. One of the features of advancing age is the gradual decrease in endogenous melatonin synthesis. A limited number of therapeutic trials have indicated that melatonin has a potential therapeutic value as a neuroprotective drug in the treatment of AD, minimal cognitive impairment (which may evolve to AD), and PD. Both in vitro and in vivo, melatonin prevented the neurodegeneration seen in experimental models of AD and PD. For these effects to occur, doses of melatonin about two orders of magnitude higher than those required to affect sleep and circadian rhythmicity are needed. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50-100 mg/day are needed to assess its therapeutic validity in neurodegenerative disorders.

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“…Significant decreases in agitated behaviour and daytime sleepiness were also noted in this study. Reduction of sun downing with the use of 3 mg of melatonin was reported using actigraphy in 7 AD patients [84]. In a double blind study conducted on AD patients, it was noted that 3 mg/day of melatonin significantly prolonged actigraphically evaluated sleep time, decreased activity at night-time and improved cognitive functions [85].…”

Section: Melatonin's Potential Therapeutic Value In Alzheimer's Diseasementioning

confidence: 99%

Alzheimer’s Disease: Focus on the Neuroprotective Role of Melatonin

Srinivasan¹

2012

J Neurol Res

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Alzheimer's disease (AD) is characterized by a progressive loss of memory and cognitive function, and by behavioural and sleep disturbances, including insomnia. The pathophysiology of AD has been attributed to oxidative stress-induced amyloid-β protein (Aβ) deposition. Abnormal tau protein, mitochondrial dysfunction and protein hyper-phosphorylation have been demonstrated in neural tissues of AD patients. AD patients exhibit severe sleep-wake disturbances and these sleep disturbances are associated with rapid cognitive decline and memory impairment. Optimally effective management of AD patients will likely require a drug that can arrest Aβ -induced neurotoxic effects and can also restore the disturbed sleep-wake rhythm, with improvement in sleep quality. In this context, the pineal hormone melatonin has been demonstrated to be an effective antioxidant that can prevent Aβ -induced neurotoxic effects through a variety of mechanisms. Sleep deprivation itself produces many effects including oxidative damage, impaired mitochondrial function, neurodegenerative inflammation, altered proteosomal processing and abnormal activation of enzymes. In addition to treating the signs and symptoms of AD, treatment of sleep disturbances may also be necessary for preventing and arresting AD progression. Besides melatonin, a number of melatonergic agonists such as ramelteon, agomelatine and tasimelteon are now used clinically for treating insomnia and other sleep disorders. Their use may also be beneficial in treating Alzheimer's disease.

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Melatonin Treatment of Day-Night Rhythm Disturbances and Sundowning in Alzheimer Disease

Cited by 89 publications

References 11 publications

Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice

Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice

Therapeutical Implications of Melatonin in Alzheimer’s and Parkinson’s Diseases

Alzheimer’s Disease: Focus on the Neuroprotective Role of Melatonin

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