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Keywords:

  • aging;
  • Alzheimer's disease;
  • circadian rhythm;
  • melatonin;
  • pineal gland

Abstract

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

Abstract:  The pineal gland is a central structure in the circadian system which produces melatonin under the control of the central clock, the suprachiasmatic nucleus (SCN). The SCN and the output of the pineal gland, i.e. melatonin, are synchronized to the 24-hr day by environmental light, received by the retina and transmitted to the SCN via the retinohypothalamic tract. Melatonin not only plays an important role in the regulation of circadian rhythms, but also acts as antioxidant and neuroprotector that may be of importance in aging and Alzheimer's disease (AD). Circadian disorders, such as sleep–wake cycle disturbances, are associated with aging, and even more pronounced in AD. Many studies have reported disrupted melatonin production and rhythms in aging and in AD that, as we showed, are taking place as early as in the very first preclinical AD stages (neuropathological Braak stage I–II). Degeneration of the retina-SCN-pineal axis may underlie these changes. Our recent studies indicate that a dysfunction of the sympathetic regulation of pineal melatonin synthesis by the SCN is responsible for melatonin changes during the early AD stages. Reactivation of the circadian system (retina-SCN-pineal pathway) by means of light therapy and melatonin supplementation, to restore the circadian rhythm and to relieve the clinical circadian disturbances, has shown promising positive results.


Pineal gland and melatonin

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

In humans, the pineal gland is 5 mm long, 1–4 mm thick and weighs about 100 mg, both in men and in women [1]. The pineal gland contains two major cell types: neuroglial cells and the predominant pinealocytes that produce melatonin.

The pineal gland is a central structure in the circadian system that is innervated by a neural multi-synaptic pathway originating in the suprachiasmatic nucleus (SCN) that is located in the anterior hypothalamus. The SCN is the major circadian pacemaker of the mammalian brain and plays a central role in the generation and regulation of biological rhythms [2, 3]. The pineal gland produces melatonin in a marked circadian fashion [4], reflecting signals originating in the SCN. The human SCN innervates only a small number of hypothalamic nuclei directly [5, 6]. However, it may impose circadian fluctuations indirectly on the organism by means of melatonin released from the pineal gland [7].

The biosynthetic pathway of pineal melatonin has been studied thoroughly. l-Tryptophan is taken up from the circulation and converted to serotonin (5-HT) by tryptophan hydroxylase. 5-HT is metabolized by the rate-limiting enzyme arylalkylamine N-acetyltransferase (AA-NAT) to N-acetyl-5-hydroxytryptamine, and in turn by hydroxyindole-o-methyltransferase to melatonin. 5-HT can also be oxidized by monoamine oxidase A (MAOA) to 5-hydroxyindoleacetic acid [4, 8]. In all vertebrates, the activity of the rhythm-generating enzyme AA-NAT increases at night by a factor 7–150, depending on the species. The molecular mechanisms regulating AA-NAT are also remarkably different among species. For instance, in the rat, pineal AA-NAT is regulated at both mRNA level and protein level; however, in sheep and rhesus macaque, pineal AA-NAT mRNA levels show relatively little change over a 24-hr period and changes in AA-NAT activity are primarily regulated at the protein level [9, 10]. In the human pineal gland, significant daily fluctuations in AA-NAT mRNA levels were not detected either [11], which suggests that pineal AA-NAT activity may be mainly regulated on the post-transcriptional level in human.

The main environmental control of the pineal melatonin synthesis is light intensity. Light perceived by the retina reaches the SCN through the retinohypothalamic tract, which has been revealed by an in vitro postmortem tracing procedure, also in the human hypothalamus [12]. The SCN innervates the pineal gland via the dorsomedial hypothalamic nucleus, the upper thoracic intermediolateral cell columns of the spinal cord and the superior cervical ganglia (SCG), resulting in the rhythmic secretion of melatonin [13, 14]. The importance of ocular light as a temporal cue has been clearly demonstrated in circadian studies of blind people, who were bilaterally enucleated, showing desynchronized melatonin and cortisol rhythm [15, 16]. Abundant evidence indicates that in humans the sympathetic stimulus is crucial for melatonin secretion. A very large goiter may compress the SCG, thus altering melatonin synthesis in patients [17]. After bilateral T1–T2 ganglionectomy in a patient with hyperhidrosis, melatonin levels in the cerebrospinal fluid (CSF) and plasma were markedly reduced and the diurnal rhythm was abolished [18]. A circadian rhythm of β1-adrenergic receptors has been found in human pinealocytes [19]. Propanolol, a β-adrenergic receptor antagonist, causes a dose-dependent decrease in melatonin levels, or even totally abolishes the nighttime surge [20, 21]. In turn, melatonin elicits two distinct, separable effects on the SCN, i.e. acute neuronal inhibition and phase shifting, through melatonin receptors in the SCN [22]. The ability of melatonin to phase-shift the circadian system has been extensively investigated in humans [23–26]. Moreover, melatonin acts as an effective free radical scavenger [27] and indirect antioxidant, i.e. it stimulates antioxidative enzymes [28], and functions as neuroprotector that may be of importance in aging and in Alzheimer disease (AD) (reviewed in Refs [29, 30]).

Circadian rhythms disruptions in aging

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

There is a great deal of evidence indicating that aging is characterized by a progressive deterioration of circadian timekeeping (reviewed in Ref. [31]). Changes in the intrinsic free-running period of the clock during aging have been reported but remain equivocal [32–34]. In addition, aged people frequently show a spontaneous internal desynchronization of rhythms [32]. For instance, the onset of the activity cycle is earlier than that of the morning rise in body temperature, which may affect sleep–wake patterns [35, 36]. Changes in circadian rhythms are frequently associated with a reduction in nighttime sleep quality, a decrease in daytime alertness, and an attenuation in cognitive performance (reviewed in Ref. [31]).

Melatonin production during aging

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

Reduced melatonin concentrations during aging, especially nocturnal levels, have been extensively reported in the pineal gland, plasma, CSF and in urine as 6-hydroxymelatonin (reviewed in Refs [2, 37]), although in some studies the age-related melatonin difference was not statistically significant [38–40]. Recently, our group measured circadian salivary free melatonin levels in 52 healthy young (21–25 yr of age), middle-aged (41–53 yr of age), old (60–72 yr of age) and very old volunteers (80–93 yr of age). A clear circadian rhythm of salivary melatonin was present in all age groups. We found, however, that a step-wise decrease in the circadian amplitude of salivary melatonin occurred early in life, around 40 yr of age. The amplitude in the middle-aged subjects was only 60% of that of the young subjects. Both the old and very old subjects showed increased daytime (baseline) melatonin levels [41]. Studies of the melatonin metabolite 6-sulfatoxymelatonin show that age-related decrease in melatonin production occurs even as early as 20–30 yr of age [42]. Zhao et al. [43] found that a decline of the nocturnal serum melatonin peak was significant at the age of 60 and further declined from 70 yr of age onwards. The discrepancies among different studies may be due to the differences in methods, criteria for selecting subjects (health conditions, medical history, etc.), and experimental conditions. Moreover, the inconsistency may depend on the large (20-fold) genetically determined inter-individual variability in human nightly melatonin secretion [44] and on the size of pineal gland [45]. In view of the large individual variability, longitudinal studies assessing melatonin rhythmicity within subjects across time need to be performed to resolve the question when exactly melatonin begins to decline with age in an individual. Besides the age-related decline of melatonin production, age-related changes in the timing of the melatonin rhythm have also been reported [46]. Moreover, older subjects enter sleep and awake earlier relative to their nightly melatonin secretory episode [46], which indicates that aging is also associated with a change in the internal phase relationship between the sleep–wake cycle and the output of the circadian pacemaker.

Possible mechanisms for age-related melatonin changes

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

There are some observations that give insight into the possible mechanisms of the decreased melatonin levels during aging.

The pineal gland shows clear age-related changes. Human pineal gland calcification increases with age [47]. Some studies have related calcification of the pineal gland to a disturbed circadian rhythmicity in the sleep–wake cycle [48] and a decline in melatonin production with age [45, 49]. However, Bojkowski and Arendt [50] have reported there was no relationship between plasma melatonin or the metabolite of melatonin in urine, 6-sulphatoxymelatonin, and pineal calcification. Indeed, there is no direct evidence that pineal calcification affects pineal metabolism. Moreover, the pineal gland shows no obvious signs of degeneration [51–53]; even in very old subjects the pineal parenchyma is histologically still apparently active [54]. However, the only histological study available on this topic suggests that the noradrenergic innervation of the pineal gland originating from the SCN may be affected during aging [55].

The central clock SCN shows age-related degenerative alterations. The circadian rhythm of melatonin levels is regulated by the SCN, the clock of the brain. Age-related alterations have been noted in the human SCN. Circadian and circannual rhythmicity of neuropeptide synthesizing neurons of the human SCN, such as vasopressin, are reduced with aging [56–58]. It has been shown that the number of vasopressin-immunoreactive neurons in the human SCN exhibits a marked diurnal oscillation in young subjects, with low vasopressin neuron numbers during the night and peak values during the early morning. However, this rhythm disappeared in subjects over the age of 50 [56]. The marked annual oscillation of vasopressin-expressing neurons in the SCN of young subjects, i.e. low vasopressin neuron numbers during the summer and peak values in autumn, was also disrupted in subjects over 50 yr [57]. A significant decrease in the number of vasopressin-expressing neurons in the SCN was found only in subjects of 80–100 yr of age [59]. How these changes in the SCN translate into the observed changes in circadian rhythmicity is a topic of current research. In addition to the changes in SCN vasopressin and in melatonin rhythms, age-related changes in the amplitude of other circadian rhythms have also been reported in human, e.g. core body temperature, cortisol, vasopressin, blood pressure, pulsatile LH, testosterone secretion, β-endorphine levels, etc. (reviewed in Ref. [2]). These findings suggest that the changes observed in the melatonin rhythm may be part of a general effect of aging on the central clock SCN and/or its regulation.

Both zeitgebers and synchronization are disturbed during aging. Light has significant effects on melatonin synthesis in the pineal gland via the SCN and a multisynaptic pathway thereafter. Reports suggest that aged people are exposed to reduced illumination levels in their daily lives (reviewed in Ref. [31]), and there are studies showing a negative correlation between environmental light intensity and sleep disturbances in the aged and in AD patients [60–62]. In addition, the capacity of the lens to transmit light progressively decreases during aging, which may also contribute to disrupted melatonin production and circadian disturbances in the elderly [63]. Nevertheless, elderly people have a maintained responsiveness of the circadian pacemaker to light, which implies that scheduled bright light exposure can be used to treat circadian phase disturbances and related sleep disorders in older people [64].

Circadian rhythm disruptions in AD

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

The fragmented sleep–wake pattern which occurs in elderly, is even more pronounced in AD patients [65, 66]. Continuous measurement of the circadian rest–activity cycle for 589 days in a demented patient with probable AD revealed slowly progressive changes in temporal organization until death [67]. Many AD patients also often suffer from circadian system related behavioral disturbances, such as daytime agitation and nightly restlessness [62, 68]. In AD, circadian rhythm disturbances are often so severe that they are even thought to contribute to mental decline [69]. Moreover, nocturnal insomnia and wandering in AD patients often pose unbearable problems for caregivers, and are the principal causes of institutionalization [70]. However, until now there is no successful pharmaceutical treatment for the circadian disturbances in AD. Hypnotic or antipsychotic medication is only slightly effective for relieving circadian disturbances [71]. Benzodiazepines have insignificant effects on sundowning [72], while sleep–wake cycle disturbances may even be aggravated by a classic neuroleptic like haloperidol [73].

Melatonin changes in preclinical AD and clinical AD

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

Impairment of melatonin secretion is not only related to age but also to severity of mental impairment [74]. Numerous studies demonstrate that nocturnal melatonin levels are selectively decreased in AD [11, 75], and that daytime melatonin levels are increased in AD patients [76], indicating that the neurodegenerative process affects the circadian-pineal system (reviewed in Ref. [2]). AD patients with disturbed sleep–wake cycle possess melatonin secretion rhythm disorders [77] and the disappearance of daily melatonin rhythm in AD patients is consistent with clinical circadian rhythm disorders, such as delirium, agitation and sleep–wake disturbance [78, 79].

We have observed a strong reduction in postmortem CSF melatonin levels in Alzheimer patients. CSF melatonin levels of AD patients were only one-fifth those in control subjects. The melatonin levels of patients with apolipoprotein (APOE) ɛ4/4 type were even significantly lower than those expressing APOE ɛ3/4 [80]. Interestingly, the melatonin levels in CSF decrease with the progression of AD neuropathology as determined by the Braak stages [81]. More strikingly, CSF melatonin levels are already reduced in preclinical ‘AD’ subjects, who are cognitively still intact ‘control’ subjects that show only the earliest signs of AD neuropathology (Braak stages I–II) [81]. Also, in the postmortem human pineal gland, we found reduced nocturnal melatonin production and a disappearance of day/night variations of melatonin content already from the earliest, preclinical AD stages (Braak stages I–II) onwards [11]. A significant high correlation exists between pineal melatonin content and CSF melatonin levels [11] and between CSF and plasma melatonin levels [82], suggesting that reduced melatonin levels may serve as an early marker for the very first stages of AD that could so far not be monitored in any other way.

Melatonin deficiency is possibly not only a consequence of the AD process, it may contribute to the pathogenesis of AD, as melatonin was found both in in vitro and in vivo experiments to act as an antioxidant and neuroprotector (reviewed in Refs [29, 30]). A recent study reported that melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic mouse model of AD [83].

Mechanisms underlying the melatonin changes in the progress of AD

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

The pineal gland shows molecular changes both in preclinical and clinical AD. However, in the pineal gland of AD patients, cells or afferent fibers are clear from neuropathological hallmarks of AD, i.e. neurofibrillary tangles, the accumulation of neurofilaments, tau, hyperphosphorylated tau or β/A4 amyloid deposition [53]. There was, moreover, no alternation in calcium deposition in the pineal or choroid plexus in AD [84]. Neither pineal weight nor pineal total protein content show changes in AD [11].

Recently we have taken a comprehensive approach to study the molecular changes in the melatonin synthesis pathway and its noradrenergic innervation in human postmortem pineal glands from age and sex matched controls, ‘preclinical AD’ subjects (Braak stages I–II) and clinical AD patients (Braak stage VI). The circadian melatonin rhythm disappears because of decreased nocturnal melatonin levels in both ‘preclinical AD’ and AD patients. Moreover the circadian rhythm of β1-adrenergic receptor mRNA disappears in both patient groups, which suggests a dysfunction of the SCN innervation to the pineal. The precursor of melatonin, serotonin, was stepwise depleted during the course of AD, as indicated by the up-regulated MAOA activity and gene expression. We concluded from our study that a dysregulation of noradrenergic innervation and the depletion of serotonin by increased MAOA resulted in the loss of melatonin rhythm and reduced melatonin levels from the earliest AD stages onwards [11]. In fact, the dysfunction of the SCN innervation to the pineal in AD has also been suggested by previous morphological studies, which demonstrated that the SCG, and the noradrenergic fibers in the pineal gland show swollen axons in AD patients [53, 55]. Actually the SCN of AD patients is severely affected [56, 59], which may well be responsible for a disrupted sympathetic control of melatonin synthesis. Increased MAOA activity and mRNA levels, as found in the AD pineal gland, seem to be a general phenomenon in AD, as it was also reported in the cortex, thalamus, hypothalamus and white matter of AD patients [85–87]. Interestingly, MAOA gene polymorphisms are suggested to be associated with an increased susceptibility for AD [88]. However, these polymorphisms have not been studied relative to the changes in pineal melatonin synthesis in AD.

The biological clock SCN is severely affected in AD. It shows prominent degenerative changes in AD [59, 89, 90], and also the typical cytoskeletal AD alterations of pretangles [91–93] and tangles [94]. Diffuse amyloid plaques, however, are infrequently noted in this nucleus of AD patients [93, 94]. The vasopressin-expressing neuron numbers in the SCN decrease earlier and are more dramatic in AD than in aged controls [59]. In addition, the total amount of vasopressin mRNA is three times lower in AD patients than in elderly controls, and the diurnal rhythm of vasopressin mRNA apparent in controls is no longer visible in AD patients [90]. The density of vasopressin and neurotensin neuron is decreased, while the glial fibrillary acidic protein stained astrocytes are increased in the SCN of AD patients [94]. We propose that these degenerative changes in the SCN most probably result in a disrupted melatonin synthesis, and may underlie the clinically common circadian rhythm disorders in AD. The question whether the SCN shows such alterations already in the earliest AD stages and thus causes the changes in the pineal gland in preclinical AD stages, is now under our investigation.

The input of environmental light to the circadian timing system is also disrupted in AD. Besides the degenerative changes that are present in the SCN of AD, it is also important to note that several factors attenuate the input of environmental light to the circadian timing system during AD. AD patients are exposed to less environmental light than their age-matched controls [95]. Furthermore, the retina and optic nerve show degenerative changes in AD, however, without neurofibrillary tangles, neuritic plaques or amyloid angiopathy [96, 97]. Moreover, age-related maculopathy is associated with AD [98] and ‘glaucoma’ was found five times more frequently in AD patients than in aged controls [99]. In contrast to the observed degenerative changes mentioned above, some studies did not find significant AD-related changes in the retina and optic nerve cells [100–102]. Anyhow, the retiohypothalamic connection and SCN efferents are still present in AD [6, 12], and studies on the reactivation of the circadian system (retina-SCN-pineal pathway) by means of light therapy and melatonin supplementation to restore the circadian rhythm and relieve the symptoms are commonly carried out (see below).

Melatonin supplementation

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

In AD patients, melatonin has been suggested to improve circadian rhythmicity, decreasing agitated behavior, confusion and ‘sundowning’ in uncontrolled studies [103–105]. Melatonin has also been suggested to have beneficial effects on memory in AD [104–107], possibly through protection against oxidative stress and neuroprotective capabilities (reviewed in Refs [29, 30]). However, these suggestions need to be confirmed in well-controlled studies, and it should be noted that a few randomized placebo-controlled trials of melatonin administration to AD patients did not find improved sleep–wake pattern [108, 109]. If there are beneficial effects of melatonin in AD, it may relate both to the indole's ability to synchronize circadian rhythms and to the antioxidant action of melatonin.

Light therapy and other nonpharmaceutical stimuli

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

Supplementary exposure to morning bright light has shown beneficial effects on sleep quality and daytime vigilance of elderly [110]. It also significantly increases melatonin secretion in aged people, to levels similar to those in young adults [61] and it improves body temperature rhythm [64], which implies that scheduled bright light exposure can be expected to facilitate the circadian rhythm entrainment and synchronization.

In AD patients, bright light therapy improved both sleep–wake rhythm disorders and behavioral disorders, such as sundowning, wandering, agitation and delirium [108, 111, 112]. Moreover, it appeared to improve the cognitive state of AD patients [113], especially in the early stages of the disease [112]. In contrast to the literature mentioned above, Mishima et al. [114] found that bright daytime light treatment induced a significant reduction in nighttime activity, but only in patients with vascular dementia and not in patients with AD. It should be noted, however, that the proportion of vascular dementias has always been overestimated when no neuropathological confirmation is performed, as in most demented patients with vascular lesions Alzheimer changes are found as well.

Other nonpharmacological means to improve the circadian rhythmicity in aging and in AD are also reported. An increased level of physical activity improves circadian rhythmicity in healthy elderly people, as was found following a 3-month fitness training period [115]. Pacing also improves the synchronization of the rest activity cycle in AD patients [67]. Improved circadian rest activity rhythmicity was also observed following transcutaneous electrical nerve stimulation (TENS) in AD patients [116, 117].

In summary, pineal melatonin rhythms and production decrease in aging and in AD, even as early as in the very first preclinical AD stages (Braak stage I–II). Our recent studies indicate that it is the sympathetic regulation of pineal melatonin synthesis by the SCN that is dysfunctioning and is responsible for melatonin changes during the early AD stages. There is still plasticity in the circadian system (retina-SCN-pineal pathway) in aging and in AD, and stimulation of the circadian system by nonpharmacological means, such as light therapy, melatonin, or TENS, has shown important therapeutic consequences for elderly and AD patients. Whether, in addition to light, the administration of melatonin is more effective in cases of circadian rhythm disorders and cognitive function decline, is currently under investigation by our group.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References

This study was supported by the China committee of the Royal Netherlands Academy of Arts and Sciences (01CDP019, 02CDP014), by the National Key project for Basic Science of China (G1999054007), by the Hersenstichting Nederland and by the Research Institute for Diseases in the Elderly, funded by the Ministry of Education & Science and the Ministry of Health, Welfare and Sports, through the Netherlands Organization for Scientific Research (NWO). We are grateful to W.T.P. Verweij for secretarial help, M.A. Hofman, A. Kalsbeek, and E.J.W. Van Someren for their critical comments.

References

  1. Top of page
  2. Abstract
  3. Pineal gland and melatonin
  4. Aging
  5. Circadian rhythms disruptions in aging
  6. Melatonin production during aging
  7. Possible mechanisms for age-related melatonin changes
  8. Alzheimer's disease
  9. Circadian rhythm disruptions in AD
  10. Melatonin changes in preclinical AD and clinical AD
  11. Mechanisms underlying the melatonin changes in the progress of AD
  12. Melatonin supplementation
  13. Light therapy and other nonpharmaceutical stimuli
  14. Acknowledgments
  15. References
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