Ageing Research Reviews 12 (2013) 188 200

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Ageing Research Reviews

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Review

Reciprocal interactions between sleep, circadian disease: Focus on the role of hypocretin and mela

Diane Sla eeka Radboud Univ 6500Hb Radboud Univ , Nijmc Radboud Univ 5, 650d Alzheimer Cee Donders Insti therla

a r t i c l

Article history:Received 19 JaReceived in reAccepted 23 AAvailable onlin

Keywords:DementiaSleep disorderCircadian rhythmHypocretinMelatonin

ologyrbance thwe dek to cent ourotr

a roonset of AD.

2012 Elsevier B.V. All rights reserved.

1. Introdu

Alzheimexpected tothe next 40disease are ies have dismodiable discovered one of thesboth circadhave a majcaregivers (estingly, cirrole in the plink betweeamyloid pin AD (Kang

CorresponNijmegen MedTel.: +31 24 36

E-mail add(M.M. Verbeek

URL: http:

1568-1637/$ http://dx.doi.oction

ers disease (AD) is a neurodegenerative disorder evolve into a disastrous worldwide epidemic within

years, unless treatment options delaying or curing thefound (Brookmeyer et al., 2007). Epidemiological stud-covered many potential risk factors for AD, includinglife style factors, and still more risk factors are being(Ballard et al., 2011). There is growing evidence thate factors is sleep. Clinical AD is often complicated byian rhythm disruptions and sleep disturbances, whichor impact on the quality of life of patients and theirBianchetti et al., 1995; Pollak and Perlick, 1991). Inter-cadian and sleep disorders may in turn have a causalathophysiology of AD. Remarkable new data points to an hypocretin, a sleep-related neurotransmitter, and therotein (A), the protein accumulating in senile plaques

et al., 2009). A similar relation has been demonstrated

ding author at: Department of Neurology, Radboud Universityical Centre, 325, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.1 5192; fax: +31 24 366 8754.resses: Dianeslats@gmail.com (D. Slats), M.Verbeek@neuro.umcn.nl).//www.neurochemistry.nl (M.M. Verbeek).

for the circadian rhythm regulating hormone melatonin, and ADpathophysiology (Wang and Wang, 2006).

In this review we describe the current knowledge on the possibly reciprocal interactions between sleep and circadian dis-turbances and AD. After a description of the physiology of sleep andcircadian regulatory systems, we discuss the impairments of thesesystems in clinical AD and provide a clinical overview on diagno-sis and treatment of homeostatic sleep disorders in AD. Finally, wediscuss the possible link between sleep and circadian rhythms andthe onset of AD.

2. Sleep physiology

2.1. Sleep regulating systems

Sleep is a complex physiological state characterized by reducedor absent consciousness, relatively suspended sensory activity, andinactivity of nearly all voluntary muscles. The purpose and mech-anisms of sleep are only partially clear and are subject of intenseresearch (Siegel, 2009). Sleep and wakefulness are regulated by anintricate network of several separate brain mechanisms. The mainbuilding blocks are 2 pathways, generating sleep and wakefulnessrespectively (Fig. 1). The brain circuitry that produces wakefulness,including the ascending arousal system (AAS), consists of severalmonoaminergic cell groups in the brainstem, hypothalamus and

see front matter 2012 Elsevier B.V. All rights reserved.rg/10.1016/j.arr.2012.04.003tsa,d,e, Jurgen A.H.R. Claassena,d,e, Marcel M. Verbersity Nijmegen Medical Centre, Department of Geriatric Medicine, P.O. Box 9101/925,ersity Nijmegen Medical Centre, Department of Neurology, P.O. Box 9101/325, 6500HBersity Nijmegen Medical Centre, Department of Laboratory Medicine, P.O. Box 9101/92

ntre Nijmegen, P.O. Box 9101/925, 6500 HB, Nijmegen, The Netherlandstute for Brain, Cognition and Behaviour, P.O. Box 9101/204, 6500 HB, Nijmegen, The Ne

e i n f o

nuary 2012vised form 4 April 2012pril 2012e 30 April 2012

s

a b s t r a c t

AD, sleep and circadian rhythm physiogy leads to sleep and circadian distuother hand, there is increasing evidenence on AD pathology. In this review circadian rhythms in AD and their linpriate diagnosis and adequate treatmregulating systems, and especially nepathophysiology, as this may provideom/ locate /ar r

rhythms and Alzheimerstoninb,c,d,, Sebastiaan Overeemb,e

B, Nijmegen, The Netherlandsegen, The Netherlands0HB, Nijmegen, The Netherlands

nds

display an intricate relationship. On the one hand, AD pathol-ces, with a clear negative inuence on quality of life. On theat both sleep and circadian regulating systems exert an inu-scribe the impairments of both sleep regulating systems andlinical symptoms, as this may increase knowledge on appro-f sleep problems in AD. Furthermore we discuss how sleepansmitters such as melatonin and hypocretin, may affect ADle for lack of sleep and circadian rhythm deterioration in the

D. Slats et al. / Ageing Research Reviews 12 (2013) 188 200 189

Fig. 1. Schematic representations of the anatomical brain structures and their projections involved in sleep and waking. Originally published and reprinted from Saperet al. (2005). (A) Arousal pathway. The cholinergic pathway (yellow pathway) originates from cholinergic (ACh) cell groups in the upper pons, the pedunculopontine (PPT)and laterodorsal tegmental nuclei (LDT). A second pathway (red) activates the cerebral cortex and arises from neurons in the monoaminergic cell groups, including thetuberomammi mine (and the locus c ons frohypocretin/ore neuroThe ventrolate tuberand the locus c includthe cholinergi al nuc

basal forebmarily activthe hypothaarousal patet al., 2002bistable swin rapid chintermediatThe hypothins, form anip-op (Pe

In AD sebecome imp

ta su paturot

The r neuby a c

Fig. 2. The hypThe 2 circuits gsystem, a ip-while during sLC: locus coerullary nucleus (TMN) containing histamine (His), the A10 cell group containing dopaoeruleus (LC) containing noradrenaline (NA). This pathway also receives contributixin (ORX) or melanin-concentrating hormone (MCH), and from basal forebrain (BF)ral preoptic nucleus (VLPO) inhibits the monoaminergic cell groups (red) such as theoeruleus (LC). It also innervates neurons in the lateral hypothalamus (LHA; green),c (ACh) cell groups (yellow), the pedunculopontine (PPT) and laterodorsal tegment

rain. The brain mechanisms active during sleep is pri-ated by the ventrolateral preoptic nucleus (VLPO) oflamus (Sherin et al., 1996). Interestingly, the sleep andhways have reciprocal inhibitory connections (Chou; Szymusiak et al., 1998). This network results in aitching system, which is called a ip-op, resultinganges between states of consciousness, and avoiding

new daand ADthis ne

2.1.1. The

duced

e states (Fig. 2) (Peyron et al., 1998; Saper et al., 2001).alamic hypocretin neuropeptides, also known as orex-

important regulating system acting on the sleepwakeyron et al., 1998; Saper et al., 2010).veral of these sleep related mechanisms are known toaired, as we will discuss in chapter 3. Recently, exciting

(de Lecea ediffusely thdense inneAAS (Bonnaand de Lecetin on posts

ocretin regulated ip-op switch that stabilizes the transition between sleep and wake senerating sleep and wakefulness, the VLPO and the AAS (TMN, DR and LC), respectively, hop, allowing rapid transitions. Hypocretin neurons stabilize this switch. During wakefulleep they are inhibited by the VLPO, on which they have no inuence. VLPO: ventrolaterleus, HCRT: hypocretin.DA), the dorsal and median raphe nuclei containing serotonin (5-HT),m peptidergic neurons in the lateral hypothalamus (LHA) containingns that contain -aminobutyric acid (GABA) or ACh. (B) Sleep pathway.omammillary nucleus (TMN), the A10 cell group, the raphe cell groupsing the perifornical (PeF) orexin (ORX) neurons, and interneurons inlei (LDT).

ggest a relation between hypocretin neurotransmissionhophysiology. Therefore we will further elaborate onransmitter below.

ole of hypocretinrotransmitters hypocretin-1 and -2 are exclusively pro-luster of neurons in the posterior lateral hypothalamus

t al., 1998; Sakurai et al., 1998). These neurons projectroughout the central nervous system with particularlyrvations in regions related to wakefulness, such as thevion and de Lecea, 2010; Peyron et al., 1998; Sutcliffea, 2000; van den Pol et al., 2002). The actions of hypocre-ynaptic neurons are mediated by two G protein-coupled

tages. Originally published and reprinted from Fronczek et al. (2009).ave reciprocal inhibitory connections which form a bistable switchingness, hypocretin neurons project to cell groups of the arousal systems,al preoptic area, TMN: tuberomammillary nucleus, DR: dorsal raphe,

190 D. Slats et al. / Ageing Research Reviews 12 (2013) 188 200

receptors, Hcrt receptors 1 and 2 (Sakurai et al., 2010). Hypocre-tin neurons receive input from multiple specic brains regions,including several nuclei in the hypothalamus; the posterior anddorsomedial hypothalamus, the medial preoptic nucleus, and theVLPO (Sakuthey projecet al., 1998)which theytin system keeping it i

Besides variety of pdiovascularenergy hom2010; Yamsleep/wakesleep disorboth huma2000). CSF hcataplexy pof narcoleptin mRNA aThannickal

Several regulation iincrease timwave and Rof hypocretransitions wakefulnestting withrole in arousleep/wake

2.2. Circadi

The circais organized(SCN) whicWeaver, 20on a daily bcycle by me1986; Johnsroute on theinuences Thompson hypocretin,through whmone melamelatonin ireview.

2.2.1. The rMelaton

important sized from and then methyltranduring theis released Macchi and(Leston et apineal glanphase, wheDuring the gland to pr

he totlami d and

25threacti

had ahypot

= 21,0

ced rhyt

an inellul

glans tran

repr

laton regue funs (Prelati

effeeen d

mely exan wting melaans,n ind, andan scircarly ndministered in the second half of the night or at early dayelays the circadian rhythm (Lack and Wright, 2007; Pandi-al et al., 2006). These studies indicate that melatonin exertslex inuence on sleep, on the one hand through its effect oncadian regulation of sleep and wakefulness, and on the othery a direct, sleep promoting effect (Zisapel, 2001).

aired sleep physiology in AD

paired sleep regulating systems

eral anatomical elements of the AAS are affected in AD,ing the nucleus basalis of Meynert in the basal forebrain, theus, and several nuclei in the brainstem; the locus coeruleus,per raphe nuclei, and the tegmentopontine reticular nuclei

and Braak, 1991b). The thalamus itself, which is thought tolved in arousal, is severely affected in AD as well; neurob-changes occur in the anteroventral nucleus of the thalamusrai, 2006; Yoshida et al., 2001). During wakefulness,t to cell groups of the arousal systems, the AAS (Peyron, while during sleep they are inhibited by the VLPO, on

have no inuence (Marcus et al., 2001). The hypocre-acts as a stabilizing factor on the sleepwake ip-op,n the wake state (Saper et al., 2005) (Fig. 2).sleep regulation, the hypocretins play a role in a widehysiological functions, such as the control of the car-

system, neuroendocrine regulation, locomotor activity,eostasis, pain and stress (Bonnavion and de Lecea,

anaka et al., 2003). The importance of hypocretin in regulation is demonstrated by the discovery that theder narcolepsy is caused by hypocretin deciency inns and animals (Peyron et al., 2000; Thannickal et al.,ypocretin-1 is undetectable in up to 95% of narcolepsy-atients (Nishino et al., 2000) and in post-mortem brainssy-cataplexy patients drastic reductions of hypocre-nd immunoreactivity was shown (Peyron et al., 2000;et al., 2000).other studies further implicate the role of hypocretinn sleep. Intracerebroventricular injections of hypocretine spent awake and decrease time spent in slow-

EM sleep (Bourgin et al., 2000). Repeated stimulationtin neurons increases the number of wakefulness(Adamantidis et al., 2007), and hypocretin inducess from sleep (Bonnavion and de Lecea, 2010). Thus

the neuronal projections hypocretins have a directsal, but also exert a delicate stabilizing inuence on

switching.

an rhythm regulating systems

dian regulation of sleep and wakefulness mechanisms by a pacemaker located in the suprachiasmatic nucleush serves as a master clock (Jin et al., 1999; Reppert and02). The SCN is most active during the day and resetsasis by light input from the retina and during the darklatonin secretion from the pineal gland (Cassone et al.,on et al., 1988). The SCN projects mainly via an indirect

VLPO and hypocretin neurons, through which the SCNthe wakesleep-regulatory system (Chou et al., 2003;et al., 1996) (Fig. 3a). It inhibits the VLPO and activates

promoting wakefulness. One of the major regulatorsich the SCN inuences the circadian rhythm, is the hor-tonin. An important body of data supports a role forn AD pathophysiology, which is described later in this

ole of melatoninin, N-acetyl-5-methoxytryptamine, is one of the mosttiming signals generated by the SCN. It is synthe-serotonin, which is converted into N-acetylserotonininto melatonin by the enzyme hydroxyl-indole-O-sferase. This synthesis occurs mainly in the pineal gland

dark phase of the circadian cycle. Once formed, itboth into capillaries (Cardinali and Golombek, 1998;

Bruce, 2004) and via the third ventricle into the CSFl., 2010; Tricoire et al., 2003). The SCN connects to thed via an indirect inhibitory pathway. During the lightn the SCN is active, melatonin production is inhibited.dark phase, SCN activity is inhibited allowing the pinealoduce melatonin (Gerdin et al., 2004). As melatonin is

Fig. 3. Thypothapublishemedian,immunopatientsin their (median

inuencadianbeforeOn a cpinealvariouwhich2011).

Mewhichimmunfunctiofor its motinghave bhumanticularcircadipromosleep, in humistratiowavescircadiof the and eatonin atime dPeruma compthe cirhand b

3. Imp

3.1. Im

Sevincludthalamthe up(Braakbe invorillary al number of hypocretin-1 immunoreactive neurons in postmortemof AD patients (N = 10) and matched controls (N = 10). Originally

reprinted from Fronczek et al. (2011). The box plot shows the75th percentiles, and the range of total number hypocretin-1ve neurons in controls and AD patients. Alzheimers disease (AD)

signicant lower number of hypocretin-1 immunoreactive neuronshalamus (median = 12,935 (997219,050)) compared with controls02 (16,43925,765); P = 0.049).

by the light and dark cycle, its production follows a cir-hm, with the onset of nighttime melatonin secretion 2 hdividuals habitual bedtime (Tzischinsky et al., 1993).

ar level this circadian rhythmicity of the SCN and thed is regulated by a the complex interaction betweenscription factors, commonly described as CLOCK genes,esent an internal timekeeping system (Thome et al.,

in has a wide variety of physiological functions amonglation of body temperature, sexual maturation, mood,nction, antioxidant mechanisms, and cardiovascularandi-Perumal et al., 2005). However, it is mostly knownon to circadian rhythms and sleep. The exact sleep pro-cts of melatonin are unknown, but several interactionsiscovered, due to their relation to the two subtypes of

latonin binding receptors (MT1 and MT2). MT1 is par-pressed in the SCN and involved in the inhibition of aakefulness-generating mechanism in the SCN therebysleep (Benarroch, 2008). Next to this direct effect ontonin also advances the endogenous circadian rhythm

by acting on the MT2 receptors in the SCN. Oral admin-uces sleepiness and on EEG it increases theta and delta

spindle bursts (Satomura et al., 2001). However, thehifting effect of melatonin is dependent on the phasedian cycle. Melatonin administered during the eveningight phase-advances the circadian clock, while mela-

D. Slats et al. / Ageing Research Reviews 12 (2013) 188 200 191

and, to a lesser extent, in the adjoining reticular nucleus (Braakand Braak, 1991a). The impairments in the locus coeruleus, thetegmentopontine reticular nuclei, and regions of superior and dor-sal brainstem may lead to failing motor inhibition during REM,causing RBDcoeruleus eet al., 1982in clinical d

3.1.1. HypoA recent

and controlof hypocret(Fig. 3). Alspost-mortenot been rehypocretin-(Baumann eSlats et al., ancy in cenCSF has be2008). Hypo2006). In pdian rhythmis completeOur group aan indwellihypocretin-was found itrol group. lower hypocircadian rhogy and hyhypocretin-related withfar studies ber, but totHypocretinyet.

3.2. Impair

Impairmmelatonin documente

3.2.1. SCN iExtensiv

orating witdecrease inmortem samyoung and density of neuron typet al., 2000decreased S3 times lownal rhythmgene expresof AD, althocells is not (ilar changegenerated ttau) knownvasoactive iwithin the

onset of A neuropathology (Sterniczuk et al., 2010). The numberof MT1-expressing neurons in the SCN decreases with aging and inlate stage AD, but not yet in early AD (Wu et al., 2006). AD relatedneuropathological changes have also been found in the SCN; pre-

(Sw et al

Nes

Mela pine990)pinel AD l corasedtionisap

geneglandt theN is tion e theealoearlies alrdecrereduSouenicaOhasortemf the4/4 a

et ated wels aWu aet alears 990;

in Aretioa etes afnin ll rhy

usahys

far, mentinglevera

meogy.

ypocr

ecenng o009)an Cthat ed be (Braak and Braak, 1991b; Parvizi et al., 2001). The locusven loses about 70% of its neurons in AD (Bondareff). These studies demonstrate impairments in the AASementia stages of AD.

cretin impairments study on post-mortem hypothalami of AD patientss demonstrated a signicant decrease in the numberin-1 immunoreactive neurons (Fronczek et al., 2011)o, lower hypocretin-1 concentrations were found inm ventricular CSF of AD patients. These ndings haveplicated in lumbar CSF from living AD patients, where1 levels were in the normal range in several studiest al., 2006; Friedman et al., 2007; Ripley et al., 2001;2011; Thannickal et al., 2007). A comparable discrep-tral hypocretin levels and measurements in lumbaren described in Parkinsons disease (Fronczek et al.,cretin is distributed in a circadian fashion (Grady et al.,atients with depression the amplitude of this circa-

decreases, while in Parkinsons disease this rhythmly absent (Poceta et al., 2009; Salomon et al., 2003).ssessed diurnal hypocretin levels of AD patients usingng spinal catheter (Slats et al., unpublished results). A1 circadian rhythm of with an amplitude of 11.5 pg/mln clinical AD patients, which did not differ from the con-However, lower mean CSF A42 levels were related tocretin-1 levels and a higher amplitude of the hypocretinythm, suggesting a relationship between AD pathol-pocretin disturbance. Another study describes that1 levels in CSF of 15 AD patients are signicantly cor-

wake fragmentation (Friedman et al., 2007). Thus, sohave found that hypocretin neurons decrease in num-al CSF hypocretin levels and diurnal rhythm do not.

disturbances in early AD have not been investigated

ed circadian rhythm regulators

ents of circadian rhythm regulation, SCN function andregulation in the pineal gland, have been extensivelyd in AD.

mpairmentse SCN pathology and impairment is seen in AD, deteri-h progression of the disease. Atrophy of the SCN with

volume and total cell count was demonstrated in post-ples of patients with dementia (n = 4) versus healthy

elderly controls (Swaab et al., 1985). The number andvasopressin and neurotensin neurons, two importantes in the SCN, is dramatically decreased in AD (Liu; Stopa et al., 1999; Zhou et al., 1995), indicating aCN activity (Stopa et al., 1995). Vasopressin levels areer in AD than in age matched controls and its diur-

disappears (Liu et al., 2000). Vasopressin mRNA andsion levels are already decreased in a preclinical stageugh the total cell number of vasopressin-expressingLiu et al., 2000; Wu et al., 2006). In animal models sim-s are seen. A triple transgenic mice model (3xTg line),o express three major gene mutations (APP, PS-1, and

to cause human AD, exhibited signicant decreases inntestinal polypeptide and vasopressin containing cellsSCN, prior to the onset of tau pathology, but after he

tangles(Stopavan de

3.2.2. The

et al., 1of the clinicamutuaa decreconnecplete dCLOCKpineal ing thathe SCregulabecausthe pinin the tonin ilevels found 1990; are sig2000; postmlevels oapoE-AD (Liucorrelanal lev2003; (Zhou disappet al., 1rhythmits secMishimbecommelatodiurna

4. A capathop

So impairInteresship: srelatedpathol

4.1. H

A rsignaliet al., 2in hum9 p.m. occurraab et al., 1992; van de Nes et al., 1998, 1994), tangles., 1999), and diffuse amyloid plaques (Stopa et al., 1995;et al., 1998).

tonin impairmentsal gland itself is not affected by AD pathology (Friedland. However, the expression of CLOCK genes, under controlal gland, does become impaired. In clinical and pre-the diurnal expression of these CLOCK genes and theirrelations are lost (Wu et al., 2006). This may be due to

output of the SCN: in rats, disruption of the functional between the SCN and the pineal gland led to a com-pearance of the day-night expression patterns of theses (Wu et al., 2006). These changes in the denervated rat

mirror the changes in the CLOCK genes in AD, suggest- synchronization of the pineal gland via output fromlost in both clinical and preclinical AD. Noradrenergicof the pineal gland by the SCN may also be disrupted,

rhythmic expression of the noradrenergic receptors incytes is lost (Wu et al., 2003). Another study found thatst preclinical AD stages the melatonin precursor sero-eady depleted (Cardinali et al., 2010). Total melatoninase during aging but patients with AD show more pro-ctions (Mishima et al., 1999; Reiter, 1992; Skene et al.,tre et al., 1989). Levels of lumbar CSF melatonin in ADntly lower than in age matched controls (Ferrari et al.,hi et al., 1999; Uchida et al., 1996), which is also seen in

CSF melatonin levels (Wu and Swaab, 2005). Lowest hormone occur in patients who are homozygous for thellele, the largest known genetic risk factor for late-onsetl., 1999). Although CSF melatonin levels are negativelyith disease state (Zhou et al., 2003), total and noctur-re already decreased in preclinical stages (Wu et al.,nd Swaab, 2007). The same is seen in the pineal gland., 2003). Strikingly, the circadian rhythm of melatoninwith progression of the disease (Liu et al., 1999; Skene

Wu et al., 2003). With the disturbance of the circadianD patients melatonin levels are not only reduced but

n also becomes highly irregular (Cardinali et al., 2002; al., 1999). Altogether this means that the pineal glandfected, probably through an impaired SCN control, withevels becoming decreased early in the disease, while itsthm disappears at a later stage.

l role for sleep mechanisms in ADiology?

we have described pathophysiological evidence ofts in sleep regulating systems, caused by AD pathology.y, there are also indications for a reciprocal relation-l studies have shown an inuence of sleep and circadianchanisms on A dynamics, impairments and even AD

etin and AD pathophysiology

t study provided evidence of effects of hypocretinn A metabolism in human and animal studies (Kang. First of all, this study demonstrated a circadian rhythmSF A levels with mean peak levels between 7 p.m. andwere 28% higher than the mean trough levels, whichtween 9 a.m. and 11 a.m. A similar rhythm was found in

192 D. Slats et al. / Ageing Research Reviews 12 (2013) 188 200

mice, with increased A levels in brain interstitial uid (ISF) whileawake, compared to the sleep, both in wild type C57BL6 mice andhuman APP transgenic mice, Tg2576 (Kang et al., 2009). Hypocretinrelease from hypothalamic hypocretin neurons showed a diurnaluctuation

Furthermlight periodcompared t2009). Folloand showedimply that associated w

MoreoveAlmorexantpressed anLikewise, unicantly idemonstratmented in deposition more remarfor 8 weekdeprived, Aimplies tharegulation amotes subs

4.2. Melato

4.2.1. EffectSeveral

demonstratsecretion ofby interferigins, levelsconditionedinhibited sAeffect reverand Lahiri, 1reduction owell (Lahirition of -shmelatonin tron microsthis way, inand amyloid1998). MorapoE resultformation taining A conformatibrain.

Finally, mto reduced mice melatof cortical tonin admiof AD amyexpected agin increaseddid not lasdeposition same was schronic meMelatonin tmation afte

mmunoreactive A deposition in brains of AD transgenic mice with and long-term melatonin administration. Originally published and reprintedcese et al. (2009). To determine the potential for long-term melatonin toAD transgenic mice against development of A neuropathology, melatonininistered in the drinking water of APP and PS1 double transgenic (Tg) mice

to 2.5 months of age to their killing at age 7.5 months. Immunoreactivesition was reduced in both hippocampus and entorhinal cortex. (A) Pho-graphics show the clear reductions of A immunostained plaques in bothgions for animals given melatonin compared to Tg controls. (B) Quantica- burden (percent of total area immunostained for A deposition) for Tgand Tg/Mel mice. All group data (N = 910) are presented as mean S.E.M.001 versus Tg group.

conrmed that early administration of melatonin could becial: APP + PS1 double transgenic mice treated with mela-ere protected from cognitive impairment and A depositionnicantly reduced (Fig. 4). However, soluble and oligomericof A40 and A42 in the hippocampus and cortex remainedged (Olcese et al., 2009).t to these anti-amyloidgenic effects in the early phasesosition, melatonin also efciently attenuates tau hyper-orylation, both in vitro and in vivo. Preincubation oflastoma cells with melatonin attenuated tau hyper-orylation due to administration of wortmannin (Deng et al.,

Calyculin A incubation is also known to cause tau hyper-orylation in neuroblastoma cells. Co-incubation with both

lin A and melatonin attenuated tau hyper-phosphorylationl (Li et al., 2005). In a rat study haloperidol injection into the

ventricle and peritoneal cavity compromised spatial mem-ention and induced tau hyper-phosphorylation. Melatoninmentation prior to and during the haloperidol administra-nicantly improved memory retention decits and arrestedper-phosphorylation (Zhu et al., 2004).similar to that of ISF A in rats (Yoshida et al., 2001).ore, when sleep deprivation was applied during the

in Tg2576 mice, ISF A levels were signicantly highero a light period with unrestricted sleep (Kang et al.,wing sleep deprivation mice spent more time sleeping

an immediate reduction in ISF A levels. This wouldthe state of wakefulness, and not the time of day isith increased ISF A.r, when a dual hypocretin receptor antagonist,, was infused in the ventricles, ISF A levels were sup-d the natural diurnal variation of A was abolished.pon infusion of hypocretin, ISF A levels were sig-ncreased. Finally, an effect on plaque formation wased (Fig. 5). When chronic sleep restriction was imple-APP transgenic mice, signicantly greater A plaquein multiple sub-regions of the cortex was seen. Evenkable, systemic treatment with Almorexant once dailys decreased the A plaque formation in aged, sleep-PP transgenic mice (Kang et al., 2009). Altogether, thist the diurnal rhythm seen in A is caused by sleep/wakend that sleep deprivation increases A levels and pro-equent deposition in transgenic mice.

nin and AD pathophysiology

s of melatonin on A physiologyanti-amyloidogenic effects of melatonin have beened in vitro and in animal studies. Melatonin reduces the

soluble derivatives of beta APP, cleaved by -secretase,ng with APP maturation. In cell lines of different ori-

of sAPP were analyzed by Western immunoblot of media. Treatment of these cell lines with melatoninPP secretion in conditioned media, and this inhibitorysed after melatonin was removed (Lahiri, 1999; Song997). In wild-type mice treated with melatonin a smallf APP levels in cerebral cortical extracts was seen as

et al., 2004). In addition, melatonin inhibits the forma-eets and amyloid brils in vitro. Interactions betweenand both A40 and A42 were demonstrated by elec-copy and nuclear magnetic resonance spectroscopy. Inhibition of the progressive formation of A beta-sheets

brils by melatonin was demonstrated (Pappolla et al.,eover, addition of melatonin to A in the presence ofed in a even more potent inhibition of amyloid bril(Poeggeler et al., 2001). It is thought that by main-in a more protease sensitive, i.e. non-amyloidogenicon, melatonin may facilitate removal of A from the

elatonin supplementation in mouse models can leadcerebral A concentrations. In a study with wild-typeonin treatment led to a signicant reduction in levelsA40 and A42 (Lahiri et al., 2004). Moreover, mela-nistration in Tg2576 mice (a transgenic mouse modelloidosis) at 4 months of age partially inhibited thee-dependent increase in A concentration and resulted

survival (Matsubara et al., 2003). However, this effectt throughout the lifespan of the mice, since amyloidat the age of 15.5 months was not alleviated. Theeen in old, plaque bearing Tg2576 mice that receivedlatonin treatment, starting treatment at 14 months.reatment failed to exert any effect on A or plaque for-r 4 months of treatment (Quinn et al., 2005). Another

Fig. 4. Iwithoutfrom Olprotect was admfrom 2 A depotomicrobrain retion of Acontrol *P < 0.00

study benetonin wwas sigforms unchan

Nexof depphosphneurobphosph2005).phosphcalycuas wellateralory retsuppletion sigtau hy

D. Slats et al. / Ageing Research Reviews 12 (2013) 188 200 193

Fig. 5. A plaqdeprivation. Oinvestigated wdeposition in were subjecteunderwent chsition in multi(**P < 0.0008, *for multiple t-of A plaquescontrol and (Eentorhinal corpiriform cortehippocampus)

Thus, allhas the abiprevent Abut fails to eafter the on

4.2.2. ProteNext to

has also derelated damroprotectivReiter et al.has an effe

in vivo (Pappolla et al., 2000; Reiter et al., 2000, 2002). PC 12 cells,pheochromocytoma cells of a rat adrenal medulla that functionas a model for neuronal differentiation, exhibited marked oxida-tive damage to mitochondrial DNA when they were exposed to A,

sim indths os, adted rona

studatonf cutrace(Pappologed Abut thethis A4 monplaquesis relaof neuin vitroto meldeath oand inof A morphabolishue deposition in brains of APP transgenic mice with and without sleepriginally published and reprinted from Kang et al. (2009). Kang et al.hether chronic sleep deprivation could ultimately affect A plaquethe brain. APP transgenic mice of the APPswe/PS1dE9 genothyped to chronic sleep restriction for 20 h daily for 21 days. (A) Mice thatronic sleep restriction showed signicantly greater A plaque depo-ple subregions of the cortex compared to age-matched control miceP < 0.008, N = 911 per group, using Bonferroni-adjusted P < 0.0083tests. For hippocampus, P < 0.009). Representative photomicrographs

are shown in (B) control and (C) sleep restricted olfactory bulb (D)) sleep restricted piriform cortex, (F) control and (G) sleep restrictedtex. Scale bar = 200 m. OB: olfactory bulb, Cing: cingulate cortex, Piri:x, Ent: entorhinal cortex, Ctx: cortex (immediately dorsal to dorsal, and HC: hippocampus.

these ndings indicate that melatonin fundamentallylity to regulate APP metabolism, reduce A levels and

aggregation, and inuence tau hyper-phosphorylation,xert anti-amyloid or antioxidant effects when providedset of A deposition.

ctive effect of melatonin on AD-associated damageits effect on amyloid and tau pathology, melatoninmonstrated a protective role against AD pathologyage. Many studies have investigated the general neu-e and antioxidant roles of melatonin (Hardeland, 2005;, 2004; Srinivasan et al., 2005). Importantly, melatoninct on A mediated oxidative injury, both in vitro and

of PC12 cemicroglial ctures of apoprior to exsuch apopto

4.3. Melato

There istion betweindication fsible interaof interest,hypocretin effect of hyMikkelsen pineal glandays while 2007). Hypexpression in the melasecretion met al., 2009demonstrattin neurons

5. Sleep di

5.1. Alzheim

Clinicallloss, initialepisodes, afering with to death of LaFerla, 201

Neuropaneurons anwith secondtwo identifgles. Plaque(Selkoe, 20ically cleavproteases; ular, is the mintra-neuroof hyper-phmay cause ultaneous addition of melatonin consistently preventeduced oxidative damage (Bozner et al., 1997). Also, inld transgenic mice mimicking accumulation of senileministration of melatonin led to a reduction of apopto-factors; Bax, caspase-3 and Par-4, indicating inhibitionl apoptosis (Feng et al., 2006). Furthermore, severalies demonstrated attenuated A-induced apoptosis duein. Melatonin was remarkably effective in preventingltured neuroblastoma cells as well as oxidative damagellular Ca2+ increases induced by a cytotoxic fragmentolla et al., 1997). Melatonin also prevented apoptotic

ical changes, inhibited apoptotic DNA degradation, and2535-induced apoptosis of rat hippocampal cells andlls (Shen et al., 2002; Feng and Zhang, 2004). Mouseells treated with A exhibited several characteristic fea-ptosis as well, while cells pre-treated with melatonin

posure to A showed a decrease in the occurrence oftic features (Jang et al., 2005).

nin and hypocretin interactions

a relatively large body of evidence showing a rela-en melatonin and AD pathophysiology, and a recentor a role of hypocretin signaling. In this context, pos-ctions between melatonin and hypocretin would be

but data on this are still scarce. In rats and pigs,neurons innervate the pineal gland, suggesting a directpocretin on melatonin synthesis (Fabris et al., 2004;et al., 2001). A seasonal effect of hypocretin on thed was seen in ewes, activating melatonin on the longinhibiting its synthesis during short days (Zieba et al.,ocretin/ mutant zebrash exhibit reduced mRNAof arylalkylamine-N-acetyltransferase, a key enzymetonin production pathway, suggesting that melatoninay be stimulated by hypocretin signaling (Appelbaum; Zhdanova, 2011). The same research group thereaftered a circadian rhythm in synaptic plasticity of hypocre-

on the pineal gland (Appelbaum et al., 2010).

sorders in Alzheimers disease

ers disease

y, AD is primarily manifested by progressive memoryly particularly memory for recent rather than remotend a gradual decline in global cognitive function inter-the functions of daily living. Eventually the disease leadsthe individual 39 years after diagnosis (Querfurth and0).thologically, AD is characterized by a dramatic loss ofd synapses, especially in the hippocampus and cortex,ary enlargement of the ventricles. Microscopically, the

ying features of AD are plaques and neurobrillary tan-s are microscopic foci of extracellular A deposition01). A is a peptide with several isoforms, enzymat-ed from the amyloid precursor protein (APP) by two-secretase and -secretase. The isoform A42, in partic-ajor component of plaques. Neurobrillary tangles are

nal accumulations composed of paired helical lamentsosphorylated tau protein. The intracellular depositiondisruption of normal cytoskeletal architecture, with

194 D. Slats et al. / Ageing Research Reviews 12 (2013) 188 200

subsequent neuronal cell death (Chun and Johnson, 2007; Goedertet al., 1991). Although it remains unknown what triggers the neu-ropathology in the majority of patients, this review follows thewidely held assumption that A42 constitutes the core pathol-ogy of AD, This hypothclearance lsubsequentneuronal de

5.2. Sleep a

Symptomcadian rhytmore prevarevealed th(Song et al.,ing of AD andisabilities AD patients2005; Morathe primaryPollak and Pvival (Gehrm

In the cturbance ofdifferent psleep regulain the circaalso be descing, but the

5.2.1. PrimaAD pati

turbances, excessive das difcultiimpairmentime betwetotal sleep tGrossberg, frequent aw(Prinz et alquent, as re

AD patieincreased net al., 2005the more frduring the These sympbut could a(see followpolysomnomovement (Bonanni etsubjects, ADREM sleep aet al., 1995been shownconicting ical muscle

5.2.2. CircaCircadia

delay of nocsleep/wake

dementia patients, developing or increasing in the late afternoonor early evening. 1025% of AD patients experience behavioraldisorders such as nocturnal confusion, agitation, or wandering(Ancoli-Israel et al., 1994; Gehrman et al., 2003; Lebert et al., 1996),

ch rec tim

rhyt to b

(Vo circed inythmactivHarp

et s ar

empedoge

iagno

003 slee2003ated d/or ed

servaing; ioor an rhwith

notcriterancenctiote a

Differe w

an d by ary sisordt wiuence, anspitan cauants se insingces iy, coing dal aess ihowepsy

erapance

atmeing

can as it is proposed in the amyloid cascade hypothesis.esis states that an imbalance in A production and

eads to an increase in A load (especially A42) and deposition, which in turn initiates tau pathology andgeneration which ultimately causes dementia.

nd circadian rhythm disturbances in AD

s of impaired sleep and progressive disruption of cir-hms can be seen in normal aging, these are strikinglylent and exaggerated in AD. Cross-sectional studies havee prevalence of sleep problems in AD to be as high as 40%

2010). These symptoms, which increase with worsen-d contribute to cognitive deterioration and functionalof AD patients, negatively affect the quality of life in

and caregivers to a considerable extent (Bonanni et al.,n et al., 2005). Furthermore, these symptoms are often

cause for institutionalization (Bianchetti et al., 1995;erlick, 1991) and even associated with decreased sur-an et al., 2004).

linical approach towards an AD patient with a dis- the sleep pattern, it is important to distinguish twoossible underlying mechanisms; impairments of theting systems causing disturbed sleep, and impairmentsdian rhythm of sleep. In clinical practice the latter mayribed by patient and care giver as problems with sleep-

underlying mechanisms are different.

ry sleep disturbancesents can experience a variety of primary sleep dis-not only nighttime disorders such as insomnia, butaytime sleepiness as well. Insomnia can be denedes initiating and/or maintaining sleep, associated withts in daytime functioning. In AD, sleep latency (theen going to bed and falling asleep) increases, whileime decreases (Vitiello et al., 1990; Weldemichael and2010). Patients also experience fragmented sleep withakenings and longer wake periods during the night

., 1982). Early morning awakenings are also more fre-ported by caregivers (McCurry et al., 1999).nts often suffer from excessive daytime sleepiness, withapping but also unintentional sleep episodes (Bonanni; Lee et al., 2007). The more the disease progresses,agmented sleep becomes, and the more naps are takenday (Ancoli-Israel et al., 1994; Vitiello et al., 1992).toms could be due to poor sleep efciency at nightlso be caused by deterioration of the circadian rhythming paragraph). The most distinct change seen withgraphic recordings in AD is a decrease of rapid eye(REM) sleep, which is typically not seen in normal aging

al., 2005; Reynolds et al., 1985). Compared to control patients display shorter periods of REM sleep, less totalnd slowing of EEG index during REM sleep (Montplaisir). Latency to the rst episode of REM sleep has also

to be increased in AD, but studies on this nding are(Bliwise et al., 1989). In some instances, the physiolog-

atonia of REM sleep disappears (Gagnon et al., 2006).

dian rhythm disruptionsn rhythm disruptions in AD patients can lead to phaseturnal sleep, sundowning and eventually to a reversed

pattern. Sundowning is a behavioral disturbance in

of whispecicadianthoughrhythm

Theobservdian rhmotor 1997; Volicerrhythmbody tthe en

5.3. D

In 2tion ofet al., AD relnia anconrmlog obfollowtime, pcircadiciated shouldthese disturba distifacilita

5.3.1. As w

circadicausedsecondatric dco-exisnal inhygienand hoday, castimulAll thediagnoturbanprimarbreathin normsleepindings snarcol

5.4. Thdisturb

Treimprovbancesstlessness is the most common (Little et al., 1995). Theing of sundowning reects the deterioration of the cir-thm (Martin et al., 2000; Okawa et al., 1991) and ise related to a phase delay in the core body temperaturelicer et al., 2001).adian rhythm disruptions of the sleep/wake cycle as

AD, are accompanied by disturbances in the circa- of other body mechanisms, such as body temperature,ity, arousal and several hormones (Ancoli-Israel et al.,er et al., 2005; Satlin et al., 1995; Van Someren, 2000;al., 2001). Reductions in the amplitude of circadiane perhaps the most prominent changes, although forrature an increased amplitude together with a delay innous circadian phase is seen (Okawa et al., 1991).

sing primary sleep disturbances in AD

, criteria were proposed to aid the proper identica-p disturbances that are associated with AD (Yesavage). In short, the criteria state that an AD patient hassleep disorders when there is a complaint of insom-excessive daytime sleepiness, which is subsequentlyby polysomnographic, actigraphic, or structured sleeption. The disturbance should entail at least two of thencreased wake after sleep onset, decreased total sleepdaytime wake continuity, and/or desynchronization ofythm. Naturally, the sleep disturbances must be asso-

AD and although other disorders can be present, these account for the primary sleep symptoms. Note thatia do not emphasize a separate appraisal of primarys of sleep versus a disrupted circadian rhythm. Suchn is customary in general sleep medicine, and wouldprecise diagnosis and subsequent treatment.

ential diagnosis of primary sleep disturbances in ADill discuss in detail later in this review, both sleep andisturbances can be a primary disease symptom in AD,degeneration of key regulating brain areas. However,leep disorders may occur as well. For example, psychi-ers, such as depression or anxiety, which are known toth AD, can contribute signicantly to insomnia. Exter-es may also contribute to sleep disturbances. Poor sleepd nightly noises or light input, especially in institutionsls, but also lack of physical and social activity during these nocturnal sleep disruption. So can excessive intake ofsuch as coffee or tea, and the use of certain medications.itiators of sleep disturbances should be ruled out when

typical AD related sleep disorders. Sometimes, sleep dis-n AD are so prominent, they should be classied as amorbid sleep disorder. For example, sleep disorderedisorders may be more prevalent in AD patients thanging (Bliwise, 2002). In some cases, excessive daytimes very severe, and additional polysomnographic recor-

alterations otherwise seen in the primary hypersomnia(Scammell et al., 2011; Wurtman, 2006).

eutic options for sleep and circadian rhythms in AD

nt can be directed either at promoting sleep or atthe circadian rhythm of sleep and waking. Sleep distur-be treated with nonpharmacological interventions, such

D. Slats et al. / Ageing Research Reviews 12 (2013) 188 200 195

as environmental changes, increased activity and exercise, and withpharmacological interventions. Interventions improving circadianrhythm include bright light therapy and melatonin suppletion.Despite these treatment options, there is currently no treatmentconsensus f

5.4.1. TreatNonphar

routines, apand disturbor tea, and efcacy of smost are eaon to pharmother possibing physicanocturnal sin the daily

Several sleep distupromote slsants, z-hypBenzodiazenitive functas donepezarousals anstrated in het al., 2003sometimes

Systemaabove has nnow, thereand dosageobserved incation diffeshould alwaa previous (Weldemich

5.4.2. TreatBecause

regulation therapeuticof AD patientrolled trialrhythms as(Ancoli-IsraMcCurry et domized cosleep, but d(Dowling esundowninet al., 2011)light therapcontrolled aet al., 1997of the effecto accomplndings indpreserve plas possibletreatment o

Melatondisorders, din blind peotreating circ

Three double-blind, randomized controlled trials and several openlabel studies and case reports in AD supported a possible effectof melatonin, with improved sleep quality, reduced sundowningand even slowed progression of cognitive impairment (Asayama

003althelaceeciaance-anat sho

blinthe e

patffectmenRiem

cussi

sleenshipan d

On tnd cogy.

pair

patieleep nt asnd aS, theep sting sonnt mamen

withen drotr2007ts to ay

at nid inp atgh sumptouenc. Themenremaate oultic

be s chroelato

thop

m reysteor sleep disturbances in AD.

ment of sleep disturbancesmacological interventions include improving bed timeplying bedtime restrictions, decreasing nightly noisesances, limiting intake of stimulants such as caffeineincreasing exercise, physical and social activities. Theome of these interventions have been proven and, assy to implement, and should be tried before movingacological treatments (McCurry et al., 1999). However,le nonpharmacological interventions, such as increas-l and social activity, shown to have a positive effect onleep, may prove to be more challenging to implement

setting of AD patients (Carvalho-Bos et al., 2007).pharmacological interventions may help to relieverbances in AD patients. Commonly used drugs toeep in case of insomnia include sedating antidepres-notics such as zolpidem, and sedating antipsychotics.pines should be avoided because they may worsen cog-ion in AD. Sometimes cholinesterase inhibitors suchil, rivastigmine and galantamine may reduce nightlyd increase the amount of REM sleep, as was demon-ealthy controls (Holsboer-Trachsler et al., 1993; Stahl). Stimulants like methylphenidate or modanil areprescribed to prevent daytime sleepiness.tic evidence for the efcacy of the drugs mentionedever been collected in this specic patient group. Forfore, the best advice would be adjust the choice for

of medication to the individual patient and to thedividual response to this treatment. The effect of medi-rs between patients, and co-medication and side effectsys be screened for and taken into account. We refer toreview for information on specic dosages to be usedael and Grossberg, 2010).

ment of circadian rhythm disruptions lack of daylight exposure contributes to circadian dys-(Ancoli-Israel et al., 2002; Campbell et al., 1988), the

value of bright light to improve the circadian rhythmts has been extensively investigated. Randomized con-s report improvements of disturbed sleep and activity

positive effects of bright light therapy in AD patientsel et al., 2003; Burns et al., 2009; Lyketsos et al., 1999;al., 2011; Riemersma-van der Lek et al., 2008). Two ran-ntrolled trials did not demonstrate a direct effect onid show an effect on stabilizing rest/activity rhythmst al., 2005a,b). The effects of bright light therapy ong were less profound (Lyketsos et al., 1999; McCurry. Some studies have failed to show any effect of brighty in AD patients, although these were not randomizednd only included small numbers of subjects (Colenda; Ohashi et al., 1999). Therefore, a systematic analysists of bright light therapy would desirable but difcultish due to the heterogeneity of the studies. Still, theseicate that the circadian rhythm regulating systems mayasticity, even in AD. Stimulating this system as early

by bright light therapy may be of great value in thef AD-related circadian rhythm disturbances.in is used regularly in for jet lag, shift work related sleepelayed sleep phase syndrome and circadian disordersple (Arendt et al., 1997). Several studies have also triedadian rhythm disorders in AD patients with melatonin.

et al., 2and Wblind, pno bendisturba metadid nodoublegated non-ADitive eimpair2004;

6. Dis

AD,relatiocircadiof life.sleep apathol

6.1. Imin AD

AD ulate sdifferesleep athe AAREM slregulational ca resulimpairtation,has bethe neuet al., patienonset mlevels ness anof sleeAlthouical syconseqlackingimpairyet it reactivably, mshouldnationand m

6.2. Pain AD

Frolating s; Cardinali et al., 2010; Dowling et al., 2008; Mahlbergr, 2007). However, a multicenter, randomized, double-bo-controlled clinical trial in 31 US AD centers showedl effects of melatonin 2,5 or 10 mg on measures of sleep

in (n = 157) AD patients (Singer et al., 2003). Moreover,lysis on the use of melatonin for cognitive impairmentw any effect of melatonin (Jansen et al., 2006). Severald, randomized placebo-controlled trials have investi-ffect of melatonin treatment on cognitively impairedients. All these studies individually demonstrated pos-s of melatonin on both sleep quality and cognitivet (Cardinali et al., 2010; Garzon et al., 2009; Peck et al.,ersma-van der Lek et al., 2008; Wade et al., 2007).

on

p and circadian rhythm physiology display an intricate. On the one hand, AD pathology leads to sleep andisturbances, with a clear negative inuence on qualityhe other hand, there is increasing evidence that bothircadian regulating systems exert an inuence on AD

ed sleep and circadian rhythm regulating systems

nts have extensive impairments in the systems that reg-and circadian rhythms, in multiple domains and withpects at difference stages of the disease. Examples ofrousal regulating systems that are impaired in AD aree VLPO and hypocretin neurons, and nuclei involved inuch as the nucleus basalis of Meynert. Circadian rhythmystems that are impaired in AD are the SCN, its func-ection to the pineal gland, and melatonin production. Asny of the clinical sleep symptoms can be traced back tots of these sleep regulating mechanisms. Sleep fragmen-

increased number and duration of nightly awakeningsemonstrated to be related to hypocretin impairment,ansmitter involved in sleep/wake transitions (Friedman). An imbalance of the sleep/wake switch may causeawake more easily during the night. A delay in sleepbe due to the lower melatonin and perhaps hypocretinght, which normally cause sleepiness. Daytime sleepi-creased napping may also be compensatory to the lack

night, or a sign of a circadian rhythm disturbance.ggestions of links between pathophysiology and clin-ms are made here, studies investigating the clinicales of impairments in these sleep regulating systems are

clinical symptoms that are caused by circadian rhythmts may be treatable with chronobiological interventions,ins unclear whether these treatments can effectivelyr substitute the involved sleep mechanisms. Prefer-entre randomized controlled, placebo-controlled trialset up to investigate the effects of both single and combi-nobiological treatments, including bright light therapy,nin suppletion.

hysiological mechanism causing sleep phenotype

search thus far, the earliest impairments in sleep regu-ms of AD patients are demonstrated in circadian rhythm

196 D. Slats et al. / Ageing Research Reviews 12 (2013) 188 200

regulating systems, namely the SCN function and impairment of itslink to the pineal gland, and total and nocturnal levels of mela-tonin. Meanwhile, for sleep regulating systems, such as hypocretinneurons, early impairments are less evident.

Some stulating sys(Skene and of input toDecreased isure (Camp(Campbell as well as drence of ca(Blanks et the SCN duon the SCNthe SCN, diHowever, dto enhance the link wit

Disturbepathology, and even min melatonimpairmenDepletion oinvolved (Cthat melatoand especiahere (Pauleand benzodet al., 1988;et al., 1989;

6.3. A causa

Excitinghave an effshown to reing A leveand inuenmediated osis. In seversleep deprivtransgenic m

Whereassiology, hypA pathophregulatory increase or els and thusthis would already prepathology, hypocretin sleep deprivin obstructisleep relatelence in ADand not slecognitive deies imply thin brain arevated abund(Bero et al.,

neuronal activity, such as in insomnia or sleep deprivation, mayaccelerate progression of A depositions.

nclu

gethnd chich

ts. Intreate thtion se (BPollaningheig

to liide tdiesulatinismnd cset opme

wled

s wo

nces

tidis, tratesre 45srael, , L., 20

rhyth36.srael, Son-inssrael, nczyklight 3.

srael, treatents. Jum, Lnot, Eticity um, Lawake reguhe Na221J., Sketonin

thms 1a, K., d studitive ol 70,C., Geimern, C.Rormach, E.Es and W., Yzmanloid-btti, A.,995.

ents 1112.udies state that the earliest impairments in sleep reg-tems of AD patients are demonstrated in the SCNSwaab, 2003). It has been hypothesized that a decrease

the SCN may underlie this (Wu and Swaab, 2007).nput could originate from reduced daytime light expo-bell et al., 1988), less outdoor and physical activityet al., 1988; Kondo et al., 1994; Van Someren, 2000),ecreased light registration caused by increased occur-taract, macula degeneration, and optic nerve atrophyal., 1996a,b; Katz and Rimmer, 1989). Dysfunction ofe to lack of light input will have an inactivating effect, its CLOCK genes, and nuclei normally inuenced byminishing circadian input to the sleep/wake circuitry.ecreased light input and less SCN activity are thoughtmelatonin production (Cardinali et al., 2010); thereforeh decreased melatonin here is unclear.d melatonin levels could be an alternative onset of sleepas melatonin levels are known to decrease with agingore with AD, even in preclinical stages. An imbalancein levels may subsequently trigger the onset of SCNt, although the cause of such an imbalance is unknown.f serotonin, from which melatonin is formed, could beardinali et al., 2010). Furthermore, studies have shownnin production is easily inhibited, for example by light,lly increased light exposure at night may be importanty, 2004). Several drugs, such as NSAIDs, beta blockers,iazepines may inhibit melatonin production (Brismar

Cardinali et al., 1982; McIntyre et al., 1988; Monteleone Murphy et al., 1994; Surrall et al., 1987).

l role for sleep in AD pathophysiology

new data demonstrate that sleep-regulating systemsect on A or even AD pathology. Melatonin has beengulate APP metabolism, prevent A pathology by reduc-ls and the formation of -sheets and amyloid brils,ce tau hyper-phosphorylation, while also decreasing Axidative damage and attenuating A mediated apopto-al studies it was demonstrated that both hypocretin andation increased A levels and subsequent deposition inice.

melatonin has a protective effect on A pathophy-ocretin signalling may have an aggravating effect onysiology. Together with the fact that hypocretin has arole in melatonin synthesis, this may suggest that andisturbance in hypocretin levels affects melatonin lev-

its protective effect on A pathophysiology. However,imply that impairments in hypocretin regulation aresent in before circadian rhythm disturbances and ADand evidence of this is thus far lacking. The effect ofchanges on AD pathology may also lie in the resultingation, similar to sleep fragmentation and AD pathologyve sleep apnea syndrome. However, a recent study ond breathing disorders, which have an increased preva-, provides evidence that hypoxia due to sleep apneas,ep deprivation in itself, may be the leading factor forcline in later life (Yaffe et al., 2011). Other recent stud-at sustained neuronal activity and elevated glycolysisas such as the default-mode network are linked to ele-ance of A and augmented formation of senile plaques

2011). These results suggest that prolonged periods of

6.4. Co

Altosleep alogy, wpatienquate becausdisrupimmen2005; postpodemic option

Besmal stuin modmechasleep athe ondevelo

Ackno

Thi

Refere

AdamansubsNatu

Ancoli-ILevidian1, 22

Ancoli-Iin n

Ancoli-IHoreand 182

Ancoli-Ilightpati

AppelbaMigplas

AppelbaT., Kwakof t2194

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Benarrotion

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er there is substantial evidence of impairments in bothircadian regulating mechanisms in AD pathophysio-

may be linked directly to clinical symptoms in ADcreasing knowledge on appropriate diagnosis and ade-ment of these sleep problems is of great importance,e impact of sleep disturbances and circadian rhythmon the quality of life of AD patients and care givers isianchetti et al., 1995; Bonanni et al., 2005; Moran et al.,k and Perlick, 1991). Moreover, as treatments curing or

AD remain elusive and its prevalence increases to epi-hts, prolonging patient independence may be a majormit costs of clinical care.his, there is signicant evidence from in vitro and ani-

for an important role of both melatonin and hypocretinng AD pathophysiology. Although the exact underlyings are unknown as of yet, examining the role of lack ofircadian rhythm deterioration as causative factors inf AD, especially in human studies, is promising for thent of new treatment opportunities.

gements

rk was funded by a grant from Alzheimer Nederland.

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