Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM sleep parasomnia characterized by the loss of the typical muscular atonia present during healthy REM sleep. RBD can occur in the absence of other neurological conditions or in association with a neurodegenerative disorder. It is now well established that RBD is a strong predictor of neurodegeneration, in particular synucleinopathies, such as Parkinson’s disease, Lewy body dementia (LBD), or multiple system atrophy. However, some longitudinal studies report that a minority of patients develop either overlapping form of dementia or Alzheimer disease’s (AD). Although AD is reported as a possible development in patients with RBD, it is in a limited number of cases and there are concerns about the accuracy of the diagnostic criteria. Neuropsychological impairments identified in cross-sectional studies of RBD patients describe a profile similar to that observed in dementia related to synucleinopathies. However, only deficits in executive function predict the development of neurodegeneration. Longitudinal studies reported the development of AD in RBD patients in about 7% of cases with variability ranging from 3% and 11%. Since the majority of longitudinal investigations do not report AD as a possible development for RBD patients the proportion may be overestimated. The study of the relationship between RBD and AD may be confounded by two factors that lead to misdiagnosis: the use of clinical criteria alone and the overlap between the clinical features and neuropathology of AD and LBD. Future studies to investigate this association must use updated diagnostic criteria incorporating ancillary investigations.
MahowaldMW, SchenckCH (2011) REM sleep parasomnias. In Principles and practice of sleep medicine, KrygerMH,
RothT,
DementC, 5th ed., Elsevier-Saunders, Philadelphia, pp. 1083–1097.
2.
BoeveBF (2010) REM sleep behor disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions. Ann N Y Acad Sci1184, 15–54.
3.
Haba-RubioJ, FrauscherB, Marques-VidalP, TorielJ, TobbackN, AndriesD, PreisigM, VollenweiderP, PostumaR, HeinzerR (2017) Prevalence and determinants of REM sleep behavior disorder in the general population. Sleep. doi: 10.1093/sleep/zsx197
4.
KangSH, YoonIY, LeeSD, HanJW, KimTH, KimKW (2013) REM sleep behavior disorder in the Korean elderly population: Prevalence and clinical characteristics. Sleep36, 1147–1152.
5.
GalbiatiA, RinaldiF, GioraE, Ferini-StrambiL, MarelliS (2015) Behavioural and cognitive-behoural treatments of parasomnias. Behav Neurol2015, 786928.
6.
McCarterSJ, BoswellCL, St LouisEK, DueffertLG, SlocumbN, BoeveBF, SilberMH, OlsonEJ, Tippmann-PeikertM (2013) Treatment outcomes in REM sleep behavior disorder. Sleep Med14, 237–242.
7.
Ferini-StrambiL, MarelliS, GalbiatiA, RinaldiF, GioraE (2014) REM Sleep Behavior Disorder (RBD) as a marker of neurodegenerative disorders. Arch Ital Biol152, 129–146.
8.
IranzoA, SantamariaJ, TolosaE (2016) Idiopathic rapid eye movement sleep behaviour disorder: Diagnosis, management, and the need for neuroprotective interventions. Lancet Neurol15, 405–419.
9.
HöglB, StefaniA, VidenovicA (2017) Idiopathic REM sleep behaviour disorder and neurodegeneration—an update. Nat Rev Neurol14, 40–55.
10.
Ferini-StrambiL (2011) Does idiopathic REM sleep behavior disorder (iRBD) really exist? What are the potential markers of neurodegeneration in iRBD?S. Sleep Med12(Suppl 2), 43–49.
11.
SchenckCH, BundlieSR, MahowaldMW (1996) Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology46, 388–393.
12.
SchenckCH, BoeveBF, MahowaldMW (2013) Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: A 16-year update on a previously reported series. Sleep Med14, 744–748.
SasaiT, MatsuuraM, InoueY (2013) Electroencephalographic findings related with mild cognitive impairment in idiopathic rapid eye movement sleep behavior disorder. Sleep36, 1893–1899.
15.
PostumaRB, GagnonJF, VendetteM, DesjardinsC, MontplaisirJY (2011) Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder. Ann Neurol69, 811–818.
16.
YounS, KimT, YoonIY, JeongJ, KimHY, HanJW, KimJM, KimKW (2016) Progression of cognitive impairments in idiopathic REM sleep behaviour disorder. J Neurol Neurosurg Psychiatry87, 890–896.
17.
Génier MarchandD, MontplaisirJ, PostumaRB, RahayelS, GagnonJF (2017) Detecting the cognitive prodrome of dementia with Lewy bodies: A prospective study of REM sleep behavior disorder. Sleep40. doi: 10.1093/sleep/zsw014
18.
IranzoA, SantamaríaJ, ValldeoriolaF, SerradellM, SalameroM, GaigC, Niñerola-BaizánA, Sánchez-ValleR, LladóA, De MarziR, StefaniA, SeppiK, PaviaJ, HöglB, PoeweW, TolosaE, LomeñaF (2017) Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder. Ann Neurol82, 419–428.
19.
PostumaRB, GagnonJF, BertrandJA, Génier MarchandD, MontplaisirJY (2015) Parkinson risk in idiopathic REM sleep behavior disorder Preparing for neuroprotective trials. Neurology84, 1104–1113.
20.
WingYK, LiSX, MokV, LamSP, TsohJ, ChanA, YuMW, LauCY, ZhangJ, HoCK (2012) Prospective outcome of rapid eye movement sleep behaviour disorder: Psychiatric disorders as a potential early marker of Parkinson’s disease. J Neurol Neurosurg Psychiatry83, 470–472.
GagnonJF, BertrandJA, Génier MarchandD (2012) Cognition in rapid eye movement sleep behavior disorder. Front Neurol3, 82.
23.
ManniR, SinforianiE, PacchettiC, ZucchellaC, CremascoliR, TerzaghiM (2013) Cognitive dysfunction and REM sleep behavior disorder: Key findings in the literature and preliminary longitudinal findings. Int J Psychophysiol89, 213–217.
24.
Ferini-StrambiL, Di GioiaMR, CastronovoV, OldaniA, ZucconiM, CappaSF (2004) Neuropsychological assessment in idiopathic REM sleep behavior disorder (RBD): Does the idiopathic form of RBD really exist?Neurology62, 41–45.
25.
Massicotte-MarquezJ, DécaryA, GagnonJF, VendetteM, MathieuA, PostumaRB, CarrierJ, MontplaisirJ (2008) Executive dysfunction and memory impairment in idiopathic REM sleep behavior disorder. Neurology70, 1250–1257.
26.
TerzaghiM, SinforianiE, ZucchellaC, ZambrelliE, PasottiC, RustioniV, ManniR (2008) Cognitive performance in REM sleep behaviour disorder: A possible early marker of neurodegenerative disease?Sleep Med9, 343–351.
27.
GagnonJF, VendetteM, PostumaRB, DesjardinsC, Massicotte-MarquezJ, PanissetM, MontplaisirJ (2009) Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson’s disease. Ann Neurol66, 39–47.
28.
MarquesA, DujardinK, BoucartM, PinsD, DelliauxM, DefebvreL, DerambureP, MonacaC (2010) REM sleep behaviour disorder and visuoperceptive dysfunction: A disorder of the ventral visual stream?J Neurol257, 383–391.
29.
TerzaghiM, ZucchellaC, RustioniV, SinforianiE, ManniR (2013) Cognitive performances and mild cognitive impairment in idiopathic rapid eye movement sleep behavior disorder: Results of a longitudinal follow-up study. Sleep36, 1527–1532.
30.
MolanoJ, BoeveB, FermanT, SmithG, ParisiJ, DicksonD, KnopmanD, Graff-RadfordN, GedaY, LucasJ, KantarciK, ShiungM, JackC, SilberM, PankratzVS, PetersenR (2010) Mild cognitive impairment associated with limbic and neocortical Lewy body disease: A clinicopathological study. Brain133, 540–556.
31.
FantiniML, FariniE, OrtelliP, ZucconiM, ManconiM, CappaS, Ferini-StrambiL (2011) Longitudinal study of cognitive function in idiopathic REM sleep behavior disorder. Sleep34, 619–625.
32.
ChwiszczukL, BreitveMH, BrønnickK, GjerstadMD, HynninenM, AarslandD, RongveA (2017) REM sleep behavior disorder is not associated with a more rapid cognitive decline in mild dementia. Front Neurol8, 375.
33.
American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC.
BraakH, Del TrediciK, RübU, De VosRA, SteurENJ, BraakE (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging24, 197–211.
37.
LuppiPH, ClémentO, GarciaSV, BrischouxF, FortP (2013) New aspects in the pathophysiology of rapid eye movement sleep behavior disorder: The potential role of glutamate, gamma-aminobutyric acid, and glycine. Sleep Med14, 714–718.
38.
Valencia GarciaS, LibourelPA, LazarusM, GrassiD, LuppiPH, FortP (2016) Genetic inactivation of glutamate neurons in the rat sublaterodorsal tegmental nucleus recapitulates REM sleep behaviour disorder. Brain140, 414–428.
39.
FermanTJ, BoeveBF, SmithGE, SilberMH, KokmenE, PetersenRC, IvnikRJ (1999) REM sleep behavior disorder and dementia Cognitive differences when compared with AD. Neurology52, 951–951.
40.
GagnonJF, PetitD, FantiniML, RompréS, GauthierS, PanissetM, RobillardA, MontplaisirJ (2006) REM sleep behavior disorder and REM sleep without flatonia in probable Alzheimer disease. Sleep29, 1321–1325.
41.
WangP, WingYK, XingJ, LiuY, ZhouB, ZhangZ, YaoH, ShangY, ZhangX (2016) Rapid eye movement sleep behavior disorder in patients with probable Alzheimer’s disease. Aging Clin Exp Res28, 951–957.
42.
KimHJ, ImHK, KimJ, HanJY, de LeonM, DeshpandeA, MoonWJ (2016) Brain atrophy of secondary REM-sleep behavior disorder in neurodegenerative disease. J Alzheimers Dis52, 1101–1109.
43.
PostumaRB, GagnonJF, VendetteM, FantiniML, Massicotte-MarquezJ, MontplaisirJ (2009) Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology72, 1296–1300.
44.
PostumaRB, GagnonJF, RompréS, MontplaisirJY (2010) Severity of REM atonia loss in idiopathic REM sleep behavior disorder predicts Parkinson disease. Neurology74, 239–244.
45.
SchenckCH, MontplaisirJY, FrauscherB, HoglB, GagnonJF, PostumaR, SonkaK, JennumP, PartinenM, ArnulfI, de CockVC, DauvilliersY, LuppiPH, HeidbrederH, MayerG, Sixel DöringnF, TrenkwalderC, UngerM, YoungP, WingYK, Ferini-StrambiL, FerriR, PlazziG, ZucconiM, InoueY, IranzoA, SantamariaJ, BassettiC, MöllerJC, BoeveBF, LaiaYY, PavlovaM, SaperC, SchmidtP, SiegelJM, SingerC, St LouisE, VidenovicA (2013) Rapid eye movement sleep behavior disorder: Devising controlled active treatment studies for symptomatic and neuroprotective therapy—a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group. Sleep Med14, 795–806.
46.
SchenckCH, MahowaldMW, AndersonML, SilberMH, BoeveBF, ParisiJE (1997) Lewy body variant of Alzheimer’s disease (AD) identified by postmortem ubiquitin staining in a previously reported case of AD associated with REM sleep behavior disorder. Biol Psychiatry42, 527–528.
47.
HansenLA, SamuelW (1997) Criteria for Alzheimer’s disease and the nosology of dementia with Lewy bodies. Neurology48, 126–132.
48.
JichaGA, SchmittFA, AbnerE, NelsonPT, CooperGE, SmithCD, MarkesberyWR (2010) Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease. Neurobiol Aging31, 1805–1813.
49.
BoeveBF (2012) Mild cognitive impairment associated with underlying Alzheimer’s disease versus Lewy body disease. Parkinsonism Relat Disord18, S41–S44.
50.
CagninA, BussèC, JelcicN, GnoatoF, MitoloM, CaffarraP (2015) High specificity of MMSE pentagon scoring for diagnosis of prodromal dementia with Lewy bodies. Parkinsonism Relat Disord21, 303–305.
CooksonMR (2009) α-Synuclein and neuronal cell death. Mol Neurodegener4, 9.
54.
KauferDI, TrösterAI (2008) Neuropsychology of dementia with Lewy bodies. Handb Clin Neurol88, 549–566.
55.
GeserF, WenningGK, PoeweW, McKeithI (2005) How to diagnose dementia with Lewy bodies: State of the art. Mov Disord20, Suppl 12:S11–20.
56.
PalmqvistS, HanssonO, MinthonL, LondosE (2009) Practical suggestions on how to differentiate dementia with Lewy bodies from Alzheimer’s disease with common cognitive tests. Int J Geriatr Psychiatry24, 1405–1412.
57.
MerdesAR, HansenLA, JesteDV, GalaskoD, HofstetterCR, HoGJ, ThalLJ, Corey-BloomJ (2003) Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology60, 1586–1590.
58.
WalkerZ, JarosE, WalkerRW, LeeL, CostaDC, LivingstonG, IncePG, PerryR, McKeithI, KatonaCLE (2007) Dementia with lewy bodies: A comparison of clinical diagnosis, FP-CIT SPECT imaging and autopsy. J Neurol Neurosurg Psychiatry78, 1176–1181.
59.
BoeveBF, SilberMH, ParisiJE, DicksonDW, FermanTJ, BenarrochEE, SchmeichelAM, SmithGE, PetersenRC, AhlskogJE, MatsumotoJY, KnopmanDS, SchenckCH, MahowaldMW (2003) Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology61, 40–45.
60.
FermanTJ, BoeveBF, SmithGE, LinSC, SilberMH, PedrazaO, WszolekZ, Graff-RadfordNR, UittiR, Van GerpenJ, PaoW, KnopmanD, PankratzVS, KantarciK, BootB, ParisiJE, DuggerBN, FujishiroH, PetersenRC,DicksonDW (2011) Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies. Neurology77, 875–882.
61.
McKhannG, DrachmanD, FolsteinM, KatzmanR, PriceD, StadlanEM (1984) Clinical diagnosis of Alzheimer’s disease Report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology34, 939–939.
MinoshimaS, FosterNL, SimaAA, FreyKA, AlbinRL, KuhlDE (2001) Alzheimer’s disease versus dementia with Lewy bodies: Cerebral metabolic distinction with autopsy confirmation. Ann Neurol50, 358–365.
64.
McKeithIG, DicksonDW, LoweJ, EmreM, O’BrienJT, FeldmanH, CummingsJ, DudaJE, LippaC, PerryEK, AarslandD, AraiH, BallardCG, BoeveB, BurnDJ, CostaD, Del SerT, DuboisB, GalaskoD, GauthierS, GoetzCG, Gomez-TortosaE, HallidayG, HansenLA, HardyJ, IwatsuboT, KalariaRN, KauferD, KennyRA, KorczynA, KosakaK, LeeVM, LeesA, LitvanI, LondosE, LopezOL, MinoshimaS, MizunoY, MolinaJA, Mukaetova-LadinskaEB, PasquierF, PerryRH, SchulzJB, TrojanowskiJQ, YamadaM, Consortium onDLB (2005) Diagnosis and management of dementia with Lewy bodies third report of the DLB consortium. Neurology65, 1863–1872.
65.
ShimadaH, HiranoS, ShinotohH, AotsukaA, SatoK, TanakaN, OtaT, AsahinaM, FukushiK, KuwabaraS, HattoriT, SuharaT, IrieT (2009) Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology73, 273–278.
66.
WarrenJD, FletcherPD, GoldenHL (2012) The paradox of syndromic diversity in Alzheimer disease. Nat Rev Neurol8, 451–464.
67.
American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders (3rd ed., text rev.). Washington, DC.
68.
SperlingRA, AisenPS, BeckettLA, BennettDA, CraftS, FaganAM, IwatsuboT, JackCRJr, KayeJ, MontineTJ, ParkDC, ReimanEM, RoweCC, SiemersE, SternY, YaffeK, CarrilloMC, ThiesB, Morrison-BogoradM, WagsterMV, PhelpsCH (2011) Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging- Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 280–292.
69.
HughesAJ, Ben-ShlomoY, DanielSE, LeesAJ (1992) What features improve the accuracy of clinical diagnosis in Parkinson’s disease: A clinicopathologic study. Neurology42, 1142–1146.
70.
NishinoS, TaftiM, ReidMS, SheltonJ, SiegelJM, DementWC, MignotE (1995) Muscle atonia is triggered by cholinergic stimulation of the basal forebrain: Imlication for the pathophysiology of canine narcolepsy. J Neurosci15, 4806–4814.
71.
MizunoS, KamedaA, InagakiT, HoriguchiJ (2004) Effects of donepezil on Alzheimer’s disease: The relationship between cognitive function and rapid eye movement sleep. Psychiatry Clin Neurosci58, 660–665.
72.
BonanniL, ThomasA, TiraboschiP, PerfettiB, VaraneseS, OnofrjM (2008) EEG comparisons in early Alzheimer’s disease, dementia with Lewy bodies and Parkinson’s disease with dementia patients with a 2-year follow-up. Brain131, 690–705.
73.
Gómez-IslaT, GrowdonWB, McNamaraM, NewellK, Gómez-TortosaE, Hedley-WhyteET, HymanBT (1999) Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies. Neurology53, 2003–2009.
74.
JellingerKA (2003) Neuropathological spectrum of synucleinopathies. Mov Disord18, 2–12.
75.
SchneiderJA, ArvanitakisZ, BangW, BennettDA (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology69, 2197–2204.
76.
WalkerL, McAleeseKE, ThomasAJ, JohnsonM, Martin-RuizC, ParkerC, CollobySJ, JellingerK, AttemsJ (2015) Neuropathologically mixed Alzheimer’s and Lewy body disease: Burden of pathological protein aggregates differs between clinical phenotypes. Acta Neuropathol129, 729–748.
77.
BrenowitzWD, KeeneCD, HawesSE, HubbardRA, LongstrethWTJr, WoltjerRL, CranePK, LarsonEB, KukullWA (2017) Alzheimer’s disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic-and community-based samples. Neurobiol Aging53, 83–92.
MontineTJ, PhelpsCH, BeachTG, BigioEH, CairnsNJ, DicksonDW, DuyckaertsC, FroschMP, MasliahE, MirraSS, NelsonPT, SchneiderJA, ThalDR, TrojanowskiJQ, VintersHV, HymanBT, National Institute on Aging, Alzheimer’s Association (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathol123, 1–11.
80.
PostumaRB, LanfranchiPA, BlaisH, GagnonJF, MontplaisirJY (2010) Cardiac autonomic dysfunction in idiopathic REM sleep behavior disorder. Mov Disord25, 2304–2310.
