Electroencephalographic Finding in Idiopathic REM

Sleep Behavior Disorder

Yuichi Inoue

Tokyo Medical University Neuropsychiatric Research Institute, Tokyo, Japan

Key Note Presentation August 10, 2015 during 10:40-11:20

Conflict of Interest Disclosures – Authors/Presenters

Type of Potential Conflict Details of Potential Conflict

Grant/Research Support -

Consultant -

Speakers’ Bureaus Otsuka Pharmaceutical Co., Ltd, Astellas Pharma Inc, Eisai Co., Ltd.,Philips Respironics GK, Takeda Pharmaceutical Company Limited, Alfresa Pharma Corporation, MSD K.K.

Financial support -

Other HISAMITSU PHARMACEUTICAL Co., Inc.（Investigational Device/Drug）

The authors do not have any potential conflicts of interest to disclose,

OR

The authors wish to disclose the following potential conflicts of interest related to content in this lecture: ✔

REM sleep behavior disorder (RBD)

1. Dream enactment behavior based on REM without atonia (kicking, punching and shouting etc), a possible cause of sleep related injury (at least 0.5%)

2. Prevalent in elderly population 3. Male predominance 4. Chronic course 5. One of prodromal symptoms of alpha-

synucleinopathies ＪＳＣ

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REM Sleep Behavior Disorder Diagnostic Criteria Criteria A-D must be met A.Repeated episodes of sleep related vocalization and/or

complex motor behaviors.

B.These behaviors are documented by polysomnography to occur during REM sleep or, based on clinical history of dream enactment, are presumed to occur during REM sleep.

C.Polysomnographic recording demonstrates REM sleep without atonia (RWA)

D.The disturbance is not better explained by another sleep disorder, mental disorder, medication, or substance use.

ＪＳＣ (International Classification of Sleep Disorders Third Edition. American Academy of Sleep Medicine. 2014; pp246-247.)

REM sleep PSG showing submental EMG activity (9) despite the emergence of gross arm and leg movements that are noted by the technician and reflected by prominent

twitching in the upper and lower extremity EMGs (10, 11, 13, 14). REM (7, 8) immediately precedes the onset of complex behavior.

ＪＳＣ (Inoue Y, et al. Neuropsychobiology. 2015; 71: 25–33.)

F = Frontal; M = mastoid; C = central; O = occipital; LEOG/REOG = left/right electrooculogram; Ant Tib = anterior tibialis.

REM sleep without atonia

REM sleep without atonia -Phasic electromyographic (EMG) activity defined as 3-second mini-epochs including phasic EMG activity with any burst of EMG activity lasting between 0.1 and 5.0 s and an amplitude exceeding twice the background EMG activity. -Tonic EMG activity with an amplitude of at least twice the background EMG muscle tone or more than 10 μV for more than 50% of a 30-second epoch. –Both of these are mixed into normal REM episodes.

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In the third edition of The International Classification of Sleep Disorders (ICSD-3), any (tonic/phasic) chin EMG activity combined

with bilateral phasic activity of the flexor digitorum superficialis muscles in >27% of REM sleep, scored in 30-second epochs, is

recommended to distinguish RBD patients reliably from controls.

Appearance of stage REM and Stage RWA in the parasomnia group(a) and the control group(b).

The ordinate is the mean percentages of Stage REM (shaded area) and Stage RWA (unshaded area) in each 5-min sleep.

Tachibana N et al. Biol Psychiatry. 1991

□ Stage RWA ■ Stage REM

(a)

(b)

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Average REM densities in the first, Second, and third 3-hr period of nocturnal sleep in the subjects with parasomnia

and the controls. (*p

Five domain scores in NEO-PIR for groups of iRBD and HC Areas between dotted lines represent normal levels in the five domains.

ＪＳＣ (Sasai T, Inoue Y, et al. Parkinsonism Relat Disord. 2012; 18(5): 616-618.)

NEO-PIR, the revised version of NEO personality inventory; iRBD, idiopathic rapid eye movement sleep behavior disorder; HC, healthy control. Student t-test.

Patients with iRBD do not have

any specific character trait.

Ach, acetylcholine; BF, Basal Forebrain; PH, posterior hypothalamus; SLD, sublaterodorsal nucleus; vlPAG, ventrolateral periaqueductal gray; GiV, ventral gigantocellular reticular nucleus; LC, locus coeruleus; DPGi, dorsal paragigantocellular reticular nucleus; DRN, dorsal raphe nucleus; TMN, tuberomammillary nucleus.

(Luppi PH et al. Sleep Med Rev. 2011; 15(3): 153-163)

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In healthy REM sleep, the SLD–GiV circuit inhibits motoneurons, which prevents pyramidal neurons in the motor cortex from producing movement. However, in patients with RBD, degeneration of the SLD–GiV circuit releases motoneurons from their normal source of inhibition, which allows excitatory projections from the motor cortex (via brainstem reticular neurons) to produce motor behaviors during REM sleep.

Circuitry responsible for motor control in rapid eye movement (REM) sleep and its potential involvement in REM sleep behavior disorder (RBD).

ＪＳＣ (Peever J et al. Trends Neurosci. 2014; 37(5): 279-88.)

During REM sleep, the descending REM-ON glutamatergic neurons of the sublaterodorsal tegmental nucleus (SLD) excite the REM-ON GABA- and glycine-releasing neurons in the ventral gigantocellular reticular nucleus (GiV). These GiV neurons project to and inhibit skeletal motoneurons, which causes REM sleep atonia. Another population of ascending SLD neurons induce activation of the cortex during REM sleep (including the motor cortex) by exciting intralaminar thalamocortical neurons. In healthy REM sleep, the SLD–GiV circuit inhibits motoneurons, which prevents pyramidal neurons in the motor cortex from producing movement. However, in patients with RBD, degeneration of the SLD–GiV circuit releases motoneurons from their normal source of inhibition, which allows excitatory projections from the motor cortex (via brainstem reticular neurons) to produce motor behaviors during REM sleep.

Statistical parametric mapping (t) axial intensity projection maps rendered onto a stereotactically normalized magnetic resonance imaging (MRI) scan, showing areas of

significant increases of mean diffusivity values (color code, yellow to orange) in a cohort of patients with idiopathic rapid eye movement (REM) sleep behavior disorder versus healthy

control subjects.

Scherfler C et al. Ann Neurol. 69:400-7 (2011) ＪＳＣ

The REM-off region is represented by the periaqueductal gray matter (PAG) in red, and the REM-on region is represented by the precoeruleus (PC) and sublaterodorsal nucleus (SLD) in green. Nuclei in yellow and blue are known to influence REM and non-REM sleep circuits. LC 5 locus coeruleus; PPN 5 pedunculopontine nucleus.

Ictal SPECT of Patient RD, male with

idiopathic REM sleep behaviour disorder.

ＪＳＣ (Mayer G et al. Brain. 2015; 138(Pt 5): 1263-1270 .)

Difference images of cerebral perfusion, measured by Tc-99m ECD SPECT (in colour), overlaid on T1-MRI (greyscale). The colour of the SPECT indicates the degree of ictal hyperperfusion, ranging from weak (blue and green) to strong (orange and red). The arrows indicate hyperperfusion in brain regions. Bifrontal activation in premotor area, pons and anterior cerebellum. A =anterior; H =head; P =posterior; F =foot; R =right; L=left.

Neuropathologic findings in the locus ceruleus of a case with idiopathic RBD

Uchiyama M et al. Neurology. 1995

(A) Control: Melanized cells are not present in the locus ceruleus. Hematoxylin-eosin, X160 before 3% reduction. (B) iRBD patient: Typical eosinophilic Lewy body with a halo and core in a melanized cell was observed in the locus ceruleus.

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Postuma RB, et al. Neurology 2009.

Risk of the development of neurodegenerative disease in idiopathic RBD patients

Subject patients in = 93 ↓

26 patients (30.0%) developed neurodegenerative disorder within 5 years (PD in =14, DLB in = 7, AD in = 4, MSA in = 1)

Rates of neurological-disease-free survival according to the time of iRBD diagnosis ( a ) and estimated RBD onset ( b ).

ＪＳＣ (Inoue Y, et al. Neuropsychobiology. 2015; 71: 25–33.)

（Braak H, et al. J Neurol 2002; 249 (Suppl 3): III/ 1-III/ 5） ＪＳＣ

Stage 1 : Olfactory dysfunction

Autonomic dysfunction

Stage 2 : REM-Sleep-behaviour disorder

Stage 3 : Nigrostriatal degeneration

Dopamine-Transporter-SPECT

Motor symptoms

Akinesia, Rigidity, Tremor ? ＪＳＣ

rCBF decrease (A) and increase (B) in patients with iRBD in comparison with controls

Vendette M et al.: Mov Disord. 2011; 26(9): 1717-24.

t value

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Biological markers of α-synucleinopathies in iRBD

1. Mild motor symptoms 2. Sensory disturbances

• Olfactory deficits • Color identification deficits

3. Autonomic dysfunction 4. Slowing of EEG (awake and REM sleep) 5. Cognitive deficits

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1. いおう 2. 墨汁 3. ニス 4. 畳

5. 分からない 6. 無臭

Odor Stick Identification test for Japanease (OSIT-J)

臭素 12種類

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Olfactory discrimination in patients with idiopathic REM sleep behavior disorder (iRBD), Parkinson’s disease (PD), and Controls.

Shown are scatter plots of individual scores for the odor stick identification test for Japanese (OSOT-J). Horizontal lines indicate mean levels.

Miyamoto T, Hirata K et al. Mov Disord (2009)

Controls

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RBD 78years, male Control

Disturbance in color identification

Total Error Score 204 Total Error Score 36 Fransworth-Munsell 100 Hue Test

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Control RBD patient

delayed image

Almost no uptake

Cardiac 123I-MIBG uptake in a patients with RBD Miyamoto T, Hirata K, Inoue Y et al. Neurology (2006)

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Cardiac 123I-MIBG scintigraphy in RDB

Miyamoto T, Hirata K, Inoue Y Neurol（2007） ＪＳＣ

Boxplot presentation of blood pressure changes measured by orthostatic standing test in controls, iRBD patients and PD patients.

Systolic blood pressure (p = 0.034), Diastolic blood pressure (p = 0.017). White bars systolic blood pressure values; grey bars

diastolic blood pressure values Frauscher B, Inoue Y. et al. J Neurol. 2012; 259(6):1056-1061.

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Which parameter can predict the early development of α-synucleinopathies from iRBD？

1. Larger amount of RWA (Postuma, 2009)

2. Low cardiac MIBG uptake? -Positivity is too high and not suitable for the

prediction,

3. Visa-spatial function? 4. Olfactory dysfunction? (Mahlknecht P et al, 2015)

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Baseline evaluations in patients with iRBD who developed disease or remained disease-free

ＪＳＣ (Mahlknecht P et al. Neurology. 2015; 84(7): 654-658.)

Abbreviations: AUC = area under the curve; CI = confidence interval; UPDRS-III = motor section of Unified Parkinson’s Disease Rating Scale. The AUC values give an estimate of the diagnostic accuracy of the motor examination and olfactory testing for predicting the transition to a Lewy body disease. a Results represent means ± SD; p values calculated with an unpaired t test. b The p value calculated with a x2 test. c Results represent means (95% CIs) adjusted for age and sex; p values calculated with an analysis of covariance with age as factor and sex as covariate.

Previous reports on quantitative and qualitative EEG findings in iRBD

Increased slow wave sleep and increased delta power (Massicotle-Marquez, 2005)

Negative findings for slow wave abnormality (Massicotle-Marquez, 2011) -possibly due to the inclusion of dementia or early parkinsonism in their former report

Higher theta power in frontal, temporal and occipital region while awake with a lower β power in the occipital region while awake and during REM sleep (Fantini, 2003). The dominant occipital frequency was lower in iRBD.

Suggestive of impaired cortical activation during both wakefulness and REM sleep in iRBD

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⇒ Age effect should be considered…

Study by Rodrigues-Brazète J et al (2013)

1. Their study found that RBD + MCI patients had higher relative θ power in the parietal, temporal and occipital regions, and lower relative α power in the occipital region compared to RBD – MCI patients and controls. The dominant occipital frequency was also slower in RBD + MCI patients compared to controls.

2. Moreover, RBD + MCI patients had lower relative β power in the central, parietal and temporal regions compared to controls.

3. No between-group differences were observed between RBD – MCI and controls.

4. These findings strongly suggested the relationship between cognitive decline and EEG slowing in patients with iRBD.

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Clinical, polysomnographic and neuropsychological findings

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・ Scores of MoCA and MMSE were lower in younger iRBD compared with controls. ・RWA measures and odor function were not different between younger and older RBD patients. (Sasai T, Inoue Y, et al. Sleep. 2013; 36(12): 1893-1899.)

Control for younger RBD (3)

Distribution of the MoCA and MMSE scores among ages

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・Age dependent decrease in the scores of MoCA and MMSE were found in all the subject groups ・The MoCA score was lower than the cutoff (25 of 26) for detecting MCI in 13 of 17 (76.5%) of the

younger iRBD group, 13 of 14 (92.9%) of the older iRBD group, and 1 of 17 (5.9%) of control patients. The MMSE score was lower than the cutoff (29 of 30) for detecting MCI in 10 of 17 (58.8%) of the younger iRBD group, 13 of 14 (92.9%) of the older iRBD group, and 4 of 17 (23.5%) of control patients.

(Sasai T, Inoue Y, et al. Sleep. 2013; 36(12): 1893-1899.)

● : younger RBD ▲ : older RBD ■ : control

Comparison of electroencephalographic spectral power during wake, REM sleep, and NREM sleep in patients with

young iRBD and controls

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Black bars show data for the younger rapid eye movement sleep behavior disorder group. White bars show data for the age-matched control group. *P < 0.05, values are expressed as mean ± standard deviation.

(Sasai T, Inoue Y, et al. Sleep. 2013; 36(12): 1893-1899.)

Partial correlation coefficients of the Montreal Cognitive Assessment score to clinical rapid eye movement sleep disorder-

related variables or polysomnographic variables

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Partial correlation analyses controlled for age were conducted on all subject patients with iRBD (n = 31). EMG, electromyogram; n.s., not significant; RBD, rapid eye movement sleep disorder; RBDQ-JP, Japanese version of REM sleep behavior disorder questionnaire; SPT, sleep period time; SWS, slow wave sleep; TDI, threshold–discrimination–identification.

(Sasai T, Inoue Y, et al. Sleep. 2013; 36(12): 1893-1899.)

Partial correlation between scores of Montreal Cognitive Assessment

and electroencephalogram spectral powers in respective

frequency bands after controlling for age

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Partial correlation analyses controlled by age for all patients with rapid eye movement sleep behavior disorder (n = 31). NREM, nonrapid eye movement; n.s., not significant; REM, rapid eye movement.

(Sasai T, Inoue Y, et al. Sleep. 2013; 36(12): 1893-1899.)

Multiple Regression Analysis

Results indicated the following multiple regression equation:

MoCA score = 50.871-0.116*age-5.307*log (δ power during REM sleep in occipital regions) + 0.086*TDI score.

-For this equation, the R value was 0.773, R2 was 0.598, and the regression coefficients were -0.558 for age, -0.468 for δ power, and 0.357 for TDI score (F = 9.900, P < 0.001).

Electroencephalographic slowing, especially during REM sleep and olfactory dysfunction, was revealed to be associated with cognitive decline in idiopathic rapid eye movement sleep behavior disorder.

ＪＳＣ (Sasai T, Inoue Y, et al. Sleep. 2013; 36(12): 1893-1899.)

Controlled studies of cognitive performance in iRBD

ＪＳＣ (Inoue Y, et al. Neuropsychobiology. 2015; 71: 25–33.)

Yes = Patients show poorer performance than controls (p < 0.05); No = similar performance between patients and controls. a, b Share common participants.

Cognitive domains Terzaghi et al. (2008)

Massicotte- Marquez et al. (2008)a

Gagnon et al. (2009)a

Marques et al. (2010)

Ferini- Strambi et al. (2004)b

Fantini et al. (2011)b

Attention/executive functions Yes Yes Yes Yes Yes Yes

Verbal episodic memory Yes Yes Yes Yes Yes Yes

Nonverbal memory Yes – – – Yes Yes

Visuospatial abilities No No No Yes Yes Yes

MCI occurs in approximately 50% of iRBD patients (controls : 8%). Attention, executive function, episodic verbal memory

(mainly free recall capacities) and nonverbal learning are the most affected domains.

Comparision of performance in Iowa Gambling Task performance of idiopathic RBD patients and healthy controls.

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(a) Total gain (point), (b) IGT score (C + D) － (A + B), (c) IGT scores for each block (C + D) － (A + B). *: p < .05, † p < .01, compared to the HC group. The boxes show mean ± SD and the error bars show the area between the lowest score and the highest score. IGT, Iowa Gambling Task; HC, healthy control; iRBD, idiopathic rapid eye movement sleep behavior disorder.

(Sasai T, Inoue Y, et al. Sleep Med. 2012; 13(3): 301-306.)

Total gain and IGT score as well as IGT scores in the first, third and final banks were lower than these of the control group.

Hypocholinergic function? Evidence of the involvement of the pons including PPN, laterodorsal

segmental nucleus, LC and peri-LC derives from neurpathological studies on iRBD patients.

The PPN and LC representing the largest clusters of cholinergic function are known to play a role in arousal, cortical activation and cognitive function.

It is also known that cholinergic activity promotes REM sleep, and that cholinergic denervation of the limbic system is a robust determinant of hyposmia.

The short latency afferent inhibition (SAI) of the motor cortex with transcranial magnetic stimulation manifests the cholinergic function of the brain, and the SAI is clearly impaired in iRBD patients (with MCI). In these patients, SAI values are also correlated with executive functions or verbal memory (Nardone et al , 2012)

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Cholinergic neuronal loss in PPN/LDT in LBD.

Dugger BN et al.: Neuropathol Appl Neurobiol. 2012; 38(2): 142-52.

(a) Choline acetyl transferase (ChAT) staining in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT) of normal, Alzheimer’s disease (AD), and Lewy body disease (LBD) cases without rapid eye movement sleep behaviour disorder (RBD) (LBD NRBD) and with RBD (LBD RBD). Photos taken at \ 20. (b) Quantification of percentages of ChAT-positive neurones out of total neurones in the PPN/LDT. *LBD RBD contained significantly less ChAT-positive neurones than normals and AD.

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Log-transformed spectral EEG power during REM sleep in controls (black bars) patients with IRBD (gray bars) and patients with RBD who later developed mild

cognitive impairment (white bars) in C3, C4, O1 and O2 regions across delta, theta, alpha, beta1 and beta2 frequency bands.

ＪＳＣ (Iranzo A et al. Sleep Med. 2010;11(6): 534-539.)

x = p < 0.05, xx = p < 0.01, xxx = p < 0.001.

Patients with RBD + MCI had marked EEG slowing (increased delta and theta activity) in central and occipital regions during wakefulness and REM sleep, particularly in the right hemisphere, when

compared with controls and, with IRBD subjects who remained idiopathic.

The EEG spectral pattern of the RBD + MCI group was similar to that seen in patients with dementia with Lewy bodies and Parkinson’s disease associated with dementia.

Three-dimensional views of decreased studies showed (a) regional cerebral blood flow (rCBF) at first single photon emission computed tomography (SPECT) and (b) second SPECT of rapid eye movement sleep behavior disorder (iRBD) patients compared with

normal controls. Three-dimensional views of (c) decreased rCBF at second SPECT compared with first SPECT of iRBD patients.

ＪＳＣ (Sakurai H, Inoue Y, et al. Geriatr Gerontol Int. 2014; 14(1): 115-120.)

Conclution

EEG slowing is one of specific findings in iRBD, and this may become a candidate of the predictors of the development of neurodegeneration.

Future studies should clarify the cutoff EEG power (especially for younger patients) for the prediction.

The corresponding area of EEG abnormalities should also be investigated with neuroimaging studies especially by using acetylcholine ligands .

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2009.9.17 長岡

Summary of participants.

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Data are expressed as mean ± SD.iRBD; idiopathic rapid eye movement behavior disorder, RBDSQ-J; Japanese version of RBD Screening Questionnairre. n.s.: Not significant. a The levels of fatigue and sleepiness before performing Iowa Gambling Task were evaluated using the visual analogue scale (0–100).

(Sasai T, Inoue Y, et al. Sleep Med. 2012; 13(3): 301-306.)

Comparison of EEG spectral power during wake ( a ),

REM sleep ( b ) and NREM sleep ( c ) in patients with

iRBD and controls.

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■ = Younger RBD group; □ = age-matched control group. * p < 0.05, means ± SD.

(Inoue Y, et al. Neuropsychobiology. 2015; 71: 25–33.)

Diagnostic accuracy of olfactory assessment and its value for potential interventional trials in patients with iRBD

ＪＳＣ (Mahlknecht P et al. Neurology. 2015; 84(7): 654-658.)

Scatterplots of the identification subscore (A) and the Sniffin’ Sticks total score (B) in subjects with iRBD developing a Lewy body disease and in those remaining disease-free. Single values are given with the respective group median and the 25th and 75th percentiles. The dotted lines represent the receiver operating characteristic–based cutoff values (