Sleep Disorders Pertinent To Dementia Research

Bradley F. Boeve, M.D.Professor of Neurology

Divisions of Behavioral Neurology and Movement Disorders, and Center for Sleep Medicine

Alzheimer’s Disease Research CenterMayo Clinic

Rochester, Minnesota

Sleep Disorders Pertinent to Dementia Research:REM Sleep Behavior Disorder and

Obstructive Sleep Apnea

Disclosures

Financial/Other Investigator for a clinical trial sponsored by GE Healthcare Royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009) Advisor for the Tau Consortium Honoraria from the American Academy of Neurology Research support from the NIA, NINDS, Alzheimer's Association, Mangurian Foundation

Off-label and/or Investigational Use May discuss use of some medications and/or devices not FDA-approved for the indications to be reviewed

REM Sleep Behavior Disorder (RBD)

• To review the clinical features and pathophysiology of RBD

• To review the relevance of RBD to dementia research

Obstructive Sleep Apnea (OSA)

• To review the clinical features and pathophysiology of OSA

• To review the relevance of OSA to dementia research

ADC Program/NACC• To underscore the importance of recording sleep-related

issues in UDS 3.0

Sleep Disorders Pertinent to Dementia Research:REM Sleep Behavior Disorder and Obstructive Sleep Apnea

Objectives

REM Sleep Behavior Disorder

States of Being

• Wakefulness

• Non-REM Sleep• Stage N1• Stage N2• Stage N3

• REM sleep (Stage R)

Normal REM Sleep

Normal REM Sleep

• Simple or complex limb movements and/or vocalizations during rapid eye movement (REM) sleep

• Behaviors typically mirror the content of the dream when a patient is awakened and questioned

• Dream content often involves animals and/or people with chasing or attacking theme

• Behaviors can be violent, and patient and bedpartner injuries can occur

REM Sleep Behavior DisorderClinical Features

Normal REM Sleep vs REM Sleep Without Atonia

Normal REM Sleep

REM SleepWithoutAtonia

(RSWA)

REM Sleep Behavior Disorder

RBD Pathophysiology

Adapted from Boeve BF, Lancet Neurol 2013

GluGly

GABA

SLD

MCRF

RBD Pathophysiology

Adapted from Boeve BF, Lancet Neurol 2013

RBD is Associated with the Synucleinopathies

http://0.tqn.com/d/geography/1/0/z/K/namerica.jpg

http://0.tqn.com/d/geography/1/0/z/K/namerica.jpg

http://0.tqn.com/d/geography/1/0/1/L/europe.jpg

http://0.tqn.com/d/geography/1/0/1/L/europe.jpg

Boeve BF et al, Sleep Med 2013

LBD +/- AD

MSA

AD

PSP

Other

RBD is Associated with the Synucleinopathies –Which is Typically Lewy Body Disease

AmyloidopathyAlzheimer’s disease (AD)

PrionopathyCreutzfeldt-Jakob disease (CJD)Fatal familial insomnia (FFI)Gerstmann-Straussler-Scheinker (GSS)

TauopathyPick’s diseaseCorticobasal degeneration (CBD)Progressive supranuclear palsy (PSP)Argyrophilic grain disease (AGD)Frontotemporal dementia with

parkinsonism linked to chromosome 17 (FTDP-17MAPT)

Guadeloupean parkinsonism

SynucleinopathyLewy Body Disease

Parkinson’s disease (PD)Dementia with Lewy bodies (DLB)Pure autonomic failure (PAF)

Multiple system atrophy (MSA)

TDP-43opathyFrontotemporal lobar degeneration (FTLD) with

TDP-43-positive inclusionsFTLD with motor neuron disease (FTLD-MND)Hippocampal sclerosis (HS)Amyotrophic lateral sclerosis (ALS)Frontotemporal dementia with parkinsonism

linked to chromosome 17 (FTDP-17PGRN)

Trinucleotide Repeat DisordersSpinocerebellar Atrophy-3 (SCA-3)Huntington’s Disease (HD)

RBD Associated with Neurodegenerative Disease

RBD and the Association With Lewy Body Disease/Dementia With Lewy Bodies

McKeith et al, Neurology 2005

McKeith et al, Neurology 2005


Ferman et al, Neurology 2011


Claassen et al, Neurology 2011

RBDonset

Cognitive impairmentand/or parkinsonism

onset

Idiopathic RBD

RBD Tends to Precede Cognitive Impairment and/or Parkinsonism by Years or Decades

20 30 40 50 60 70 80

PD/PDD

MCI/DLB

MSA


20 30 40 50 60 70 80

PD/PDD

MCI/DLB

MSA

Mean=27 yearsRange=15-50 years


Func

tion

Age

NeurodegenerativeSyndrome

Cognitive Impairment

Prodromal

Early Symptomatic

RBD

DLBMCI


Salient Points:

REM Sleep Behavior Disorder and RelevanceTo Dementia/Neurodegenerative Disease

• RBD is often associated with the synucleinopathies, and usually precedes the other “classic” features of DLB, PD or MSA by years

• RBD associated with cognitive impairment/dementia almost always reflects underlying Lewy body disease (ie, DLB)

• Treatment directed toward LBD pathophysiology in those with RBD could delay the onset or prevent the development of DLB


Obstructive Sleep ApneaClinical Features

• loud and disruptive snoring

• witnessed snorts, gasps, and apnea

• snort arousals

• daytime hypersomnolence

• cognitive impairment

• depression, irritability

• reduced quality of life

Obstructive Sleep ApneaPolysomnographic Features

O2

EMG

EEG

arousal arousal

Obstructive Sleep ApneaEtiology/Pathophysiology

• Repetitive episodes of reduced or ceased airflow due to obstruction in the oropharynx during sleep

• Often associated with:

• obesity

• excessive neck tissue (collar size >17 ½)

• large tonsils

• retrognathia

Obstructive Sleep ApneaOffice Tasks

Friedman et al, Laryngoscope 2004;114:454–459

Friedman Palate Position

Grade III and IV – associated

with increased frequency of OSA

• nasal continuous positive airway pressure (CPAP)

• positional OSA - “tennis balls in a T-shirt” technique

• oral appliance

• uvulopalatopharyngoplasty (UPPP)

Obstructive Sleep ApneaManagement

Obstructive Sleep ApneaNasal CPAP

http://www.advanscpap.net/catalog/item/210845/48954.htm




• Untreated OSA in the nondemented population causes cognitive impairment, excessive daytime somnolence (EDS), and diminished mood and quality of life

• Treatment of OSA with nasal continuous positive airway pressure (CPAP) improves cognitive performance, EDS, mood and quality of life

• Neuropsychological analyses have revealed that in patients with OSA, cognitive flexibility, attention, processing speed, and memory all improve with CPAP therapy


OSA should be considered one of the reversible causes of cognitive

impairment/delirium/dementia


JAGS 2008

JCSM 2009

Obstructive Sleep ApneaRelevance to MCI/AD

JAMA 2011

Adjusted odds ratio of 1.85


Kang et al., Science Express 2009


Ju et al., Nature Rev Neurosci 2014


Osario et al., Neurology 2015




OSA ~ sleep disordered breathing (SDB)

+SDB compared to no SDB was associated with earlier age of onset of MCI (and AD)



Among those with SDB:

CPAP use associated with delayed age of onset of MCI

Salient Points:

Obstructive Sleep Apnea and RelevanceTo Dementia/Neurodegenerative Disease

• OSA is associated with cognitive impairment, MCI and AD

• Evidence suggests:• OSA increases risk of MCI/AD• OSA decreases age of onset of MCI +/- AD• CPAP improves cognition in those with MCI/AD• CPAP delays development of MCI +/- AD

• OSA may alter intracranial amyloid physiology

Sleep-Related Topics of Interestin the ADC Program/NACC




Reminder: RBD is recorded under the “behavior” domain, and when present, usually precedes changes in cognition and motor functioning – this box should be checked in such instances


Collaborators/SupportRick Caselli, MDDaniel Drubach, MDJon Graff-Radford, MDNeill Graff-Radford, MBChBDavid Jones, MDKeith Josephs, MDDavid Knopman, MDRonald Petersen, PhD, MD

Tanis Ferman, PhDGlenn Smith, PhDRobert Ivnik, PhDJohn Lucas, PhD

Departments of Neurology, Psychiatry and Psychology, Diagnostic Radiology, Pathology andLaboratory Medicine, Neuropathology Laboratory, Community Internal Medicine,

Health Sciences Research, and Center for Sleep Medicine,Mayo Clinic Rochester and Mayo Clinic Jacksonvile;

Mayo Alzheimer’s Disease Research Center, Mayo Foundation; andM.H. Udall PD Center of Excellence Grant, Mayo Foundation

Supported by grants AG015866, AG006786, AG016574 from the NIA, the Alzheimer’s Association, and the Mangurian Foundation

Joseph Parisi, MDDennis Dickson, MDMelissa Murray, PhD

Dana Swenson-DravisMayo ADRC Staff

Mike Silber, MBChBErik St. Louis, MDSuresh Kotagal, MDSiong-Chi Lin, MDMaja Tippmann-Peikert, MDMithri Junna, MDMelissa Lipford, MD

Cliff Jack, Jr., MDKejal Kantarci, MDJennifer Whitwell, PhDVal Lowe, MDPrashanthi Vemuri, PhD

International Dementia with Lewy Bodies Conference

December 1-4, 2015

Marriott Harbor Beach Resort & Spa

Fort Lauderdale, Florida

Abstract Deadline – June 2015

DiagnosisEpidemiologyClinical aspectsNeuropsychologyNeuroimagingTherapeutics

GeneticsBiofluid markersNeuropathologyMolecular biologyAnimal modelsControversies

RBD – Lewy Body Disease Association

Molano et al, Brain 2010

RBD-LBD AssociationRBD Precedes Cognitive Impairment/Parkinsonism

MCIC65 70

P61R

71

88

MCIC

83R

84 85 86 90VH

DLBP F

DLBMCIC, R* R P,FVH

89 90 91 92 94

MCIC,P7427

R75 77 78 81

FDLB

76

DLB

75C, P F6957

R72 74VH

MCI

C P69

VH, F60R

71 72 73 76

DLBMCI

67

MCIC6251

R66 68 71

FP, VHDLB

Molano et al, Brain 2010


General Timeline of Features

CR FP VH

Age

Death

Adapted from Molano et al, 2010 and Fields et al, 2011


Func

tion

Age

NeurodegenerativeSyndrome

Prodromal

Early Symptomatic

RBDMCI

DLB

Consider screening for OSA with overnight oximetry in appropriate patients

Normal OSA


• 67 yr old woman with 2 year history of cognitive decline

• Forgetful, errors in arranging family activities, multi-tasking difficult

• Rare errors balancing checkbook, but living independently, driving OK

• MMSE 27/30

• General neurologic exam normal

• Crowded oropharynx

Obstructive Sleep ApneaCase Example

Neuropsychologic Profile

0

2

4

6

8

10

12

14

DRS-2 WMS-RLM % R

WMS-RVR % R

AVLTDelay

BNT Letter Flu CategFlu

TMT A TMT B StroopCW

Rey O WAIS-BD

JLO

Cognitive Measures and Domains

MOA

NS (M

ean

10, S

D 3)

Memory Language AttentionExecutive VisuospatialGlobal


• Labs normal, MRI head normal

• Dx: mild cognitive impairment

• Overnight oximetry:


Case example (cont)

• PSG – moderately severe OSA (AHI >30)

• Commenced on nasal CPAP

• Excellent response, tolerated CPAP well

• Within 1-2 months cognitive problems resolved

• Returned 1 year later


Neuropsychologic Profile

0

2

4

6

8

10

12

14

DRS-2 WMS-RLM % R

WMS-RVR % R

AVLTDelay

BNT Letter Flu CategFlu

TMT A TMT B StroopCW

Rey O WAIS-BD

JLO

Cognitive Measures and Domains

MO

ANS

(Mea

n 10

, SD

3)

Memory Language AttentionExecutive VisuospatialGlobal


Dementia with Lewy BodiesMany Sleep Issues in DLB

Pao et al, The Neurologist 2013

Dementia with Lewy Bodies Many Sleep Issues in DLB

Main points• RBD is common (83%)• PLM arousals are common

• 45% had >5 arousals/hr• AFNARs are very common

• 76% had >5 arousals/hr• Sleep efficiency is poor

• 72% had <80%• 49% had <70%

Pao et al, The Neurologist 2013

Dementia with Lewy Bodies DLB Patients Are Hypersomnolent

Ferman et al, Alz Res Therapy 2014

DLB: 57AD: 27

DLB: 31AD: 14

The data confirms subjective (ESS) and objective evidence of EDS (MSLT) is present in DLB and not in AD.

Dementia with Lewy Bodies DLB Patients Are Hypersomnolent

Ferman et al, Alz Res Therapy 2014

The data suggests that hypersomnia is present in DLB and not in AD.

Dementia with Lewy Bodies DLB Patients Struggle to Maintain Wakefulness

Boeve et al, AAN 2012

Epworth Sleepiness Scale Results

0

4

8

12

16

20

24

Tota

l Sco

reBaseline

Maintenance of Wakefulness Test Results

Baseline

Mea

n IS

L (m

inut

es)

0

5

10

15

20

25

30

35

40

45

Dementia with Lewy Bodies DLB Patients Struggle to Maintain Wakefulness


Epworth Sleepiness Scale Results

0

4

8

12

16

20

24

Tota

l Sco

reBaseline Armodafinil 250 mg

p=0.0001

Subjects who improvedSubject who worsened

Maintenance of Wakefulness Test Results

Baseline Armodafinil 250 mg

Mea

n IS

L (m

inut

es)

0

5

10

15

20

25

30

35

40

45

p=0.003

Subjects who improvedSubjects who worsened

Open label pilot study of armodafinil for treatment of hypersomnia associated with DLB

Salient Points:

REM Sleep Behavior Disorder and RelevanceTo Neurodegenerative Disease

• RBD is common in MCI/DLB and usually precedes the cognitive features by years or decades

• Many other sleep issues in DLB, including hypersomnia

Parkinson’s Disease/Dementia With Lewy Bodies/Lewy Body Disease Phenomenology:

LBD Phenomenology


Lewy Body Disease

Lewy body

Lewy Body Disease

A B C

A

B

C

Ach

DA

5-HT

HCT

GluNE

Lewy Body Disease

anosmia

dysrythmia

constipation

erectile dysfunctionurinary dyscontrol

cognitive impairment

hypersomnia

sleep fragmentationparkinsonism

RBD

visual hallucinations

orthostatic hypotension

depressionanxiety

Lewy Body Disease

Cognitive

Neuropsychiatric

Motor

Sleep

Autonomic

Smell

LBD

Parkinson’s Disease/Dementia With Lewy Bodies/Lewy Body Disease Phenomenology:

The PD-Predominant Phenotype

The DLB-Predominant Phenotype


Lewy Body DiseaseMajor Clinical Phenotypes

NormalMild

Cognitive Impairment

Dementia withLewy Bodies

NormalMild

ParkinsonianSigns

PD + MCI

Parkinson’sDisease

Parkinson’sDisease

+ Dementia

Cognitive

Motor

Nl

Nl

MCI DLB

MPS PD PDD

Lewy Body DiseaseFu

nctio

ning

Time

MCIMPS

DementiaParkinsonism

Lewy Body DiseaseParkinson’s Disease-Predominant Phenotype

Func

tioni

ng

Time

MPS PD PD+MCI PDD

Lewy Body DiseaseDementia with Lewy Bodies-Predominant Phenotype

Func

tioni

ng

Time

MCI DLB

Lewy Body DiseaseFu

nctio

ning

Time

MCIMPS


RBDonset

RBD

Idiopathic RBD Analyses

Retrospective Analyses


Idiopathic RBD

Definition• Presence of RBD in the absence of any other obvious neurologic signs/symptoms or disorders

Prevalence• 0.5% to 9% (depending on population studied)

Boeve BF et al, Sleep Med 2013

LBD +/- AD

MSA

AD

PSP

Other

RBD preceded neurodegenerative syndrome (n=170):

>50% of cases• mean – 10 years• range – 1-61 years

Pathology in PSG proven cases (n=82):

Idiopathic RBDRetrospective Analyses

Idiopathic RBDRetrospective Analyses

Salients Points

Analyses have repeatedly shown that when RBD is associated with a neurodegenerative disease:

• The neurodegenerative syndrome is almost always (>95%) within the presumed synucleinopathy spectrum (eg, PD, DLB, MSA, PAF)

• RBD usually precedes the onset of cognitive impairment, parkinsonism or autonomic dysfunction by years or decades

Idiopathic RBD Analyses

Cross-Sectional Correlative Analyses


Lewy Body DiseaseFu

nctio

ning

Time

MCIMPS


RBDonset

RBD

Idiopathic RBDCorrelative Analyses

Numerous investigators

Abnormalities demonstrated on measures of:

• Olfaction• Color vision• Motor functioning• Mood• Anxiety• Apathy

• Neuropsychologicalfunctioning

• Autonomic testing

• EEG

• MRI/MRS/fMRI/DTI

• MIBG

• Perfusion SPECT• DaTscan• FDG-PET• FD-PET

AD

mPOR 2.41

RBD + DLB

mPOR 1.01

DaTscanCorrelative Analyses

AD

mPOR 2.41

aMCI

mPOR 2.31

RBD+naMCI

mPOR 2.1

RBD+DLB

mPOR 1.01



ADmPOR

2.41

aMCImPOR

2.31

RBD+naMCImPOR

2.1

RBD+DLBmPOR

1.01


iRBDmPOR

1.29

iRBDmPOR

2.49

Idiopathic RBDCorrelative Analyses

Salient Points

• A significant proportion of iRBD patients have demonstrable abnormalities on 1 or more measures

• Abnormalities on these measures are most consistent with early/evolving Lewy body disease

Theoretical Evolution of Clinical Manifestations According to Braak Stagein the Prototypical DLB Phenotype of Lewy Body Disease

Parkinson’s Disease/Lewy Body DiseaseBraak Staging Scheme

Boeve BF. Lancet Neurology 2013

Framework of RBD Within Braak Staging Scheme

Braak 2 Braak 3 Braak 4 Braak 5

Func

tion

Age

Normal iRBDMCIMPS

DLBPD


Func

tion

Age

Normal iRBDMCIMPS

DLBPD


Braak 3 Braak 4 Braak 5/6Braak 0

Func

tion

Age

Normal ProdromalRBD iRBD

MCIMPS

DLBPD


Func

tion

Age

Normal iRBDMCIMPS

DLBPD

ProdromalRBD


Braak 3 Braak 4 Braak 5/6Braak 0 Braak 2

Planning for Disease-Modifying Therapies in LBD:

“The RBD Window of Opportunity”


Func

tioni

ng

Time

MCIMPS


Planning for Disease-Modifying Therapies in LBD

Func

tioni

ng

MCIMPS


Assessment Measures

Time


Func

tioni

ng

MCIMPS


Assessment Measures

Time


Rx

Func

tioni

ng

MCIMPS


Time


RBDonset

Func

tioni

ng

MCIMPS


Assessment Measures

Time


RBDonset


Sleep Medicine 2013

Assessment MeasuresClinical

Screening mental status exam (MMSE, MoCA)Motor examination (UPDRS)Olfactory, color vision

NeuropsychologicalMeasure each cognitive domain

ElectrophysiologicEEG, PSG, MSLT, MWT

BiofluidBloodCSF (amyloid, tau, TDP-43, α-synuclein)

NeuroimagingMR – MRI, MRS, fMRI, DTIPET – FDG, PiBSPECT – DaTSCAN, MIBGTCS

Deg

ree

of A

bnor

mal

ity

RBD DLB

Age

MCI

Cognition

DaTscan

FDG-PET

Planning for Disease-Modifying Therapies in LBDTheoretical Considerations for RBD to MCI to DLB

Deg

ree

of A

bnor

mal

ity

RBD DLB

Age

MCI

Cognition

DaTscan

FDG-PET


Deg

ree

of A

bnor

mal

ity

RBD DLB

Age

MCI

Cognition

DaTscan

FDG-PET



Func

tioni

ng

MCIMPS


Assessment Measures

Time

RBDonset


Rx


Tran et al, Cell Reports 2014

Pharm Ther 2013

Func

tioni

ng

Time

MCIMPS

DLBPD

Rx

RBDonset

Assessment Measures


Delay the onset and/or slow the course of parkinsonism and/or

dementia

• Advance our understanding of the pathophysiology of human RBD

• Which specific nuclei/networks are involved?

• Are networks involved in REM sleep control selectively vulnerable to neurodegeneration, particularly in the synucleinopathies? If so, why?

Future Directions

Future Directions

• Study the natural history of RBD, RBD+MCI, RBD+MPS to prepare for future disease modifying therapies

• Identify which iRBD pts have an underlying neurodegenerative disorder• Identify which proteinopathy (ie, α-synuclein, tau, etc.) is causing RBD in those with an underlying neurodegenerative disorder• Identify which phenotype will evolve, and when• Identify those at short-term risk of developing parkinsonism and/or cognitive impairment for treatment trials

• Support or refute the Braak staging scheme as it relates to RBD, and to the MCI/DLB phenotype

• Screen for RBD to assess epidemiology of the parasomnia, and to detect those who could benefit from eventual therapy

• Characterize “prodromal RBD” by quantifying the degree of RSWA on PSGs for clinical and research purposes; characterize REM behavioral events

• Develop or refine more optimal biomarkers for the synucleinopathies

Future Directions

International Dementia with Lewy Bodies Conference

December 1-4, 2015

Marriott Harbor Beach Resort & Spa

Fort Lauderdale, Florida

Abstract Deadline – June 2015

DiagnosisEpidemiologyClinical aspectsNeuropsychologyNeuroimagingTherapeutics

GeneticsBiofluid markersNeuropathologyMolecular biologyAnimal modelsControversies

Collaborators/SupportMike Silber, MBChBErik St. Louis, MDSuresh Kotagal, MDSiong-Chi Lin, MDMaja Tippmann-Peikert, MDMithri Junna, MDMelissa Lipford, MD

Tanis Ferman, PhDGlenn Smith, PhDRobert Ivnik, PhDJohn Lucas, PhD

Departments of Neurology, Psychiatry and Psychology, Diagnostic Radiology, Pathology andLaboratory Medicine, Neuropathology Laboratory, Community Internal Medicine,

Health Sciences Research, and Center for Sleep Medicine,Mayo Clinic Rochester and Mayo Clinic Jacksonvile;

Mayo Alzheimer’s Disease Research Center, Mayo Foundation; andM.H. Udall PD Center of Excellence Grant, Mayo Foundation

Supported by grants AG015866, AG006786, AG016574 from the NIA, the Alzheimer’s Association, and the Mangurian Foundation

Joseph Parisi, MDDennis Dickson, MDMelissa Murray, PhD

Clif Saper, MD, PhDHeiko Braak, MDKelly Del Tredici, MD, PhDAlon Avidan, MD, MPHMark Mahowald, MDRon Postuma, MD, MPHAlex Iranzo, MDCarlos Schenck, MDMany others

Rick Caselli, MDDaniel Drubach, MDNeill Graff-Radford, MBChBKeith Josephs, MDDavid Knopman, MDRonald Petersen, PhD, MDBrendon Boot, MD

Cliff Jack, Jr., MDKejal Kantarci, MDJennifer Whitwell, PhDVal Lowe, MD

Date post:	12-Dec-2016
Category:	Documents
Upload:	haliem
View:	224 times
Download:	1 times

Sleep Disorders Pertinent To Dementia Research

Documents