Roma, 14-15 novembre 2019, Istituto Superiore di Sanità
Il contributo dei centri per i disturbi cognitivi e le demenze nella gestione
integrata dei pazienti
Aspetti preventivi
nella gestione dei disturbi del sonno
Biancamaria GuarnieriNeurologa, Esperto in medicina del sonno (AIMS), Somnologist (ESRS)
Centro di Medicina del Sonno riconosciuto A.I.M.S. ,
Casa di Cura Villa Serena, Città S. Angelo (Pescara)
Disturbi del sonno oltre l’insonnia
e con l’insonnia
• Insonnia: inziale , di mantenimento , terminale
• Eccessiva sonnolenza diurna (EDS)
• Disturbi respiratori nel sonno (OSA in particolare)
• Sindrome delle gambe senza riposo(RLS) ( spesso associata a riscontro
PSG di mioclono periodico notturno-PLM)
• Parasonnie: in particolare disturbo del comportamento in sonno REM
(RBD)
• Disturbi del ritmo circadiano del sonno (CSWRD), in particolare S. da
anticipata fase di sonno (ASPD), S. da ritmo sonno-veglia
irregolare(ISWRD), S. da posticipata fase di sonno(DSPD)
10 Italian sleep and dementia
centersDementia until CDR 2
High prevalence ( 65-90%) of all sleep
disturbances since MCI
higher for SDB, RBD, EDS in men
higher fo RLS in women
No significant sex differences for insomnia
( insomnia patients were older)
Score for depressive symptoms more
severe in persons with any sleep
disorders
Two or more sleep disturbances almost invariably present in the
same patient
Sleep Med Rev 2018
Sleep disturbances increase the risk of dementia:
A systematic review and meta-analysisShi LChen SJ Ma MY Bao YPHan Y Wang YM Shi J Vitiello MVLu L.
• insomnia, sleep disordered breathing [SDB] excessive daytime sleepiness, sleep-related movement disorder, circadian rhythm sleep disorder, and nonspecific sleep problems
• longitudinal studies published up to October 28, 2016
12,926 papers18 longitudinal studies , 246,786 subjects at baseline and 25,847 dementia cases
average 9.49 y of follow-up
subjects who reported sleep disturbances
higher risk of incident all-cause dementia,
AD, and vascular dementia
• Insomnia: increased risk of AD but not vascular or all-cause dementia
• SDB( OSA in particular) : higher incidence of all-cause dementia, AD, and vascular dementia
Osorio R. et al
655 normal volunteers ( 24-96 yrs)
Normal-AD: 25 Normal-Normal :321
Items 4-5-6 Hamilton Depression Rating Scale
Insomnia :higher risk for dementia OR 2.37
Excluding patients with depression:OR 3.32
Insomnia patients : faster cognitive decline
479 frail elderly - 70 and over - Multidomain Preventive Trial(MAPT)
63 developed cognitive decline between M24 and M36
EDS , increased risk of MMSE decline
( OR 2.46, 95% CI, P-0.007)
longer time in bed during night with higher WASO ( reduced night sleep efficiency)
increased 24 h-total sleep time risk cognitive compose score ( OR 1.32, P- 0.03)
2017
Clinical interview
number of naps and total sleep
time during the day
ESS
Insomnia Severity Scale
Berlin Questionnaire
Italian multicenter study( 2012) EDS prevalence from 44.5 (AD) to 71 % (DLB)
prospective longitudinal
cohort study
up to 6 years follow-up
698 community-dwelling older adults without dementia (mean age,
81.7 years; 77% women )
actigraphic recordings
Autopsies on 201 participants
98 individuals developed AD
Better sleep consolidation attenuates the effect of APOE
genotype on incident AD and development of neurofibrillary
tangle pathology
JAMA Neurol 2013
Metodological problems in
studying AD
complex etiology
uncertain onset and preclinical phases
sex and gender differences. Higher
risk in women (oophorectomy-
education)
timing effects( timing hypothesis,
age is the driver)
Three population studies Sweden– Finland
Late life analysis all three studies
3-10 years follow up ( 1446 persons)
Midlife analysis only Finland, two studies
21 and 32 years follow up ( 1407 persons)
Midlife insomnia and late life terminal insomnia or long sleep
duration ( in 24 hours) :higher late life dementia risk
13 studies (6
prospective and 7
cross-sectional)
SBD :
slightly worse
executive function
26% more likely to
develop cognitive
impairment
SDB: effects on executive functions,
vigilance, psychomotor speed
Mixed findings on memory
2017
almost 50% AD patients
experienced OSA
an incentive to alert
clinicians on the importance
of screening patients for
OSA
OSA has been shown to cause progressive central nervous changes
and excessive daytime somnolence in susceptible patients, and this
can contribute to further cognitive decline or AD progression
(Rosenzweig et al.,2013, 2015)
2016
«To facilitate the
development of novel
therapies to atreat
and potentially
prevent both sleep
disturbances and
cognitive
impairment»
K.Yaffe et al.
Lancet Neurol 2014
Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M,
et al.
Sleep drives metabolite clearance from the adult brain
Science 342, 373 (2013)
real-time assessments of tetramethylammonium
diffusion and two-photon imaging in live mice
• natural sleep or anesthesia are associated
with a 60% increase in the CNS
interstitial space, resulting in a striking
increase in convective exchange of
cerebrospinal fluid with interstitial fluid.
• In turn, convective fluxes of interstitial fluid
increased the rate of β-amyloid clearance during
sleep(levels falled at twice during sleep )
• The restorative function of sleep may be a
consequence of the enhanced removal of
potentially neurotoxic waste products that
accumulate in the awake CNS
Glymphatic clearance
2017Disruption of sleep –wake rhythm =>
increased oxidative stress/ impaired BBB/more
neuronal activity ( glymphatic system involved),
disruption of central circadian clocks
before the clinical onset of AD
• Medial prefrontal cortex beta amyloid
• Impaired sleep (SWA)
• Hippocampal dependent memory
2015
17persons 35-65years
one night SWS deprivation: lower CSF amyloid beta
5-14 days actigrapic detection of poor sleep
higher CSF tau levels
119 cognitively normal over 60 persons
6 nights, single channel frontal EEG, Actigraphy, sleep log
CSF a beta 42, p-tau and t-tau (104 persons)
Amyloid and Tau PET ( 38 persons)
Reduced 1-2Hz SWS:
correlation with a Aβ 42
but higher correlation with
TAU
• Therapeutic interventions to restore non REM Slow Wave Sleep
might be used as a preventive measure to reduce AD risk in younger
patients or in high vulnerability populations.
• Mander et al 2016
MS(GABA) neuronal activity specifically during REMS is required for normal
memory consolidation
20 MCI- 26controls
REM sleep disruption and sleep
fragmentation related to higher
CSF-orexin levels in
MCI due to AD,
the orexin system may be involved even in
the earliest stages of AD
resulting in prolonged sleep latency,
reduced sleep efficiency and REM
impairment
orexinergic upregulation in AD
Science 2009
Amyloid-beta dynamics are regulated by orexinand the sleep-wake cycleKang JE et al ( Holtzman DM group)
Chronic sleep restrictionsignificantly increasedAβ plaque formation
The amount of ISF Aβ alsosignificantly increased duringacute sleep deprivation and during orexin infusion
amyloid precursor protein transgenic
mice in vivo microdialysis
Circadian influences on neurodegenerative protein aggregation.
Pro-neurodegenerative mechanisms have been identified at every stage, leading to the aggregation
of otherwise soluble proteins and their spreading through prion-like mechanisms.
Significantly, many, if not most, of these physiological and pro-neurodegenerative mechanisms
are under circadian regulation.
Thus, in addition to neurodegenerative diseases affecting the circadian clock, the
circadian clock has the potential to promote (or hinder) disease progression
Curr Opin
Neurobiol.
2013
Circadian
clocks and
neurodegene
rative
diseases:
time to
aggregate?
Hastings MH,
Goedert M
TAU
Mouse ISF tau increased ~90% during normal wakefulness versus sleep and ~100%
during Sleep deprivation (SD)
In a tau seeding-and-spreading model, chronic SD increased tau pathology
spreading ( 28 days SD)
Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ
and tau.
Human CSF tau also increased more than 50% during SD
The sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau (as
well as tau pathology spreading- in mice)- synuclein too
February 2019
ChemogeneticSleep deprivation
Photic input to SCNLight
Non photic input to SCN
• Exercise
• Social zeitgebers
• Feeding times
Regolazione del ritmo circadiano del sonno
Modificata da Hastings MH, Goedert M 2013, Zee et al 2013, Coogan et al 2012,
Benarroc 2008, Panda et al 2002
Overall these data support the idea that mRGC loss may contribute to
circadian dysfunction in AD
Annals Neurol 2016
1) Loss of retinal nerve fibers in AD patients by optical
coherence tomography
2) Variable degrees of circadian dysfunction in AD patients
compared to controls as evaluated by actigraphic recordings
3) Loss of melanopsin retinal ganglion cells in AD
4) Presence of amyloid plaques in AD retinas
5) Aβ deposits in mRGCs implying primary AD pathology in
these cells
neuroendocrine
neuroinflammatory
signaling
IMPARING
ADULT
HYPPOCAMPAL
NEUROGENESIS
through sleep and SW
rhythm disturbances
APOE, PS1, APP can modulate adult hyppocampal
neurogenesis AD reduced neurogenesis
Sleep disruption impairs neurogenesis :
sleep remediations, a new therapeutic approach
OSA patients : reduced CSF A β 42Higher CSF lactate and t-tau/A β 42 ratioas compared to controls and OSA-CPap patients
Neurology 2015
New treatment opportunities: CPAP ventilation
Diversi livelli di rischio tra uomini e donne Gender differences in clinical and polysomnographic features
of obstructive sleep apnea: a clinical study of 2827 patients
Ozen K Basoglu and Mehemet Sezai Tasbakan
Sleep Breath 2017
and thus women are less likely to be referred for the
evaluation of OSA
So, the diagnosis of OSAS may be missed in women, and
they have worse clinical course
RBD :contributo del sonno all’’esplorazione
delle sinucleinopatie
Parasonnia
formalmente
identificata nel 1986
Schenk C, Manhowald M.
“ REM sleep beahvior
disorder: clinical ,
developmental and
neuroscience perspective 16
years after its formal
identification
Sleep 2002
• Comportamenti motori rapidi, bruschi, talora
vigorosi e spesso violenti, di solito associati a sogni
spiacevoli con contenuto di aggressione(“ dream
enacting behaviors”)
• Incubo tipico dell’RBD: essere attaccati da animali
o persone sconosciute e anche combattere per
autodifesa o tentativo di fuggire. Contenuti più
quieti sono presenti ( spesso connessione con attivtà
lavorativa attuale o pregressa)
• Perdita dell’inibizione muscolare in REM , aumento
del drive motorio (PSG)
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al., 2001)
Sporadically
reported in
tauopathies
(overlap LBD
neuropathology?)
• Parkinson’s disease (PD) ++
• Lewy Body Dementia (LBD) +++
• Multiple System Atrophy (MSA) +++
• Progressive Supranuclear Palsy (PSP)
• Cortico-Basal degeneration (CBD)
• Alzheimer’s disease
RBD = Positive predicting value for α-synucleinopathies > 90%
The international RBD study group
24 centri
1280 pazienti
Conversione di
iRBD in sinucleinopatia
73.5% a 12 anni
56% in PD
43.5% demenza
4.5 % MSA
Tempo mediano di
conversione :8 anni
sample size estimation for neuroprotective trials
2017
16 pazienti VPSG per dream enacting
behaviors e sogni spiacevoli suggestivi
di RBD, russamento ed ipersonnolenza
diurna ( più controlli) :
AH Index medio di 67.5 ±18.7 fasi /ora
non REM senza atonia in PSG
Arousal respiratori in REM e non
REM
Trattamento ventilatorio:
risoluzione di eventi
Sleep 2005
NPS measures
should be included in alla sleep research
objective sleep measures
should be included in NPS studies
few farmacologic treatment option
CRSD in AD
Profoundly disrupted circadian rhythms in
moderate/severe dementia
Sundowning
Volicer L.Harper D., Manning BC, Goldstein R. Satlin A “ Sundowning and circadian rhythms
in Alzheimer’s disease” Am J Psychiatry 2001
Inpatients on the dementia
study unit at Dept Veterans
Affairs Hospital
25 MALES
AD dementia
mean duration of ilness:
11 yrs
Though with some dispute in the
literature, in 1993, Bliwise and
colleagues found that there is a
seasonal effect in sundowning
more common in the time of the
year when daylight hours are
shorter (winter )
(not all authors agree)
Alzheimer and Lewy body
dementia are the two conditions
most routinely studied in relation to
sundowning.
SundowningA formally undefined but very often
observed and cited entity
Ewen Cameron's 1941 first report
a collection of neuropsychiatric symptoms
that can present in patients with and
without dementia
Occuring during a specific
part of the day
The exact timing of sundowning behaviors
is contested, but most can agree that it
occurs in the
afternoon ( generally between 3:00-
7:00 pm ) and/or early evening
Dementia ,sleep and neurogenetic centers
involved (*)
Pisa (*) Bologna (*)
Pescara Firenze Genova Pavia Messina
Conceived and promoted by the Italian Association of Sleep Medicine (AIMS) Committee
on Sleep and Neurodegenerative Disorders in collaboration with the Italian Neurological
Society for dementia research (SINdem)
Italian multicenter actigraphic study on clock and
melanopsin genes in MCI , AD and controls
Bonanni Enrica ., Guarnieri B., Faraguna U., Mancuso M., La Morgia C.,
Arnaldi D., Manni R., Silvestri R., Sorbi S., et al- in preparation
Clin Interv Aging. 2014
Tailored lighting
intervention improves
measures of sleep,
depression, and agitation in
persons with Alzheimer’s
disease and related
dementia living in long-
term care facilities
Figueiro MG et al
J Alzheimer Dis. Jan 2013
Light Therapy and Alzheimer’s Disease and
Related Dementia: Past, Present, and FutureFigueiro M G
Different protocols for
EDS, Advanced or
delayed sleep phase
disturbance/ISWRD,
Sundowning , insomnia
timing of light exposure
exposure to bright light in the early morning ( after the
nadir of the core body temperature rhythm)
induces phase advance
exposure to bright light in the evening ( before the nadir of
the core body temperature rhythm)
induces phase delay
Timed melatonin administration
according to the type of circadian sleep-wake rhythm disorder
Strumenti pratici di identificazione dei disturbi del
sonno e del ritmo sonno- veglia
• Osservazione diretta del paziente
• Attenta anamnesi sonnologica
• Testistica sonnologica ( discreti/ buoni livelli di sensibilità e
specificità)
• Actigrafia ( per tempi di sonno, parametri circadiani)
• Melatonina salivare
• Poligrafia dinamica ambulatoriale ( monitoraggio cardio
respiratorio completo)
• Polisonnografia notturna ambulatoriale
• PSG- video PSG in laboratorio
• Sviluppi di ingegneria biomedica : sistemi contact e non contact
per PSG
FUTURI STRUMENTI DI
IDENTIFICAZIONE
Precision medicine
Time Signature, a machine learning
( predictor)
clock genes expression based
predictor of physiological
circadian time of a person
Algorithm to learn the time of dayas a function of gene expression in
blood
predictions that reflect the internal state of the subjects’ biological clockUseful in clinical practice and
experimental settings
2 prelievi di sangue nelle 24 ore / 41 geni
A.I.M.S. contribution
Approved by the Italian
Society of Neurology on
February 2014
Revision/updating needed
20/9/2019Tra gli elementi innovativi del documento tecnico
«La polisonnografia e/o la video-
polisonnografia sono indicate in funzione del
quadro clinico, in pazienti selezionati con
attente anamnesi e testistica
sonnologica….»
Indicazioni :
diagnosi differenziale in MCI e demenze
diagnosi definita di RBD
PDTA demenze Regione Abruzzo
nel documento tecnico
«Regolatori dei disturbi del sonno nella demenza»
• «Nei soggetti con demenza i principali disturbi del sonno includono: insonnia, eccessiva sonnolenza diurna, alterazione del ritmo sonno-veglia, alterazione della respirazione durante il sonno (tra cui OSAS), parasonnie durante la fase REM del sonno (RBD) e sindrome delle gambe senza riposo…..»
• Per i trattamenti, approccio integrato per i vari disturbi de sonno
• Trattamenti non farmacologici
• ventilazione per OSAS
Commissione AIMS « sonno e malattie
neurodegenerative» (2012)
Gruppo di studio « Sonno» SINdem (2006)
“When we try to encourage a good night’s
sleep for our patients perhaps we are doing them
more good than we thought”
John Mc Kinley et al.
Frontiers in Neurology 2013
Centro di
Medicina del
Sonno
riconosciuto
A.I.M.S.
U.O. Neurologia
Casa di Cura
Villa Serena
Città S. Angelo
(Pescara)
