distinguere la demenza di alzheimer dalla demenza a corpi di lewy · 2019. 10. 29. · transient...
TRANSCRIPT
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Distinguere la demenza di Alzheimer dalla demenza a corpi di Lewy
Annachiara CagninDipartimento di Neuroscienze
Padova
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What’s on in DLB?
Challange 1: sensitivity of diagnostic criteria
Challange 2: diagnostic specificity and pathological comoribidity
Challange 3: Definition of prodromal DLB
…and hence need of biomarkers
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Not so rare
Lewy bodies pathology is common:community dwelling older subjects: 18% of casesdementia patients: 15-20%
Alzheimer’s disease comorbidity in half cases
Prevalence (clinical diagnosis)- Community setting: 4.2%- Secondary care setting: 7.5%
Schneider et al, Brain 2012, Jellinger; 2011; Vann Jones, Psychol Med 2014
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But…
O’ Brien 2018
4.6% of all diagnoses(ranging 2.5-6%)
More frequently diagnosedin young subjects
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Why revised diagnostic criteria?
Low sensitivity in clinical setting (Nelson, 2014)
Atypical DLB is now recognized
Some core features may never be present (25% no motor signs)
More weight on “indicative” biomarkers
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Core clinical features
FluctuationsVisual
HallucinationsRBD Parkinsonism
Indicative Biomarkers
DA uptake in the basal ganglia (SPECT o PET)
Polysomnography (confirmed REM without atonia)
Uptake 123I-MIBG (cardiac scintigraphy)
McKeith 2017
Essential
Dementia (visual-
spatial/attention)
• PROBABLE DLB= – 2 core features– 1 core feature + 1 indicative biomarker
• POSSIBLE DLB= – 1 core feature– 1 indicative biomarker
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Lewy body composite risk score (≥3)
motor
Sleep/wake, fluctuation, RBD,VH
3 minutes to make diagnosis of DLB
Galvin, Alz&Dementia 2015
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EXTRAPYRAMIDAL SIGNS IN DLB
AARSLAND, 2001
DLD>PD
DLB<PD
98 DLB patients
130 PD patients
68 % EPS +
• Body bradykinesia• Action tremor• Facial expression• Gait instability
• Rest tremor• Rigidity
Severity did not correlate with age, disease duration, cognition
PIGD
MIXED TREMOR
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Sleep-wake/fluctuationcluster
RBD upgraded to core featureHypersomnolenceTransient episodes of unconsiousnessadded among suggestive features
Polysomnography added as indicative biomarker
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Sleep
frequent RBD-like symptoms (70%)
Wake
increased somnolence
increased number of daytime naps
daytime dysfunction due to somnolence
fluctuation of attention (associated with RBD+)
SLEEP-WAKE in DLB
Cagnin et al, JAD 2017
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FLUCTUATIONS
Spontaneous alterations in
– Cognition
– Attention
– Arousal
• Behavioural inconsistency
• Disorganized speech
• Altered consciousness-lethargy
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Brain 2019
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Analisi degli spettri:
Studio delle sorgenti di attività elettrica cerebrale:
Studio di complessità:
EEG nella DLB
- frequenza dominante: pre- alfa / theta (5,6- 7,9 Hz)prevalente nelle derivazioni posteriori
- fluttuazioni delta- theta/pre- alfa o theta- pre- alfa/alfa
- correlazioni con fluttuazioni cognitive
- attività diminuite nelle derivazioni occipitali e sensori- motorie.
- correlazioni con peggiori funzioni cognitive.
Nessuno studio a disposizione nella DLB
Cromarty, R. A. et al., 2016, Clin. Neurophysiol.; Bonanni, L. et al., 2008, Brain ; Stylianou, M. et al., 2008, Clin. Neurophysiol.Bonanni, L. et al., 2016, Alzheimer’s Dis.; Babiloni, C. et al., 2018, Alzheimer’s Dis.; Aoki, Y. et al., 2019, Neuropsychobiology
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Open issues
PSG versus RBD questionnaires?
Diagnosis of RBD versus NON REM sleep
behavioural disorder (i.e. confusional awakenings, …..)?
ESS versus other scales dedicated to dementia
Definition of outcomes for interventional
treatments?
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• Associated with poor visual attention
• Long fibers tracts dysconnection mainly in the righy hemisphere
• Imbalance between attentional functionalnetworks
Anatomical correlates of VH
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FUNCTIONAL CORRELATES OF VH
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What’s on in DLB?
Challange 1: sensitivity of diagnostic criteria
Challange 2: diagnostic specificity and pathological comorbidity
Challange 3: Definition of prodromal DLB
…and hence need of biomarkers
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Brain comorbidity in real life
Rabinovici, 2017
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Ann Neurol, 2018
Comorbidity is the rule : 3/4 has 2 or more co-pathologies
230 combinations
AD is the most virulent accounting for an average of 50%
cognitive loss but individual contribution is variable
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Heterogeneity of presentations
Additional pathology
Age
Genetic variability of
a-synuclein
Different route of entry
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Additional pathology
66% of DLB brains will have AD pathology
DLB phenotype is driven by alpha synuclein and neuritic plaques
AD pathology has an additive effect on clinical variables
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Lemstra, JNNP 2016
DLB/AD+ DLB/AD-
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Bussè et al, JAD 2018
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AD-like CSF biomarkers
Stenooven, JAD 2016
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Cortical thinning
Seok, Neurobiol Aging 2018
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What’s on in DLB?
Challange 1: sensitivity of diagnostic criteria
Challange 2: diagnostic specificity and pathological comoribidity
Challange 3: Definition of prodromal DLB
…and hence need of biomarkers
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Prodromal DLB
Postuma et al, Brain 2019
iRBD population followed for 14 years
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Optical Coherence tomography
Retinal thinning in DLB
Papilla Macula
Frag
iaco
mo
, Cag
nin
, Mo
vD
is2
01
9
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Prodromal DLB
McKeith et al, 2017
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Cognitive impairment in prodromal DLB
Ferman et al, Neurology 2013
DIAGNOSIS OF AD
DIAGNOSIS OF DLB
PROGRESSION RATEincidence/100 person-years
naMCI: 20% DLB, 1.6% AD
aMCI: 17% AD, 1.5% DLB
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IMPAIRED NUMBER OF ANGLES
MCI-DLB: 45.1% versus MCI-AD: 8.3%, p = 0.005
SENSITIVITY = 41.4% PPV: 86%SPECIFICITY = 91% NPV: 54%
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Tryciclic antidepressant
Conventional antypsychotic
Benzodiazepine
SSRI
ChEI
MMSE: 22/30 MMSE: 30/30
• M; 72 yrs
• RBD
2-month time
Neurotransmission in visuospatial performance
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Clinical similarities
Delirium more common in predementia phase of DLB than AD (Vardy, 2014)
Severe cholinergic dysfunction
Higher frequency of APOE4 (?)
Therapeutic implications (no haloperidol)
Delirium in the spectrum of DLB
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DLB-psychiatric onsetSupportive features
……….
Hallucinations in other modalities
Sistematized delusions
Depression-apathy
……….
core feature Complex recurrent visual hallucinations
Late-onset Affective disorder
Late-onset psychosis
Treatment refractory
Neuroleptic adverse sensitivity
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Sea-monster with 50 tentacles?
R Williams
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What’s on in DLB?
New revised diagnostic criteria
Heterogeneity of presentation
Definition of prodromal DLB
…and hence need of biomarkers
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Biomarkers
• Dat scan has well established utility (Se 78%, Sp 90%)
Only in cases of no or uncertain parkinsonism
• PSG: high likeliwood of synucleopathy but difficult to perform in older demented patients
• MIBG: high specificity
• Need of biomarkers mirroring the molecular pathology(CSF RTQuic?)
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Future scenario
Cohort of at risk patients
Possible prodromalDLB
Probable prodromalDLB
• RBD• IPOSMIA• Pentagon copy- MMSE• DELIRIUM
• TCS• DAT-SCAN• Markers α-syn ?
Screening for core/suggestive features
Search for• α syn pathology• Neuronal dysfunction
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Sea-monster with 50 tentacles
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Neurology, 2017
“False negative”: 10%“False positive”: FTD-parkinsonism
DAT SPECT: SE 80%, SP 92%CLINICAL DIAGNOSIS: SE 87%, SP 72%
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HC
PDMSA
PSP
AD
HOW DOES IT LOOK LIKE?
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Kantarci, Neurology 2017
CingulateIsland Sign
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Motor cluster
“One of the motor signs of Parkinson diseaseamong bradykinesia, rigidity, rest tremor.”
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What’s on in DLB?
New revised diagnostic criteria
Heterogeneity of presentation
Definition of prodromal DLB
…and hence need of biomarkers
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• Recurrent complex VH (human faces, animals)
• Preserved environment
• Poor/lack insight
• Coping strategies
• Pre-hallucinatory episodes:
o Feeling of presence or of passage
o Visual illusions
• Secondary related delusions
Visual Hallucinations
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Anatomical correlates of VH
Cagnin et al, submitted
DTI-MRI
R L
T1-volumetric MRI
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In PD the lateral part of SN always degenerates first
=
Preferential loss in putamen relative to caudate
PUTAMEN
“From comma to full stop !”
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18F-DOPA PET
Acquisizione 5 min !
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123I-FP-CIT scans
CTRL PD
AD DLB
Walker, Neurology 2004
DAT scan in DLB
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123I-MIBG
“INDICATIVE BIOMARKER”
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TRACERS USED FOR CARDIAC SYNAPTISTARGETS FOR DOPAMINERGIC LIGANDS
Receptors
L-tyrosine
dopa
Dopamine
11C-CGP12177
11C-carazolol
11C-MQNB
Noradrenaline
MYOCITE
11C-Hydroxyephedrine
11C-epinephrine
123I-MIBG
DOPAMINE18F-FDOPA
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Atypical pattern of tau deposition
Amy +
Amy -
AV 1451 TAU +
AV 1451 TAU +
Temporo-parietal regionsDLB
Kantarci, Ann Neurol 2017
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Kovacs, 2019
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Jellinger, 2015
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Cross seed with other proteins
a-synuclein strains
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• Severe sensitivity to antipsychotics
• Postural instability
• Falls/syncope
• Transient episodes unconsiousness
• Autonomic dysfunction
• Hypersomnolence
• Hyposmia
• Hallucinations in other modalities
• Systematized delusions
• Apathy-anxiety-depression
• Relative preservation MTL
• General low PET uptake with
reduced occipital activity +/-
cingulate island sign
• Posterior slow-wave activity on
EEG with periodic fluctuations
Supportive features Supportive biomarkers