ALS FTD

Milano 05 Luglio 2016
Decadimento cognitivo patologico
nella donna anziana
Vincenzo Silani
UO Neurologia-Stroke Unit e Lab. Neuroscienze
Università degli Studi di Milano
IRCCS Istituto Auxologico Italiano
CLASSIFICAZIONE
EZIOLOGICA
Demenze primarie o degenerative:
Demenza di Alzheimer
Demenze Fronto-Temporali
Demenza a corpi di Lewy
Parkinson-demenza
Corea di Huntington
Paralisi sopranuclare progressiva
Degenerazione cortico-basale
CLASSIFICAZIONE
EZIOLOGICA
Demenze secondarie:
Demenza vascolare
Disturbi endocrini e metabolici
Malattie metaboliche ereditarie
Malattie infettive e infiammatorie
SNC
Stati carenziali
Sostanze tossiche
Processi espansivi intracraniche
Idrocefalo normoteso
POTENZIALMENTE
REVERSIBILE
Clinical features of the major dementing conditions
DEMENTIA
FIRST SYMPTOM
COGNITIVE
PATTERN
NEUROLOGY
EXAMINATION
NEUROIMAGING
TREATMENT
AD
Memory loss
Amnesia, word
fluency
Normal till late
Posteriorior
temporal/parietal,
PIB positive
Cholinestarese
inhibition, NMDA
antagonist
FTD
Behavior-apathy,
disinhibition,
overeating
Loss of executive
control
Normal (look for
PSP, CBD, ALS)
Anterior
frontotemporal
insular, basal ganglia
SSRI, NMDA
antagonist?
PNFA
Speech, word finding
Non-fluent,
dysarthric, apractic
speach
Sometimes
asymmetric
parkinsonism, axial
rigidity
Left frontoinsular,
basal ganglia
Speech therapy,
treat
parkinsonism,
depression
DLB
Hallucination,
parkinsonism,
delirium
Visuospatial,
attentional
PD (can be normal
at first)
Posterior inferior,
some are PIB
positive
Cholinesterase
inhibition,
carbidopalevodopa
SD
Word finding, loss of
word meaning
Semantic loss,
anomia
Normal till later
Anterior temporal
Consider
cholinesterase
inhibition
Vascular
Variable
Variable,
subcortical lesions
cause frontal
syndrome
Variable,
asymmetric
pyramidal deficits
Multiple stroke
and/or subcortical
white matter lesions
Stroke prevention,
consider
cholinesterase
inhibition
CBD
Asymmetric
parkinsonism, PNFA
or behavioral
Like FTD or PNFA,
sometimes parietal
Asymmetric PD,
dystonia, ocular
apraxia, alien hand
Frontal, basal
ganglia, sometimes
parietal
Exercise, treat
parkinsonism,
treat depression
PSP
Falls, PNFA, behavior
Loss of executive
control
Supranuclear gaze
palsy, axial rigidity
Midbrain atrophy
(variable)
Exercise, treat PD
CJD
Rapid dementia,
parkinsonism
Variable
PD, variable
Cortical ribbon, basal
ganglia
hyperintensity
None
ALSbi
ALSci
Dubois et al., 2007
Underlying biology of dementias
DEMENTIA
HISTOLOGY
GENES FOR
MOLECULES
TOPOGRAPHY
AD
Amyloid plaques,
neurofibrialry tangles
Causal: APP, PS1, PS2
Susceptibility: ApoE4,
SIRT-1
Ab-42, tau
Posterior
temporal/parietal
FTD
Gliosis, spongiosus, pick
bodies, uniquitin-TDP43, FUS/TLS
Causal: progranulin,
tau, VCP, TDP-43,
FUS/TLS, CHMP2B
Tau, TDP-43, FUS/TLS,
C9orf72
Anterior forntotemporal
insular, basal ganglia
PNFA
Gliosis, CBD or PSP
pathology
Causal: progranulin,
rarely tau, often
sporadic
Tau
Left frontoinsular, basal
ganglia
DLB
Lewy bodies, nigral loss,
often amyloid plaques
Causal: rarely
asynuclein, often
sporadic
A-Synuclein, often
comorbid, Ab-42
Posterior parietal,
amygdala, basal
ganglia, brainstem
SD
Gliosis, ubiquitin-TDP43
Causal: rarely
progranulin, tau, often
sporadic
TDP-43
Anterior temporal,
amygdala, eventualy
basal ganglia
Vascular
Infarctions, hyalinization
of blood vessels
No specific causal genes
No
Subcortical white matter
vulnerable with aging
CBD
Gliosis (cortical,
subcortical), coiled
tangles, astrocytic,
plaques
Progranulin, tau,
susceptibility
polymorphisms is H1/H1
tau
Tau
Frontal, basal ganglia,
sometimes parietal
PSP
Globose tangles, tufted
astrocytes,
neurofibrilalry tangles
Rarely tau susceptibility
polymorphism is H1/H1
tau
Tau
Midbrain, caudate,
putamen, braintsem,
cerebellum, some
frontal
CJD
Astrocytosis, spongiosus
Prion gene mutation
Prion
Cortical, basal ganglia,
cerebellum
Bertram and Tanzi, J Clin Inv 2005
Epidemiologia
P
E
R
C
E
N
T
U
A
L
E
Prevalenza
40
AD
VaD
altre deg
secondarie
60%
(raddoppia ogni 5 anni dopo i 65):
ETA’ – fattore di rischio primario
30
20
10
0
60
65
70
75
80
85
90
95
Donna e Decadimento Mentale
Malattia
Donna
Uomo
Malattia di
Alzheimer
FTD
>
2 su 3 ?
=
<
Demenza a
corpi di Lewy
CVD
=
=
=
=
Caregiver
Donna
Uomo
>
in crescita
=
Condizioni sistemiche
Normale invecchiamento
Insulto
Addizionale
Funzioni
Cognitive
Alterazioni cognitive
Soglia della Demenza
Anni
Daffner, 2010
MCI
Riserva Cognitiva
Attività stimolanti
Livello occupazionale
Anni di educazione
Migliore compenso
di una severa patologia
Riserva
cognitiva
Malattia di Alzheimer:
multifactorial disease
Number of patients
Familial cases (autosomal dominant)
Genetics
Early-onset
molecular
genetics
genetics
epidemiology
epidemiology
Risk factors
genetics
genetics +
environment
environment
Environment
Late-onset
cascata
Clinica: esordio AD
Cooper and Greene, 2005
Sintomi non-cognitivi
Behavioral and Psychological Symptoms of
Dementia (BPSD)
•
•
•
•
•
•
•
•
•
•
Apathy (72%)
Agitation (60%)
Anxiety (48%)
Dysphoria (38%)
Euphoria (8%)
Irritability (42%)
Aberrant motor behavior (38%)
Disinhibition (36%)
Delusions (22%)
Hallucinations (10%)
• Estimated overall prevalence at 65% (range from 25%
up to 86% )
Gornbein et al, 1996
APP e cleavage
Genetica: AD autosomica dominante
Genetic markers for AD
Apo E polymorphisms
ApoE gene is located on
chromosome
19
and
presents as 3 alleles: ε2,
ε3, ε4.
The ε4 allele of the ApoE
is associated with the
early-onset familial and
late-onset sporadic forms
of AD.
ε4 allele is involved in enhanced aggregation and/or
decreased clearance of Aβ42
Genetic markers for AD
Apo E polymorphisms
A ε4 allele was detected in about 40-50% of all AD patients
Correspondence between the presence of the ApoE e4 allele and
the pathological diagnosis of AD in 2188 patients with dementia
(Mayeux R et al.,NEJM 1998)
APO E GENOTYPE
PATHOLOGICAL DIAGNOSIS
AD
Other causes of
Dementia
no. of patients
> 1 e4 alleles
1142
133
No e4 alleles
628
285
Total
1770
418
Sensitivity: 65 % (1142 / 1770; 95 percent confidence interval, 62 to 67 %)
Specificity: 68 % (285 / 418; 95 percent confidence interval, 64 to 73 %)
ApoE is regarded as a risk factor indicator rather than
an actual genetic marker of AD
Mayeux R et al.,NEJM 1998
Encefalo
PiB >
LCR
Plasma
Ab42
<
-
TAU
>
-
FosfoTAU >
-
Biomarkers liquorali e AD
Neuroimaging
AD - RM
PET Molecular imaging of AD
[18F]fluorodeoxyglucose-PET
A retrospective clinical-pathological
analysis using visual interpretation
of PET images found 93%
sensitivity and 76% specificity for
the prediction of pathological AD
Silverman DH et al, JAMA 2001
Pittsburgh compund
(PiB)
Biomarker sequence in Alzheimer’s Disease
Malattia di Alzheimer’s : storia naturale
Ipotesi colinergica-taupatia (Mesulam et al, 2004)
Inibitori delle colinesterasi: caratteristiche
Rivastigmina
Donepezil
Galantamina
Caratteristiche
Enzimi inibiti
Inibizione ChE
Prolungata dopo tratt.
A lungo termine
Modulazione
nAChR
Emivita plasmatica
(ore)
Reversibilità
AChE and BuChE
AChE
AChE
Yes
No
No
No
Yes
Yes
1–2
~70
~6
Reversibilità lenta
Reversibile
Reversibile
Sifton (Physician’s Desk Reference), 2002; Svensson, 1997; Weinstock, 1999; Samochocki et al. 2000
Amici et al. 2001; Davidsson et al. 2001; Darreh-Shori et al. 2002; Parnetti et al. 2002
Inoltre
MEMANTINA
• Antagonista non competitivo del recettore NMDA che
blocca i recettori-canali del glutammato in fase di
riposo
• Impiego anche nelle forme gravi di AD
• Associazione con AChI
Tariot, 2006
Active Immunization in AD (1)
• Anti-Ab inducible modify the amyloid cascade preventing AD
progression (Schenk et al., 1999)
• Transgenig mice demostated prevented deposition or reduced
load after active immunization, preventing memory loss
(Morgan et al., 2000)
• Phase I Clinical Trial in AD using Ab did not show efficacy but
development of antibodies (Bayer et al., 2005)
• Phase IIa Clinical Trial halted when 6% patients developed a
sterile meningoencephalitis (Orgogozo et al., 2003). No major
differences in cognitive outcomes (Hock et al., 2003)
Active Immunization in AD (2)
• 8 AD patients showed removal of amyloid plaque proportional
to antibody response but no advantage in time to severe
dementia (Holmes et al., 2008)
• Finding that plaque removal is not enough to halt progressive
neurodegeneration in AD poses challenges to the amyloid
hypothesis
• Recent clinical trials with Ab fragments less likely to activate
unwanted immune response are in progress
Demenza Frontotemporale
(bvFTD)
Clinical Diagnostic Characteristics of FTLD
Sex Distribution
1:1
Age of onset (years)
45-65 (range 21-85)
Duration of illness (years) 6-8 (3 in FTD-MND)
Family History
50%
Presenting Symptoms
Behavioral changes
Cognitive Features
Executive deficits, language and speech changes
Neurological signs
Parkinsonism late; MND in small proportion
Neuroimaging
Abnormalities in frontotemporal lobes
Neary, Lancet Neurol 2005
Gorno-Tempini, Neurology 2011
Pressmann, Biol Psych 2014
Eterogeneità delle FTD
Geni delle FTD
familial
40 - 45%
SOD1
TARDBP
FUS
Others
MAPT
C9ORF72
GRN
VCP
CHMP2B
Counselling Genetico: quale gene?
Genes
Proteins
Inclusions
Phenotype
MAPT
Microtubule
network
TAU inclusions
bv-FTD (often with
parkinsonism);
PSP; PPA
GRN
Growth factor
Ub/TDP-43
inclusions
bv-FTD; SD; PPA;
CBS; AD
VCP
Vescicle transport
Ub/VCP inclusions
IBMPFD; FTD/ALS
CHMP2B
Endosomal
trafficking
Ub inclusions
FTD/ALS
TARDBP
DNA
binding/regulating
protein
TDP-43 inclusions
ALS/FTD
FUS
DNA regulating
protein
FUS inclusions
ALS/FTD
C9orf72
Unknown
Unknown
ALS/FTD/psychosis
Figure 1 Proposed molecular diagnostics on the basis of clinical phenotype
and pattern of brain atrophy
Borroni, B. & Padovani, A. (2013) A new algorithm for molecular diagnostics in FTLD
Nat. Rev. Neurol. doi:10.1038/nrneurol.2013.72
SLA-FTD: continuum clinico !
FTLD
social
language
non-fluent
bvFTD
bvFTD
10%
FTD-MND
10%
ALS-FTD
cognitive
impairment
ALS-bi/ci
PNFA
SD
ALS-PNFA
ALS-SD
lvPPA
no cognitive impairment
60%
40%
PMA
fluent
ALS
PLS
ALS-FTD: genetic continuum (2016)
>24 genes
6 genes
50-65% familial ALS
5-10% sporadic ALS
40-80% familial FTD
<10% sporadic FTD
ALS
FTD
c9orf72
c9orf72
SOD1
TARDBP
FUS
GRN
MAPT
ANG
OPTN
VCP
PFN1
CHMP2B
UBQLN2
VAPB
SPG11
ALS2
ATXN2
FIG4
SETX
hnRNPs
MATR3
ERBB4
“pure”
ALS genes
VCP
CHMP2B
TREM2
ALS-FTD
genes
“pure”
FTD genes
ALS and FTD: further alliance for future therapies
Ittner et al., 2015
FTD
Earliest differences:
MAPT
Boston Naminf Testgand CBI-R
GRN
Digit Span backwards
C9orf72 CBI-R
Volumetric MRI
GENFI
Rohrer et al., 2015
FTD
-25
-20
-15
-10
-5
MAPT
hyppocampus
amygdala
temporal lobe
insula
GRN
insula
temporal
parietal lobe
striatum
asymmetry
C9orf72
thalamus
insula
posterior
cortex
frontal
temporal
lobe
cerebellum
Rohrer et al., 2015
Precision Medicine: AD ed FTD
Montine and Montine, 2015
Demenza con Corpi di Lewy (DLB)
• Okazaki (1961), ritenuta erroneamente rara
• Spesso corpi di Lewy + istopatologia AD (placche
senili)
Demenza Corticobasale
Donna e Caregiving
Caregiver
Donna
Uomo
>
in crescita
IRCCS Istituto Auxologico Italiano
Centro “Dino Ferrari”
Università degli Studi di Milano
ICGEB Trieste
Francisco E. Baralle
Emanuele Buratti
Fondazione IRCCS Istituto “Carlo
Besta”
Cinzia Gellera
Barbara Castellotti, Viviana Pensato
Caterina Mariotti, Franco Taroni
UMass Medical School
Dept. Neurologia
Stroke Unit
Laboratorio di
Neuroscienze
Laura Adobbati
Luca Campana
Andrea Ciammola
Barbara Corrà
Alberto Doretti
Riccardo Doronzo
Alberto Lerario
Carolina Lombardi
Luca Maderna
Niccolò Mencacci
Stefano Messina
Claudia Morelli
Barbara Poletti
Davide Sangalli
Nicola Ticozzi
Antonia Ratti
Patrizia Bossolasco
Claudia Colombrita
Lidia Cova
Valentina Diana
Annamaria Maraschi
Elisa Onesto
Francesca Sassone
Cinzia Tiloca
Isabella Fogh
Claudia Fallini
Niccolò Mencacci
Federico Verde
London, UK
Worcester, USA
London, UK
Ulm, Germany
John E. Landers
Chi-Hong Wu, Jenni Adams, Desiree
M. Baron, Daryl A. Bosco,
Robert H. Brown Jr.
Claudia Fallini
Weill Cornell Medical College
New York
Dale J. Lange
SPONSORS
STRENGTH