Demenza Fronto-Temporale e
Malattia del Motoneurone
Vincenzo Silani
Dept. Neurology-Stroke Unit - Laboratory of Neuroscience
“Dino Ferrari” Center
IRCCS Istituto Auxologico Italiano
University of Milan Medical School
1869
ALS: disease
due to selective
vulnerability
atrophy
weakness
tone
tendon reflexes
abnormal reflexes
CRITERI CLINICI
Trofismo
Tono
Stenia
ROT
Segni patologici
REGIONS
Bulbar
Thoracic
Cervical Abdominal Lombar
UMN
+
+
+/-
+
LMN
+
+
+
+
Clinically definite ALS
ALS: disease due to selective vulnerability
El Escorial (1990)
Nature, 1993
Airlie House (1994)
Airlie House (1998)
AAN (1999)
Awaji Consensus (2008)
…………
Different clinical phenotypes !
Sabatelli et al., 2013
Amyotrophic Lateral Sclerosis
Jean-Martin Charcot, 1874
“ patients are not demented
and cognition is spared “
ALS: The extramotor “Moveable Feast”
•
•
•
•
•
•
•
•
•
•
•
•
•
Marie, 1892
Dornbluth, 1889
Raymond, Cestan, 1905
Fragnito, 1907
van Bogaert 1925
Meyer, 1929
Zieger, 1930
Braunmuhl, 1932 (single case report, link ALS-Pick)
De Caro, 1941
Michaux, 1951
Delay, 1959
Van Reeth, Coers e van Bogaert, 1961
……
but
• Poloni et al. 1986: no neupsychological deficits in ALS !
Annali di Neurologia, 25, 273-287, 1907
Encephale, 20, 27- 47, 1925
Zeitschrift für die Gesamte Neurologie und Psychiatrie, 121, 107-138, 1929
Ludo van Bogaert
(1897-1989)
Rassegna di Studi Psichiatrici, 30, 705-722, 1941
• frontal impairment clearly mentioned
The clinical diagnosis and the various types of FTLD
Neary et al, 1998, 2005, 2011
--- mild frontal deficits as a group effect
--- impaired word and design fluency
--- correlation with decreased glucose metabolism
Clear-cut group differences, but also large
interindividual differences
ALS
ALS
Normal
Frontal functions were predominantly affected………..
- „your hypothesis is wrong, Dr.Ludolph“ (Editor of……1988)
Regional brain atrophy in ALS patients with unknown cognitive status
P
50%
F
32%
I
38%
O
12%
T
20%
+ white matter degeneration
• left middle/inferior
front gyri
• anterior portion
sup front gyri
• sup temp gyri
• temp poles
• left post thalamus
• amigdala
• medial temp lobe
• > severe frontal
atrophy ALS + FTLD
ALS
Leigh and Lowe (1988- 2006): ubiquitin deposits
2006
Ubiquitin
2006
TDP-43
TDP-43: scoperta legata alla immunoistochimica
*
*
Neumann et al., 2006
TDP-43 aggregates in the cytoplasm *,
leading to its loss from the nucleus *
Model of TDP-43 disease
pathogenesis
ALS & FTD: making connections
2008
2008
• 149 French FTLD-MND (71 familial – 78 sporadic)
• 3 variants in 9 patients
Coorte studiata:
FALS 6/125 4.8%
SALS 12/541 2.2%
first evidence of pathogenic mutation as causative of behavioural
variant of FTD without MND – 74 y/o - bvFTD
2011
Proteinopatie TDP-43
Neumann, et al., 2006
più comune sottotipo
istolopatologico
Cairns and Ghoshal, 2010 modified
Science 26 Feb 2009
FUS/TLS in Italian FALS
FTD
bvFTD
= FTLD-FUS
• aFLTD-U, sporadic
• no FUS mutations
• 10 % cases
• tau/TDP-43 neg
• glial localization
Proteinopatie TDP-43 e FUS
Cairns and Ghoshal, 2010
Novel molecular classification / Nomenclature of FTLD
No
Inclusions
Inclusions
TAU+
Old nomenclature
Tau-positive
FTLD
Ubiquitin-only+
Intermediate
Filaments
Basophilic
Inclusions
FTLD-U
NIFID
BIBD
TDP-43 +
DLDH
TDP-43 -
FUS -
FUS+
FUS+
FUS+
Consensus 2009 and 2010
FTLD-tau
40%
FTLD-TDP
50%
FTDL
UPS
<1%
FTLD-FUS
8%
FTLD
-ni
<1%
TDP43 e FUS: studi funzionali in vitro
TDP-43
Colture primarie di Motoneuroni
FUS
Cellule HEK293
Nei pazienti SLA e FTLD TDP-43 forma aggregati anche se non è mutato
Nei pazienti SLA, ma non FTLD, FUS forma aggregati solo se è mutato
2011
TET family of
DNA/RNAbinding proteins:
FUS, EWS, TAF15
No coding variants in EWS
Supplementary Figure 2: Additional Pedigrees with TAF15 Variants. Individuals with dementia are shown in grey and
individual with ALS and FTD dementia are shown by a checkerboard pattern. Arrows indicate the individual originally identified
harboring the mutation.
ALS-FTD
FDT
FTLD-FUS
No TAF15 and EWS
pathology in ALS-FUS
(no colocalization)
TAF15
FTLD-FUS
NIFID
BIBD
lmn
glia
EWS
FTLD-FUS
NIFID
BIBD
lmn
glia
Neumann et al., 2011
August 2011
UBQLN2
FALS 3/132 2.3%
SALS 6/605 0.9%
1
P-4S
123
K17E
Chr14:20.222.176-20.232185
H133135K40H114
Q12L S28N C39W
I46V
K17I R31K
K40I
P112L V113I H114R
+ FTD
-24
M-24I F-13S
F-13L
+ FTD
6/161 FALS (1.2%)
4/113 SALS (3.5%)
JNNP, 2011
UMN
No mutation identified in FTD (Muruyama et al., 2010; Rollison et al., 2010)
OPT
OPT&TDP-43
Other FTLD mutations:
chromosome 9
• 2001 - valosin containing protein (VCP) mutations: associated
with FTD, inclusion body myopathy (IBM) and Paget’s disease
(IBMPFD, Kovach et al.)
• Dementia: presents later than both IBM and Paget’s disease
• VCP: molecular chaperone in several processes related with
ubiquitin-dependent protein degradation
To date, 9 mutations in
VCP reported
Guinto et al., 2007
Neuron, 2010
Classical ALS phenotype
Johnson et al., 2010
Progranulin gene (GRN)
located 1.7 Mb
centromeric to MAPT
Arch Neurol, 2010
FTLD-TDP
TDP-43 and progranulin: possible link?
J Neurosci, 2007
> Cleaved Caspase 3
PGRN knockdown
Other FTLD mutations:
chromosome 3
- FTD with parkinsonism, dystonia and pyramidal signs
(Gydesen et al, 1987)
- linkage to chromosome 3 (Brown et al., 1995; Yancopoulou et
al., 2003): FTD-3
- mutation of the splice acceptor site of exon 6 of CHMP2B
(charged multivescicular body protein 2B) in a Danish
pedigree (Skibinski et al., 2005).
2010
spinal
cord
oligodedroglial coiled bodies
TDP43
p62
ALS8
Ch9: an ongoing saga
Chromosome 9p and FTLD-MND
• 15 pedigrees with linkage to a 3,6Mbp
minimal disease region between
markers D9S169 and D9S51(ALSFTD2
locus)
• Candidate genes analyzed for a
mutation with cosegregation: SIGMAR1
Luty et al., 2010
SLA, PD, FTD
C9orf72
GWA in SALS (and FTLD)
2010
Neuron, September 22, 2011
(VS20)
TDP43
ALS: Expansion Disease !
SLA
GGGGCC (G4C2)
3-48% FFTLD, 3-46% FALS, 2-23% FTLD, 0,4-21% SALS, 10-88% combined syndromes
72.000 case and control samples screened, 3.300 C9orf72 reported
Wollacott and Mead, 2014
Origin and global spread of C9orf72
• Finnish population carrying the 232-kb haplotype
• Association between risk haplotype and expansion holds across the
globe
• Single risk haplotype
• First appeared in the Finnish population 100 generation ago (58128) – transported in the Finnish population?
• Smith et al. (2013) in UK, Italy, Sweden: 157-479 generations ago
• In 500 A.D.(fall of Rome in 410 A.D.)
• “Viking Ordy” theory of spreading in Europe – reduced penetrance
North
America
C9orf72
•
•
•
•
•
•
dominant inheritance
high penetrance (anticipation ?)
earlier onset than classic ALS
rapid disease course (?)
site of onset: mostly upper limbs or bulbar onset
phenotype:
– prominent UMN signs
– cognitive impairment (bvFTD)
– psychiatric features (hallucinations, paranoid behavior, delusions, suicidal
thoughts
•
atypical phenotypes
– extrapyramidal features (CBS, PSP)
– cerebellar features (OPCA, cerebellar ataxia, palatal myoclonus)
•
association with other neurodegenerative diseases
–
–
–
–
–
AD
PD
CBS/PSP
HD-like sy
sCJD
controversial data
“intermediate alleles” ?
isolated reports
1.7%
0.2%
Psychiatric Diseases
Knock et al. 2014
C9orf72: broad clinical expression
Liu et al., August 2013
delusions, but also hallucinations
apathy, loss of empathy, visuospatial deficits
cerebellar features as ataxia
episod memory loss
Wollacott and Mead, 2014
0.9%
Wollacott and Mead, 2014
October, 2013
177
107
190
103
33,3% vs 8,1% (C9 non carriers)
Hallucinations = 4
Delusions = 5
Aggressiveness - hypomanic status = 1
Genotype-Phenotype C9orf72
ALS, ALSCi/Bi, ALS/FTLD, FTLD/MND, FTLD,
ALS/PD, ALS/MSA, ALS/PSP, ALS/CBS, PLS/CBS
HDL, ATX, FTLD/PSYCH, (AD) !
common founder of
Scandinavian origin
shared in the Italian
population
survival
Milan cohort
C9ORF72 Repeat Expansion
Group
Subjects
C9ORF72 RE
FALS
259
62
23.9%
FALS-U
194
56
28.9%
FALS-FTD
10
5
50.0%
FALS-M
55
1
1.8%
SALS
1275
66
5.2%
SALS-U
1164
58
5.0%
SALS-FTD
66
7
10.6%
SALS-M
45
1
2.2%
CTRL
862
2
0.2%
• higher frequency in
ALS-FTD patients
Ratti et al., Neurobiol Aging, 2012
ALS/FTD Genetics in Italy:
The SLAGEN CONSORTIUM ( > 4000 cases)
Gene
Frequency
Frequency
FALS
SALS
FALS
SALS
c9orf72
23.9%
5.1%
40%
7%
SOD1
11.0%
1.3%
12%
1-2%
FUS
6.7%
1.2%
4%
1%
TARDBP
4.1%
2.5%
4%
1%
ANG
3.0%
0.5%
UBQLN2
1.8%
0.1%
<1%
<1%
OPTN
1.2%
0.5%
<1%
<1%
PFN1
1.0%
0.1%
<1%
<1%
Altri geni
<1.0%
0%
Totale
52.7%
11.3%
European ancestry
Renton et al., 2014
C9orf72 in Italy
• 0, 17 % mutations in controls
• 102.000 subjects in italy carrying aC9orf72 expansion !
• How many developing clinical ALS, ALS/FTD?
• Anticipation ? Probably yes
• Grey Zone (premutation with 23 - 30 expansion)
• C9orf72 represents a public health problem
Sensitivity 100%
Specificity 67%
(no pts. with normal cognition/behaviour and no familial
history of ALS or FTD has C9ORF72 expansion)
Familial FTD/ALS (VS20)
TDP43
neocortex
spinal cord MN
hippocampus
cerebellum
DeJesus-Hemandez et al., 2011
TDP43
smear
NCI + NII
45kDa
Glial
25kDa
Mackenzie et al., 2014
TDP43 pathology not associated to expansion lenght
NCI positive for ubiquitin, ubiquilins and p62, negative for TDP-43
Mackenzie et al., 2014
Technology for diagnosis
repeat-primed PCR
Amplicon-length analysis
standard Southern blot
modified Southern
direct hybridisation
Clinical Phenotype !?
(no association between expansion size
and clinical phenotype)
• substantial
variation in repeat size in cerebellum, frontal cortex, blood
• longer repeat size in cerebellum associated with < survival
• expansion size not affecting disease phenotype (?)
Lancet Neurol 2013
C9orf72: Somatic Mosaicism
Southern blot in 30 ALS, 16 ALS/FTD, 35 FTD
Van Blitterswijk et al, Lancet Neurol 2013
expansion size
clinical phenotype
Akimoto et al., 2014
?
Double Mutations: C9orf72 and……
Van Blitterswijk et al., 2012
Genetic Counseling and Screening Algorithm
ALS
patient
FALS
SALS
C9orf72
Dementia
TARDBP
FUS
LMN
Atypical Features
C9orf72
PDism
Limb Girdle
SOD1
Onset < 40 yrs
SOD1
FUS
Geography
SOD1
TARDBP
SOD1
C9orf72
TARDBP
MAPT
FUS
TARDBP
FUS
no testing
Milano Algorithm, 2014
ALS C9orf72
Non-Genetic Non-Genetic
Biomarkers Biomarkers
Patients’
Stratification
Genetic Biomarkers
Clinical onset
Years
ALS:
FTLD:
4-8 per 100.000
15-20 per 100.000
• 20-40% FTD/ALS carry the expansion, up to 50% with positive family history
• men = women
• average 55 years
• de novo expansions
• anticipation
• unknown minimum number of repeats that confers phenotype
• predictive testing only after mutation demonstrated in the family
Fong et al., 2012
FTD & ALS – Genetic Continuum
PNF1
Al-Chalabi et al., Acta Neuropath, Sept. 2012, modified
EPHA4
SQSTM1
Many genes, a common patway ? TDP-43
PNF1
LMN
TDP-43 aggregates
Turner et al., Lancet Neurol 2013
ALS: TDP-43 as common final pathway for C9orf72 ?
different
mechanisms
Different
clinical
phenotypes
SLA
FTD
……
Ruolo emergente alterata processazione RNA & hnRBPS
Janssens and Van Broeckhoven, HMG 2013
cleavage into C-terminl fragments
Colombrita et al., 2009
TDP-43
Janssens and Van Broeckhoven, HMG 2013
pTDP-43 diffusion in ALS/FTD
Heiko
Braak
• C9orf72 amplification induces
a greater regional burden of
lesions
Brettschneider et al., 2014
Diffusione della patologia con pTDP-43 in SLA/FTD
STAGES
AREA
Stage 1
agranular motor neocortex (Brodman 4,6), brainstem motor
nuclei of cranial nerves XII-X, VII, V and spinal a-motoneurons
Stage 2
prefrontal neocortex (middle frontal gyrus), brainstem reticular
formation, precerebellar nuclei (inferior olivary complex),
pontine gray matter, and the red nucleus
Stage 3
prefrontal neocortex (e.g., gyrus rectus, orbital gyri) and then
postcentral neocortex and striatum (accumbens)
Stage 4
anteromedial portion of the temporal lobe including the
hippocampal formation
When assigning stages, the extent is accorded more weight than the TDP-43 severity
• at all stages, lesions accompanied by pTDP-43 oligodendroglial aggregates
• C9orf72 amplification induces a greater regional burden of lesions
• TDP-43 pathology propagated along axonal pathways
Brettschneider et al., May 2013
intraxonal pTDP-43
aggregates
affected oligodendrocytes
Immunoreactive
oligodendrocytes
a-motoneurons – Layer 9
Brettschneider et al., May 2013
BDNF sensibile
mRBP
CTF
intraaxonal pTDP-43
aggregates
Hypoglossal Nuclei (XII)
Superior accessory olivary nucleus
Immunoreactive
oligodendrocytes
Inferior olive
Medium-sized projection neurons in the striatum
Hippocampus: granular cells of the dentate fascia
+ pyramidal neurons in the Ammon’s horn (CA),
Initaily in sector CA1-CA2 and then CA3-CA4
Cerebellar cortical white matter and
deep portions of the cerebellar granular layer
Anteromedial portions of the temporal lobe
Neocortical Layers
Entorhinal region
Pyramidal cells of the entorhinal region
Transentorhinal region
Diffusion Tensor Imaging (DTI)
•
Multiple DTI studies consistently reported decreased FA within the CST
in keeping with the involvement of the UMN in all cases of ALS
•
Extramotor involvement
Agosta et al., 2010
AJNR 20!2
Cingulum
Uncinate fasciculi
PET
DTI
Filippini et al., Neurology, 2010
11C-flumazenil
(GABAA receptor) = reduced binding suggesting
loss of interneuronal inhibitory circuits,
inducing dysregulation of the glutamate system
Turner et al., 2005
VBM
DTI MRI + VBM
<
FA
in
PLS
vs
ALS
>
>
>
T
B
S
S
pTDP-43 diffusion in ALS/FTD
Brettschneider et al., 2014
Vulnerabilità Selettiva vs Continuum
Bertram and Tanzi, J Clin Inv 2005
AMYOTROPHIC LATERAL
SCLEROSIS
and FRONTOTEMPORAL
DEGENERATIONS
2012
Impatto sulla clinica
Michael J Strong
5 to 15%
25 to 50%
Strong et al., 2009
2014: A Spectrum of Dysfunction
ALS to FTD
ALS-FTD
A subgroup of ALS patients (up to 15%) meet criteria for
Frontotemporal Dementia
FTD 4 variants
- frontal/behavioural variant (fvFTD)
- temporal variant (semantic dementia)
- progressive non-fluent aphasia
- logopenic
ALS
ALS-FTD
………………spectrum ………...........
FTD
2012: A Spectrum of Dysfunction
ALS
to FTD
mild
ALS with “mild” cognitive impairment
Larger proportion (~1/3) have cognitive deficits
Rackowicz and Hodges (1998) 38%
Lomen-Hoerth et al (2003) 33%
Ringholz et al. (2005) 37%
Elamin et al (2010) 35%
ALS
ALS-FTD
ALS with “mild” cognitive impairment
FTD
2012: A Spectrum of Dysfunction
ALS to FTD
ALS with “mild” cognitive impairment
Larger proportion (~1/3) have cognitive deficits
Rackowicz and Hodges (1998) 38%
Lomen-Hoerth et al (2003) 33%
Ringholz et al. (2005) 37%
Elamin et al (2010) 35%
ALS
Subclinical FTD?
ALS-FTD
FTD
Prevalence and patterns of cognitive
impairment in sporadic ALS
G.M. Ringholz, MD, PhD; S.H. Appel, MD; M. Bradshaw,
PhD; N.A. Cooke, PhD; D.M. Mosnik, PhD; and P.E. Schulz,
MD
NEUROLOGY 2005;65:586-590
Conclusions: These data confirm the
presence of cognitive impairment in 50% of
patients with ALS and particularly implicate
executive dysfunction and mild memory
decline in the disease process.
Age-matched control (n = 122)
More severe impairment occurs in a
subsetof patients with ALS and has
features consistent with FTD.
Sporadic ALS (n = 136)
2012
1. Behaviour Change
ALS-FTD
Significant personality change “not the same person”
Disinhibition, impulsivity
Perseveration
Eating behaviour change
Loss of emotional understanding
Withdrawn and apathetic
Awareness Limited
2.Cognitive Change
a) Executive Dysfunction
Planning and organisational deficit
Attention deficit,
Inflexible thinking, Failure to initiate ideas
b) Language Dysfunction
Verbal expression reduced
MND-Aphasia Bak et al. 2001
ALS-FTD vs FTD
 Executive Dysfunction – ALS-FTD = FTD
 Behaviour symptoms – ALS-FTD = FTD
Psychotic symptoms (delusions) more prominent in fvFTD
who develop ALS (50% vs 18.6%) Lillo et al. 2010
 Language dysfunction
MND-Aphasia similar but not identical to PNFA
Deficits in comprehension and expression Bak et al. 2001
 Distribution of Atrophy
Similar but not identical to fvFTD
ALS-FTD (8 cases) - frontal lobes
FTD (39 cases) – frontal and anterior temporal
PNFA (6 cases) – asymmetric perisylvian
SD (9 cases) – asymmetric bitemporal atrophy
Snowden et al. 2007
Cognition in ALS-FTD
ALS-FTD
Executive Dysfunction
Language
Dysfunction
Behaviour
Dysfunction
Zago, Poletti, Silani, 2011
Cognition in classical ALS
ALS cog impairment ~
35-40% of ALS cases
?
?
?
Cognition in classical ALS
ALS cog impairment ~
35-40% of ALS cases
Executive Dysfunction
?
?
Letter Fluency
Ship, Shore, Snake, Silly, Send, Silver, Sonnet, Sun…
Healthy control
The most striking and consistently
ALS
reported deficit in ALS LomenHoerth et al 2003, Ringholz et
al, 2005, Flaherty-Craig et al,
2006
Verbal Fluency Index
Controls for motor speed
20
18
16
14
12
Seconds 10
8
6
4
2
0
Average time to ‘think’ of each word
Vfi = time of test – time to copy words
number of words
Healthy Controls
ALS
ALS-FTD
ALS: deficit Vfi
Puchan et al., 2007
Cognitive Studies of Fluency
•
Deficits in semantic and design fluency – rapid generation Abrahams et al.
•
Deficits in other executive functions tests (WCST, Tower of London)
•
Vfi deficit present very soon after diagnosis Abrahams et al. 2005
•
Vfi deficit exacerbated by respiratory dysfunction Newsome-Davis et al. 2001
•
Vfi deficit more prominent in pseudobulbar palsy but not restricted to
these patients, Abrahams et al. 1997
•
Vfi deficit more prominent in familial (non-SOD1) ALS patients, absent
in SOD1 familial, Wicks et al. 2008
•
Vfi deficit absent in Progressive Muscular Atrophy Wicks et al. 2006
•
Vfi deficit correlates with occular fixation abnormalities in ALS Donaghy et
•
Vfi deficit does not correlate with emotional lability Palmieri et al. 2009
2000
Abrahams et al. 1997
al. 2009
Why is Letter Fluency so Sensitive?
Initiation Deficit or Fatigue?
Rate of
verbal
fluency
index (VFI)
S words
Slowed
Word
Generation
Throughout
the test
Seconds
VFI- Average time to think of each word
14
12
10
8
6
4
2
0
Controls
ALS
30
60
90 120 150 180 210 240 270 300
Seconds
Significant effect of Group p< 0.02
Significant effect of Time p<0.001
Interaction NS
Courtesy of S. Abrahams
Other Cognitive Processes
in Letter Fluency?
1. Short Term Memory - Phonological Loop
Phonological Store
Sand Sea Sun
Surf Sail...
Subvocal Rehearsal
Rehearse
2. Simple Word Retrieval
Normal Sentence Completion
Normal Object Naming
Further
• Intrinsic Word Generation : deficient
• Working Memory: deficient
Abrahams et al., 2013,
Functional Imaging
of Letter fluency in
ALS
Konrad et al., 2006
Letter
Fluency
< fMRI
activation
Confrontation
Naming
Agosta et al. AJNR, 2010
Structural and Functional Imaging of ALS with
Letter Fluency deficits
White matter changes in 11 ALS
with verbal fluency deficit in
structural MRI
Reduced PET flumazenil binding
correlates with poor verbal fluency
in ALS (< in right inferior frontal gyrus,
superior temporal gyrus, anterior insula)
Wicks et al. 2007
Diffusion Tensor Imaging in ALS
Corpus Callosum FA differentiated ALS patients from healthy
controls
Filippini et al. 2011
Attention and executive dysfunction correlate with reduced WM
integrity in CC, CST, Uncinate Fas. Cingulum etc Sarro et al., 2011
Executive dysfunction vs
Slowed Processing Speed
Correlations with pathway integrity
Primary Lateral Sclerosis
Neurology, 2007
Strong et al., 2006, 2009
• In 18 PLS, 61% with MCI
• Deficits in executive
functioning, working
memory, learning efficiency
• Oral word efficiency as the
most sensitive measure,
followed by delayed
alternation
Piquard et al., 2006
• 20 PLS
• None demented, but all with
memory deficits reflecting an
executive dysfunction
• 17 with signs of premotor/or
prefrontal cortex deficit
• Dysorthographia observed
4,06 yrs average
3 items /12 total scores
VBM
DTI MRI + VBM
<
FA
in
PLS
vs
ALS
>
>
>
T
B
S
S
Cognition in classical ALS
Executive Dysfunction
Language
Dysfunction
?
Language dysfuntion
• language changes have received less attention
• dissociation between noun (temporal) and verbal (>
impaired ) (frontal) processing both in production
and in comprehension tasks
• linked to changes in Brodmann 44 and 45
Bak and Hodges, 2004
Language dysfuntion
• deficit not confined to verbs as words but extends to
non-verbal association tasks requiring the processsing
of abstract concepts of actions as opposed to that of
objects
• deficit in action processing confirmed in non-demented
ALS patients
Language Dysfunction
 Word finding deficit in a subgroup of ALS
Abrahams et al. 2005; Rakovicz and Hodges 1999
 Writing errors in ALS-Dementia
Japanese: Kana characters
Ichikawa et al. 2010
Language Pathways are affected in some ALS patients
Reduced fMRI activation in
inferior frontal, middle
temporal, middle occipital gyri
in ALS during Object Naming
Reduced PET flumazenil
binding correlates with poor
naming in inferior/middle
frontal gyri
Wicks et al. 2007
Cognition in classical ALS
Executive Dysfunction
Language
Dysfunction
Behaviour
Dysfunction
Behavioural Syndrome in classical
ALS
 Apathy in 30% of cases (FrSBe) Witgert and Salamone et al. 2010
 81 carers of ALS patients
41% moderate to severe apathy
20% moderate to severe abnormal and stereotypical behaviour
11% reached criteria for FTD Lillo et al. 2011
 Self centeredness/selfishness
Loss of interest/apathy
Social disinhibition
Gibbons et al. 2008
11/16
6/16
2/16
Theory of Mind (ToM) - ALS
 The ability to infer mental state
(thoughts, feelings, desires,
intentions) of another
 To understand that they have
different mental states from one’s
own
 Impairment in ToM is associated with
early change in orbito/medial
prefrontal cortex in FTD
What is he thinking?
a
Theory of mind deficit
in understanding
social situations
(frontal)
12
8
With Distractor
6
Without Distractor
4
2
No. Correct (max = 12)
10
10
8
With Distractor
6
Without Distractor
4
2
0
0
MND Patients
Healthy Controls
MND Patients
Healthy Controls
7/15 ALS patients scored within the abnormal range
No emotional involvement
Look At Condition
12
No. Correct (max = 12)
Judgment of Preference Task
Like Best Condition
Eye Gaze Test: Simple Theory of Mind
*
ALS
Controls
Cognitive:
Which picture
is Jane thinking
of?
Affective:
Which picture
does Jane
love?
Look At:
Which picture
is Jane looking
at?
Complex and Simple Emotion Recognition
36
No. Correct (max = 36)
30
24
18
12
6
Reading the Mind in the Eyes
HAPPINESS
SADNESS
ANGER
DISGUST
FEAR
SURPRISE
0
MND Patients
Healthy Controls
10
8
6
MND Patients
Controls
4
2
Facial Expressions
of Emotions Test
0
Anger
Disgust
Fear
Happiness
Sadness
Surprise
Girardi et al., 2010
ALS with subclinical FTD
ALS
ALS-FTD
ALS with ‘subclinical FTD’
Executive
Social Cog or
Behaviour
Language
Screening in the Clinic:
The development of the
Edinburgh Cognitive ALS Screen (ECAS)
Abrahams, Newton and Bak
Aim
 To develop a 15-20 min multidomain screen

To be sensitive to cognitive impairment in ALS
ALS-Typical Score

To be specific to impairment in ALS
to distinguish from AD or low global performance
ALS- Non-Typical Score

To minimize effect of physical disability – interchangeable
tests
Screening in the Clinic:
The development of the
Edinburgh Cognitive ALS Screen (ECAS)
Abrahams, Newton and Bak
VALIDATED the ITALIAN VERSION OF ECAS
Poletti et al., 2014
Why Care about Cognition in ALS?
1. Marker: an early indicator of involvement of
pathways within the prefrontal cortex
2. Heterogeneity in cognition (executive, language and
behaviour)
3. Screening for cognitive impairment is effective when
using the right tools
4. End of life decisions
How many ALS in a fvFTLD population ?
(Lomen-Hoerth et al, 2002)
EMG
36 FTD
definite ALS ( 14% )
EMG abnormalities
in one limb (5.5%)
neuromuscular
abnormalities
clinical examination
5
Swallowing
difficulty
(16.5%)
6
2
1
4
ALS
fasciculations (14%)
As a whole
longitudinal studies
demonstrate a
minimal progression
of cognitive decline
in ALS patients
Elamin M., et al., 2012 - ENCALS
• No conversion to FTD after 6 months in
“mild” cognitive impaired ALS
• FTD occurs in few ALS patients with
frank executive and/or behavioural
changes at baseline
• Cognition is a useful clinical biomarker
in ALS
Neurologo
Neuropsicologo
Psicologo
THERAPHY
TEAM
research
AISLA
Psichiatra
26/05/2014
NeuroBiomarkers of
Frontotemporal Dysfunction
PET
right inferior frontal gyrus
superior temporal gyrus
antorior insula
Voxel-based morphometry (VBM)
Grosskreutz et al., 2006
Direct correlations (cognitive functions/cortical atrophy)
Task
requiring
action
knowledge
object
knowledge
Diffusion tensor imaging (DTI)
axial diffusivity of the
AJNR, 2011
NiSALS - 2011
uncinate fasciculus (UF)
Diffusion tensor imaging (DTI)
Filippini et al., Neurology, 2010
More thalamic,
posterior insula,
cerebellar atrophy
NiSALS, Lancet Neurol 2011
C9orf72 Repeats :Phenotype
& Genotype Correlations
Neurology 2013
Orla Hardiman
Beaumont Hospital
& Trinity College Dublin
DTI
Eye Movements – Eye Tracking
• Eye movement abnormalities are sensitive markers of
neurological diseases and have been studied in a variety
of neurological conditions (Garbutt et al., 2008; Meyniel et
al.2005).
• The analysis of saccadic eye movements has been
described as a useful tool for investigating neurological or
psychiatric disorders in which the frontal lobe is impaired.
Eye tracking – Frontal function
•
Involvement of frontal function has recently
been studied in neurodegenerative diseases,
exploring ocular fixation with the aid of an eyetracking technology, thus suggesting its possible
role in detecting the whole spectrum of frontal
involvement characterizing cognitive pattern of
ALS .
•
Anti-saccade paradigm is ideal in exploring
frontal cognitive functions.
Anti-saccade paradigm
•
In the anti-saccade paradigm subjects are
instructed not to make a reflexive saccade to
an appearing lateral target but to make an
intentional saccade to the opposite side. This
ability depends on the integrity of the
dorsolateral prefrontal cortex (Garbutt et al.
(Brain, 2008)
ANTISACCADE PARADIGM
Looks promising !
Poletti et al., in press, 2012
Cognition/Behaviour in ALS
still debated !
but
Istituto Auxologico Italiano
“Dino Ferrari” Center
University of Milan Medical School
ICGEB Trieste
Francisco E. Baralle
Emanuele Buratti
Fondazione IRCCS Istituto “Carlo
Besta”
Dept. NeurologyStroke Unit
Laboratory of
Neuroscience
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
Federico Verde
Antonia Ratti
Patrizia Bossolasco
Daniela Calini
Claudia Colombrita
Lidia Cova
Valentina Diana
Annamaria Maraschi
Elisa Onesto
Francesca Sassone
Jenny Sassone
Cinzia Tiloca
Isabella Fogh
Claudia Fallini
Cinzia Calzarossa
London, UK
Boston, USA
Stockholm, SV
Cinzia Gellera
Barbara Castellotti, Viviana Pensato
Caterina Mariotti, Franco Taroni
University of Massachusetts
Medical School
John E. Landers,
Chi-Hong Wu, Jenni Adams, Desiree
M. Baron, Daryl A. Bosco, Andrew D.
Fox, Paloma Gonzalez-Perez, Pamela,
Katarzyna Piotrowska, Peter C. Sapp,
Zuo-Shang Xu, Jill A. Zitzewitz
Robert H. Brown Jr.
Istituto Auxologico Italiano
“Dino Ferrari” Center
University of Milan Medical School
HSR, Milano
ITALIAN SLAGEN CONSORTIUM
IRCCS Istituto Auxologico Italiano
Fondazione IRCCS Istituto “Carlo Besta”
NiSALS
Ospedale Maggiore - Università di Milano
Giacomo Comi
Roberto Del Bo
Stefania Corti
Università del Piemonte Orientale
Sandra D’Alfonso
Lucia Corrado
Università di Padova
Massimo Filippi
Federica Agosta
Elisa Canu
Giancarlo Comi
Gianni Sorarù
Istituto Neurologico “Casimiro Mondino”
Cristina Cereda
Univ. Brescia
Univ. Firenze
Univ. Catanzaro
Univ. Napoli
Univ. Pisa
Univ. Roma
Andrea Falini
Univ. Ferrara
SPONSORS
STRENGTH