Transcript ALS with - Univa Calabria
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
UMN LMN
REGIONS
Bulbar
+
Cervica l Thoracic Abdominal Lombar
+ +/ + + + + + 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% 32% F I 38% T 20% O 12%
+ 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 2006 Ubiquitin 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 Inclusions No Inclusions TAU+ Old nomenclature Tau-positive FTLD Ubiquitin-only+ FTLD-U Intermediate Filaments Basophilic Inclusions NIFID BIBD TDP-43 + TDP-43 FUS FUS+ Consensus 2009 and 2010 FTLD-tau FTLD-TDP 40% 50% FTD L UPS <1% FUS+ FTLD-FUS 8% FUS+ DLDH FTLD -ni <1%
TDP43 e FUS: studi funzionali
in vitro
TDP-43 FUS
Colture primarie di Motoneuroni 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
TET family of DNA/RNA binding proteins:
FUS, EWS, TAF15
No coding variants in
EWS
2011
Supplementary Figure 2: Additional Pedigrees with TAF15 Variants.
harboring the mutation.
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 ALS-FTD FDT
No TAF15 and EWS pathology in ALS-FUS (no colocalization)
TAF15
FTLD-FUS NIFID BIBD lmn
EWS
FTLD-FUS glia NIFID BIBD lmn glia Neumann et al., 2011
August 2011
UBQLN2
+ FTD + FTD FALS 3/132 2.3% SALS 6/605 0.9%
JNNP, 2011 6/161 FALS (1.2%) 4/113 SALS (3.5%) 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
with FTD , inclusion body myopathy (IBMPFD, Kovach et al.)
(
VCP) mutations: associated (IBM) and Paget’s disease • 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
VCP mutations in 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 PGRN knockdown > Cleaved Caspase 3
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
C9orf72
SLA, PD, FTD
GWA in SALS (and FTLD)
2010
Neuron
, September 22, 2011 (VS20) TDP43
ALS: Expansion Disease !
SLA GGGGCC (G 4 C 2 )
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 (58 128) – 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 controversial data – PD – CBS/PSP – HD-like sy – sCJD “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 177 190 107 103
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 FALS
FALS-U FALS-FTD FALS-M
SALS
SALS-U SALS-FTD SALS-M
CTRL Subjects 259
194 10 55
1275
1164 66 45
862
C9ORF72
RE 62
56
23.9%
28.9% 5 1
66
58 7 1
2
50.0% 1.8%
5.2%
5.0% 10.6% 2.2%
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
c9orf72 SOD1 FUS TARDBP ANG UBQLN2 OPTN PFN1 Altri geni
Totale Frequency
FALS SALS
23.9% 11.0% 5.1% 1.3% 6.7% 4.1% 3.0% 1.8% 1.2% 1.0% <1.0%
52.7%
1.2% 2.5% 0.5% 0.1% 0.5% 0.1% 0%
11.3% Frequency
FALS
40%
SALS
7% 12% 4% 4% 1-2% 1% 1% <1% <1% <1% <1% <1% <1% European ancestry Renton et al., 2014
C9orf72
in Italy
• 0, 17 % mutations in controls • 102.000 subjects in italy carrying a
C9orf72
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 hippocampus spinal cord MN cerebellum DeJesus-Hemandez et al., 2011
TDP43 NCI + NII smear 45kDa Glial Mackenzie et al., 2014 TDP43 pathology not associated to expansion lenght 25kDa
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
C9orf7
2: Somatic Mosaicism
Southern blot in 30 ALS, 16 ALS/FTD, 35 FTD Van Blitterswijk et al,
Lancet Neurol
2013
expansion size Akimoto et al., 2014 clinical phenotype ?
Double Mutations:
C9orf72
and……
Van Blitterswijk et al., 2012
Genetic Counseling and Screening Algorithm
ALS patient FALS
C9orf72 SOD1 TARDBP FUS
SALS no testing Dementia Atypical Features Onset < 40 yrs Geography
C9orf72 TARDBP FUS
LMN PDism Limb Girdle
SOD1 FUS SOD1 TARDBP C9orf72 TARDBP MAPT SOD1 FUS
Milano Algorithm, 2014
ALS
C9orf72
Non-Genetic Biomarkers Non-Genetic 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
EPHA4 SQSTM1 Al-Chalabi et al., Acta Neuropath, Sept. 2012, modified
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
TDP-43
cleavage into C-terminl fragments Colombrita et al., 2009 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
Stage 1
AREA
agranular motor neocortex (Brodman 4,6), brainstem motor nuclei of cranial nerves XII-X, VII, V and spinal a -motoneurons Stage 2 Stage 3 Stage 4 prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei (inferior olivary complex), pontine gray matter, and the red nucleus prefrontal neocortex (e.g., gyrus rectus, orbital gyri) and then postcentral neocortex and striatum (accumbens) 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 a motoneurons – Layer 9 affected oligodendrocytes Immunoreactive oligodendrocytes Brettschneider et al., May 2013
BDNF sensibile CTF mRBP
intraaxonal pTDP-43 aggregates Hypoglossal Nuclei (XII) Superior accessory olivary nucleus Inferior olive Immunoreactive oligodendrocytes
Medium-sized projection neurons in the striatum Cerebellar cortical white matter and deep portions of the cerebellar granular layer Hippocampus: granular cells of the dentate fascia + pyramidal neurons in the Ammon’s horn (CA), Initaily in sector CA1-CA2 and then CA3-CA4
Anteromedial portions of the temporal lobe Neocortical Layers Pyramidal cells of the entorhinal region 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
11 C-flumazenil (GABA A receptor) = reduced binding suggesting loss of interneuronal inhibitory circuits, inducing dysregulation of the glutamate system Turner et al., 2005
< FA in PLS vs ALS > > > DTI MRI + VBM VBM 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
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
Age-matched control (n = 122) Conclusions:
These data confirm the presence of decline cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory in the disease process.
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…
The most striking and consistently reported deficit in ALS
2006 Lomen Hoerth et al 2003, Ringholz et al, 2005, Flaherty-Craig et al,
Healthy control ALS Verbal Fluency Index Controls for motor speed Average time to ‘think’ of each word
Seconds
Vfi = time of test – time to copy words number of words
20 18 16 14 12 10 8 6 4 2 0 Healthy Controls ALS ALS-FTD
ALS: deficit V
fi
Puchan et al., 2007
Cognitive Studies of Fluency
• Deficits in semantic and design fluency – rapid generation
Abrahams et al. 2000
• Deficits in other executive functions tests (WCST, Tower of London)
Abrahams et al. 1997
• • • • • • • V
fi
deficit present very soon after diagnosis
Abrahams et al. 2005
V
fi
deficit exacerbated by respiratory dysfunction
Newsome-Davis et al. 2001
V
fi
deficit more prominent in
pseudobulbar palsy
these patients,
Abrahams et al. 1997
but not restricted to V
fi
deficit more prominent in
familial
in SOD1 familial,
Wicks et al. 2008
(non-SOD1) ALS patients, absent V
fi
deficit absent in Progressive Muscular Atrophy
Wicks et al. 2006
V
fi
deficit correlates with occular fixation abnormalities in ALS
al. 2009 Donaghy et Vfi
deficit does not correlate with emotional lability Palmieri et 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
VFI- Average time to think of each word 14 12 10 8 6 4 2 0 30 60 90 120 150 180 210 240 270 300 Seconds Controls ALS
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 Subvocal Rehearsal Sand Sea Sun Surf Sail...
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 most sensitive measure, followed by delayed alternation as the
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
< FA in PLS vs ALS > > > DTI MRI + VBM VBM 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)
Like Best Condition
2 0 6 4 12 10 8 MND Patients Healthy Controls With Distractor Without Distractor
Look At Condition
6 4 2 0 12 10 8 MND Patients Healthy Controls With Distractor Without Distractor
7/15 ALS patients scored within the abnormal range
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 12 6 0 30 24 18 Reading the Mind in the Eyes HAPPINESS SADNESS ANGER DISGUST FEAR SURPRISE Facial Expressions of Emotions Test MND Patients Healthy Controls 2 0 6 4 10 8 Anger Disgust MND Patients Controls Fear Happiness Sadness Surprise Girardi et al., 2010
ALS with subclinical FTD
ALS ALS-FTD ALS with ‘subclinical FTD’ Executive Language Social Cog or Behaviour
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 clinical examination neuromuscular abnormalities definite ALS ( 14% ) EMG abnormalities in one limb (5.5%) Swallowing difficulty (16.5%)
6 5 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
26/05/2014
Neurologo
THERAPHY AISLA TEAM
Neuropsicologo
Psicologo research Psichiatra
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 uncinate fasciculus (UF)
NiSALS - 2011
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 eye tracking 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 (Brain, 2008) 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.
ANTISACCADE PARADIGM
Looks promising !
Poletti et al., in press, 2012
Cognition/Behaviour in ALS still debated !
but
Dept. Neurology Stroke Unit 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 Istituto Auxologico Italiano “Dino Ferrari” Center University of Milan Medical School Laboratory of Neuroscience 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 ICGEB Trieste Francisco E. Baralle Emanuele Buratti Fondazione IRCCS Istituto “Carlo Besta” 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.
HSR, Milano Istituto Auxologico Italiano “Dino Ferrari” Center University of Milan Medical School
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
Massimo Filippi Federica Agosta Elisa Canu Giancarlo Comi Sandra D’Alfonso Lucia Corrado
Università di Padova
Gianni Sorarù
Istituto Neurologico “Casimiro Mondino”
Cristina Cereda Univ. Brescia Univ. Firenze Univ. Catanzaro Univ. Napoli Andrea Falini Univ. Ferrara Univ. Pisa Univ. Roma
STRENGTH