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Demenza Fronto-Temporale e Malattia del
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
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