ALS FTD
Transcript
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