Lamezia Terme- 14 Maggio 2014- Update sulla Demenza Frontotemporale Barbara Borroni Clinica Neurologica Università degli Studi di Brescia FTD prevalence in Brescia County Borroni et al., 2011 Grey: behavioural variant Frontotemporal Dementia, black: Semantic Dementia; white: progressive Non-Fluent Aphasia. FTD dementia: 3.5/100 cases AD dementia: 0.6/100 cases FTD criteria over time 1994 Lund-Manchester 1998/2001 Neary/McKhann Early loss of personal and social awareness, Clinical features FTD Clinical features: FTLD dishinibition, mental rigidity, hyperorality, stereopypies, Neuroimag features Neuroimag features utilisation beh, impulsivity, progressive reduction of speech. Neuropath Neuropath Inflated neurons and Pick bodies, which are silver positive, tau and ubiquitin immunoreactive. There is more intense white matter involvement. 2011 TODAY (revised bvFTD and PPA) Clinical features: FTLD Neuroimag features: supportive of diagnosis Neuropath a COMPLEX DISORDER Genetics Clinical features of Frontotemporal Lobar Degeneration Behavioural variant FTD Semantic Variant PPA Non-fluent/Agrammatic variant PPA Clinical features of Frontotemporal Lobar Degeneration Behavioural variant FTD Semantic Dementia Progressive Non-Fluent Aphasia Raskovsky , 2011; Gorno-Tempini, 2011 Variant Clinical feature Cortical atrophy Pathology bvFTD Behavioural disturbances, executive dysfunction Frontal lobe FTLD-TDP FTLD-Tau svPPA Poor confrontation naming Impaired single word comprehension Anterior temporal lobe FTLD-TDP AD FTLD-tau navPPA Grammatical simplification and errors in language production Effortful speech Left posterior frontoinsular region FTLD-tau AD FTLD-TDP Flessibilità cognitiva Test di Fluenza Verbale Fonemica I pazienti con deficit delle funzioni esecutive mostrano: • • • • Scarsa produzione verbale per scarsa iniziativa Scelte secondo categoria sbagliata Perseverazioni Dissociazione prestazione semantica/fonemica: FLUENZA SEMANTICA la prestazione è migliore perché utilizza una ricerca compatibile a quella in atto nella vita di tutti i giorni FLUENZA FONEMICA in difficoltà a causa del tipo di strategia di ricerca insolita Astrazione e Giudizio e Critica Test dei Giudizi verbali (Spinnler e Tognoni, 1987) Stime cognitive (Shallice and Evans, 1978) 1. Differenze Es. Nano/bambino Cespuglio/albero 2. Proverbi Es. Una rondine non fa primavera A caval donato non si guarda in bocca 3. Assurdità Es. Un giudice disse al condannato: “Ti condanno all’impiccagione e spero che ciò ti serva come avvertimento”. Un signore ricevette una lettera con scritto: “Se non dovessi ricevere questa lettera, fammelo sapere”. 4. Classificazioni Es. Pantaloni, mutande, giacca, scarpe, calze Perseverazioni e pianificazione Perseverazioni ricorrenti Es. Fluenza fonemica “P”: - “pane, pasta, palo, poltrona, pane, pila, palo” … Perseverazioni continue Figura di Rey Inibizione e autocontrollo Gli aspetti più superficiali di una situazione, anche se inutili per lo scopo del soggetto, possono “catturare” il paziente. Questo tipo di deficit causa la cosiddetta “sindrome da dipendenza ambientale” (Lhermitte, 1983). Questa sindrome è caratterizzata da due comportamenti specifici : Il comportamento d’uso Il comportamento di imitazione svPPa vs. avPPA Right temporal lobe atrophy Clinical features of Frontotemporal Lobar Degeneration Behavioural variant FTD Semantic Variant PPA Non-fluent/Agrammatic variant PPA When diagnosis is more difficult? CSF determinations Abeta1-42=430 pg/ml Tau protein= 792 pg/ml phospho-TAU= 81 pg/ml SCOLARITA R R OCCUPAZIONE R R RESERVE INDEX R Neuropathological hallmark of FTD FTLD neuropath Tau-, ubiquitin+ Tau+ Tau-/TDP43+ Tau-/TDP43-/FUS+ Neuropathological criteria 2010 (Mackenzie et al) Neuropath vs. clinical phenotype: the mismatch Tau+ Tau-/TDP43+ Tau-/TDP43-/ FUS+ ? The crucial role of genetics in FTLD • Earlier age at onset compared to AD or DLB. • Higher positive family history (40%) for dementia, psychiatric disturbances or parkinsonism, compared to AD, DLB or VaD. • No recognised enviromental risk factors or related comorbidities compared to AD or VaD. …it was 1997: Ann Arbour meeting Tau protein is the key player in FTD …. despite previous descriptions that have emphasized one or another clinical or neuropathological feature, the kindreds share clinical and neuropathological features…. …1998-2005 : looking at Tau biology Pedigree Beyond Tau Protein ….we identified an ancestral 8cM MAPT containing haplotype in which FTLD was conclusively linked to 17q21. No MAPT mutations were identified. Van der Zee, 2006 …it was 2006: new player in FTLD GRN mutations!!!! Tau-negative, ubiquitin-positive Neumann, 2006; Baker 2006, Crutz 2006 …it will be 2012: looking for new genes C9orf72 expansion: Finnish population familial ALS sporadic ALS FTLD 46% 21% 29% USA Familial ALS Familial FTLD 21% 11% Neuron 2011 FTD mutations: clinical features MAPT GRN C9orf72 N. mutations reported 44 69 1 Mode of inheritance AD AD AD Penetrance >95% 90% by age 70 ? Gender M=F M=F M=F onset 25-65 45-85 Behavioural changes +++ +++ +++ PNFA/apraxia ++ +++ + Parkinsonism ++ +++ ? ALS - - +++ Parietal atrophy + ++ ++ Altered Tau Loss of progranulin Gain/loss function Alter protein-protein interaction Replace or increase progranulin ? Variable Mechanism Treatment options MAPT vs. GRN mutations: Parkinsonism Variable MAPT GRN Parkinsonism ++ +++ (100% in late stages) Symmetry at onset yes no Myoclonus +/- ++ Dystonia - ++ (in late stages) Response to L-dopa - - CBS (with PNFA) + +++ PSP + - C9orf72: ALS (bulbar and somatic), psychosis, pure behavioural PGRN mutation markers: Serum PGRN dosage Borroni et al., 2011 Clinicopathological associations in FTLD Clinical syndrome Behavioural variant (bvFTD) Semantic variant (svPPA) Agrammatic variant (avPPA) FTD-MND CBS PSPs Frontotemporal Lobar Degeneration (FTLD) FTLDTau Pick's 3R-tau CBD PSP 4R-tau 4R-tau Tau NOS FTDP-17 MSTD/AG (MAPT) D FTLDTDP Type A (GRN) Type C Type B (c9orf72, TARDBP) Type D (VCP) Alzheimer's Disease FTLDFUS aFTLDU BIBD NIFID (FUS) Neuropathology FTLDUPS p62 (CHMP2 B) Modified from Seeley WW, UCSF FTLD with Predictable Neuropathology Clinical syndrome Neuropathology Genetics PSPs FTD-MND FTLD-Tau FTLD-TDP MAPT GRANULI N C9ORF72 TARDBP VCP Hu WT, Neurology, 2010 MacKenzie I, Neuropathol, 2010 Results FTLD-Tau FTLD-TDP (n=27) (n=22) Mean±SD Mean±SD CSF Aβ42 794.5±339.3 784.0±332.7 0.922 CSF p-Tau181 50.9.8±57.0 47.0±23.1 0.630 CSF Tau 236.8±100.3 493.1±321.2 0.001 0.22±0.15 0.11±0.05 0.000 CSF analysis, pg/ml p-Tau/Tau ratio p-value1 1 Mann-Whitney U ROC curve analysis AUC = 0.87 CSF p-Tau/Tau ratio cut-off value = 0.13 Sensitivity = 92.6% Specificity = 77.3% in differentiating FTLD-TDP from FTLDTau From bench to bedside - Gender - Age at onset - Family history - Neuropsychology - Behaviour - Disease progression - Genetic screening - Biological markers Tau+ Tau-/TDP+ Tau-/TDP-/FUS+ From bedside to bench Cluster 1 =Tau+ Cluster 2 =TDP+ Treatment A efficacy Treatment B efficacy tDCS in PPA patient: a rehabilitative approach Number of correct responses in naming subtest of AAT 120 AtDCS+ICAT PtDCS+ICAT 110 * 100 * 90 80 70 T0 T1 T2 Percentage of correct responses (%) in experimental naming 100 AtDCS+ICAT * 90 PtDCS+ICAT 80 70 * * 60 50 40 30 20 10 0 T0 T1 Treated stimuli T2 T0 T1 Untreated stimuli T2 Neurobiology of Disease Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar ATPase Anja Capell, Sabine Liebscher, Katrin Fellerer, Nathalie Brouwers, Michael Willem, Sven Lammich, Ilse Gijselinck, Tobias Bittner, Aaron M. Carlson, Florenz Sasse, Brigitte Kunze,Heinrich Steinmetz, Rolf Jansen, Dorothee Dormann, Kristel Sleegers, Marc Cruts, Jochen Herms, Christine Van Broeckhoven, and Christian Haass1,2 The Journal of Neuroscience, February 2, 2011 • 31(5):1885–1894 • 1885 Progranulin Deficiency Rescue in Frontotemporal Lobar Degeneration: a Phase II Study. 120 100 80 Patient 1 Patient 2 60 Patient 3 Patient 4 Patient 5 40 20 0 EuDract number: 2011-004571-37 Se un uomo parte con delle certezze finirà con dei dubbi, ma se si accontenta di iniziare con qualche dubbio, arriverà alla fine a qualche certezza. F. Bacon Mesulam et al., 2014
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