Tre dei dieci pazienti arruolati nello studio hanno mostrato una PET positiva per la deposizione di placche di β-amiloide. La prevalenza di amiloidopatia nel nostro campione di pazienti è del 33% ed è, pertanto, in linea con quella riportata in letteratura. L’accumulo di β-amiloide non sembra quindi elemento necessario per lo sviluppo di demenza nei pazienti con MP, sebbene una sua presenza, in quantità non rilevabili con metodica PET, potrebbe contribuire al deterioramento cognitivo. E’ ormai noto infatti che, nella complessa neuropatologia sottostante la demenza nella MP, l’amiloidopatia rappresenta un substrato di frequente riscontro.
Dal nostro studio emerge una correlazione fra la deposizione di β-amiloide corticale, in particolare nella corteccia parietale, temporale ed occipitale e l’entità del declino cognitivo. L’accumulo della β-amiloide sembra confermarsi associato, quindi, ad una maggiore severità del deterioramento cognitivo. Una sua localizzazione preferenziale in determinate aree corticali potrebbe inoltre sostenere la tesi di una genesi anche amiloidopatica di specifici deficit cognitivi (quali ad es. la memoria) nei pazienti con PDD.
Due dei tre pazienti con PET positiva hanno mostrato un rapido declino delle funzioni cognitive, con decremento di oltre 10 punti del MMSE negli ultimi due anni prima dell’esecuzione della PET. Pur con i limiti di una valutazione quasi esclusivamente osservazionale, possiamo ipotizzare che la deposizione di β-amiloide contribuisca ad accelerare il declino cognitivo nei pazienti con una concomitante sinucleinopatia.
In conclusione, l’amiloidopatia non è un substrato neuropatologico necessario allo sviluppo di demenza nei pazienti con malattia di Parkinson; è stato dimostrato, infatti, che il solo accumulo corticale di corpi di Lewy è in grado di determinare un quadro dementigeno. Nella maggior parte dei pazienti con PDD la demenza è da interpretare
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verosimilmente quale il risultato della convergenza di più substrati neuropatologici; tra questi un ruolo centrale, sebbene ancora da definire, è svolto dalle placche di β-amiloide. Arrestare la formazione di tali placche nei pazienti con MP mediante specifiche terapie target potrebbe quindi rallentare la progressione del declino cognitivo.
Sarebbe tuttavia necessaria una migliore comprensione delle modalità cronologiche con cui la β-amiloide si accumula nei pazienti con MP: questo, infatti, consentirebbe di identificare il momento, nella storia naturale della malattia, in cui queste terapie potrebbero apportare il maggior beneficio. A questo proposito sono necessari studi prospettici, che, mediante l’utilizzo di traccianti selettivi per la β-amiloide, possano far nuova luce sul complesso rapporto fra amiloidopatia e la malattia di Parkinson.
L’ipotesi di lavoro da sviluppare in futuri studi è che entrambi i substrati neuropatologici, β-amiloide e α-sinucleina, contribuiscano alla patogenesi della demenza associata alla malattia di Parkinson, probabilmente ciascuno di essi modulando differenti profili cognitivi e differente tempo di comparsa della demenza rispetto all’esordio motorio della malattia. La comprensione del peso reciproco di questi substrati nel singolo paziente risulta cruciale nella prospettiva sempre più concreta e prossima di terapie che non solo siano in grado di agire da “scavenger” o “inibitore della formazione” delle placche di β-amiloide, ma anche di farmaci in grado di svolgere con medesimo meccanismo (anticorpi monoclonali- immunizzazione passiva) una risposta immunitaria diretta contro gli accumuli di α- sinucleina.
Pertanto risulterà cruciale nei prossimi anni avere strumenti in grado di indicare con buona approssimazione quale terapia, tra queste, considerare come prioritaria nel singolo caso individuale di MP con demenza.
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Poichè non può essere esclusa a priori un’azione sinergica di β-amiloide e α-sinucleina e quindi una teorica opzione di doppia terapia, indagare in vivo il ruolo di questa interazione rappresenta la prossima frontiera.
Data, tuttavia, la non disponibilità attuale di traccianti PET per l’α-sinucleina, il prossimo step del nostro studio sarà esplorare il ruolo delle proteine eteromeriche e la relazione tra i livelli liquorali di β-amiloide e α-sinucleina e la PET con 18F-Florbetapir nella MP con differenti gradi di disturbo cognitivo (PDD, MCI-PD, MP senza disturbi cognitivi e DLB).
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RINGRAZIAMENTI
Osservare un sentiero dalla fine può essere ingannevole. Le sue forme possono apparire distorte, i paesaggi che ha attraversato confondersi; la concezione della distanza percorsa può farsi evanescente.
Giunti alla fine di un sentiero è forse meglio chiudere gli occhi ed ascoltarsi. E, prima di decidere se voltarsi, valutare due elementi: la fatica e la soddisfazione. Se non si è stanchi e soddisfatti, significa che il sentiero è stato troppo semplice, o poco fruttuoso. Voltarsi, a questo punto, ci restituirebbe una visione deformata del nostro percorso. Tuttavia, se si è stanchi e soddisfatti, significa che è stato un bel cammino: e adesso, sì, è possibile girarsi ed osservare il sentiero dalla fine. Al suo posto, tuttavia, non si vedrà più un districarsi di curve ed ostacoli, come ci era apparso in durante, ma soltanto un fiume di persone: perché adesso quel sentiero esiste solo nella memoria, e la memoria è fatta di persone. E a questo punto verrà voglia di abbracciarle tutte.
Quelle più forti, da cui ti sei fatto trascinare nei momenti di stanchezza. Quelle più fresche e brillanti, che hanno reso questo percorso, prima di tutto, una festa. Quelle che hanno disegnato le curve e disposto gli ostacoli, perché senza di loro, forse, la stanchezza non sarebbe stata abbastanza da consentirci di guardare indietro. Quelle più piccole, di cui forse non ricorderemo nemmeno il nome, perché anche grazie a loro il cammino non è stato mai banale. E, infine, riserveremo l’abbraccio più forte a quelle più importanti, che ci hanno seguito durante tutto il cammino, dal momento del primo passo, fino a quest’ultima parola. Grazie.
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