53 results on '"L. Tremolizzo"'
Search Results
2. New insights into the genetic etiology of Alzheimer's disease and related dementias
- Author
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Bellenguez, C. Küçükali, F. Jansen, I.E. Kleineidam, L. Moreno-Grau, S. Amin, N. Naj, A.C. Campos-Martin, R. Grenier-Boley, B. Andrade, V. Holmans, P.A. Boland, A. Damotte, V. van der Lee, S.J. Costa, M.R. Kuulasmaa, T. Yang, Q. de Rojas, I. Bis, J.C. Yaqub, A. Prokic, I. Chapuis, J. Ahmad, S. Giedraitis, V. Aarsland, D. Garcia-Gonzalez, P. Abdelnour, C. Alarcón-Martín, E. Alcolea, D. Alegret, M. Alvarez, I. Álvarez, V. Armstrong, N.J. Tsolaki, A. Antúnez, C. Appollonio, I. Arcaro, M. Archetti, S. Pastor, A.A. Arosio, B. Athanasiu, L. Bailly, H. Banaj, N. Baquero, M. Barral, S. Beiser, A. Pastor, A.B. Below, J.E. Benchek, P. Benussi, L. Berr, C. Besse, C. Bessi, V. Binetti, G. Bizarro, A. Blesa, R. Boada, M. Boerwinkle, E. Borroni, B. Boschi, S. Bossù, P. Bråthen, G. Bressler, J. Bresner, C. Brodaty, H. Brookes, K.J. Brusco, L.I. Buiza-Rueda, D. Bûrger, K. Burholt, V. Bush, W.S. Calero, M. Cantwell, L.B. Chene, G. Chung, J. Cuccaro, M.L. Carracedo, Á. Cecchetti, R. Cervera-Carles, L. Charbonnier, C. Chen, H.-H. Chillotti, C. Ciccone, S. Claassen, J.A.H.R. Clark, C. Conti, E. Corma-Gómez, A. Costantini, E. Custodero, C. Daian, D. Dalmasso, M.C. Daniele, A. Dardiotis, E. Dartigues, J.-F. de Deyn, P.P. de Paiva Lopes, K. de Witte, L.D. Debette, S. Deckert, J. Del Ser, T. Denning, N. DeStefano, A. Dichgans, M. Diehl-Schmid, J. Diez-Fairen, M. Rossi, P.D. Djurovic, S. Duron, E. Düzel, E. Dufouil, C. Eiriksdottir, G. Engelborghs, S. Escott-Price, V. Espinosa, A. Ewers, M. Faber, K.M. Fabrizio, T. Nielsen, S.F. Fardo, D.W. Farotti, L. Fenoglio, C. Fernández-Fuertes, M. Ferrari, R. Ferreira, C.B. Ferri, E. Fin, B. Fischer, P. Fladby, T. Fließbach, K. Fongang, B. Fornage, M. Fortea, J. Foroud, T.M. Fostinelli, S. Fox, N.C. Franco-Macías, E. Bullido, M.J. Frank-García, A. Froelich, L. Fulton-Howard, B. Galimberti, D. García-Alberca, J.M. García-González, P. Garcia-Madrona, S. Garcia-Ribas, G. Ghidoni, R. Giegling, I. Giorgio, G. Goate, A.M. Goldhardt, O. Gomez-Fonseca, D. González-Pérez, A. Graff, C. Grande, G. Green, E. Grimmer, T. Grünblatt, E. Grunin, M. Gudnason, V. Guetta-Baranes, T. Haapasalo, A. Hadjigeorgiou, G. Haines, J.L. Hamilton-Nelson, K.L. Hampel, H. Hanon, O. Hardy, J. Hartmann, A.M. Hausner, L. Harwood, J. Heilmann-Heimbach, S. Helisalmi, S. Heneka, M.T. Hernández, I. Herrmann, M.J. Hoffmann, P. Holmes, C. Holstege, H. Vilas, R.H. Hulsman, M. Humphrey, J. Biessels, G.J. Jian, X. Johansson, C. Jun, G.R. Kastumata, Y. Kauwe, J. Kehoe, P.G. Kilander, L. Ståhlbom, A.K. Kivipelto, M. Koivisto, A. Kornhuber, J. Kosmidis, M.H. Kukull, W.A. Kuksa, P.P. Kunkle, B.W. Kuzma, A.B. Lage, C. Laukka, E.J. Launer, L. Lauria, A. Lee, C.-Y. Lehtisalo, J. Lerch, O. Lleó, A. Longstreth, W., Jr Lopez, O. de Munain, A.L. Love, S. Löwemark, M. Luckcuck, L. Lunetta, K.L. Ma, Y. Macías, J. MacLeod, C.A. Maier, W. Mangialasche, F. Spallazzi, M. Marquié, M. Marshall, R. Martin, E.R. Montes, A.M. Rodríguez, C.M. Masullo, C. Mayeux, R. Mead, S. Mecocci, P. Medina, M. Meggy, A. Mehrabian, S. Mendoza, S. Menéndez-González, M. Mir, P. Moebus, S. Mol, M. Molina-Porcel, L. Montrreal, L. Morelli, L. Moreno, F. Morgan, K. Mosley, T. Nöthen, M.M. Muchnik, C. Mukherjee, S. Nacmias, B. Ngandu, T. Nicolas, G. Nordestgaard, B.G. Olaso, R. Orellana, A. Orsini, M. Ortega, G. Padovani, A. Paolo, C. Papenberg, G. Parnetti, L. Pasquier, F. Pastor, P. Peloso, G. Pérez-Cordón, A. Pérez-Tur, J. Pericard, P. Peters, O. Pijnenburg, Y.A.L. Pineda, J.A. Piñol-Ripoll, G. Pisanu, C. Polak, T. Popp, J. Posthuma, D. Priller, J. Puerta, R. Quenez, O. Quintela, I. Thomassen, J.Q. Rábano, A. Rainero, I. Rajabli, F. Ramakers, I. Real, L.M. Reinders, M.J.T. Reitz, C. Reyes-Dumeyer, D. Ridge, P. Riedel-Heller, S. Riederer, P. Roberto, N. Rodriguez-Rodriguez, E. Rongve, A. Allende, I.R. Rosende-Roca, M. Royo, J.L. Rubino, E. Rujescu, D. Sáez, M.E. Sakka, P. Saltvedt, I. Sanabria, Á. Sánchez-Arjona, M.B. Sanchez-Garcia, F. Juan, P.S. Sánchez-Valle, R. Sando, S.B. Sarnowski, C. Satizabal, C.L. Scamosci, M. Scarmeas, N. Scarpini, E. Scheltens, P. Scherbaum, N. Scherer, M. Schmid, M. Schneider, A. Schott, J.M. Selbæk, G. Seripa, D. Serrano, M. Sha, J. Shadrin, A.A. Skrobot, O. Slifer, S. Snijders, G.J.L. Soininen, H. Solfrizzi, V. Solomon, A. Song, Y. Sorbi, S. Sotolongo-Grau, O. Spalletta, G. Spottke, A. Squassina, A. Stordal, E. Tartan, J.P. Tárraga, L. Tesí, N. Thalamuthu, A. Thomas, T. Tosto, G. Traykov, L. Tremolizzo, L. Tybjærg-Hansen, A. Uitterlinden, A. Ullgren, A. Ulstein, I. Valero, S. Valladares, O. Broeckhoven, C.V. Vance, J. Vardarajan, B.N. van der Lugt, A. Dongen, J.V. van Rooij, J. van Swieten, J. Vandenberghe, R. Verhey, F. Vidal, J.-S. Vogelgsang, J. Vyhnalek, M. Wagner, M. Wallon, D. Wang, L.-S. Wang, R. Weinhold, L. Wiltfang, J. Windle, G. Woods, B. Yannakoulia, M. Zare, H. Zhao, Y. Zhang, X. Zhu, C. Zulaica, M. Farrer, L.A. Psaty, B.M. Ghanbari, M. Raj, T. Sachdev, P. Mather, K. Jessen, F. Ikram, M.A. de Mendonça, A. Hort, J. Tsolaki, M. Pericak-Vance, M.A. Amouyel, P. Williams, J. Frikke-Schmidt, R. Clarimon, J. Deleuze, J.-F. Rossi, G. Seshadri, S. Andreassen, O.A. Ingelsson, M. Hiltunen, M. Sleegers, K. Schellenberg, G.D. van Duijn, C.M. Sims, R. van der Flier, W.M. Ruiz, A. Ramirez, A. Lambert, J.-C. EADB GR@ACE DEGESCO EADI GERAD Demgene FinnGen ADGC CHARGE
- Abstract
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. © 2022. The Author(s).
- Published
- 2022
3. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- Author
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de Rojas, I. Moreno-Grau, S. Tesi, N. Grenier-Boley, B. Andrade, V. Jansen, I.E. Pedersen, N.L. Stringa, N. Zettergren, A. Hernández, I. Montrreal, L. Antúnez, C. Antonell, A. Tankard, R.M. Bis, J.C. Sims, R. Bellenguez, C. Quintela, I. González-Perez, A. Calero, M. Franco-Macías, E. Macías, J. Blesa, R. Cervera-Carles, L. Menéndez-González, M. Frank-García, A. Royo, J.L. Moreno, F. Huerto Vilas, R. Baquero, M. Diez-Fairen, M. Lage, C. García-Madrona, S. García-González, P. Alarcón-Martín, E. Valero, S. Sotolongo-Grau, O. Ullgren, A. Naj, A.C. Lemstra, A.W. Benaque, A. Pérez-Cordón, A. Benussi, A. Rábano, A. Padovani, A. Squassina, A. de Mendonça, A. Arias Pastor, A. Kok, A.A.L. Meggy, A. Pastor, A.B. Espinosa, A. Corma-Gómez, A. Martín Montes, A. Sanabria, Á. DeStefano, A.L. Schneider, A. Haapasalo, A. Kinhult Ståhlbom, A. Tybjærg-Hansen, A. Hartmann, A.M. Spottke, A. Corbatón-Anchuelo, A. Rongve, A. Borroni, B. Arosio, B. Nacmias, B. Nordestgaard, B.G. Kunkle, B.W. Charbonnier, C. Abdelnour, C. Masullo, C. Martínez Rodríguez, C. Muñoz-Fernandez, C. Dufouil, C. Graff, C. Ferreira, C.B. Chillotti, C. Reynolds, C.A. Fenoglio, C. Van Broeckhoven, C. Clark, C. Pisanu, C. Satizabal, C.L. Holmes, C. Buiza-Rueda, D. Aarsland, D. Rujescu, D. Alcolea, D. Galimberti, D. Wallon, D. Seripa, D. Grünblatt, E. Dardiotis, E. Düzel, E. Scarpini, E. Conti, E. Rubino, E. Gelpi, E. Rodriguez-Rodriguez, E. Duron, E. Boerwinkle, E. Ferri, E. Tagliavini, F. Küçükali, F. Pasquier, F. Sanchez-Garcia, F. Mangialasche, F. Jessen, F. Nicolas, G. Selbæk, G. Ortega, G. Chêne, G. Hadjigeorgiou, G. Rossi, G. Spalletta, G. Giaccone, G. Grande, G. Binetti, G. Papenberg, G. Hampel, H. Bailly, H. Zetterberg, H. Soininen, H. Karlsson, I.K. Alvarez, I. Appollonio, I. Giegling, I. Skoog, I. Saltvedt, I. Rainero, I. Rosas Allende, I. Hort, J. Diehl-Schmid, J. Van Dongen, J. Vidal, J.-S. Lehtisalo, J. Wiltfang, J. Thomassen, J.Q. Kornhuber, J. Haines, J.L. Vogelgsang, J. Pineda, J.A. Fortea, J. Popp, J. Deckert, J. Buerger, K. Morgan, K. Fließbach, K. Sleegers, K. Molina-Porcel, L. Kilander, L. Weinhold, L. Farrer, L.A. Wang, L.-S. Kleineidam, L. Farotti, L. Parnetti, L. Tremolizzo, L. Hausner, L. Benussi, L. Froelich, L. Ikram, M.A. Deniz-Naranjo, M.C. Tsolaki, M. Rosende-Roca, M. Löwenmark, M. Hulsman, M. Spallazzi, M. Pericak-Vance, M.A. Esiri, M. Bernal Sánchez-Arjona, M. Dalmasso, M.C. Martínez-Larrad, M.T. Arcaro, M. Nöthen, M.M. Fernández-Fuertes, M. Dichgans, M. Ingelsson, M. Herrmann, M.J. Scherer, M. Vyhnalek, M. Kosmidis, M.H. Yannakoulia, M. Schmid, M. Ewers, M. Heneka, M.T. Wagner, M. Scamosci, M. Kivipelto, M. Hiltunen, M. Zulaica, M. Alegret, M. Fornage, M. Roberto, N. van Schoor, N.M. Seidu, N.M. Banaj, N. Armstrong, N.J. Scarmeas, N. Scherbaum, N. Goldhardt, O. Hanon, O. Peters, O. Skrobot, O.A. Quenez, O. Lerch, O. Bossù, P. Caffarra, P. Dionigi Rossi, P. Sakka, P. Hoffmann, P. Holmans, P.A. Fischer, P. Riederer, P. Yang, Q. Marshall, R. Kalaria, R.N. Mayeux, R. Vandenberghe, R. Cecchetti, R. Ghidoni, R. Frikke-Schmidt, R. Sorbi, S. Hägg, S. Engelborghs, S. Helisalmi, S. Botne Sando, S. Kern, S. Archetti, S. Boschi, S. Fostinelli, S. Gil, S. Mendoza, S. Mead, S. Ciccone, S. Djurovic, S. Heilmann-Heimbach, S. Riedel-Heller, S. Kuulasmaa, T. del Ser, T. Lebouvier, T. Polak, T. Ngandu, T. Grimmer, T. Bessi, V. Escott-Price, V. Giedraitis, V. Deramecourt, V. Maier, W. Jian, X. Pijnenburg, Y.A.L. Smith, A.D. Saenz, A. Bizzarro, A. Lauria, A. Vacca, A. Solomon, A. Anastasiou, A. Richardson, A. Boland, A. Koivisto, A. Daniele, A. Greco, A. Marianthi, A. McGuinness, B. Fin, B. Ferrari, C. Custodero, C. Ferrarese, C. Ingino, C. Mangone, C. Reyes Toso, C. Martínez, C. Cuesta, C. Muchnik, C. Joachim, C. Ortiz, C. Besse, C. Johansson, C. Zoia, C.P. Laske, C. Anastasiou, C. Palacio, D.L. Politis, D.G. Janowitz, D. Craig, D. Mann, D.M. Neary, D. Jürgen, D. Daian, D. Belezhanska, D. Kohler, E. Castaño, E.M. Koutsouraki, E. Chipi, E. De Roeck, E. Costantini, E. Vardy, E.R.L.C. Piras, F. Roveta, F. Piras, F. Prestia, F.A. Assogna, F. Salani, F. Sala, G. Lacidogna, G. Novack, G. Wilcock, G. Thonberg, H. Kölsch, H. Weber, H. Boecker, H. Etchepareborda, I. Piaceri, I. Tuomilehto, J. Lindström, J. Laczo, J. Johnston, J. Deleuze, J.-F. Harris, J. Schott, J.M. Priller, J. Bacha, J.I. Snowden, J. Lisso, J. Mihova, K.Y. Traykov, L. Morelli, L. Brusco, L.I. Rainer, M. Takalo, M. Bjerke, M. Del Zompo, M. Serpente, M. Sanchez Abalos, M. Rios, M. Peltonen, M. Herrman, M.J. Kosmidis, M.H. Kohler, M. Rojo, M. Jones, M. Orsini, M. Medel, N. Olivar, N. Fox, N.C. Salvadori, N. Hooper, N.M. Galeano, P. Solis, P. Bastiani, P. Mecocci, P. Passmore, P. Heun, R. Antikainen, R. Olaso, R. Perneczky, R. Germani, S. López-García, S. Love, S. Mehrabian, S. Bagnoli, S. Kochen, S. Andreoni, S. Teipel, S. Todd, S. Pickering-Brown, S. Natunen, T. Tegos, T. Laatikainen, T. Strandberg, T. Polvikoski, T.M. Matoska, V. Ciullo, V. Cores, V. Solfrizzi, V. Lisetti, V. Sevillano, Z. Abdelnour, C. Aguilera, N. Alarcon, E. Alegret, M. Benaque, A. Boada, M. Buendia, M. Cañabate, P. Carracedo, A. Corbatón-Anchuelo, A. Diego, S. Espinosa, A. Gailhajenet, A. Gil, S. Guitart, M. Hernández, I. Ibarria, M. Lafuente, A. Macias, J. Maroñas, O. Martín, E. Martínez, M.T. Marquié, M. Mauleón, A. Montrreal, L. Moreno-Grau, S. Moreno, M. Orellana, A. Ortega, G. Pancho, A. Pelejá, E. Pérez-Cordon, A. Pineda, J.A. Preckler, S. Quintela, I. Real, L.M. Rosende-Roca, M. Ruiz, A. Sáez, M.E. Sanabria, A. Serrano-Rios, M. Sotolongo-Grau, O. Tárraga, L. Valero, S. Vargas, L. Adarmes-Gómez, A.D. Alarcón-Martín, E. Alonso, M.D. Álvarez, I. Álvarez, V. Amer-Ferrer, G. Antequera, M. Antúnez, C. Baquero, M. Bernal, M. Blesa, R. Boada, M. Buiza-Rueda, D. Bullido, M.J. Burguera, J.A. Calero, M. Carrillo, F. Carrión-Claro, M. Casajeros, M.J. Clarimón, J. Cruz-Gamero, J.M. de Pancorbo, M.M. del Ser, T. Diez-Fairen, M. Escuela, R. Garrote-Espina, L. Fortea, J. Franco-Macías, E. Frank-García, A. García-Alberca, J.M. Garcia Madrona, S. Garcia-Ribas, G. Gómez-Garre, P. Hernández, I. Hevilla, S. Jesús, S. Labrador Espinosa, M.A. Lage, C. Legaz, A. Lleó, A. Lopez de Munain, A. López-García, S. Macias-García, D. Manzanares, S. Marín, M. Marín-Muñoz, J. Marín, T. Marquié, M. Martín Montes, A. Martínez, B. Martínez, C. Martínez, V. Martínez-Lage Álvarez, P. Medina, M. Mendioroz Iriarte, M. Mir, P. Molinuevo, J.L. Pastor, P. Pérez Tur, J. Periñán-Tocino, T. Pineda-Sanchez, R. Piñol-Ripoll, G. Rábano, A. Real de Asúa, D. Rodrigo, S. Rodríguez-Rodríguez, E. Royo, J.L. Ruiz, A. Sanchez del Valle Díaz, R. Sánchez-Juan, P. Sastre, I. Valero, S. Vicente, M.P. Vigo-Ortega, R. Vivancos, L. Macleod, C. McCracken, C. Brayne, C. Bresner, C. Grozeva, D. Bellou, E. Sommerville, E.W. Matthews, F. Leonenko, G. Menzies, G. Windle, G. Harwood, J. Phillips, J. Bennett, K. Luckuck, L. Clare, L. Woods, R. Saad, S. Burholt, V. Jansen, I.E. Rongve, A. Kehoe, P.G. Garcia-Ribas, G. Sánchez-Juan, P. Pastor, P. Pérez-Tur, J. Piñol-Ripoll, G. Lopez de Munain, A. García-Alberca, J.M. Bullido, M.J. Álvarez, V. Lleó, A. Real, L.M. Scheltens, P. Holstege, H. Marquié, M. Sáez, M.E. Carracedo, Á. Amouyel, P. Schellenberg, G.D. Williams, J. Seshadri, S. van Duijn, C.M. Mather, K.A. Sánchez-Valle, R. Serrano-Ríos, M. Orellana, A. Tárraga, L. Blennow, K. Huisman, M. Andreassen, O.A. Posthuma, D. Clarimón, J. Boada, M. van der Flier, W.M. Ramirez, A. Lambert, J.-C. van der Lee, S.J. Ruiz, A. EADB contributors The GR@ACE study group DEGESCO consortium IGAP (ADGC, CHARGE, EADI, GERAD) PGC-ALZ consortia
- Abstract
Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
- Published
- 2021
4. LATE-ONSET EPILEPSY WITH UNKNOWN ETIOLOGY: A PILOT STUDY ON NEUROPSYCHOLOGICAL PROFILE, CEREBROSPINAL FLUID BIOMARKERS, AND QUANTITATIVE EEG CHARACTERISTICS
- Author
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Nardi Cesarini, E, Babiloni, C, Salvadori, N, Farotti, L, Del Perci, C, Pascarelli, M, Noce, G, Lizio, R, Dare, F, Isella, V, Tremolizzo, L, Calvello, C, Romoli, M, Difrancesco, J, Parnetti, L, Costa, C, E. Nardi Cesarini, C. Babiloni, N. Salvadori, L. Farotti, C. Del Perci, M. Pascarelli, G. Noce, R. Lizio, F. DaRe, V. Isella, L. Tremolizzo, C. Calvello, M. Romoli, J. DiFrancesco, L. Parnetti, C. Costa, Nardi Cesarini, E, Babiloni, C, Salvadori, N, Farotti, L, Del Perci, C, Pascarelli, M, Noce, G, Lizio, R, Dare, F, Isella, V, Tremolizzo, L, Calvello, C, Romoli, M, Difrancesco, J, Parnetti, L, Costa, C, E. Nardi Cesarini, C. Babiloni, N. Salvadori, L. Farotti, C. Del Perci, M. Pascarelli, G. Noce, R. Lizio, F. DaRe, V. Isella, L. Tremolizzo, C. Calvello, M. Romoli, J. DiFrancesco, L. Parnetti, and C. Costa
- Published
- 2020
5. LONGITUDINAL PATTERNS OF ATROPHY IN CLINICAL VARIANTS OF FRONTOTEMPORAL LOBAR DEGENERATION
- Author
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Spinelli, E, Basaia, S, Cividini, C, Riva, N, Magnani, G, Caso, F, Caroppo, P, Prioni, S, Tremolizzo, L, Appollonio, I, Silani, V, Carrera, P, Filippi, M, Agosta, F, E. G. Spinelli, S. Basaia, C. Cividini, N. Riva, G. Magnani, F. Caso, P. Caroppo, S. Prioni, L. Tremolizzo, I. Appollonio, V. Silani, P. Carrera, M. Filippi, F. Agosta, Spinelli, E, Basaia, S, Cividini, C, Riva, N, Magnani, G, Caso, F, Caroppo, P, Prioni, S, Tremolizzo, L, Appollonio, I, Silani, V, Carrera, P, Filippi, M, Agosta, F, E. G. Spinelli, S. Basaia, C. Cividini, N. Riva, G. Magnani, F. Caso, P. Caroppo, S. Prioni, L. Tremolizzo, I. Appollonio, V. Silani, P. Carrera, M. Filippi, and F. Agosta
- Published
- 2020
6. CLEARANCE OF BETA-AMYLOID OLIGOMERS BY PERIPHERAL MONOCYTES: FURTHER OBSERVATIONS REGARDING THE MODULATORY ROLE OF DONEPEZIL
- Author
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Karantzoulis, A, Conti, E, Slongo, M, Rodriguez-Menendez, V, Mauri, M, Da Re, F, Aliprandi, A, Basilico, P, Salmaggi, A, Appollonio, I, Ferrarese, C, Tremolizzo, L, A. Karantzoulis, E. Conti, M. Slongo, V. Rodriguez-Menendez, M. Mauri, F. Da Re, A. Aliprandi, P. Basilico, A. Salmaggi, I. Appollonio, C. Ferrarese, L. Tremolizzo, Karantzoulis, A, Conti, E, Slongo, M, Rodriguez-Menendez, V, Mauri, M, Da Re, F, Aliprandi, A, Basilico, P, Salmaggi, A, Appollonio, I, Ferrarese, C, Tremolizzo, L, A. Karantzoulis, E. Conti, M. Slongo, V. Rodriguez-Menendez, M. Mauri, F. Da Re, A. Aliprandi, P. Basilico, A. Salmaggi, I. Appollonio, C. Ferrarese, and L. Tremolizzo
- Published
- 2020
7. BRAIN MRI SIGNATURES OF ATROPHY IN GENETIC FRONTOTEMPORAL LOBAR DEGENERATION
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Agosta, F, Spinelli, E, Ghirelli, A, Riva, N, Basaia, S, Cividini, C, Magnani, G, Caso, F, Caroppo, P, Prioni, S, Tremolizzo, L, Appollonio, I, Silani, V, Carrera, P, Filippi, M, F. Agosta, E. Spinelli, A. Ghirelli, N. Riva, S. Basaia, C. Cividini, G. Magnani, F. Caso, P. Caroppo, S. Prioni, L. Tremolizzo, I. Appollonio, V. Silani, P. Carrera, M. Filippi, Agosta, F, Spinelli, E, Ghirelli, A, Riva, N, Basaia, S, Cividini, C, Magnani, G, Caso, F, Caroppo, P, Prioni, S, Tremolizzo, L, Appollonio, I, Silani, V, Carrera, P, Filippi, M, F. Agosta, E. Spinelli, A. Ghirelli, N. Riva, S. Basaia, C. Cividini, G. Magnani, F. Caso, P. Caroppo, S. Prioni, L. Tremolizzo, I. Appollonio, V. Silani, P. Carrera, and M. Filippi
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- 2020
8. Do outcome measures used in neurological clinical research realistically represent the needs and the expectations of patients and their care givers?
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C Motto, L Tremolizzo, E Susani, V Oppo, M Congedo, Angelo A. Bignamini, M Carlini, C Cusi, A Serafini, S Macone, P Candelaresi, M G Celani, K Nardi, Annalisa Sgoifo, Teresa Anna Cantisani, C Piersanti, M Cecconi, MC Bassi, S Cuzzubbo, V Piras, M Melis, D Guerra, and R Papetti
- Subjects
medicine.medical_specialty ,media_common.quotation_subject ,Alternative medicine ,Medicine (miscellaneous) ,Disease ,Bioinformatics ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,medicine ,Dementia ,Pharmacology (medical) ,030212 general & internal medicine ,media_common ,Selection bias ,business.industry ,030503 health policy & services ,medicine.disease ,Focus group ,Clinical research ,Systematic review ,Family medicine ,Poster Presentation ,0305 other medical science ,business - Abstract
Methods Stroke, dementia and epilepsy are the greater and most common disabling neurological diseases and were considered in this study. For each mentioned disease we will perform a Systematic reviews of all randomized clinical trials published in any language over the last 5 years with the aim of identifying and analyzing the outcome measures used in the evaluation of any kind of intervention. Fifteen Neurologists are filling out a single computerized form for each single trial assigned. The form has the following information: Characteristics of the trial with relevance on quality, Extent of variability in end points selected and their domains, Scales or techniques used to make the measurement, type of analysis applied and time of measurement, Presence of attrition bias in terms of fraction of patients reported by end points on the number enrolled in the study, Presence of outcome reporting bias in terms of end points declared and non-reported, end points not declared but reported, Source of funding. The valuation of patient and career needs and emotions will be performed with focus group discussions in a parallel section of the study.
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- 2015
9. Italian Frontotemporal Dementia Network (FTD Group-SINDEM): sharing clinical and diagnostic procedures in Frontotemporal Dementia in Italy
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Borroni B., Turrone R., Galimberti D., Nacmias B., Alberici A., Benussi A., Caffarra P., Caltagirone C., Cappa S. F., Frisoni G. B., Ghidoni R., Marra C., Padovani A., Rainero I., Scarpini E., Silani V., Sorbi S., Tagliavini F., Tremolizzo L., Bruni A. C., Agosta F., Alberoni M., Appollonio I., Arighi A., Avanzi S., Baglio F., Benussi L., Bianchetti A., Binetti G., Bonanni L., Bottacchi E., Bruno G., Canevelli M., Canu E., Cerami C., Chiari A., Conti M. Z., Costa A., Costa M., Cotelli M., Cotelli M. S., Cupidi C., Daniele A., D'Anna S., de Caro M. F., De Togni L., Dell'Osa M. T., Di Stefano F., Ferrarese C., Ferrari C., Filastro F., Floris G., Franceschi M., Gennuso M., Ghidoni E., Giordana M. T., Gragnaniello D., Grimaldi L., Lanari A., Le Pira F., Lombardi G., Lorusso S., Ludovico L., Luzzi S., Magnani G., Manfredi L. G., Marano P., Marcone A., Marrosu M. G., Martorana A., Mascia M. G., Masullo C., Mauri M., Mazzone A., Mela A., Merlo P., Micheli A., Milia A., Mina C., Montella P., Mura G., Murru M. R., Nemni R., Paci C., Pantieri R., Panza F., Parnetti L., Perini M., Pettenati C., Piccininni M., Piccoli T., Pilia G., Pinessi L., Piras M. R., Realmuto S., Ricca I., Rizzetti M. C., Rozzini L., Rubino E., Sambati L., Seripa D., Siano P., Sinforiani E., Sorrentino G., Specchio L. M., Stracciari A., Susani E., Talarico G., Tartaglione B., Tessitore A., Thomas A., Tiezzi A., Tiraboschi P., Tognoni G., Tondelli M., Trebbastoni A., Turla M., Ursini F., Valluzzi F., Vista M., Zannino G., Zanusso G., Piccoli, T, B. Borroni, R. Turrone, D. Galimberti, B. Nacmia, A. Alberici, A. Benussi, P. Caffarra, C. Caltagirone, S. F. Cappa, G. B. Frisoni, R. Ghidoni, C. Marra, A. Padovani, I. Rainero, E. Scarpini, V. Silani, S. Sorbi, F. Tagliavini, L. Tremolizzo, A. C. Bruni, The FTD Group-SINDEM, Borroni, B, Turrone, R, Galimberti, D, Nacmias, B, Alberici, A, Benussi, A, Caffarra, P, Caltagirone, C, Cappa, Sf, Frisoni, Gb, Ghidoni, R, Marra, C, Padovani, A, Rainero, I, Scarpini, E, Silani, V, Sorbi, S, Tagliavini, F, Tremolizzo, L, Bruni, Ac, The FTD, Group-SINDEM, Agosta, F, Cappa, S, Frisoni, G, Bruni, A, Alberoni, M, Appollonio, I, Arighi, A, Avanzi, S, Baglio, F, Benussi, L, Bianchetti, A, Binetti, G, Bonanni, L, Bottacchi, E, Bruno, G, Canevelli, M, Canu, E, Cerami, C, Chiari, A, Conti, M, Costa, A, Costa, M, Cotelli, M, Cupidi, C, Daniele, A, D'Anna, S, de Caro, M, De Togni, L, Dell'Osa, M, Di Stefano, F, Ferrarese, C, Ferrari, C, Filastro, F, Floris, G, Franceschi, M, Gennuso, M, Ghidoni, E, Giordana, M, Gragnaniello, D, Grimaldi, L, Lanari, A, Le Pira, F, Lombardi, G, Lorusso, S, Ludovico, L, Luzzi, S, Magnani, G, Manfredi, L, Marano, P, Marcone, A, Marrosu, M, Martorana, A, Mascia, M, Masullo, C, Mauri, M, Mazzone, A, Mela, A, Merlo, P, Micheli, A, Milia, A, Mina, C, Montella, P, Mura, G, Murru, M, Nemni, R, Paci, C, Pantieri, R, Panza, F, Parnetti, L, Perini, M, Pettenati, C, Piccininni, M, Pilia, G, Pinessi, L, Piras, M, Realmuto, S, Ricca, I, Rizzetti, M, Rozzini, L, Rubino, E, Sambati, L, Seripa, D, Siano, P, Sinforiani, E, Sorrentino, G, Specchio, L, Stracciari, A, Susani, E, Talarico, G, Tartaglione, B, Tessitore, A, Thomas, A, Tiezzi, A, Tiraboschi, P, Tognoni, G, Tondelli, M, Trebbastoni, A, Turla, M, Ursini, F, Valluzzi, F, Vista, M, Zannino, G, and Zanusso, G
- Subjects
Counseling ,Male ,medicine.medical_specialty ,Neurology ,Network ,Frontotemporal dementia ,Frontotemporal lobar degeneration ,Genetics ,Survey ,Aged ,Aged, 80 and over ,Caregivers ,Female ,Frontotemporal Dementia ,Humans ,Italy ,Prevalence ,Community Networks ,Information Dissemination ,Medicine (all) ,2708 ,Neurology (clinical) ,Psychiatry and Mental Health ,Dermatology ,ddc:616.89 ,Caregivers/psychology ,Epidemiology ,mental disorders ,medicine ,80 and over ,Dementia ,Disease management (health) ,Psychiatry ,MED/26 - NEUROLOGIA ,Italian network ,FRONTO Temporal dementia ,business.industry ,Frontotemporal dementia, Frontotemporal lobar degeneration, Network, Survey, Genetics, Counseling ,General Medicine ,Frontotemporal Dementia/diagnosis/epidemiology ,medicine.disease ,Clinical trial ,Settore MED/26 - Neurologia ,Neurosurgery ,business - Abstract
In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.
- Published
- 2014
10. Corticosteroid treatment for acute hydrocephalus in neurosarcoidosis: a case report.
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Schilke ED, Remoli G, Cutellé C, Balducci C, Cereda D, Fusco ML, Tremolizzo L, Ferrarese C, Appollonio I, and Frigo M
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- Humans, Male, Adult, Adrenal Cortex Hormones therapeutic use, Seizures complications, Central Nervous System Diseases complications, Central Nervous System Diseases drug therapy, Central Nervous System Diseases diagnosis, Hydrocephalus complications, Hydrocephalus drug therapy, Sarcoidosis complications, Sarcoidosis drug therapy, Sarcoidosis diagnosis
- Abstract
Background: Neurosarcoidosis occurs symptomatically in 5-10% of patients with sarcoidosis, and hydrocephalus is a rare complication of neurosarcoidosis, with either acute or subacute onset and presenting symptoms related to increased intracranial pressure. It represents a potentially fatal manifestation with a mortality rate of 22% (increased to 75% in case of coexistence of seizures) that requires a prompt initiation of treatment. High-dose intravenous corticosteroid treatment and neurosurgical treatment must be considered in all cases of neurosarcoidosis hydrocephalus., Case Presentation: Here we present a case of hydrocephalus in neurosarcoidosis, complicated by generalized seizures, in a 29-year-old Caucasian male patient treated with medical treatment only, with optimal response., Conclusion: Since neurosurgery treatment can lead to severe complications, this case report underlines the possibility to undergo only medical treatment in selected cases. Further studies are needed to stratify patients and better identify those eligible for only medical approach., (© 2024. The Author(s).)
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- 2024
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11. Brain Health and Cognition in Older Adults: Roadmap and Milestones towards the Implementation of Preventive Strategies.
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Pozzi FE, Remoli G, Tremolizzo L, Appollonio I, Ferrarese C, and Cuffaro L
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In this narrative review, we delve into the evolving concept of brain health, as recognized by the WHO, focusing on its intersection with cognitive decline. We emphasize the imperative need for preventive strategies, particularly in older adults. We describe the target population that might benefit the most from risk-based approaches-namely, people with subjective cognitive decline. Additionally, we consider universal prevention in cognitively unimpaired middle-aged and older adults. Delving into multidomain personalized preventive strategies, we report on empirical evidence surrounding modifiable risk factors and interventions crucial in mitigating cognitive decline. Next, we highlight the emergence of brain health services (BHS). We explain their proposed role in risk assessment, risk communication, and tailored interventions to reduce the risk of dementia. Commenting on ongoing BHS pilot experiences, we present the inception and framework of our own BHS in Monza, Italy, outlining its operational structure and care pathways. We emphasize the need for global collaboration and intensified research efforts to address the intricate determinants of brain health and their potential impact on healthcare systems worldwide.
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- 2024
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12. Neuropathological hints from CSF and serum biomarkers in corticobasal syndrome (CBS): a systematic review.
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Remoli G, Schilke ED, Magi A, Ancidoni A, Negro G, Da Re F, Frigo M, Giordano M, Vanacore N, Canevelli M, Ferrarese C, Tremolizzo L, and Appollonio I
- Abstract
Corticobasal syndrome (CBS) is a clinical syndrome determined by various underlying neurodegenerative disorders requiring a pathological assessment for a definitive diagnosis. A literature review was performed following the methodology described in the Cochrane Handbook for Systematic Reviews to investigate the additional value of traditional and cutting-edge cerebrospinal fluid (CSF) and serum/plasma biomarkers in profiling CBS. Four databases were screened applying predefined inclusion criteria: (1) recruiting patients with CBS; (2) analyzing CSF/plasma biomarkers in CBS. The review highlights the potential role of the association of fluid biomarkers in diagnostic workup of CBS, since they may contribute to a more accurate diagnosis and patient selection for future disease-modifying agent; for example, future trial designs should consider baseline CSF Neurofilament Light Chains (NfL) or progranulin dosage to stratify treatment arms according to neuropathological substrates, and serum NfL dosage might be used to monitor the evolution of CBS. In this scenario, prospective cohort studies, starting with neurological examination and neuropsychological tests, should be considered to assess the correlations of clinical profiles and various biomarkers., (© 2024. The Author(s).)
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- 2024
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13. BPSDiary study protocol: a multi-center randomized controlled trial to compare the efficacy of a BPSD diary vs. standard care in reducing caregiver's burden.
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Pozzi FE, Calì L, D'Antonio F, Altomare AI, Sepe Monti M, Panigutti M, Di Crosta A, Palumbo R, Bonanni L, Carlucci V, Bussè C, Cagning A, Urso D, Vilella D, Logroscino G, Alberoni M, Bellinvia A, Farina E, de Rino F, Gavazzi A, Zuffi M, Bruno G, Bessi V, Cotta Ramusino M, Perini G, Costa A, Ferrarese C, Appollonio I, and Tremolizzo L
- Abstract
Behavioral and Psychological Symptoms of Dementia (BPSD) are a heterogeneous set of psychological and behavioral abnormalities seen in persons with dementia (PwD), significantly impacting their quality of life and that of their caregivers. Current assessment tools, such as the Neuropsychiatric Inventory (NPI), are limited by recall bias and lack of direct observation. This study aims to overcome this limitation by making caregiver reports more objective through the use of a novel instrument, referred to as the BPSDiary. This randomized controlled trial will involve 300 caregiver-PwD dyads. The objective is to evaluate whether the use of the BPSDiary could significantly reduce caregiver burden, assessed using the Zarit Burden Interview (ZBI), compared to usual care. The study will include adult PwD, caregivers living with or close to the patient, and BPSD related to the HIDA (hyperactivity, impulsivity, irritability, disinhibition, aggression, agitation) domain. Caregivers randomized to the intervention arm will use the BPSDiary to record specific BPSD, including insomnia, agitation/anxiety, aggression, purposeless motor behavior, and delusions/hallucinations, registering time of onset, severity, and potential triggers. The primary outcome will be the change in ZBI scores at 3 months, with secondary outcomes including changes in NPI scores, olanzapine equivalents, NPI-distress scores related to specific BPSD domains, and caregiver and physician satisfaction. The study will be conducted in 9 Italian centers, representing diverse geographic and sociocultural contexts. While potential limitations include the relatively short observation period and the focus on specific BPSD disturbances, the BPSDiary could provide physicians with objective data to tailor appropriate non-pharmacological and pharmacological interventions. Additionally, it may empower caregivers by encouraging reflection on BPSD triggers, with the potential to improve the quality of life for both PwD and their caregivers., Trial Registry: NCT05977855., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Pozzi, Calì, D'Antonio, Altomare, Sepe Monti, Panigutti, Di Crosta, Palumbo, Bonanni, Carlucci, Bussè, Cagning, Urso, Vilella, Logroscino, Alberoni, Bellinvia, Farina, de Rino, Gavazzi, Zuffi, Bruno, Bessi, Cotta Ramusino, Perini, Costa, Ferrarese, Appollonio and Tremolizzo.)
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- 2023
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14. Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
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Le Guen Y, Luo G, Ambati A, Damotte V, Jansen I, Yu E, Nicolas A, de Rojas I, Peixoto Leal T, Miyashita A, Bellenguez C, Lian MM, Parveen K, Morizono T, Park H, Grenier-Boley B, Naito T, Küçükali F, Talyansky SD, Yogeshwar SM, Sempere V, Satake W, Alvarez V, Arosio B, Belloy ME, Benussi L, Boland A, Borroni B, Bullido MJ, Caffarra P, Clarimon J, Daniele A, Darling D, Debette S, Deleuze JF, Dichgans M, Dufouil C, During E, Düzel E, Galimberti D, Garcia-Ribas G, García-Alberca JM, García-González P, Giedraitis V, Goldhardt O, Graff C, Grünblatt E, Hanon O, Hausner L, Heilmann-Heimbach S, Holstege H, Hort J, Jung YJ, Jürgen D, Kern S, Kuulasmaa T, Lee KH, Lin L, Masullo C, Mecocci P, Mehrabian S, de Mendonça A, Boada M, Mir P, Moebus S, Moreno F, Nacmias B, Nicolas G, Niida S, Nordestgaard BG, Papenberg G, Papma J, Parnetti L, Pasquier F, Pastor P, Peters O, Pijnenburg YAL, Piñol-Ripoll G, Popp J, Porcel LM, Puerta R, Pérez-Tur J, Rainero I, Ramakers I, Real LM, Riedel-Heller S, Rodriguez-Rodriguez E, Ross OA, Royo LJ, Rujescu D, Scarmeas N, Scheltens P, Scherbaum N, Schneider A, Seripa D, Skoog I, Solfrizzi V, Spalletta G, Squassina A, van Swieten J, Sánchez-Valle R, Tan EK, Tegos T, Teunissen C, Thomassen JQ, Tremolizzo L, Vyhnalek M, Verhey F, Waern M, Wiltfang J, Zhang J, Zetterberg H, Blennow K, He Z, Williams J, Amouyel P, Jessen F, Kehoe PG, Andreassen OA, Van Duin C, Tsolaki M, Sánchez-Juan P, Frikke-Schmidt R, Sleegers K, Toda T, Zettergren A, Ingelsson M, Okada Y, Rossi G, Hiltunen M, Gim J, Ozaki K, Sims R, Foo JN, van der Flier W, Ikeuchi T, Ramirez A, Mata I, Ruiz A, Gan-Or Z, Lambert JC, Greicius MD, and Mignot E
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- Humans, Histocompatibility Antigens, HLA Antigens, Alzheimer Disease genetics, HLA-DRB1 Chains genetics, Parkinson Disease genetics
- Abstract
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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- 2023
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15. Assessing behavioral and psychological symptoms of dementia: a comprehensive review of current options and future perspectives.
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Pozzi FE, Calì L, Ferrarese C, Appollonio I, and Tremolizzo L
- Abstract
The behavioral and psychological symptoms of dementia (BPSD) are a heterogeneous set of challenging disturbances of behavior, mood, perception, and thought that occur in almost all patients with dementia. A huge number of instruments have been developed to assess BPSD in different populations and settings. Although some of these tools are more widely used than others, no single instrument can be considered completely satisfactory, and each of these tools has its advantages and disadvantages. In this narrative review, we have provided a comprehensive overview of the characteristics of a large number of such instruments, addressing their applicability, strengths, and limitations. These depend on the setting, the expertise required, and the people involved, and all these factors need to be taken into account when choosing the most suitable scale or tool. We have also briefly discussed the use of objective biomarkers of BPSD. Finally, we have attempted to provide indications for future research in the field and suggest the ideal characteristics of a possible new tool, which should be short, easy to understand and use, and treatment oriented, providing clinicians with data such as frequency, severity, and triggers of behaviors and enabling them to find appropriate strategies to effectively tackle BPSD., Competing Interests: FP, CF, IA, and LT declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pozzi, Calì, Ferrarese, Appollonio and Tremolizzo.)
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- 2023
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16. Editorial: Strategies to fight exercise intolerance in neuromuscular disorders, volume II.
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Lanfranconi F, Tremolizzo L, Marzorati M, and D'Antona G
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2023
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17. Plasma and cerebrospinal fluid cholesterol esterification is hampered in Alzheimer's disease.
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Turri M, Conti E, Pavanello C, Gastoldi F, Palumbo M, Bernini F, Aprea V, Re F, Barbiroli A, Emide D, Galimberti D, Tremolizzo L, Zimetti F, and Calabresi L
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- Humans, Esterification, High-Density Lipoproteins, Pre-beta, Cholesterol, Biomarkers, Alzheimer Disease cerebrospinal fluid
- Abstract
Objective: The purpose of this study was to evaluate cholesterol esterification and HDL subclasses in plasma and cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients., Methods: The study enrolled 70 AD patients and 74 cognitively normal controls comparable for age and sex. Lipoprotein profile, cholesterol esterification, and cholesterol efflux capacity (CEC) were evaluated in plasma and CSF., Results: AD patients have normal plasma lipids but significantly reduced unesterified cholesterol and unesterified/total cholesterol ratio. Lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate (CER), two measures of the efficiency of the esterification process, were reduced by 29% and 16%, respectively, in the plasma of AD patients. Plasma HDL subclass distribution in AD patients was comparable to that of controls but the content of small discoidal preβ-HDL particles was significantly reduced. In agreement with the reduced preβ-HDL particles, cholesterol efflux capacity mediated by the transporters ABCA1 and ABCG1 was reduced in AD patients' plasma. The CSF unesterified to total cholesterol ratio was increased in AD patients, and CSF CER and CEC from astrocytes were significantly reduced in AD patients. In the AD group, a significant positive correlation was observed between plasma unesterified cholesterol and unesterified/total cholesterol ratio with Aβ
1-42 CSF content., Conclusion: Taken together our data indicate that cholesterol esterification is hampered in plasma and CSF of AD patients and that plasma cholesterol esterification biomarkers (unesterified cholesterol and unesterified/total cholesterol ratio) are significantly associated to disease biomarkers (i.e., CSF Aβ1-42 )., (© 2023. The Author(s).)- Published
- 2023
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18. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease.
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Luo J, Thomassen JQ, Bellenguez C, Grenier-Boley B, de Rojas I, Castillo A, Parveen K, Küçükali F, Nicolas A, Peters O, Schneider A, Dichgans M, Rujescu D, Scherbaum N, Jürgen D, Riedel-Heller S, Hausner L, Porcel LM, Düzel E, Grimmer T, Wiltfang J, Heilmann-Heimbach S, Moebus S, Tegos T, Scarmeas N, Clarimon J, Moreno F, Pérez-Tur J, Bullido MJ, Pastor P, Sánchez-Valle R, Álvarez V, Boada M, García-González P, Puerta R, Mir P, Real LM, Piñol-Ripoll G, García-Alberca JM, Royo JL, Rodriguez-Rodriguez E, Soininen H, Kuulasmaa T, de Mendonça A, Mehrabian S, Hort J, Vyhnalek M, van der Lee S, Graff C, Papenberg G, Giedraitis V, Boland A, Bacq-Daian D, Deleuze JF, Nicolas G, Dufouil C, Pasquier F, Hanon O, Debette S, Grünblatt E, Popp J, Benussi L, Galimberti D, Arosio B, Mecocci P, Solfrizzi V, Parnetti L, Squassina A, Tremolizzo L, Borroni B, Nacmias B, Sorbi S, Caffarra P, Seripa D, Rainero I, Daniele A, Masullo C, Spalletta G, Williams J, Amouyel P, Jessen F, Kehoe P, Tsolaki M, Rossi G, Sánchez-Juan P, Sleegers K, Ingelsson M, Andreassen OA, Hiltunen M, Van Duijn C, Sims R, van der Flier W, Ruiz A, Ramirez A, Lambert JC, and Frikke-Schmidt R
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- Humans, Female, Aged, Aged, 80 and over, Male, Cholesterol, HDL, Risk Factors, Causality, Alzheimer Disease epidemiology, Alzheimer Disease genetics
- Abstract
Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia., Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention., Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022., Exposures: Genetically determined modifiable risk factors., Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors., Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50])., Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
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- 2023
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19. The HFE p.H63D (p.His63Asp) Polymorphism Is a Modifier of ALS Outcome in Italian and French Patients with SOD1 Mutations.
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Canosa A, Calvo A, Mora G, Moglia C, Brunetti M, Barberis M, Borghero G, Caponnetto C, Trojsi F, Spataro R, Volanti P, Simone IL, Salvi F, Logullo FO, Riva N, Tremolizzo L, Giannini F, Mandrioli J, Tanel R, Murru MR, Mandich P, Conforti FL, Zollino M, Sabatelli M, Tarlarini C, Lunetta C, Mazzini L, D'Alfonso S, Guy N, Meininger V, Clavelou P, Camu W, Chiò A, and On Behalf Of Italsgen Consortium
- Abstract
Background : Data from published studies about the effect of HFE polymorphisms on ALS risk, phenotype, and survival are still inconclusive. We aimed at evaluating whether the p.H63D polymorphism is a modifier of phenotype and survival in SOD1 -mutated patients. Methods : We included 183 SOD1 -mutated ALS patients. Mutations were classified as severe or mild according to the median survival of the study population. Patients were screened for the HFE p.H63D polymorphism. Survival was calculated using the Kaplan-Meier modeling, and differences were measured by the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model (stepwise backward). Results : SOD1 severe mutation carriers show more frequent familial history for ALS and shorter survival compared to mild mutation carriers. Carriers and non-carriers of the p.H63D polymorphism did not differ in terms of sex ratio, frequency of positive familial history, age at onset, and bulbar/spinal ratio. In univariate and in Cox multivariable analysis using sex, age at onset, site of onset, family history, country of origin, and mutation severity as covariates, p.H63D carriers had a longer survival ( p = 0.034 and p = 0.004). Conclusions : We found that SOD1 -mutated ALS patients carrying the p.H63D HFE polymorphism have a longer survival compared to non-carriers, independently of sex, age and site of onset, family history, nation of origin, and severity of mutations, suggesting a possible role as disease progression modifier for the p.H63D HFE polymorphism in SOD1 -ALS., Competing Interests: Antonio Canosa serves on the Editorial Board of Biomedicines and serves as Guest Editor for the Special Issues ‘Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology’ and ‘Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology 2.0′ of Biomedicines. Andrea Calvo received a research grant from Cytokinetics. Adriano Chiò serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Biogen, Cytokinetics, Denali, and AveXis, and received a research grant from Italfarmaco. Jessica Mandrioli received research support from Pfizer. The other authors have no conflict of interest relevant for the manuscript.
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- 2023
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20. Author Correction: Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
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de Rojas I, Moreno-Grau S, Tesi N, Grenier-Boley B, Andrade V, Jansen IE, Pedersen NL, Stringa N, Zettergren A, Hernández I, Montrreal L, Antúnez C, Antonell A, Tankard RM, Bis JC, Sims R, Bellenguez C, Quintela I, González-Perez A, Calero M, Franco-Macías E, Macías J, Blesa R, Cervera-Carles L, Menéndez-González M, Frank-García A, Royo JL, Moreno F, Huerto Vilas R, Baquero M, Diez-Fairen M, Lage C, García-Madrona S, García-González P, Alarcón-Martín E, Valero S, Sotolongo-Grau O, Ullgren A, Naj AC, Lemstra AW, Benaque A, Pérez-Cordón A, Benussi A, Rábano A, Padovani A, Squassina A, de Mendonça A, Arias Pastor A, Kok AAL, Meggy A, Pastor AB, Espinosa A, Corma-Gómez A, Martín Montes A, Sanabria Á, DeStefano AL, Schneider A, Haapasalo A, Kinhult Ståhlbom A, Tybjærg-Hansen A, Hartmann AM, Spottke A, Corbatón-Anchuelo A, Rongve A, Borroni B, Arosio B, Nacmias B, Nordestgaard BG, Kunkle BW, Charbonnier C, Abdelnour C, Masullo C, Martínez Rodríguez C, Muñoz-Fernandez C, Dufouil C, Graff C, Ferreira CB, Chillotti C, Reynolds CA, Fenoglio C, Van Broeckhoven C, Clark C, Pisanu C, Satizabal CL, Holmes C, Buiza-Rueda D, Aarsland D, Rujescu D, Alcolea D, Galimberti D, Wallon D, Seripa D, Grünblatt E, Dardiotis E, Düzel E, Scarpini E, Conti E, Rubino E, Gelpi E, Rodriguez-Rodriguez E, Duron E, Boerwinkle E, Ferri E, Tagliavini F, Küçükali F, Pasquier F, Sanchez-Garcia F, Mangialasche F, Jessen F, Nicolas G, Selbæk G, Ortega G, Chêne G, Hadjigeorgiou G, Rossi G, Spalletta G, Giaccone G, Grande G, Binetti G, Papenberg G, Hampel H, Bailly H, Zetterberg H, Soininen H, Karlsson IK, Alvarez I, Appollonio I, Giegling I, Skoog I, Saltvedt I, Rainero I, Rosas Allende I, Hort J, Diehl-Schmid J, Van Dongen J, Vidal JS, Lehtisalo J, Wiltfang J, Thomassen JQ, Kornhuber J, Haines JL, Vogelgsang J, Pineda JA, Fortea J, Popp J, Deckert J, Buerger K, Morgan K, Fließbach K, Sleegers K, Molina-Porcel L, Kilander L, Weinhold L, Farrer LA, Wang LS, Kleineidam L, Farotti L, Parnetti L, Tremolizzo L, Hausner L, Benussi L, Froelich L, Ikram MA, Deniz-Naranjo MC, Tsolaki M, Rosende-Roca M, Löwenmark M, Hulsman M, Spallazzi M, Pericak-Vance MA, Esiri M, Bernal Sánchez-Arjona M, Dalmasso MC, Martínez-Larrad MT, Arcaro M, Nöthen MM, Fernández-Fuertes M, Dichgans M, Ingelsson M, Herrmann MJ, Scherer M, Vyhnalek M, Kosmidis MH, Yannakoulia M, Schmid M, Ewers M, Heneka MT, Wagner M, Scamosci M, Kivipelto M, Hiltunen M, Zulaica M, Alegret M, Fornage M, Roberto N, van Schoor NM, Seidu NM, Banaj N, Armstrong NJ, Scarmeas N, Scherbaum N, Goldhardt O, Hanon O, Peters O, Skrobot OA, Quenez O, Lerch O, Bossù P, Caffarra P, Dionigi Rossi P, Sakka P, Mecocci P, Hoffmann P, Holmans PA, Fischer P, Riederer P, Yang Q, Marshall R, Kalaria RN, Mayeux R, Vandenberghe R, Cecchetti R, Ghidoni R, Frikke-Schmidt R, Sorbi S, Hägg S, Engelborghs S, Helisalmi S, Botne Sando S, Kern S, Archetti S, Boschi S, Fostinelli S, Gil S, Mendoza S, Mead S, Ciccone S, Djurovic S, Heilmann-Heimbach S, Riedel-Heller S, Kuulasmaa T, Del Ser T, Lebouvier T, Polak T, Ngandu T, Grimmer T, Bessi V, Escott-Price V, Giedraitis V, Deramecourt V, Maier W, Jian X, Pijnenburg YAL, Kehoe PG, Garcia-Ribas G, Sánchez-Juan P, Pastor P, Pérez-Tur J, Piñol-Ripoll G, Lopez de Munain A, García-Alberca JM, Bullido MJ, Álvarez V, Lleó A, Real LM, Mir P, Medina M, Scheltens P, Holstege H, Marquié M, Sáez ME, Carracedo Á, Amouyel P, Schellenberg GD, Williams J, Seshadri S, van Duijn CM, Mather KA, Sánchez-Valle R, Serrano-Ríos M, Orellana A, Tárraga L, Blennow K, Huisman M, Andreassen OA, Posthuma D, Clarimón J, Boada M, van der Flier WM, Ramirez A, Lambert JC, van der Lee SJ, and Ruiz A
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- 2023
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21. Standardization of the Italian ALS-CBS™ Caregiver Behavioral Questionnaire.
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Aiello EN, Solca F, Greco LC, La Tona A, Torre S, Carelli L, Morelli C, Doretti A, Colombo E, Messina S, Pain D, Radici A, Lizio A, Casiraghi J, Cerri F, Brugnera A, Compare A, Woolley S, Murphy J, Tremolizzo L, Appollonio I, Verde F, Sansone VA, Lunetta C, Silani V, Ticozzi N, and Poletti B
- Abstract
Background: The present investigation aimed at testing the psychometrics and diagnostics of the Italian version of the Caregiver Behavioral Questionnaire (CBQ) from the ALS Cognitive Behavioral Screen (ALS-CBS™), as well as its case-control discrimination, in a cohort of non-demented patients with ALS., Methods: The caregivers of N = 265 non-demented patients with ALS and N = 99 healthy controls (HCs) were administered the CBQ and the Edinburgh Cognitive and Behavioural ALS Screen-Carer Interview (ECAS-CI). For N = 98 patients, an in-depth behavioural/psychopathological assessment via the Frontal Behavioural Inventory (FBI), the Dimensional Apathy Scale (DAS), the State and Trait Anxiety Inventory-Form Y (STAI-Y), and the Beck Depression Inventory (BDI) was also available. Factorial and construct validity, internal reliability, and diagnostics against an abnormal ECAS-CI score were tested in patients. Case-control discrimination was explored through logistic regression., Results: The CBQ was internally reliable (McDonald's ω = 0.90) and underpinned by a simple, unidimensional structure; it converged with ECAS-CI, FBI, and DAS scores and diverged from STAI-Y and BDI ones. A cutoff of ≤ 33 accurately detected abnormal ECAS-CI scores (AUC = 0.85), yielding optimal error- and information-based diagnostics. The CBQ was independent of demographic and disease-related variables and discriminated patients from HCs ( p < 0.001)., Discussion: The Italian version of the CBQ from the ALS-CBS™ is a valid, reliable, diagnostically sound, and feasible screener for detecting frontotemporal-like behavioural changes in non-demented patients with ALS. Its adoption is thus recommended within clinical practice and research in the view of providing preliminary information on whether the administration of more extensive behavioural instruments is needed., Competing Interests: VS received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., and Novartis Pharma AG and receives or has received research supports from the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. He is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology and the American Journal of Neurodegenerative Diseases. BP and LC received compensation for consulting services and/or speaking activities from Liquidweb S.r.l. NT received compensation for consulting services from Amylyx Pharmaceuticals and Zambon Biotech SA. CL received compensation for consulting services and/or speaking activities from Cytokinetics, Italfarmaco, and Mitsubishi Tanabe Pharma Europe. VAS participates in Advisory Boards or teaching activities for Biogen, Roche, Avexis, PTC, Santhera, Sarepta, and Dyne. SW is employed by Syneos Health. Additionally, SW receives licensing fees when the ALS Cognitive Behavioural Screen (ALS-CBS™) is used in pharmaceutical trials. JM is employed full time at Biogen. JM does not receive compensation related to the ALS-CBS™. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Aiello, Solca, Greco, La Tona, Torre, Carelli, Morelli, Doretti, Colombo, Messina, Pain, Radici, Lizio, Casiraghi, Cerri, Brugnera, Compare, Woolley, Murphy, Tremolizzo, Appollonio, Verde, Sansone, Lunetta, Silani, Ticozzi and Poletti.)
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- 2023
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22. Predictors of response to acetylcholinesterase inhibitors in dementia: A systematic review.
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Pozzi FE, Conti E, Appollonio I, Ferrarese C, and Tremolizzo L
- Abstract
Background: The mainstay of therapy for many neurodegenerative dementias still relies on acetylcholinesterase inhibitors (AChEI); however, there is debate on various aspects of such treatment. A huge body of literature exists on possible predictors of response, but a comprehensive review is lacking. Therefore, our aim is to perform a systematic review of the predictors of response to AChEI in neurodegenerative dementias, providing a categorization and interpretation of the results., Methods: We conducted a systematic review of the literature up to December 31
st , 2021, searching five different databases and registers, including studies on rivastigmine, donepezil, and galantamine, with clearly defined criteria for the diagnosis of dementia and the response to AChEI therapy. Records were identified through the string: predict* AND respon* AND (acetylcholinesterase inhibitors OR donepezil OR rivastigmine OR galantamine) . The results were presented narratively., Results: We identified 1,994 records in five different databases; after exclusion of duplicates, title and abstract screening, and full-text retrieval, 122 studies were finally included., Discussion: The studies show high heterogeneity in duration, response definition, drug dosage, and diagnostic criteria. Response to AChEI seems associated with correlates of cholinergic deficit (hallucinations, fluctuating cognition, substantia innominate atrophy) and preserved cholinergic neurons (faster alpha on REM sleep EEG, increased anterior frontal and parietal lobe perfusion after donepezil); white matter hyperintensities in the cholinergic pathways have shown inconsistent results. The K-variant of butyrylcholinesterase may correlate with better response in late stages of disease, while the role of polymorphisms in other genes involved in the cholinergic system is controversial. Factors related to drug availability may influence response; in particular, low serum albumin (for donepezil), CYP2D6 variants associated with reduced enzymatic activity and higher drug doses are the most consistent predictors, while AChEI concentration influence on clinical outcomes is debatable. Other predictors of response include faster disease progression, lower serum cholesterol, preserved medial temporal lobes, apathy, absence of concomitant diseases, and absence of antipsychotics. Short-term response may predict subsequent cognitive response, while higher education might correlate with short-term good response (months), and long-term poor response (years). Age, gender, baseline cognitive and functional levels, and APOE relationship with treatment outcome is controversial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pozzi, Conti, Appollonio, Ferrarese and Tremolizzo.)- Published
- 2022
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23. Donepezil-Induced Complex Multimodal Hallucinations: Two Cases and a Review of the Literature.
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Pozzi FE, Tremolizzo L, Ferrarese C, and Appollonio I
- Abstract
Hallucinations are common in neurodegenerative dementias, being present in a significant proportion of patients. Most of the available studies show that acetylcholinesterase inhibitors may be beneficial in preventing and treating hallucinations in patients with neurodegenerative and even psychiatric disorders, even though there are reports that they might also develop as an adverse effect of such therapy. However, a clear causal relationship for the latter association was not previously established. Here we describe 2 cases of patients treated with donepezil who developed complex multimodal hallucinations, which could be causally linked to the drug by means of a challenge-dechallenge (and rechallenge in one case) paradigm. We also provide a narrative review of the literature regarding donepezil and hallucinations and propose a hypothesis to explain the occurrence of this phenomenon., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)
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- 2022
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24. Clinical Perception and Treatment Options for Behavioral and Psychological Symptoms of Dementia (BPSD) in Italy.
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D'Antonio F, Tremolizzo L, Zuffi M, Pomati S, and Farina E
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Background: Behavioral and psychological symptoms of dementia (BPSD) have a high prevalence, and their presence is associated with a severe impact in terms of social costs. However, dedicated clinical tools or biomarkers to detect these symptoms are lacking. Thus, BPSD management in clinical settings is challenging. The aim of this study was to investigate the perception and the treatment strategies for BPSD in Italian centers working in the dementia field., Methods: A multicenter, national survey was developed by BPSD Study Group of the Italian Neurological Society for Dementia (SINDEM). The survey consisted of a semi-structured questionnaire that was e-mailed to SINDEM members, dementia centers part of the national network of memory clinics (Centers for Cognitive Deterioration and Dementia [CDCD]), and clinicians working in dementia care settings. The questions were focused on (1) perceived global frequency and relevance of BPSD; (2) tools used to assess BPSD; (3) pharmacological treatment for psychosis, apathy, agitation, aggression, depression, anxiety, sleep, and nutrition disturbances; (4) non-pharmacological treatments; (5) drugs side effects., Results: One-hundred and thirty-six clinicians participated in this study. Seventy-nine participants worked in a CDCD and 57 in other settings. The perceived frequency of BPSD was 74%. BPSD are detected by means of a clinical assessment for 96.3% or a caregiver interview for 97%. For psychosis treatment the first choice was atypical antipsychotics (83.3%), followed by typical antipsychotic (8.9%) and antidepressants (4.8%). For agitation, atypical antipsychotics were the first-choice treatment in 64% of cases and antidepressants in 16.1%. For aggression, the most used drugs were atypical antipsychotics (82.9%). For anxiety, 55.2% use antidepressants, 17.9% use atypical antipsychotics, and 16.9% use benzodiazepines. Interestingly, most of the centers apply non-pharmacological treatments for BPSD. Some differences emerged comparing the responses from CDCD and other care settings., Conclusion: The survey results revealed many differences in BPSD perception, treatment options, and observed side effect according to the clinical setting. This variability can be explained by the absence of clear guidelines, by differences in patients' characteristics, and by clinical practice based on subjective experience. These results suggest that producing guidelines for the pharmacological treatment of BPSD is a major need., Competing Interests: EF was employed by IRCCS Don Gnocchi Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 D'Antonio, Tremolizzo, Zuffi, Pomati, Farina and the Sindem BPSD Study Group.)
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- 2022
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25. Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs.
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Sierri G, Dal Magro R, Vergani B, Leone BE, Formicola B, Taiarol L, Fagioli S, Kravicz M, Tremolizzo L, Calabresi L, and Re F
- Subjects
- Alzheimer Disease metabolism, Apolipoprotein A-I metabolism, Biological Transport physiology, Biomimetics methods, Blood-Brain Barrier metabolism, Brain metabolism, Cell Line, Humans, ATP Binding Cassette Transporter 1 metabolism, Amyloid beta-Peptides metabolism, Astrocytes metabolism, Cholesterol metabolism, Lipoproteins, HDL metabolism
- Abstract
The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins' synthesis and lipoproteins' assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ
1-42 -induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins' levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood-brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.- Published
- 2021
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26. A Case of Reversible Dementia Due to a Strictly Fruitarian Diet: If an Apple a Day Keeps the Doctor Away, a Fruitarian Diet Throws Your Mind Away.
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Storti B, Nastasi G, Acampora R, Ferri F, Isella V, Ferrarese C, Appollonio I, and Tremolizzo L
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- 2021
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27. Blood-Based Biomarkers of Neuroinflammation in Alzheimer's Disease: A Central Role for Periphery?
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Angiulli F, Conti E, Zoia CP, Da Re F, Appollonio I, Ferrarese C, and Tremolizzo L
- Abstract
Neuroinflammation represents a central feature in the development of Alzheimer's disease (AD). The resident innate immune cells of the brain are the principal players in neuroinflammation, and their activation leads to a defensive response aimed at promoting β-amyloid (Aβ) clearance. However, it is now widely accepted that the peripheral immune system-by virtue of a dysfunctional blood-brain barrier (BBB)-is involved in the pathogenesis and progression of AD; microglial and astrocytic activation leads to the release of chemokines able to recruit peripheral immune cells into the central nervous system (CNS); at the same time, cytokines released by peripheral cells are able to cross the BBB and act upon glial cells, modifying their phenotype. To successfully fight this neurodegenerative disorder, accurate and sensitive biomarkers are required to be used for implementing an early diagnosis, monitoring the disease progression and treatment effectiveness. Interestingly, as a result of the bidirectional communication between the brain and the periphery, the blood compartment ends up reflecting several pathological changes occurring in the AD brain and can represent an accessible source for such biomarkers. In this review, we provide an overview on some of the most promising peripheral biomarkers of neuroinflammation, discussing their pathogenic role in AD.
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- 2021
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28. Coming to Terms with a Conundrum: A Case of Primary Progressive Apraxia of Speech due to Corticobasal Degeneration?
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Karantzoulis A, Susani E, Ferrarese C, Appollonio I, and Tremolizzo L
- Abstract
Primary progressive apraxia of speech (PPAOS) is a progressive disorder impairing the motor speech act leaving linguistic function unattained. Although apraxia of speech frequently co-occurs with other neurodegenerative conditions, PPAOS defines a clinical syndrome where apraxia of speech is the sole or prominent symptom for much of the disease's natural history. Mounting evidence is beginning to fully define this disease as the epiphenomenon of 4-repeat (4R) tau pathology although other pathologic signatures have been reported. Indeed, PPAOS patients generally present a parkinsonian syndrome late into their natural history mostly qualifying for either corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP). This is starting to be reflected in diagnostic criteria for PSP, namely, in the PSP speech and language (SL) subcategory; however, this inclusion is not reflected for CBS. Here, we present a single case of a patient with PPAOS and her clinical follow-up lasting 6 years, from the time she sought our attention to her death which occurred 8 years into the disease. PPAOS was the only and prominent symptom for most of the illness with extrapyramidal signs overtly presenting in the last months of its course. Clinical evaluation, imaging, genetic, and cerebrospinal fluid biomarkers all pointed toward an underlying CBD pathology, albeit the eventual anatomopathological confirmation was not performed. Had her clinical course been more suggestive of PSP, she would have qualified for criteria as PSP-SL. Our case therefore suggests the hypothetic need to discuss the broadening of the existing CBS criteria to encompass isolated PPAOS., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 by S. Karger AG, Basel.)
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- 2021
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29. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
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de Rojas I, Moreno-Grau S, Tesi N, Grenier-Boley B, Andrade V, Jansen IE, Pedersen NL, Stringa N, Zettergren A, Hernández I, Montrreal L, Antúnez C, Antonell A, Tankard RM, Bis JC, Sims R, Bellenguez C, Quintela I, González-Perez A, Calero M, Franco-Macías E, Macías J, Blesa R, Cervera-Carles L, Menéndez-González M, Frank-García A, Royo JL, Moreno F, Huerto Vilas R, Baquero M, Diez-Fairen M, Lage C, García-Madrona S, García-González P, Alarcón-Martín E, Valero S, Sotolongo-Grau O, Ullgren A, Naj AC, Lemstra AW, Benaque A, Pérez-Cordón A, Benussi A, Rábano A, Padovani A, Squassina A, de Mendonça A, Arias Pastor A, Kok AAL, Meggy A, Pastor AB, Espinosa A, Corma-Gómez A, Martín Montes A, Sanabria Á, DeStefano AL, Schneider A, Haapasalo A, Kinhult Ståhlbom A, Tybjærg-Hansen A, Hartmann AM, Spottke A, Corbatón-Anchuelo A, Rongve A, Borroni B, Arosio B, Nacmias B, Nordestgaard BG, Kunkle BW, Charbonnier C, Abdelnour C, Masullo C, Martínez Rodríguez C, Muñoz-Fernandez C, Dufouil C, Graff C, Ferreira CB, Chillotti C, Reynolds CA, Fenoglio C, Van Broeckhoven C, Clark C, Pisanu C, Satizabal CL, Holmes C, Buiza-Rueda D, Aarsland D, Rujescu D, Alcolea D, Galimberti D, Wallon D, Seripa D, Grünblatt E, Dardiotis E, Düzel E, Scarpini E, Conti E, Rubino E, Gelpi E, Rodriguez-Rodriguez E, Duron E, Boerwinkle E, Ferri E, Tagliavini F, Küçükali F, Pasquier F, Sanchez-Garcia F, Mangialasche F, Jessen F, Nicolas G, Selbæk G, Ortega G, Chêne G, Hadjigeorgiou G, Rossi G, Spalletta G, Giaccone G, Grande G, Binetti G, Papenberg G, Hampel H, Bailly H, Zetterberg H, Soininen H, Karlsson IK, Alvarez I, Appollonio I, Giegling I, Skoog I, Saltvedt I, Rainero I, Rosas Allende I, Hort J, Diehl-Schmid J, Van Dongen J, Vidal JS, Lehtisalo J, Wiltfang J, Thomassen JQ, Kornhuber J, Haines JL, Vogelgsang J, Pineda JA, Fortea J, Popp J, Deckert J, Buerger K, Morgan K, Fließbach K, Sleegers K, Molina-Porcel L, Kilander L, Weinhold L, Farrer LA, Wang LS, Kleineidam L, Farotti L, Parnetti L, Tremolizzo L, Hausner L, Benussi L, Froelich L, Ikram MA, Deniz-Naranjo MC, Tsolaki M, Rosende-Roca M, Löwenmark M, Hulsman M, Spallazzi M, Pericak-Vance MA, Esiri M, Bernal Sánchez-Arjona M, Dalmasso MC, Martínez-Larrad MT, Arcaro M, Nöthen MM, Fernández-Fuertes M, Dichgans M, Ingelsson M, Herrmann MJ, Scherer M, Vyhnalek M, Kosmidis MH, Yannakoulia M, Schmid M, Ewers M, Heneka MT, Wagner M, Scamosci M, Kivipelto M, Hiltunen M, Zulaica M, Alegret M, Fornage M, Roberto N, van Schoor NM, Seidu NM, Banaj N, Armstrong NJ, Scarmeas N, Scherbaum N, Goldhardt O, Hanon O, Peters O, Skrobot OA, Quenez O, Lerch O, Bossù P, Caffarra P, Dionigi Rossi P, Sakka P, Mecocci P, Hoffmann P, Holmans PA, Fischer P, Riederer P, Yang Q, Marshall R, Kalaria RN, Mayeux R, Vandenberghe R, Cecchetti R, Ghidoni R, Frikke-Schmidt R, Sorbi S, Hägg S, Engelborghs S, Helisalmi S, Botne Sando S, Kern S, Archetti S, Boschi S, Fostinelli S, Gil S, Mendoza S, Mead S, Ciccone S, Djurovic S, Heilmann-Heimbach S, Riedel-Heller S, Kuulasmaa T, Del Ser T, Lebouvier T, Polak T, Ngandu T, Grimmer T, Bessi V, Escott-Price V, Giedraitis V, Deramecourt V, Maier W, Jian X, Pijnenburg YAL, Kehoe PG, Garcia-Ribas G, Sánchez-Juan P, Pastor P, Pérez-Tur J, Piñol-Ripoll G, Lopez de Munain A, García-Alberca JM, Bullido MJ, Álvarez V, Lleó A, Real LM, Mir P, Medina M, Scheltens P, Holstege H, Marquié M, Sáez ME, Carracedo Á, Amouyel P, Schellenberg GD, Williams J, Seshadri S, van Duijn CM, Mather KA, Sánchez-Valle R, Serrano-Ríos M, Orellana A, Tárraga L, Blennow K, Huisman M, Andreassen OA, Posthuma D, Clarimón J, Boada M, van der Flier WM, Ramirez A, Lambert JC, van der Lee SJ, and Ruiz A
- Subjects
- Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease epidemiology, Alzheimer Disease pathology, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Apolipoproteins E genetics, Case-Control Studies, Cohort Studies, Datasets as Topic, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment methods, Risk Factors, Alzheimer Disease genetics, Multifactorial Inheritance
- Abstract
Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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- 2021
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30. ALS Mimics due to Affection of the Cervical Spine: From Common Compressive Myelopathy to Rare CSF Epidural Collection.
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Storti B, Diamanti S, Tremolizzo L, Riva N, Lunetta C, Filippi M, Ferrarese C, and Appollonio I
- Abstract
Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disease, with chameleon presentations and several mimics. Considering the poor prognosis of ALS, their precise and timely identification is pivotal. Affection of the cervical spine represents one potential source of ALS mimics that should never be missed, since it is potentially treatable. We hereby present 5 cases initially diagnosed as ALS but eventually found to have different kinds of cervical spine affection, from a common compressive myelopathy to a rare space-occupying cystic fluid collection., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)
- Published
- 2021
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31. Serum naturally occurring anti-TDP-43 auto-antibodies are increased in amyotrophic lateral sclerosis.
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Conti E, Sala G, Diamanti S, Casati M, Lunetta C, Gerardi F, Tarlarini C, Mosca L, Riva N, Falzone Y, Filippi M, Appollonio I, Ferrarese C, and Tremolizzo L
- Subjects
- Adult, Aged, Aged, 80 and over, Alzheimer Disease blood, Alzheimer Disease genetics, Alzheimer Disease immunology, Alzheimer Disease pathology, Amyotrophic Lateral Sclerosis blood, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Antibodies, Anti-Idiotypic isolation & purification, Autoantibodies isolation & purification, DNA-Binding Proteins genetics, Female, Frontotemporal Dementia blood, Frontotemporal Dementia genetics, Frontotemporal Dementia immunology, Frontotemporal Dementia pathology, Frontotemporal Lobar Degeneration blood, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration immunology, Frontotemporal Lobar Degeneration pathology, Humans, Inclusion Bodies genetics, Inclusion Bodies immunology, Inclusion Bodies pathology, Male, Middle Aged, Motor Neuron Disease blood, Motor Neuron Disease genetics, Motor Neuron Disease immunology, Motor Neuron Disease pathology, Mutation genetics, Amyotrophic Lateral Sclerosis immunology, Antibodies, Anti-Idiotypic blood, Autoantibodies blood, DNA-Binding Proteins immunology
- Abstract
Amyotrophic Lateral Sclerosis (ALS) patients express significant clinical heterogeneity that often hinders a correct diagnostic definition. Intracellular deposition of TDP-43, a protein involved in RNA metabolism characterizes the pathology. Interestingly, this protein can be detected in serum, wherein cognate naturally-occurring auto-antibodies (anti-TDP-43 NAb) might be also present, albeit they have never been documented before. In this exploratory study, we quantified the levels of both anti-TDP-43 NAb and TDP-43 protein as putative accessible markers for improving the ALS diagnostic process by using ELISA in N = 70 ALS patients (N = 4 carrying TARDBP mutations), N = 40 age-comparable healthy controls (CTRL), N = 20 motor neuron disease mimics (MN-m), N = 20 Alzheimer's disease (AD) and N = 15 frontotemporal lobar degeneration (FTLD) patients. Anti-TDP-43 NAb were found to be significantly increased in ALS patients compared to all the other groups (p < 0.001). On the other hand, the distribution of serum levels of TDP-43 protein was highly variable among the various groups. Levels were increased in ALS patients, albeit the highest values were detected in MN-m patients. NAb and protein serum levels failed to correlate. For the first time, we report that serum anti-TDP-43 NAb are detectable in human serum of both healthy controls and patients affected by a variety of neurodegenerative disorders; furthermore, their levels are increased in ALS patients, representing a potentially interesting trait core marker of this disease. Further studies are needed to clarify the exact role of the NAb. This information might be extremely useful for paving the way toward targeting TDP-43 by immunotherapy in ALS.
- Published
- 2021
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32. Editorial: Strategies to Fight Exercise Intolerance in Neuromuscular Disorders.
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Lanfranconi F, Marzorati M, and Tremolizzo L
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- 2020
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33. Atypical parkinsonism and intrathecal anti-glutamic acid decarboxylase antibodies - an unusual association: a case report.
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Stefanoni G, Formenti A, Tremolizzo L, Stabile A, Appollonio I, and Ferrarese C
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- Humans, Male, Middle Aged, Autoantibodies cerebrospinal fluid, Glutamate Decarboxylase immunology, Parkinsonian Disorders immunology
- Abstract
Background: Immunological causes of parkinsonism are very rare and usually characterized by early presentation, poor response to levodopa, and additional clinical features., Case Presentation: We describe a 58-year-old white man who presented with a 1-year history of gait disturbance with disequilibrium leading to falls. We report an association between parkinsonism and presence of anti-glutamic acid decarboxylase antibodies in his cerebrospinal fluid, discussing clinical presentation and follow-up., Conclusions: Besides the possibility of a casual association, this case allows us to hypothesize an alternative pathophysiological mechanism of parkinsonism implying interference with glutamic acid decarboxylase and gamma-aminobutyric acid functions, eventually resulting in basal ganglia circuit dysregulation.
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- 2020
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34. Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort.
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Scarlino S, Domi T, Pozzi L, Romano A, Pipitone GB, Falzone YM, Mosca L, Penco S, Lunetta C, Sansone V, Tremolizzo L, Fazio R, Agosta F, Filippi M, Carrera P, Riva N, and Quattrini A
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, High-Throughput Nucleotide Sequencing, Humans, Italy, Kaplan-Meier Estimate, Male, Middle Aged, Motor Neuron Disease mortality, Muscular Atrophy, Spinal mortality, Polymorphism, Single Nucleotide, Prognosis, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis mortality, Motor Neuron Disease genetics, Muscular Atrophy, Spinal genetics
- Abstract
Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
- Published
- 2020
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35. Late-Onset Epilepsy With Unknown Etiology: A Pilot Study on Neuropsychological Profile, Cerebrospinal Fluid Biomarkers, and Quantitative EEG Characteristics.
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Nardi Cesarini E, Babiloni C, Salvadori N, Farotti L, Del Percio C, Pascarelli MT, Noce G, Lizio R, Da Re F, Isella V, Tremolizzo L, Romoli M, DiFrancesco JC, Parnetti L, and Costa C
- Abstract
Introduction: Despite the fact that epilepsy has been associated with cognitive decline, neuropsychological, neurobiological, and neurophysiological features in patients with late-onset epilepsy of unknown etiology (LOEU) are still unknown. This cross-sectional study aims to investigate the neuropsychological profile, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), and resting-state quantitative electroencephalographic (qEEG) cortical rhythms in LOEU patients with mild cognitive impairment (LOEU-MCI) and with normal cognition (LOEU-CN), compared to non-epileptic MCI (NE-MCI) and cognitively normal (CN) controls. Methods: Consecutive patients in two clinical Units diagnosed with LOEU-CN (19), LOEU-MCI (27), and NE-MCI (21) were enrolled, and compared to age and sex-matched cognitively normal subjects CN (11). Patients underwent standardized comprehensive neuropsychological evaluation and CSF core AD biomarkers assessment (i.e., CSF Aβ42, phospho-tau and total tau, classified through A/T/(N) system). Recordings of resting-state eyes-closed electroencephalographic (EEG) rhythms were collected and cortical source estimation of delta (<4 Hz) to gamma (>30 Hz) bands with exact Low Resolution Electromagnetic Tomography (eLORETA) was performed. Results: Most LOEU patients had an MCI status at seizure onset (59%). Patients with LOEU-MCI performed significantly worse on measures of global cognition, visuo-spatial abilities, and executive functions compared to NE-MCI patients ( p < 0.05). Regarding MCI subtypes, multiple-domain MCI was 3-fold more frequent in LOEU-MCI than in NE-MCI patients (OR 3.14, 95%CI 0.93-10.58, p = 0.06). CSF Aβ42 levels were lower in the LOEU-MCI compared with the LOEU-CN group. Finally, parietal and occipital sources of alpha (8-12 Hz) rhythms were less active in the LOEU-MCI than in the NE-MCI and CN groups, while the opposite was true for frontal and temporal cortical delta sources. Discussion: MCI status was relatively frequent in LOEU patients, involved multiple cognitive domains, and might have been driven by amyloidosis according to CSF biomarkers. LOEU-MCI status was associated with abnormalities in cortical sources of EEG rhythms related to quiet vigilance. Future longitudinal studies should cross-validate our findings and test the predictive value of CSF and EEG variables., (Copyright © 2020 Nardi Cesarini, Babiloni, Salvadori, Farotti, Del Percio, Pascarelli, Noce, Lizio, Da Re, Isella, Tremolizzo, Romoli, DiFrancesco, Parnetti and Costa.)
- Published
- 2020
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36. DWI/FLAIR Mismatch during Hyperacute Infarction of the Percheron Artery: Time Is Thalamus!
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Francioni V, Pirro F, D'Anna G, Cairo M, Appollonio I, Ferrarese C, and Tremolizzo L
- Abstract
The artery of Percheron (AOP) is a single dominant thalamo-perforating artery that supplies bilaterally the medial thalami with variable contribution to the rostral midbrain. Occlusion of the AOP causes indeed variable and unspecific clinical symptoms due to this complex anatomy, and very often this diagnosis is delayed with the impossibility of recurring to intravenous thrombolysis (rTPA). Here, we report a case of AOP stroke that received a prompt diagnosis and therapy, owing to the availability of MR brain scan, showing a DWI/FLAIR mismatch typical of hyperacute infarctions. This case points out the importance of a high level of suspicion of AOP stroke, together with the correct implementation of imaging studies., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 by S. Karger AG, Basel.)
- Published
- 2020
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37. Tailored Exercise Training Counteracts Muscle Disuse and Attenuates Reductions in Physical Function in Individuals With Amyotrophic Lateral Sclerosis.
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Ferri A, Lanfranconi F, Corna G, Bonazzi R, Marchese S, Magnoni A, and Tremolizzo L
- Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized by the progressive loss of motor neurons, which leads to a reduction in strength and exercise capacity. Although the concept of "Exercise is Medicine" is accepted for many diseases, the role of exercise in individuals with ALS is still debated. The aim of this study was to propose a tailored exercise training program that was both safe and effective for individuals with ALS, and to evaluate the effects of this combined, moderate-intensity, aerobic and strength training program on aerobic capacities, strength, and physical function. Sixteen individuals with ALS were randomly assigned to either a training (three times a week for 12 weeks; TRAIN, n = 8) or usual care (continued their usual standard of care and served as control; UC, n = 8) group. Peak power, peak oxygen uptake, as well as the gas exchange threshold (GET) during a cardiopulmonary exercise test (CPET) on a cycle ergometer, and the maximal strength (1RM) of the knee extensor muscles, were evaluated before and after 12 weeks. Participants also performed the "Timed Up and Go" (TUG) and the "6-min walking" (6MWT) tests. The ALS Functional Rating Scale revisited (ALSFRS-R), the ALS Severity Scale (ALS-SS), and the McGill quality of life (QoL) questionnaire were also measured. The GET increased from 0.94 ± 0.08 to 1.06 ± 0.10 L min
-1 in TRAIN ( p = 0.009) and decreased from 0.79 ± 0.17 to 0.72 ± 0.17 L min-1 in UC ( p = 0.001). There was a significant difference between groups for changes in TUG (9.1 ± 5.5% improvement in TRAIN and 56.8 ± 18.5% worsening in UC, p = 0.002), ALSFRS-R (4.7 ± 2.6% decrease in TRAIN and 23.0 ± 5.6% decrease in UC, p = 0.007), and for the ALS-SS (2.2 ± 2.1% decrease in TRAIN and 12.4 ± 4.4% decrease in UC, p = 0.04). Even if the 1RM of the knee-extensor muscles showed a tendency to increase in TRAIN (70.1 ± 30.0%, p = 0.07), there was not a statistically significant difference ( p = 0.57) with respect to the changes in the UC group (44.9 ± 20.7% increase, p = 0.11). This study showed that a combined moderate-intensity aerobic and strength training program, tailored to the physical capacities of each individual, can improve aerobic fitness and maintain physical function in individuals with ALS., (Copyright © 2019 Ferri, Lanfranconi, Corna, Bonazzi, Marchese, Magnoni and Tremolizzo.)- Published
- 2019
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38. Riluzole Selective Antioxidant Effects in Cell Models Expressing Amyotrophic Lateral Sclerosis Endophenotypes.
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Sala G, Arosio A, Conti E, Beretta S, Lunetta C, Riva N, Ferrarese C, and Tremolizzo L
- Abstract
Objective: Until recently, riluzole was the only drug licensed for amyotrophic lateral sclerosis (ALS). In spite of its efficacy, the mechanism of action remains elusive, and both blocking of glutamate release and antioxidant properties have been postulated. Here we characterized human SH-SY5Y neuroblastoma cell lines, taking advantage of their insensitivity to excitotoxic insults, in order to selectively assess the presence of a direct antioxidant effect of riluzole., Methods: SH-SY5Y cells, either parental or overexpressing the G93A SOD1 mutation, were exposed for 24 hours to the selected stimuli., Results: Riluzole (1‒10 µM) was able to counteract the effects of H
2 O2 exposure (200 µM/24 hr), limiting both cell death and whole-cell reactive oxygen species (ROS) increase. The same experiments were repeated using SH-SY5Y cells carrying the familial ALS-related G93A-SOD1 mutation and constitutively expressing two-fold increased whole-cell ROS levels with respect to wild-type cells: riluzole was ineffective in this paradigm. Analogously, riluzole was ineffective in preventing cell death induced by exposing SH-SY5Y cells to 3-morpholino-sydnonimine (SIN-1, 1.5 mM/24 hr), a reactive nitrogen species (RNS) donor., Conclusion: Our data support a direct antioxidant action of riluzole. Furthermore, the lack of efficacy of riluzole observed in the SOD1 cell model mirrors the lack of efficacy already demonstrated in cognate mouse models of ALS, plausibly reflecting differences in the underlying pathogenic mechanisms. Finally, riluzole inefficacy against nitrosative stress might support the idea that a combined therapeutic intervention may result more effective in ALS patients, as in the case of co-administration of edaravone, a drug known to reduce RNS.- Published
- 2019
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39. The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research.
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Gentile F, Scarlino S, Falzone YM, Lunetta C, Tremolizzo L, Quattrini A, and Riva N
- Abstract
Although amyotrophic lateral sclerosis (ALS) has been considered as a disorder of the motor neuron (MN) cell body, recent evidences show the non-cell-autonomous pathogenic nature of the disease. Axonal degeneration, loss of peripheral axons and destruction of nerve terminals are early events in the disease pathogenic cascade, anticipating MN degeneration, and the onset of clinical symptoms. Therefore, although ALS and peripheral axonal neuropathies should be differentiated in clinical practice, they also share damage to common molecular pathways, including axonal transport, RNA metabolism and proteostasis. Thus, an extensive evaluation of the molecular events occurring in the peripheral nervous system (PNS) could be fundamental to understand the pathogenic mechanisms of ALS, favoring the discovery of potential disease biomarkers, and new therapeutic targets.
- Published
- 2019
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40. Impact of Hanging Motionless in Harness on Respiratory and Blood Pressure Reflex Modulation in Mountain Climbers.
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Lanfranconi F, Ferri A, Pollastri L, Bartesaghi M, Novarina M, De Vito G, Beretta E, and Tremolizzo L
- Subjects
- Adult, Cross-Sectional Studies, Female, Healthy Volunteers, Humans, Male, Oxygen metabolism, Respiratory Function Tests, Syncope physiopathology, Time Factors, Blood Pressure physiology, Mountaineering physiology, Reflex physiology, Respiration
- Abstract
Harness hang syncope (HHS) is a risk that specifically affects safety of harness users in mountain climbing. Aims: To evaluate individual patterns of breathing resulting from deranged cardiovascular reflexes triggering a syncopal event when a mismatch between cerebral O
2 demand and supply is present. Results: Forty healthy participants [aged 39.1 (8.2) years] were enrolled in a motionless suspension test while hanging in harness. Respiratory gas exchange values were analyzed to assess the pattern of breathing (EpInWel , respiratory elastic power) and cardiovascular parameters were monitored (BP, blood pressure). Four participants experienced HHS after 30.0 (7.6) minutes, with an early manifestation of loss of control of both a sustainable EpInWel and BP, starting after 10-12 minutes. Among the other participants, two different reactions were observed during suspension: (1) group G1 tolerated 32.7 (11.4) minutes of suspension by a favorable adaptation of the EpInWel and BP parameters and (2) group G2 showed significantly shorter time of suspension 24.0 (10.4) minutes with unfavorable increase in EpInWel and BP. Conclusions: Greater resistance to HHS occurs in people developing less marked fluctuations of both respiratory and cardiovascular reflex responses. Conversely, wider fluctuations both in control of EpInWel and BP were observed in the event of decreased suspension tolerance or in syncopal events.- Published
- 2019
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41. Persistent hiccup reflex activation as a complication of dental implant surgery: a case report.
- Author
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Porcaro G, Tremolizzo L, Appollonio I, and Maddalone M
- Abstract
Persistent hiccup can conceal life-threatening clinical conditions of highly heterogeneous nature. Here, we report a case of a persistent hiccup that has been temporally associated with dental implant insertion in a patient with paroxysmal atrial fibrillation. This 67-year-old patient underwent dental implant in area 36 and the procedure was performed without acute complications. A prolonged hiccup started ~48 h after the procedure: it failed to respond to several medications and it lasted for ~18 days, after which it spontaneously disappeared. Brain imaging and neurological examination were conducted in order to rule out organic conditions, even though all the investigations resulted to be negative. We suggest that the surgical procedure might have triggered a prolonged reflex activation. Knowledge about this complication of oral surgery procedure might be useful for avoiding unnecessary hospitalization or diagnostic tests.
- Published
- 2018
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42. Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise.
- Author
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Lanfranconi F, Ferri A, Corna G, Bonazzi R, Lunetta C, Silani V, Riva N, Rigamonti A, Maggiani A, Ferrarese C, and Tremolizzo L
- Subjects
- Adult, Aged, Amyotrophic Lateral Sclerosis diagnosis, Exercise Test, Female, Humans, Lactic Acid metabolism, Male, Middle Aged, Muscle Strength, Muscle, Skeletal physiopathology, Severity of Illness Index, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis physiopathology, Exercise, Motor Neurons metabolism, Muscle, Skeletal metabolism, Oxygen Consumption
- Abstract
This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O
2 uptake ([Formula: see text]O2peak ), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ([Formula: see text]Epeak ). pALS displayed: (1) 44% lower [Formula: see text]O2peak vs. CTRL (p < 0.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p < 0.01), with a linear regression between these two variables (r2 = 0.64, p < 0.0001); (2) 46% reduced [Formula: see text]Epeak vs. CTRL (p < 0.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O2 transport and utilization chain.- Published
- 2017
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43. Anorexia nervosa of the restrictive type and celiac disease in adolescence.
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Nacinovich R, Tremolizzo L, Corbetta F, Conti E, Neri F, and Bomba M
- Abstract
Background: Anorexia nervosa (AN) is usually present in adolescence with symptoms partially overlapping celiac disease (CD), but the relationship between these two conditions has received little attention in the literature. The aim of this work was to explore this relationship, considering if CD could be associated with specific baseline AN-related clinical features., Methods: In this retrospective study, 82 adolescent female out- and inpatients with AN of the restrictive type (ANr), according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria, were recruited. CD diagnosis and related serology were recorded, including tissue transglutaminase type-2 antibodies, endomysial antibodies, and antibodies against deamidated forms of gliadin peptides. Eating disorder inventory-3, Children's Depression Inventory, body mass index, age, and disease duration data recorded at the time of blood withdrawal were also obtained from each patient., Results: Five (6.1%) subjects presented a CD disorder associated with AN: none of the collected psychometric measures was significantly correlated with any CD-related parameter or characterized as a specific subgroup., Conclusion: CD diagnosis or serology does not relate to ANr clinical or demographic characteristics. However, a slight increase in prevalence with respect to the general population might be hypothesized and possibly elucidated by further studies with an appropriate design., Competing Interests: Disclosure The authors report no conflicts of interest in this work.
- Published
- 2017
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44. Osteopathic Manual Treatment for Amyotrophic Lateral Sclerosis: A Feasibility Pilot Study.
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Maggiani A, Tremolizzo L, Della Valentina A, Mapelli L, Sosio S, Milano V, Bianchi M, Badi F, Lavazza C, Grandini M, Corna G, Prometti P, Lunetta C, Riva N, Ferri A, and Lanfranconi F
- Abstract
Background: Current interventions in amyotrophic lateral sclerosis (ALS) are focused on supporting quality of life (QoL) and easing pain with a multidisciplinary approach., Objective: Primary aim of this pilot work assessed feasibility, safety, tolerability and satisfaction of osteopathic manual treatment (OMT) in 14 ALS outpatients., Methods: Patients were randomized according to an initial single-blind design (12 weeks, T0-T1), in order to receive OMT (weekly for 4 weeks, and fortnightly for the following 8 weeks) versus usual-care (n=7 each group), followed by an OMT open period (T1-T2, once a week for 8 weeks, n=10). Secondary aims included blind osteopathic assessment of somatic dysfunctions (SD) for goal attainment scale (GAS) calculation, Brief Pain Inventory-short form and McGill QoL-16 items., Results: OMT was demonstrated feasible and safe and patients displayed high satisfaction (T1-VAS=8.34 ± 0.46; T2-VAS=8.52 ± 0.60). Considering secondary aims no significant differences emerged. Finally, at study entry (T0), a cervico-dorsal SD was found in 78% of ALS patients versus 28% of healthy matched controls (p<0.01)., Conclusion: OMT was found feasible, safe and satisfactory in ALS. The lack of secondary aim differences can be due to the limited sample size. OMT could be an interesting option to explore in ALS.
- Published
- 2016
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45. Brain targets: can you believe your own eyes?
- Author
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Stefanoni G, Tironi M, Tremolizzo L, Fusco ML, DiFrancesco JC, Patassini M, Ferrarese C, and Appollonio I
- Subjects
- Adult, Aged, Aged, 80 and over, Brain Neoplasms diagnostic imaging, Brain Neoplasms secondary, Fatal Outcome, Female, Humans, Kidney Neoplasms pathology, Male, Middle Aged, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis pathology, Neuroaspergillosis diagnostic imaging, Neuroaspergillosis pathology, Neurocysticercosis diagnostic imaging, Neurocysticercosis pathology, Radiography, Small Cell Lung Carcinoma diagnostic imaging, Small Cell Lung Carcinoma pathology, Tuberculoma, Intracranial diagnostic imaging, Tuberculoma, Intracranial pathology, Brain Diseases diagnostic imaging, Brain Diseases pathology
- Abstract
The unquestionable advantages provided by modern neuroimaging techniques have recently led some to question the duty of the neurologist, traditionally struggling first and foremost to establish the semeiotic localization of brain lesions and only then to interpret them. The present brief report of six clinical patients who came recently to our attention aims to emphasize that the interpretation of neuroimaging results always requires integration with anamnestic, clinical and laboratory data, together with knowledge of nosography and the literature. The solutions of the reported cases always originated from close interaction between the neurologist and the neuroradiologist, based on the initial diagnostic uncertainty linked to the finding of isolated or multiple brain target or ring lesions, too often considered paradigmatic examples of the pathognomonic role of neuroimaging.
- Published
- 2014
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46. Valproate Treatment in an ALS Patient Carrying a c.194G>A Spastin Mutation and SMN2 Homozygous Deletion.
- Author
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Tremolizzo L, Sala G, Conti E, Rodriguez-Menendez V, Fogli A, Michelucci A, Simi P, Penco S, Lunetta C, Corbo M, and Ferrarese C
- Abstract
Here we report the case of an ALS patient found to carry both a novel heterozygous change (c.194G>A) within the spastin gene and a homozygous deletion of the SMN2 gene. The patient was started on valproic acid (VPA, 600 mg/die per os) considering the capacity of this drug of increasing survival motor neuron through an epigenetic mechanism. Patient clinical course and molecular effects of VPA on skin fibroblasts obtained from the proband are described. This c.194G>A spastin mutation might expand the previously known borders of type 4 spastic paraplegia (SPG4) and we suggest the intriguing possibility that the absence of SMN2 might have acted as a contributory risk factor for starting lower motor neuron damage. Exploring the relationship genocopy-phenocopy in selected ALS patients might represent an interesting strategy for understanding its clinical variability.
- Published
- 2014
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47. Valproate protective effects on cisplatin-induced peripheral neuropathy: an in vitro and in vivo study.
- Author
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Rodriguez-Menendez V, Gilardini A, Bossi M, Canta A, Oggioni N, Carozzi V, Tremolizzo L, and Cavaletti G
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols toxicity, Cisplatin administration & dosage, Drug Synergism, Female, Ganglia, Spinal drug effects, Neurites drug effects, Peripheral Nervous System Diseases chemically induced, Rats, Rats, Sprague-Dawley, Rats, Wistar, Valproic Acid administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cisplatin toxicity, Peripheral Nervous System Diseases prevention & control, Valproic Acid pharmacology
- Abstract
Background: Antineoplastic drugs, such as cisplatin (CDDP), induce disabling peripheral neuropathies, representing a hindrance to effective cancer treatments. The exact pathogenesis of CDDP-induced neuropathy is not yet understood, and the dysregulation of gene expression has been proposed. Valproate (VPA) is an antiepileptic drug recently discovered to remodel gene expression, with hypothetically putative neuroprotective effects., Materials and Methods: VPA was tested in both, in vitro and in vivo models of CDDP-neurotoxicity., Results: VPA administered in combination with CDDP promoted dorsal root ganglia (DRG) neurons survival. Moreover, this treatment induced in Wistar rats an improvement of body weight, sensory nerve conduction velocity, and DRG morphometric analysis. In contrast, VPA was not able to rescue CDDP pre-treated rats., Conclusion: When used in combination with CDDP, VPA displays a protective action against neuropathy, in our models, suggesting possible future clinical applications.
- Published
- 2008
48. The relationship between facial skeletal class and expert-rated interpersonal skill: an epidemiological survey on young Italian adults.
- Author
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Senna A, Abbenante D, Tremolizzo L, Campus G, and Strohmenger L
- Subjects
- Adolescent, Adult, Age Factors, Cephalometry, Data Collection, Epidemiologic Studies, Esthetics, Female, Humans, Italy epidemiology, Italy ethnology, Male, Self Concept, Sex Factors, Beauty, Face anatomy & histology, Interpersonal Relations, Skull anatomy & histology
- Abstract
Background: The facial region plays a major role in determining physical attractiveness, so we assessed the hypothesis that the capability of successfully managing interpersonal relationships in young adults might be related to the facial skeletal class., Methods: 1,014 young subjects applying to the Military Academy of Pozzuoli, Italy, were enrolled and the cephalometric evaluation was performed by calculating the angular relationships between skeletal points localized by the lateral cephalogram of the face, sorting the subjects in three groups corresponding to each major facial skeletal class. Concurrently, the subjects were evaluated by a team of psychiatrists administering the MMPI-2 test followed by a brief colloquium with each candidate, in order to identify those subjects characterized by low skills for managing interpersonal relationships., Results: According to the psychiatric evaluation about 20% of the subjects were considered potentially unable to manage successfully interpersonal relationships (NS). Males displayed an about two-fold increased risk of being NS. No differences were shown in the distribution of the NS male subjects among the three different facial skeletal classes. On the other hand, NS females displayed a different distribution among the three facial skeletal classes, with a trend of about two-fold and four-fold, respectively, for those subjects belonging to classes II and III, respect to those belonging to class I., Conclusion: Females may be more sensitive to physical factors determining beauty, such as the facial morphology certainly is. This finding appears to be interesting especially when thinking about possible orthodontic interventions, although further study is certainly needed to confirm these results.
- Published
- 2006
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49. Substrate-induced modulation of glutamate uptake in human platelets.
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Begni B, Tremolizzo L, D'Orlando C, Bono MS, Garofolo R, Longoni M, and Ferrarese C
- Subjects
- Amino Acid Transport System X-AG metabolism, Blood Platelets metabolism, Cycloheximide pharmacology, D-Aspartic Acid pharmacology, Excitatory Amino Acid Agonists pharmacology, Excitatory Amino Acid Antagonists pharmacology, Excitatory Amino Acid Transporter 2 metabolism, Glutamate Plasma Membrane Transport Proteins, Glutamic Acid pharmacology, Glycine analogs & derivatives, Glycine pharmacology, Humans, Kainic Acid analogs & derivatives, Kainic Acid pharmacology, Symporters metabolism, Blood Platelets drug effects, Excitatory Amino Acid Transporter 1 biosynthesis, Glutamic Acid pharmacokinetics
- Abstract
In the central nervous system (CNS), glutamate rapidly upregulates the activities of different excitatory amino-acid transporter subtypes (EAATs) in order to help protect neurons from excitotoxicity. Since human platelets display a specific sodium-dependent glutamate uptake activity, and express the three major glutamate transporters, which may be affected in neurological disorders, we investigated whether platelets are subject to substrate-induced modulation as described for CNS. A time- and dose-dependent upregulation of [3H]-glutamate uptake (up to two-fold) was observed in platelets preincubated with glutamate. There was an increase in maximal velocity rate without affinity changes. Glutamate receptor agonists and antagonists did not modulate this upregulation and preincubation with glutamate analogues failed to mimic the glutamate effect. Only aspartate preincubation increased the uptake, albeit approximately 35% less with respect to glutamate. The effect of glutamate preincubation on the expression of the three major transporters was studied by Western blotting, showing an increase of approximately 70% in EAAT1 immunoreactivity that was completely blocked by cycloheximide (CEM). However, L-serine-O-sulphate, at a concentration (200 microM) known to block EAAT1/3 selectively, did not completely inhibit the effect of glutamate stimulation, indicating the possible involvement of EAAT2. In fact, glutamate stimulation was completely abolished only when, following CEM pre-incubation, the experiment was run in the presence of the selective EAAT2 inhibitor dihydrokainic acid. Since surface biotinylation experiments failed to show evidence of EAAT2 translocation, our results suggest the existence of a different way of regulating EAAT2 activity. These findings indicate that human platelets display a substrate-dependent modulation of glutamate uptake mediated by different molecular mechanisms and confirm that ex vivo platelets are a reliable model to investigate the dysfunction of glutamate uptake regulation in patients affected by neurological disorders.
- Published
- 2005
- Full Text
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50. Leber hereditary optic neuropathy mtDNA mutations disrupt glutamate transport in cybrid cell lines.
- Author
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Beretta S, Mattavelli L, Sala G, Tremolizzo L, Schapira AH, Martinuzzi A, Carelli V, and Ferrarese C
- Subjects
- Amino Acid Transport System X-AG metabolism, Biological Transport genetics, Biological Transport physiology, Cell Line, Tumor, Energy Metabolism drug effects, Energy Metabolism genetics, Energy Metabolism physiology, Excitatory Amino Acid Transporter 1 metabolism, Humans, Hydrogen Peroxide pharmacology, Mutation, Optic Atrophy, Hereditary, Leber metabolism, Reactive Oxygen Species metabolism, Rotenone pharmacology, Uncoupling Agents pharmacology, DNA, Mitochondrial genetics, Glutamates metabolism, Optic Atrophy, Hereditary, Leber genetics
- Abstract
Leber hereditary optic neuropathy (LHON) is a maternally inherited form of retinal ganglion cell degeneration leading to optic atrophy which is caused by point mutations in the mitochondrial genome (mtDNA). Three pathogenic mutations (positions 11778/ND4, 3460/ND1 and 14484/ND6) account for the majority of LHON cases and they affect genes that encode for different subunits of mitochondrial complex I. Excitotoxic injury to retinal ganglion cells and the optic nerve has been previously hypothesized, especially given the high susceptibility of this neural cell type to glutamate toxicity. Osteosarcoma-derived cytoplasmic hybrids (cybrids) generated from six unrelated LHON patients, two cell lines for each pathogenic mutation, were compared with cybrids obtained from three healthy controls. Molecular and biochemical analyses showed that excitatory amino acid transporter 1 (EAAT1)/GLAST is the most active glutamate transporter in this cellular model. The glutamate uptake maximal velocity was significantly reduced in all LHON cybrids compared with control cybrids. This reduction was correlated in a mutation-specific fashion with the degree of mitochondrial production of reactive oxygen species, which is enhanced in LHON cybrids. Our findings support the hypothesis that the genetically determined mitochondrial dysfunction in LHON patients leads to impaired activity of the EAAT1 glutamate transporter. This observation is particularly relevant since EAAT1 is the major means of glutamate removal in the inner retina and this prevents retinal ganglion cells being damaged as a result of excitotoxicity.
- Published
- 2004
- Full Text
- View/download PDF
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