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1. Exosomal tau with seeding activity is released from Alzheimer's disease synapses, and seeding potential is associated with amyloid beta

Author

Wayne W. Poon, Karen H. Gylys, Ryan C. Bohannan, Emily Miyoshi, Harry V. Vinters, Carol A. Miller, Maria M. Corrada, Tina Bilousova, Mikhail Melnik, Varghese John, Jesus Campagna, Chris Jean Elias, Danyl Fakhrutdinov, Claudia H. Kawas, Katherine N. Maina, and Chad A. Caraway

Subjects
Male, Aging, Neurodegenerative, Alzheimer's Disease, Mice, 80 and over, Pathology, 2.1 Biological and endogenous factors, Aetiology, Aged, 80 and over, Cerebral Cortex, biology, Chemistry, Vesicle, Depolarization, Alzheimer's disease, Middle Aged, Cell biology, Neurological, Female, Tauopathy, Amyloid beta, Clinical Sciences, tau Proteins, Synaptic vesicle, Protein Aggregation, Pathological, Article, Pathology and Forensic Medicine, Extracellular Vesicles, In vivo, Alzheimer Disease, Pathological, medicine, Acquired Cognitive Impairment, Animals, Humans, Molecular Biology, Aged, Amyloid beta-Peptides, HEK 293 cells, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Cell Biology, medicine.disease, Protein Aggregation, Microvesicles, Brain Disorders, Synapses, biology.protein, Dementia, Synaptosomes
Abstract

Synaptic transfer of tau has long been hypothesized from the human pathology pattern and has been demonstrated in vitro and in vivo, but the precise mechanisms remain unclear. Extracellular vesicles such as exosomes have been suggested as a mechanism, but not all tau is exosomal. The present experiments use a novel flow cytometry assay to quantify depolarization of synaptosomes by KCl after loading with FM2–10, which induces a fluorescence reduction associated with synaptic vesicle release; the degree of reduction in cryopreserved human samples equaled that seen in fresh mouse synaptosomes. Depolarization induced the release of vesicles in the size range of exosomes, along with tetraspanin markers of extracellular vesicles. A number of tau peptides were released, including tau oligomers; released tau was primarily unphosphorylated and C-terminal truncated, with Aβ release just above background. When exosomes were immunopurified from release supernatants, a prominent tau band showed a dark smeared appearance of SDS-stable oligomers along with the exosomal marker syntenin-1, and these exosomes induced aggregation in the HEK tau biosensor assay. However, the flow-through did not seed aggregation. Size exclusion chromatography of purified released exosomes shows faint signals from tau in the same fractions that show a CD63 band, an exosomal size signal, and seeding activity. Crude synaptosomes from control, tauopathy, and AD cases demonstrated lower seeding in tauopathy compared to AD that is correlated with the measured Aβ42 level. These results show that AD synapses release exosomal tau that is C-terminal-truncated, oligomeric, and with seeding activity that is enhanced by Aβ. Taken together with previous findings, these results are consistent with a direct prion-like heterotypic seeding of tau by Aβ within synaptic terminals, with subsequent loading of aggregated tau onto exosomes that are released and competent for tau seeding activity., A novel assay quantifies depolarization of synaptosomes from Alzheimer’s cortex, and the authors show that tau released from these samples is unphosphorylated and C-terminal-truncated. Most tau is exosomal, and free-floating tau did not seed aggregation. Seeding activity was lower in tauopathy than AD, and strongly related to amyloid level.

Published
2021

2. Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year phase 1 study of 113 injections in 31 patients

Author

Elisa Singh, Oleg V. Kopyov, Anthony Bravo, Benjamin Rapaport, Michael Arata, Ami R Sanathara, Kristin Scord, Sawyer Farmer, Chad A. Caraway, Sean Berman, Mark Berman, Michael Elam, Ruslana Cannell, Rory McRory, Alex Kopyov, Christian Yassa, Christopher Duma, Samuel Khoudari, Karlyssa Chung, Lian Stemler, David Weiland, Elliot B Lander, and Chace Duma

Subjects
Adult, Male, 0301 basic medicine, Traumatic brain injury, Adipose tissue, Mesenchymal Stem Cell Transplantation, Transplantation, Autologous, Ventriculoperitoneal Shunt, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Amyotrophic lateral sclerosis, Molecular Biology, Stroke, Spinal cord injury, Dexamethasone, Aged, Aged, 80 and over, business.industry, Multiple sclerosis, Hematopoietic Stem Cell Transplantation, Neurodegenerative Diseases, General Medicine, Middle Aged, Stromal vascular fraction, Hematopoietic Stem Cells, medicine.disease, Infusions, Intraventricular, Treatment Outcome, 030104 developmental biology, Adipose Tissue, 030220 oncology & carcinogenesis, Anesthesia, Female, business, medicine.drug
Abstract

We have chosen to test the safety of human intracerebroventricular (ICV) brain injections of autologous non-genetically-modified adipose-derived stromal vascular fraction (ADSVF). In this IRB-approved trial, 24 patients received ICV ADSVF via an implanted reservoir between 5/22/14 and 5/22/17. Seven others were injected via their ventriculo-peritoneal shunts. Ten patients had Alzheimer’s disease (AD), 6 had amyotrophic lateral sclerosis (ALS), 6 had progressive multiple sclerosis (MS-P), 6 had Parkinson’s “Plus” (PD+), 1 had spinal cord injury, 1 had traumatic brain injury, and 1 had stroke. Median age was 74 (range 41–83). Injections were planned every 2–3 months. Thirty-one patients had 113 injections. Patients received SVF injection volumes of 3.5–20 cc (median:4 cc) containing 4.05 × 105 to 6.2 × 107 cells/cc, which contained an average of 8% hematopoietic and 7.5% adipose stem cells. Follow-up ranged from 0 to 36 months (median: 9.2 months). MRIs post injection(s) were unchanged, except for one AD patient whose hippocampal volume increased from

Published
2019
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3. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

Author

Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A. Hickman, Thor D. Stein, Yevgeniya Abramzon, Sarah Ahmed, Marya S. Sabir, Makayla K. Portley, Arianna Tucci, Kristina Ibáñez, F.N.U. Shankaracharya, Pamela Keagle, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L. Waldo, Per M. Johansson, Christer F. Nilsson, James B. Rowe, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Edwin Jabbari, Coralie Viollet, Jonathan D. Glass, Andrew B. Singleton, Vincenzo Silani, Owen A. Ross, Mina Ryten, Ali Torkamani, Toshiko Tanaka, Luigi Ferrucci, Susan M. Resnick, Stuart Pickering-Brown, Christopher B. Brady, Neil Kowal, John A. Hardy, Vivianna Van Deerlin, Jean Paul Vonsattel, Matthew B. Harms, Huw R. Morris, Raffaele Ferrari, John E. Landers, Adriano Chiò, J. Raphael Gibbs, Clifton L. Dalgard, Sonja W. Scholz, Bryan J. Traynor, Adelani Adeleye, Camille Alba, Dagmar Bacikova, Daniel N. Hupalo, Elisa McGrath Martinez, Harvey B. Pollard, Gauthaman Sukumar, Anthony R. Soltis, Meila Tuck, Xijun Zhang, Matthew D. Wilkerson, Bradley N. Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon D. Topp, Jason Kost, Emma L. Scotter, Kevin P. Kenna, Jack W. Miller, Cinzia Tiloca, Caroline Vance, Eric W. Danielson, Claire Troakes, Claudia Colombrita, Safa Al-Sarraj, Elizabeth A. Lewis, Andrew King, Daniela Calini, Viviana Pensato, Barbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Russell L. McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Zorica Stevic, Sandra D’Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Wouter van Rheenen, Frank P. Diekstra, Rosa Rademakers, Marka van Blitterswijk, Kevin B. Boylan, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Claire Leblond-Manry, Guy A. Rouleau, Orla Hardiman, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Ammar Al-Chalabi, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Alberto García-Redondo, Zheyang Wu, Cinzia Gellera, Antonia Ratti, Robert H. Brown, Christopher E. Shaw, John C. Ambrose, Prabhu Arumugam, Emma L. Baple, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, H. Brittain, Mark J. Caulfield, Georgia C. Chan, Clare E.H. Craig, Louise C. Daugherty, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, Pedro Furió-Tarí, Joanne M. Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James E. Holman, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Lea Lahnstein, Kay Lawson, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Ellen M. McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Chris A. Odhams, Christine Patch, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Katherine R. Smith, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Ellen R.A. Thomas, Simon R. Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Sampath Arepalli, Pavan Auluck, Robert H. Baloh, Robert Bowser, Alexis Brice, James Broach, William Camu, John Cooper-Knock, Philippe Corcia, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, Faraz Faghri, Jennifer Farren, Eva Feldman, Mary Kay Floeter, Pietro Fratta, Glenn Gerhard, Summer B. Gibson, Stephen A. Goutman, Terry D. Heiman-Patterson, Dena G. Hernandez, Ben Hoover, Lilja Jansson, Freya Kamel, Janine Kirby, Neil W. Kowall, Hannu Laaksovirta, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel JL. MacGowan, Nicholas J. Maragakis, Gabriele Mora, Kevin Mouzat, Liisa Myllykangas, Mike A. Nalls, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Erik Pioro, Stefan M. Pulst, John M. Ravits, Alan E. Renton, Wim Robberecht, Ian Robey, Ekaterina Rogaeva, Jeffrey D. Rothstein, Michael Sendtner, Katie C. Sidle, Zachary Simmons, David J. Stone, Pentti J. Tienari, John Q. Trojanowski, Juan C. Troncoso, Miko Valori, Philip Van Damme, Ludo Van Den Bosch, Lorne Zinman, Diego Albani, Barbara Borroni, Alessandro Padovani, Amalia Bruni, Jordi Clarimon, Oriol Dols-Icardo, Ignacio Illán-Gala, Alberto Lleó, Adrian Danek, Daniela Galimberti, Elio Scarpini, Maria Serpente, Caroline Graff, Huei-Hsin Chiang, Behzad Khoshnood, Linn Öijerstedt, Christopher M. Morris, Benedetta Nacmias, Sandro Sorbi, Jorgen E. Nielsen, Lynne E. Hjermind, Valeria Novelli, Annibale A. Puca, Pau Pastor, Ignacio Alvarez, Monica Diez-Fairen, Miquel Aguilar, Robert Perneczky, Janine Diehl-Schimd, Mina Rossi, Agustin Ruiz, Mercè Boada, Isabel Hernández, Sonia Moreno-Grau, Johannes C. Schlachetzki, Dag Aarsland, Marilyn S. Albert, Johannes Attems, Matthew J. Barrett, Thomas G. Beach, Lynn M. Bekris, David A. Bennett, Lilah M. Besser, Eileen H. Bigio, Sandra E. Black, Bradley F. Boeve, Ryan C. Bohannan, Francesca Brett, Maura Brunetti, Chad A. Caraway, Jose-Alberto Palma, Andrea Calvo, Antonio Canosa, Dennis Dickson, Charles Duyckaerts, Kelley Faber, Tanis Ferman, Margaret E. Flanagan, Gianluca Floris, Tatiana M. Foroud, Juan Fortea, Ziv Gan-Or, Steve Gentleman, Bernardino Ghetti, Jesse Raphael Gibbs, Alison Goate, David Goldstein, Isabel González-Aramburu, Neill R. Graff-Radford, Angela K. Hodges, Heng-Chen Hu, Daniel Hupalo, Jon Infante, Alex Iranzo, Scott M. Kaiser, Horacio Kaufmann, Julia Keith, Ronald C. Kim, Gregory Klein, Rejko Krüger, Walter Kukull, Amanda Kuzma, Carmen Lage, Suzanne Lesage, James B. Leverenz, Giancarlo Logroscino, Grisel Lopez, Seth Love, Qinwen Mao, Maria Jose Marti, Elisa Martinez-McGrath, Mario Masellis, Eliezer Masliah, Patrick May, Ian McKeith, Marek-Marsel Mesulam, Edwin S. Monuki, Kathy L. Newell, Lucy Norcliffe-Kaufmann, Laura Palmer, Matthew Perkins, Olga Pletnikova, Laura Molina-Porcel, Regina H. Reynolds, Eloy Rodríguez-Rodríguez, Jonathan D. Rohrer, Pascual Sanchez-Juan, Clemens R. Scherzer, Geidy E. Serrano, Vikram Shakkottai, Ellen Sidransky, Nahid Tayebi, Alan J. Thomas, Bension S. Tilley, Ronald L. Walton, Randy Woltjer, Zbigniew K. Wszolek, Georgia Xiromerisiou, Chiara Zecca, Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Neil A. Shneider, Ernest Fraenkel, Noah Zaitlen, James D. Berry, Andrea Malaspina, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos.A. Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Matt Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler, Khaled Amar, Neil Archibald, Oliver Bandmann, Erica Capps, Alistair Church, Jan Coebergh, Alyssa Costantini, Peter Critchley, Boyd CP. Ghosh, Michele T.M. Hu, Christopher Kobylecki, P. Nigel Leigh, Carl Mann, Luke A. Massey, Uma Nath, Nicola Pavese, Dominic Paviour, Jagdish Sharma, Jenny Vaughan, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, Clinicum, Pentti Tienari / Principal Investigator, Parkinson's UK, Human Genetics, ARD - Amsterdam Reproduction and Development, ANS - Complex Trait Genetics, Pathology, ANS - Cellular & Molecular Mechanisms, AII - Inflammatory diseases, Universidad de Cantabria, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Huntington's Disease, Pathology, amyotrophic lateral sclerosis, Huntingtin, Neurology, 1702 Cognitive Sciences, International ALS/FTD Genomics Consortium, Neurodegenerative, frontotemporal dementia, 3124 Neurology and psychiatry, 0302 clinical medicine, Medicine, 2.1 Biological and endogenous factors, Psychology, Amyotrophic lateral sclerosis, Aetiology, Alzheimer's Disease Related Dementias (ADRD), NYGC ALS Consortium, Huntingtin Protein, DNA Repeat Expansion, General Neuroscience, Frontotemporal Dementia (FTD), International FTD Genetics Consortium, whole-genome sequencing, Frontotemporal Dementia, Neurological, Cognitive Sciences, Lewy body dementia, huntingtin, repeat expansions, Amyotrophic Lateral Sclerosis, Humans, Mutation, Whole Genome Sequencing, Frontotemporal dementia, Huntington’s disease, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, FALS Sequencing Consortium, Article, 03 medical and health sciences, Atrophy, Rare Diseases, American Genome Center, Clinical Research, mental disorders, Genetics, Acquired Cognitive Impairment, Dementia, PROSPECT Consortium, Neurology & Neurosurgery, Lewy body, business.industry, International LBD Genomics Consortium, Neurosciences, 3112 Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), nutritional and metabolic diseases, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genomics England Research Consortium, 1701 Psychology, ALS, business, 1109 Neurosciences, 030217 neurology & neurosurgery
Abstract

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Published
2020
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4. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture

Author

Pentti J. Tienari, James B. Leverenz, Nahid Tayebi, Gabriele Mora, Bradley F. Boeve, Laura Palmer, Steve M. Gentleman, Ellen Sidransky, Pau Pastor, Liana S. Rosenthal, G. Xiromerisiou, Sara Saez-Atienzar, Francesco Landi, Scott M. Kaiser, Qinwen Mao, Claire Troakes, Peter St George-Hyslop, Andrea Calvo, Suzanne Lesage, Mario Masellis, Randy Woltjer, Marilyn S. Albert, Thomas T. Warner, Lorraine N. Clark, Gregory Klein, Charles Duyckaerts, Seth Love, Ed Monuki, Lawrence S. Honig, Kelley Faber, Dennis W. Dickson, Lucy Norcliffe-Kaufmann, Cornelis Blauwendraat, Ronald C. Kim, Kevin Morgan, Clifton L. Dalgard, Joshua T. Geiger, Ali Torkamani, Jinhui Ding, Juan Fortea, Eliezer Masliah, Ekaterina Rogaeva, Matthew H. Perkins, Clemens R. Scherzer, John Q. Trojanowski, Zbigniew K. Wszolek, Glenda M. Halliday, Jordi Clarimón, Sonja W. Scholz, Olaf Ansorge, Makayla K. Portley, Toshiko Tanaka, Mary B. Makarious, Safa Al-Sarraj, Giancarlo Logroscino, John D. Eicher, Neill R. Graff-Radford, Carmen Lage, Ziv Gan-Or, Francesca Brett, Alison Goate, Raffaele Ferrari, John C. Morris, J. Raphael Gibbs, Lynn M. Bekris, Jose-Alberto Palma, Angela K. Hodges, Regina H. Reynolds, Alexis Brice, Monica Diez-Fairen, Coralie Viollet, Patrick May, Minna Oinas, Erika Salvi, Vivianna M. Van Deerlin, Estrella Morenas-Rodríguez, Anni Moore, Zane Jaunmuktane, Eileen H. Bigio, Daniele Cusi, Douglas Galasko, Ruth Chia, Kathy L. Newell, Isabel Santana, Claudia Schulte, David Goldstein, Thomas Gasser, Owen A. Ross, Walter A. Kukull, Tatiana Foroud, Chad A. Caraway, David A. Bennett, Samreen Ahmed, Lilah M. Besser, Antonio Canosa, Daniel Alcolea, Yevgeniya Abramzon, Elisabet Londos, Laura Parkkinen, Sandra E. Black, Eric Topol, Marya S. Sabir, Olga Pletnikova, Grisel Lopez, Tanis J. Ferman, Johannes Attems, Matthew J. Barrett, Margaret E. Flanagan, Horacio Kaufmann, Stuart Pickering Brown, Jon Infante, Ryan C. Bohannan, Alberto Lleó, Eloy Rodríguez-Rodríguez, Huw R. Morris, Gianluca Floris, Ted M. Dawson, Maura Brunetti, Alan E. Renton, Andrew B. Singleton, Karen Marder, Alan J. Thomas, Pascual Sanchez-Juan, Adriano Chiò, Nigel J. Cairns, David J. Stone, Tammaryn Lashley, Mike A. Nalls, Bernardino Ghetti, Sara Bandres-Ciga, Zalak Shah, Ian G. McKeith, Susan M. Resnick, Julia Keith, Liisa Myllykangas, Diego Albani, Christopher M. Morris, Vikram Shakkottai, M. Ryten, Ronald L. Walton, Isabel González-Aramburu, Luigi Ferrucci, Bryan J. Traynor, Amanda B. Kuzma, Afina W. Lemstra, Thomas G. Beach, Juan C. Troncoso, Emil K. Gustavsson, Maurizio Grassano, John Hardy, Geidy E. Serrano, Rejko Krüger, Dag Aarsland, Bension S. Tilley, and Dena G. Hernandez

Subjects
0303 health sciences, Lewy body, Disease, Computational biology, Biology, medicine.disease, DNA sequencing, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, medicine, Dementia, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Published
2020
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5. Upfront boost Gamma Knife 'leading-edge' radiosurgery to FLAIR MRI-defined tumor migration pathways in 174 patients with glioblastoma multiforme: a 15-year assessment of a novel therapy

Author

Christopher Duma, Ryan M Casserly, Nathan Oh, Brian S. Kim, Marianne Plunkett, Christopher M Owen, Daniela Alexandru Abrams, Azzurra-Sky Riley, Ruslana Cannell, Alexa Smith, Ralph Mackintosh, Daniel J Furman, Robert O. Dillman, Gustavo Mendez, David Weiland, Marlon S. Mathews, Michael Brant-Zawadzki, Ami R Sanathara, Lian Stemler, Garrett Smith, Chad A. Caraway, Burton L. Eisenberg, and Peter Chen

Subjects
Adult, Time Factors, medicine.medical_treatment, Brain tumor, Radiosurgery, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Cell Movement, Glioma, Multicenter trial, Medicine, Humans, Aged, Retrospective Studies, Aged, 80 and over, Chemotherapy, Temozolomide, business.industry, Brain Neoplasms, Astrocytoma, General Medicine, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Radiation therapy, Treatment Outcome, 030220 oncology & carcinogenesis, business, Nuclear medicine, Glioblastoma, 030217 neurology & neurosurgery, medicine.drug, Follow-Up Studies
Abstract

OBJECTIVEGlioblastoma multiforme (GBM) is composed of cells that migrate through the brain along predictable white matter pathways. Targeting white matter pathways adjacent to, and leading away from, the original contrast-enhancing tumor site (termed leading-edge radiosurgery [LERS]) with single-fraction stereotactic radiosurgery as a boost to standard therapy could limit the spread of glioma cells and improve clinical outcomes.METHODSBetween December 2000 and May 2016, after an initial diagnosis of GBM and prior to or during standard radiation therapy and carmustine or temozolomide chemotherapy, 174 patients treated with radiosurgery to the leading edge (LE) of tumor cell migration were reviewed. The LE was defined as a region outside the contrast-enhancing tumor nidus, defined by FLAIR MRI. The median age of patients was 59 years (range 22–87 years). Patients underwent LERS a median of 18 days from original diagnosis. The median target volume of 48.5 cm3 (range 2.5–220.0 cm3) of LE tissue was targeted using a median dose of 8 Gy (range 6–14 Gy) at the 50% isodose line.RESULTSThe median overall survival was 23 months (mean 43 months) from diagnosis. The 2-, 3-, 5-, 7-, and 10-year actual overall survival rates after LERS were 39%, 26%, 16%, 10%, and 4%, respectively. Nine percent of patients developed treatment-related imaging-documented changes due to LERS. Nineteen percent of patients were hospitalized for management of edema, 22% for resection of a tumor cyst or new tumor bulk, and 2% for shunting to treat hydrocephalus throughout the course of their disease. Of the patients still alive, Karnofsky Performance Scale scores remained stable in 90% of patients and decreased by 1–3 grades in 10% due to symptomatic treatment-related imaging changes.CONCLUSIONSLERS is a safe and effective upfront adjunctive therapy for patients with newly diagnosed GBM. Limitations of this study include a single-center experience and single-institution determination of the LE tumor target. Use of a leading-edge calculation algorithm will be described to achieve a consistent approach to defining the LE target for general use. A multicenter trial will further elucidate its value in the treatment of GBM.

Published
2016

6. iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases

Author

Monica J. Carson, Rakez Kayed, Andriy V. Yeromin, Jack P. Antel, Mathew Blurton-Jones, Ali Mortazavi, Abdullah M. Madany, Ricardo Ramirez, Chad A. Caraway, Wayne W. Poon, Cecilia H.H. Nguyen, Edsel M. Abud, Cristhian Fimbres, Sean A. Newman, Karen H. Gylys, Eric S. Martinez, Anshu Agrawal, Vanessa M. Scarfone, Luke M. Healy, Michael D. Cahalan, Brian J. Cummings, Gianna M. Fote, and Samuel E. Marsh

Subjects
0301 basic medicine, Genetically modified mouse, Synaptic pruning, Induced Pluripotent Stem Cells, Biology, Article, Amyloid beta-Protein Precursor, Mice, 03 medical and health sciences, Alzheimer Disease, In vivo, medicine, Animals, Humans, Induced pluripotent stem cell, Cells, Cultured, Amyloid beta-Peptides, Microglia, General Neuroscience, Brain, Human brain, medicine.disease, Peptide Fragments, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Cytokines, Alzheimer's disease, Neuroscience, Homeostasis
Abstract

Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.

Published
2017
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7. ACTR-25. UP-FRONT BOOST GAMMA KNIFE 'LEADING EDGE' RADIOSURGERY (LERS) TO MR FLAIR-DEFINED TUMOR MIGRATION PATHWAYS IN 174 PATIENTS WITH GLIOBLASTOMA MULTIFORME: A 15-YEAR ASSESSMENT OF A NOVEL THERAPY

Author

Gustavo Mendez, Burton L. Eisenberg, Peter Chen, Marlon Mathews, Garrett Smith, Marianne Plunkett, Michael Brant-Zawadzki, Ryan M Casserly, Daniel J Furman, Ralph Mackintosh, Brian S. Kim, Robert O. Dillman, Chad A. Caraway, Azzurra-Sky Riley, Christopher Duma, David Weiland, and Ruslana Cannell

Subjects
Cancer Research, Leading edge, medicine.medical_specialty, business.industry, medicine.medical_treatment, Fluid-attenuated inversion recovery, Gamma knife, medicine.disease, Radiosurgery, Oncology, Medicine, Neurology (clinical), Radiology, Nuclear medicine, business, Front (military), Glioblastoma
Published
2016
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