157 results on '"Jean-Paul Vonsattel"'
Search Results
2. Multi-omic analysis of Huntington’s disease reveals a compensatory astrocyte state
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Fahad Paryani, Ji-Sun Kwon, Christopher W. Ng, Kelly Jakubiak, Nacoya Madden, Kenneth Ofori, Alice Tang, Hong Lu, Shengnan Xia, Juncheng Li, Aayushi Mahajan, Shawn M. Davidson, Anna O. Basile, Caitlin McHugh, Jean Paul Vonsattel, Richard Hickman, Michael C. Zody, David E. Housman, James E. Goldman, Andrew S. Yoo, Vilas Menon, and Osama Al-Dalahmah
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Science - Abstract
Abstract The mechanisms underlying the selective regional vulnerability to neurodegeneration in Huntington’s disease (HD) have not been fully defined. To explore the role of astrocytes in this phenomenon, we used single-nucleus and bulk RNAseq, lipidomics, HTT gene CAG repeat-length measurements, and multiplexed immunofluorescence on HD and control post-mortem brains. We identified genes that correlated with CAG repeat length, which were enriched in astrocyte genes, and lipidomic signatures that implicated poly-unsaturated fatty acids in sensitizing neurons to cell death. Because astrocytes play essential roles in lipid metabolism, we explored the heterogeneity of astrocytic states in both protoplasmic and fibrous-like (CD44+) astrocytes. Significantly, one protoplasmic astrocyte state showed high levels of metallothioneins and was correlated with the selective vulnerability of distinct striatal neuronal populations. When modeled in vitro, this state improved the viability of HD-patient-derived spiny projection neurons. Our findings uncover key roles of astrocytic states in protecting against neurodegeneration in HD.
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- 2024
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3. Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
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Gary W Beecham, Kara Hamilton, Adam C Naj, Eden R Martin, Matt Huentelman, Amanda J Myers, Jason J Corneveaux, John Hardy, Jean-Paul Vonsattel, Steven G Younkin, David A Bennett, Philip L De Jager, Eric B Larson, Paul K Crane, M Ilyas Kamboh, Julia K Kofler, Deborah C Mash, Linda Duque, John R Gilbert, Harry Gwirtsman, Joseph D Buxbaum, Patricia Kramer, Dennis W Dickson, Lindsay A Farrer, Matthew P Frosch, Bernardino Ghetti, Jonathan L Haines, Bradley T Hyman, Walter A Kukull, Richard P Mayeux, Margaret A Pericak-Vance, Julie A Schneider, John Q Trojanowski, Eric M Reiman, Alzheimer's Disease Genetics Consortium (ADGC), Gerard D Schellenberg, and Thomas J Montine
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Genetics ,QH426-470 - Abstract
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
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- 2014
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4. Genome-wide methylation analyses in glioblastoma multiforme.
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Rose K Lai, Yanwen Chen, Xiaowei Guan, Darryl Nousome, Charu Sharma, Peter Canoll, Jeffrey Bruce, Andrew E Sloan, Etty Cortes, Jean-Paul Vonsattel, Tao Su, Lissette Delgado-Cruzata, Irina Gurvich, Regina M Santella, Quinn Ostrom, Annette Lee, Peter Gregersen, and Jill Barnholtz-Sloan
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Medicine ,Science - Abstract
Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina) were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1), 5 methyl-deoxycytidine (5m-dC) and 5 hydroxylmethyl-deoxycytidine (5hm-dC) in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes) that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal.
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- 2014
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5. Huntington's disease CAG trinucleotide repeats in pathologically confirmed post-mortem brains
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Francesca Persichetti, Jayalakshmi Srinidhi, Lisa Kanaley, Pei Ge, Richard H. Myers, Kenneth D'Arrigo, Glenn T. Barnes, Marcy E. MacDonald, Jean-Paul Vonsattel, James F. Gusella, and Edward D. Bird
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Huntington's disease ,mutation ,neuropathology ,phenocopy ,post-mortem brain ,trinucleotide repeat ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
CAG repeat expansion in the Huntington's disease gene (HD) was examined in postmortem brains from 310 clinically diagnosed and 15 ‘at risk’ individuals. Presence of an expanded CAG allele (>37 units) was the cause of the disorder in almost all cases (307 of 310). Despite a diversity of reporting clinicians, neurological and psychiatric onset and age at death all displayed significant inverse correlations with CAG number indicating that diagnosis of onset is reasonably accurate, and that most patients die from the disease and its complications. Neuronal changes before clinical onset are not detected by conventional microscopic examination as three out of 15 ‘at risk’ brains had an expanded CAG allele but no neuropathology. The cause of HD-like neuropathology in three exceptional brains from clinically diagnosed individuals is unclear. The disorder in these cases could be an HD phenocopy or result from alternative mutational mechanisms at theHDlocus.
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- 1994
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6. Differential Vulnerability of Hippocampal Subfields in Primary Age-Related Tauopathy and Chronic Traumatic Encephalopathy
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Kurt Farrell, Megan A Iida, Jonathan D Cherry, Alicia Casella, Thor D Stein, Kevin F Bieniek, Jamie M Walker, Timothy E Richardson, Charles L White, Victor E Alvarez, Bertrand R Huber, Dennis W Dickson, Ricardo Insausti, Kristen Dams-O'Connor, Jean-Paul Vonsattel, Andy F Teich, Marla Gearing, Jonathan Glass, Juan C Troncoso, Matthew P Frosch, Bradley T Hyman, Melissa E Murray, Johannes Attems, Margaret E Flanagan, Qinwen Mao, M-Marsel Mesulam, Sandra Weintraub, Randy L Woltjer, Thao Pham, Julia Kofler, Julie A Schneider, Lei Yu, Dushyant P Purohit, Vahram Haroutunian, Patrick R Hof, Sam Gandy, Mary Sano, Thomas G Beach, Wayne Poon, Claudia H Kawas, María M Corrada, Robert A Rissman, Jeff Metcalf, Sara Shuldberg, Bahar Salehi, Peter T Nelson, John Q Trojanowski, Edward B Lee, David A Wolk, Corey T McMillan, C Dirk Keene, Caitlin S Latimer, Thomas J Montine, Gabor G Kovacs, Mirjam I Lutz, Peter Fischer, Richard J Perrin, Nigel J Cairns, Ann C McKee, and John F Crary
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Cellular and Molecular Neuroscience ,Neurology ,Tauopathies ,Humans ,Neurofibrillary Tangles ,tau Proteins ,Neurology (clinical) ,General Medicine ,Hippocampus ,Pathology and Forensic Medicine ,Chronic Traumatic Encephalopathy - Abstract
Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p lt; 0.0001). These data demonstrate differences in hippocampal p-tau burden and regional distribution in CTE compared to PART that might be helpful in differential diagnosis and reveal insights into disease pathogenesis.
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- 2023
7. Reply: More than a co-incidence? Exploring the increased frequency of amyotrophic lateral sclerosis in Huntington disease
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Richard A. Hickman, Bryan J. Traynor, Karen S. Marder, and Jean-Paul Vonsattel
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Cellular and Molecular Neuroscience ,Neurology (clinical) ,Pathology and Forensic Medicine - Published
- 2022
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8. New insights into the genetic etiology of Alzheimer's disease and related dementias
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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., 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. E., 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., Laczo, J., Matoska, V., Serpente, M., Assogna, F., Piras, F., Ciullo, V., Shofany, J., Ferrarese, C., Andreoni, S., Sala, G., Zoia, C. P., Zompo, M. D., Benussi, A., Bastiani, P., Takalo, M., Natunen, T., Laatikainen, T., Tuomilehto, J., Antikainen, R., Strandberg, T., Lindström, J., Peltonen, M., Abraham, R., Al-Chalabi, A., Bass, N. J., Brayne, C., Brown, K. S., Collinge, J., Craig, D., Deloukas, P., Fox, N., Gerrish, A., Gill, M., Gwilliam, R., Harold, D., Hollingworth, P., Johnston, J. A., Jones, L., Lawlor, B., Livingston, G., Lovestone, S., Lupton, M., Lynch, A., Mann, D., Mcguinness, B., Mcquillin, A., O’Donovan, M. C., Owen, M. J., Passmore, P., Powell, J. F., Proitsi, P., Rossor, M., Shaw, C. E., Smith, A. D., Gurling, H., Todd, S., Mummery, C., Ryan, N., Lacidogna, G., Adarmes-Gómez, A., Mauleón, A., Pancho, A., Gailhajenet, A., Lafuente, A., Macias-García, D., Martín, E., Pelejà, E., Carrillo, F., Merlín, I. S., Garrote-Espina, L., Vargas, L., Carrion-Claro, M., Marín, M., Labrador, M., Buendia, M., Alonso, M. D., Guitart, M., Moreno, M., Ibarria, M., Periñán, M., Aguilera, N., Gómez-Garre, P., Cañabate, P., Escuela, R., Pineda-Sánchez, R., Vigo-Ortega, R., Jesús, S., Preckler, S., Rodrigo-Herrero, S., Diego, S., Vacca, A., Roveta, F., Salvadori, N., Chipi, E., Boecker, H., Laske, C., Perneczky, R., Anastasiou, C., Janowitz, D., Malik, R., Anastasiou, A., Parveen, K., López-García, S., Antonell, A., Mihova, K. Y., Belezhanska, D., Weber, H., Kochen, S., Solis, P., Medel, N., Lisso, J., Sevillano, Z., Politis, D. G., Cores, V., Cuesta, C., Ortiz, C., Bacha, J. I., Rios, M., Saenz, A., Abalos, M. S., Kohler, E., Palacio, D. L., Etchepareborda, I., Kohler, M., Novack, G., Prestia, F. A., Galeano, P., Castaño, E. M., Germani, S., Toso, C. R., Rojo, M., Ingino, C., Mangone, C., Rubinsztein, D. C., Teipel, S., Fievet, N., Deramerourt, V., Forsell, C., Thonberg, H., Bjerke, M., Roeck, E. D., Martínez-Larrad, M. T., Olivar, N., Cano, A., Macias, J., Maroñas, O., Nuñez-Llaves, R., Olivé, C., Adarmes-Gómez, A. D., Amer-Ferrer, G., Antequera, M., Burguera, J. A., Casajeros, M. J., Martinez de Pancorbo, M., Hevilla, S., Espinosa, M. A. L., Legaz, A., Manzanares, S., Marín-Muñoz, J., Marín, T., Martínez, B., Martínez, V., Martínez-Lage Álvarez, P., Iriarte, M. M., Periñán-Tocino, M. T., Real de Asúa, D., Rodrigo, S., Sastre, I., Vicente, M. P., Vivancos, L., Epelbaum, J., Hannequin, D., Campion, D., Deramecourt, V., Tzourio, C., Brice, A., Dubois, B., Williams, A., Thomas, C., Davies, C., Nash, W., Dowzell, K., Morales, A. C., Bernardo-Harrington, M., Turton, J., Lord, J., Brown, K., Vardy, E., Fisher, E., Warren, J. D., Ryan, N. S., Guerreiro, R., Uphill, J., Bass, N., Heun, R., Kölsch, H., Schürmann, B., Lacour, A., Herold, C., Powell, J., Patel, Y., Hodges, A., Becker, T., Warden, D., Wilcock, G., Clarke, R., Ben-Shlomo, Y., Hooper, N. M., Pickering-Brown, S., Sussams, R., Warner, N., Bayer, A., Heuser, I., Drichel, D., Klopp, N., Mayhaus, M., Riemenschneider, M., Pinchler, S., Feulner, T., Gu, W., van den Bussche, H., Hüll, M., Frölich, L., Wichmann, H. -E., Jöckel, K. -H., O’Donovan, M., Owen, M., Bahrami, S., Bosnes, I., Selnes, P., Bergh, S., Palotie, A., Daly, M., Jacob, H., Matakidou, A., Runz, H., John, S., Plenge, R., Mccarthy, M., Hunkapiller, J., Ehm, M., Waterworth, D., Fox, C., Malarstig, A., Klinger, K., Call, K., Behrens, T., Loerch, P., Mäkelä, T., Kaprio, J., Virolainen, P., Pulkki, K., Kilpi, T., Perola, M., Partanen, J., Pitkäranta, A., Kaarteenaho, R., Vainio, S., Turpeinen, M., Serpi, R., Laitinen, T., Mäkelä, J., Kosma, V. -M., Kujala, U., Tuovila, O., Hendolin, M., Pakkanen, R., Waring, J., Riley-Gillis, B., Liu, J., Biswas, S., Diogo, D., Marshall, C., Hu, X., Gossel, M., Graham, R., Cummings, B., Ripatti, S., Schleutker, J., Arvas, M., Carpén, O., Hinttala, R., Kettunen, J., Mannermaa, A., Laukkanen, J., Julkunen, V., Remes, A., Kälviäinen, R., Peltola, J., Tienari, P., Rinne, J., Ziemann, A., Esmaeeli, S., Smaoui, N., Lehtonen, A., Eaton, S., Lahdenperä, S., van Adelsberg, J., Michon, J., Kerchner, G., Bowers, N., Teng, E., Eicher, J., Mehta, V., Gormley, P., Linden, K., Whelan, C., Xu, F., Pulford, D., Färkkilä, M., Pikkarainen, S., Jussila, A., Blomster, T., Kiviniemi, M., Voutilainen, M., Georgantas, B., Heap, G., Rahimov, F., Usiskin, K., Lu, T., Oh, D., Kalpala, K., Miller, M., Mccarthy, L., Eklund, K., Palomäki, A., Isomäki, P., Pirilä, L., Kaipiainen-Seppänen, O., Huhtakangas, J., Lertratanakul, A., Hochfeld, M., Bing, N., Gordillo, J. E., Mars, N., Pelkonen, M., Kauppi, P., Kankaanranta, H., Harju, T., Close, D., Greenberg, S., Chen, H., Betts, J., Ghosh, S., Salomaa, V., Niiranen, T., Juonala, M., Metsärinne, K., Kähönen, M., Junttila, J., Laakso, M., Pihlajamäki, J., Sinisalo, J., Taskinen, M. -R., Tuomi, T., Challis, B., Peterson, A., Chu, A., Parkkinen, J., Muslin, A., Joensuu, H., Meretoja, T., Aaltonen, L., Mattson, J., Auranen, A., Karihtala, P., Kauppila, S., Auvinen, P., Elenius, K., Popovic, R., Schutzman, J., Loboda, A., Chhibber, A., Lehtonen, H., Mcdonough, S., Crohns, M., Kulkarni, D., Kaarniranta, K., Turunen, J. A., Ollila, T., Seitsonen, S., Uusitalo, H., Aaltonen, V., Uusitalo-Järvinen, H., Luodonpää, M., Hautala, N., Loomis, S., Strauss, E., Podgornaia, A., Hoffman, J., Tasanen, K., Huilaja, L., Hannula-Jouppi, K., Salmi, T., Peltonen, S., Koulu, L., Harvima, I., Wu, Y., Choy, D., Pussinen, P., Salminen, A., Salo, T., Rice, D., Nieminen, P., Palotie, U., Siponen, M., Suominen, L., Mäntylä, P., Gursoy, U., Anttonen, V., Sipilä, K., Davis, J. W., Quarless, D., Petrovski, S., Wigmore, E., Chen, C. -Y., Bronson, P., Tsai, E., Huang, Y., Maranville, J., Shaikho, E., Mohammed, E., Wadhawan, S., Kvikstad, E., Caliskan, M., Chang, D., Bhangale, T., Pendergrass, S., Holzinger, E., Chen, X., Hedman, Å., King, K. 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Kathleen, A Welsh-Bohmer, Patrice, L Whitehead, Ellen, M Wijsman, Kirk, C Wilhelmsen, Benjamin, Williams, Jennifer, Williamson, Henrik, Wilms, Thomas, S Wingo, Thomas, Wisniewski, Randall, L Woltjer, Martin, Woon, Clinton, B Wright, Chuang-Kuo, Wu, Steven, G Younkin, Chang-En, Yu, Lei, Yu, Yuanchao, Zhang, Zhao, Yi, Xiongwei, Zhu, Hieab, Adams, Rufus, O Akinyemi, Muhammad, Ali, Nicola, Armstrong, Hugo, J Aparicio, Maryam, Bahadori, Monique, Breteler, Daniel, Chasman, Ganesh, Chauhan, Hata, Comic, Simon, Cox, Adrienne, L Cupples, Gail, Davies, Charles, S DeCarli, Marie-Gabrielle, Duperron, Josée, Dupuis, Tavia, Evans, Frank, Fan, Annette, Fitzpatrick, Alison, E Fohner, Mary, Ganguli, Mirjam, Geerlings, Stephen, J Glatt, Hector, M Gonzalez, Monica, Goss, Hans, Grabe, Mohamad, Habes, Susan, R Heckbert, Edith, Hofer, Elliot, Hong, Timothy, Hughes, Tiffany, F Kautz, Maria, Knol, William, Kremen, Paul, Lacaze, Jari, Lahti, Quentin Le Grand, Elizabeth, Litkowski, Shuo, Li, Dan, Liu, Xuan, Liu, Marisa, Loitfelder, Alisa, Manning, Pauline, Maillard, Riccardo, Marioni, Bernard, Mazoyer, Debora Melo van Lent, Hao, Mei, Aniket, Mishra, Paul, Nyquist, Jeffrey, O'Connell, Yash, Patel, Tomas, Paus, Zdenka, Pausova, Katri, Raikkonen-Talvitie, Moeen, Riaz, Stephen, Rich, Jerome, Rotter, Jose, Romero, Gena, Roshchupkin, Yasaman, Saba, Murali, Sargurupremraj, Helena, Schmidt, Reinhold, Schmidt, Joshua, M Shulman, Jennifer, Smith, Hema, Sekhar, Reddy, Rajula, Jean, Shin, Jeannette, Simino, Eeva, Sliz, Alexander, Teumer, Alvin, Thomas, Adrienne, Tin, Elliot, Tucker-Drob, Dina, Vojinovic, Yanbing, Wang, Galit, Weinstein, Dylan, Williams, Katharina, Wittfeld, Lisa, Yanek, Yunju, Yang, Bellenguez, C, Küçükali, F, Jansen, I, Kleineidam, L, Moreno-Grau, S, Amin, N, Naj, A, Campos-Martin, R, Grenier-Boley, B, Andrade, V, Holmans, P, Boland, A, Damotte, V, van der Lee, S, Costa, M, Kuulasmaa, T, Yang, Q, de Rojas, I, Bis, J, Yaqub, A, Prokic, I, Chapuis, J, Ahmad, S, Giedraitis, V, 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M, Rossi, P, Djurovic, S, Duron, E, Düzel, E, Dufouil, C, Eiriksdottir, G, Engelborghs, S, Escott-Price, V, Espinosa, A, Ewers, M, Faber, K, Fabrizio, T, Nielsen, S, Fardo, D, Farotti, L, Fenoglio, C, Fernández-Fuertes, M, Ferrari, R, Ferreira, C, Ferri, E, Fin, B, Fischer, P, Fladby, T, Fließbach, K, Fongang, B, Fornage, M, Fortea, J, Foroud, T, Fostinelli, S, Fox, N, Franco-Macías, E, Bullido, M, Frank-García, A, Froelich, L, Fulton-Howard, B, Galimberti, D, García-Alberca, J, García-González, P, Garcia-Madrona, S, Garcia-Ribas, G, Ghidoni, R, Giegling, I, Giorgio, G, Goate, A, 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, Hamilton-Nelson, K, Hampel, H, Hanon, O, Hardy, J, Hartmann, A, Hausner, L, Harwood, J, Heilmann-Heimbach, S, Helisalmi, S, Heneka, M, Hernández, I, Herrmann, M, Hoffmann, P, Holmes, C, Holstege, H, Vilas, R, Hulsman, M, Humphrey, J, Biessels, G, Jian, X, Johansson, C, Jun, G, Kastumata, Y, Kauwe, J, Kehoe, P, Kilander, L, Ståhlbom, A, Kivipelto, M, Koivisto, A, Kornhuber, J, Kosmidis, M, Kukull, W, Kuksa, P, Kunkle, B, Kuzma, A, Lage, C, Laukka, E, Launer, L, Lauria, A, Lee, C, Lehtisalo, J, Lerch, O, Lleó, A, Longstreth, W, Lopez, O, de Munain, A, Love, S, Löwemark, M, Luckcuck, L, Lunetta, K, Ma, Y, Macías, J, Macleod, C, Maier, W, Mangialasche, F, Spallazzi, M, Marquié, M, Marshall, R, Martin, E, Montes, A, Rodríguez, C, 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, Muchnik, C, Mukherjee, S, Nacmias, B, Ngandu, T, Nicolas, G, Nordestgaard, B, 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, Pineda, J, Piñol-Ripoll, G, Pisanu, C, Polak, T, Popp, J, Posthuma, D, Priller, J, Puerta, R, Quenez, O, Quintela, I, Thomassen, J, Rábano, A, Rainero, I, Rajabli, F, Ramakers, I, Real, L, Reinders, M, Reitz, C, Reyes-Dumeyer, D, Ridge, P, Riedel-Heller, S, Riederer, P, Roberto, N, Rodriguez-Rodriguez, E, Rongve, A, Allende, I, Rosende-Roca, M, Royo, J, Rubino, E, Rujescu, D, Sáez, M, Sakka, P, Saltvedt, I, Sanabria, Á, Sánchez-Arjona, M, Sanchez-Garcia, F, Juan, P, Sánchez-Valle, R, Sando, S, Sarnowski, C, Satizabal, C, Scamosci, M, Scarmeas, N, Scarpini, E, Scheltens, P, Scherbaum, N, Scherer, M, Schmid, M, Schneider, A, Schott, J, Selbæk, G, Seripa, D, Serrano, M, Sha, J, Shadrin, A, Skrobot, O, Slifer, S, Snijders, G, Soininen, H, Solfrizzi, V, Solomon, A, Song, Y, Sorbi, S, Sotolongo-Grau, O, Spalletta, G, Spottke, A, Squassina, A, Stordal, E, Tartan, J, 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, Vance, J, Vardarajan, B, van der Lugt, A, Dongen, J, van Rooij, J, van Swieten, J, Vandenberghe, R, Verhey, F, Vidal, J, Vogelgsang, J, Vyhnalek, M, Wagner, M, Wallon, D, Wang, L, Wang, R, Weinhold, L, Wiltfang, J, Windle, G, Woods, B, Yannakoulia, M, Zare, H, Zhao, Y, Zhang, X, Zhu, C, Zulaica, M, Andreoni, S, Ferrarese, C, Sala, G, Zoia, C, Farrer, L, Psaty, B, Ghanbari, M, Raj, T, Sachdev, P, Mather, K, Jessen, F, Ikram, M, de Mendonça, A, Hort, J, Tsolaki, M, Pericak-Vance, M, Amouyel, P, Williams, J, Frikke-Schmidt, R, Clarimon, J, Deleuze, J, Rossi, G, Seshadri, S, Andreassen, O, Ingelsson, M, Hiltunen, M, Sleegers, K, Schellenberg, G, van Duijn, C, Sims, R, van der Flier, W, Ruiz, A, Ramirez, A, Lambert, J, VU University medical center, Amsterdam Neuroscience - Neurodegeneration, Neurology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, 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Sachdev, Perminder [0000-0002-9595-3220], Mather, Karen [0000-0003-4143-8941], Ikram, M Arfan [0000-0003-0372-8585], Tsolaki, Magda [0000-0002-2072-8010], Pericak-Vance, Margaret A [0000-0001-7283-8804], Amouyel, Philippe [0000-0001-9088-234X], Williams, Julie [0000-0002-4069-0259], Frikke-Schmidt, Ruth [0000-0003-4084-5027], Seshadri, Sudha [0000-0001-6135-2622], Andreassen, Ole A [0000-0002-4461-3568], Sleegers, Kristel [0000-0002-0283-2332], van Duijn, Cornelia M [0000-0002-2374-9204], Sims, Rebecca [0000-0002-3885-1199], van der Flier, Wiesje M [0000-0001-8766-6224], Ramirez, Alfredo [0000-0003-4991-763X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Complex Trait Genetics, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, Clinical Biology, Epidemiology, Internal Medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UAM. Departamento de Biología Molecular, University of Helsinki, Department of Neurosciences, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Neurocenter, Neurologian yksikkö, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (France), European Commission, LabEx DISTALZ, Pérez-Tur, Jordi, University Children’s Hospital Basel (Suiza), INSERM (Francia), Lille Métropole Communauté Urbaine, Government of France (Francia), EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Holmans, Peter A. [0000-0003-0870-9412], van der Lee, Sven J. [0000-0003-1606-8643], Costa, Marcos R. [0000-0002-4928-2163], Bis, Joshua C. [0000-0002-3409-1110], Brookes, Keeley J. [0000-0003-2427-2513], Bush, William S. [0000-0002-9729-6519], de Witte, Lot D. [0000-0002-7235-9958], del Ser, Teodoro [0000-0001-9806-7083], Fox, Nick C. [0000-0002-6660-657X], Bullido, María J. [0000-0002-6477-1117], Goate, Alison M. [0000-0002-0576-2472], Herrmann, Martin J. [0000-0001-9970-2122], Jun, Gyungah R. [0000-0002-3230-8697], Kehoe, Patrick G. [0000-0002-7542-1139], Kosmidis, Mary H. [0000-0001-8790-1220], Lunetta, Kathryn L. [0000-0002-9268-810X], MacLeod, Catherine A. [0000-0002-9314-7380], Nöthen, Markus M. [0000-0002-8770-2464], Nordestgaard, Børge G. [0000-0002-1954-7220], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis M. [0000-0003-4932-7429], Reinders, Marcel J. T. [0000-0002-1148-1562], Satizabal, Claudia L. [0000-0002-1115-4430], Schott, Jonathan M. [0000-0003-2059-024X], Shadrin, Alexey A. [0000-0002-7467-250X], Farrer, Lindsay A. [0000-0001-5533-4225], Psaty, Bruce M. [0000-0002-7278-2190], Ikram, M. Arfan [0000-0003-0372-8585], Pericak-Vance, Margaret A. [0000-0001-7283-8804], Andreassen, Ole A. [0000-0002-4461-3568], van Duijn, Cornelia M. [0000-0002-2374-9204], van der Flier, Wiesje M. [0000-0001-8766-6224], and Molecular Neuroscience and Ageing Research (MOLAR)
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tau Proteins/genetics ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,Neurologi ,MED/03 - GENETICA MEDICA ,45/43 ,Medizin ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,genetics [Alzheimer Disease] ,Genome-Wide Association Study ,Humans ,tau Proteins ,Alzheimer Disease ,Cognitive Dysfunction ,VARIANTS ,pathology [Alzheimer Disease] ,Tau Proteins ,Settore BIO/13 - Biologia Applicata ,Cognitive Dysfunction/psychology ,692/699/375/365/1283 ,IMPUTATION ,article ,1184 Genetics, developmental biology, physiology ,Biología y Biomedicina / Biología ,AMYLOID-BETA ,Settore MED/26 - NEUROLOGIA ,Neurology ,psychology [Cognitive Dysfunction] ,Medical Genetics ,Human ,Neuroscience(all) ,631/208/205/2138 ,All institutes and research themes of the Radboud University Medical Center ,SDG 3 - Good Health and Well-being ,ddc:570 ,Genetics ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,Medicinsk genetik ,MED/26 - NEUROLOGIA ,Alzheimer Disease/genetics ,neurology ,tau Protein ,NECROSIS-FACTOR-ALPHA ,RISK LOCI ,genetics [tau Proteins] ,PREDICTION MODELS ,Human medicine ,GENERATION ,RESPONSES - Abstract
25 páginas, 6 figuras, 2 tablas, 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., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not
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- 2022
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9. Patterns of <scp>TDP</scp> ‐43 Deposition in Brains with <scp> LRRK2 G2019S </scp> Mutations
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Julian Agin‐Liebes, Richard A. Hickman, Jean Paul Vonsattel, Phyllis L. Faust, Xena Flowers, Irina Utkina Sosunova, Joel Ntiri, Richard Mayeux, Matthew Surface, Karen Marder, Stanley Fahn, Serge Przedborski, and Roy N. Alcalay
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Neurology ,Neurology (clinical) - Published
- 2023
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10. Clinical and Pathological Characterization of VPS16 Dystonia (P11-11.005)
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Mariel Pullman, Deborah Raymond, Walter Molofsky, Naomi Lubarr, Katherine Leaver, Roberto Ortega, Maya Rawal, Steffany Bennett, Evan Bushnik, Azita Khorsandi, Fedor Panov, Jean Paul Vonsattel, Laurie Ozelius, Rachel Saunders-Pullman, and Susan Bressman
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- 2023
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11. Cerebral Microbleeds, Cerebral Amyloid Angiopathy, and Their Relationships to Quantitative Markers of Neurodegeneration
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Charles, Beaman, Krystyna, Kozii, Saima, Hilal, Minghua, Liu, Anthony J, Spagnolo-Allende, Guillermo, Polanco-Serra, Christopher, Chen, Ching-Yu, Cheng, Daniela, Zambrano, Burak, Arikan, Victor J, Del Brutto, Clinton, Wright, Xena E, Flowers, Sandra P, Leskinen, Tatjana, Rundek, Amanda, Mitchell, Jean Paul, Vonsattel, Etty, Cortes, Andrew F, Teich, Ralph L, Sacco, Mitchell S V, Elkind, David, Roh, and Jose, Gutierrez
- Subjects
Cerebral Amyloid Angiopathy ,Cross-Sectional Studies ,Alzheimer Disease ,Brain ,Humans ,Neurodegenerative Diseases ,Neurology (clinical) ,Middle Aged ,Magnetic Resonance Imaging ,Biomarkers ,Cerebral Hemorrhage - Abstract
Background and ObjectivesAge-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer disease. However, in the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA affect volumetric changes in the brain related to neurodegenerative disease remains unclear.MethodsWe performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer's Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between 2 related markers of cerebrovascular disease—MRI-based CMBs and autopsy-based CAA—as independent variables and volumetric markers of neurodegeneration as dependent variables. NOMAS included mostly dementia-free participants age 55 years or older from northern Manhattan. ADNI included participants living in the United States age 55–90 years with a range of cognitive status. EDIS included community-based participants living in Singapore age 60 years and older with a range of cognitive status. BARS included postmortem pathologic samples.ResultsWe included 2,657 participants with available MRI data and 82 autopsy cases from BARS. In a meta-analysis of NOMAS, ADNI, and EDIS, superficial CMBs were associated with larger gray matter (β = 4.49 ± 1.13,p= 0.04) and white matter (β = 4.72 ± 2.1,p= 0.03) volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with 1 CMB (β = 5.17 ± 2.47,p= 0.04) than in those with ≥2 CMBs (β = 1.97 ± 3.41,p= 0.56). In BARS, CAA was associated with increased cortical thickness (β = 6.5 ± 2.3,p= 0.016) but not with increased brain weight (β = 1.54 ± 1.29,p= 0.26).DiscussionSuperficial CMBs are associated with larger morphometric brain measures, specifically white matter volume. This association is strongest in brains with fewer CMBs, suggesting that the CMB/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease.
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- 2022
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12. Genome-wide association study and functional validation implicates JADE1 in tauopathy
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John F. Crary, Katia de Paiva Lopes, Bradley T. Hyman, Manav Kapoor, Gloriia Novikova, Jonathan D. Glass, Valeriy Borukov, Hadley Walsh, Erin E. Franklin, Johannes Attems, Sara Shuldberg, Shea J. Andrews, Thomas J. Montine, Julie A. Schneider, Jonathan D. Cherry, C. Dirk Keene, Towfique Raj, Charles L. White, Thor D. Stein, Evan Udine, Gai Ayalon, Thao Pham, Maria M. Corrada, Weijing Tang, Ann C. McKee, Bess Frost, Marco M. Hefti, Qinwen Mao, Lei Yu, Patrick R. Hof, Peter T. Nelson, Elias M. Gonzalez, Alan E. Renton, Corey T. McMillan, Jack Humphrey, Natalia Han, Margaret E. Flanagan, SoongHo Kim, Etty Cortes, Megan A. Iida, Inma Cobos, Jeff Metcalf, Sandra Weintraub, Julie Hunkapiller, Diana K. Dangoor, Robert A. Rissman, Marcos Otero-Garcia, John Q. Trojanowski, Dushyant P. Purohit, Caitlin S. Latimer, Marla Gearing, Claudia H. Kawas, Kathryn R. Bowles, Wayne W. Poon, Brian Fulton-Howard, Edoardo Marcora, Alison Goate, Alicia Casella, Tushar Bhangale, Richard J. Perrin, Herbert T. Cohen, Bahar Salehi, Gabor G. Kovacs, Andy F. Teich, Mary Sano, Jamie M. Walker, Dennis W. Dickson, Randy Woltjer, Kristen Whitney, M.-Marsel Mesulam, Ricardo Assunção Vialle, Peter Fischer, Kurt Farrell, Jean-Paul Vonsattel, Cheick T. Sissoko, Vahram Haroutunian, Sam Gandy, Mirjam I. Lutz, Matthew P. Frosch, Nigel J. Cairns, Melissa E. Murray, Robert R. Graham, David A. Wolk, Juan C. Troncoso, Garrett Wong, Julia Kofler, Edward B. Lee, Timothy E. Richardson, and Thomas G. Beach
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Male ,Aging ,Locus (genetics) ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Article ,Pathology and Forensic Medicine ,Progressive supranuclear palsy ,Cohort Studies ,Cellular and Molecular Neuroscience ,medicine ,Animals ,Humans ,Aged ,Genetic association ,Aged, 80 and over ,Homeodomain Proteins ,Tumor Suppressor Proteins ,Neurofibrillary tangle ,Middle Aged ,medicine.disease ,Molecular biology ,Tauopathies ,Drosophila ,Female ,Neurology (clinical) ,Tauopathy ,Alzheimer's disease ,Genome-Wide Association Study - Abstract
Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.
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- 2021
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13. Single nuclei RNAseq analysis of HD mouse models and human brain reveals impaired oligodendrocyte maturation and potential role for thiamine metabolism
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Ryan G. Lim, Osama Al-Dalahmah, Jie Wu, Maxwell P. Gold, Jack C. Reidling, Guomei Tang, Miriam Adam, David Dansu, Hye-Jin Park, Patricia Casaccia, Ricardo Miramontes, Andrea M. Reyes-Ortiz, Alice Lau, Fatima Khan, Fahad Paryani, Alice Tang, Kenneth Ofori, Emily Miyoshi, Neethu Michael, Nicolette Geller, Xena E. Flowers, Jean Paul Vonsattel, Shawn Davidson, Vilas Menon, Vivek Swarup, Ernest Fraenkel, James E. Goldman, and Leslie M. Thompson
- Abstract
The complexity of affected brain regions and cell types is a challenge for Huntington’s disease (HD) treatment. Here we used single nucleus RNA sequencing (snRNAseq) to investigate mechanism of pathology in the cortex and striatum from R6/2 mice at 8 and 12w and in three regions of human HD post-mortem tissue. We identified cell type-specific and cell agnostic signatures and found changes suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) were arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 were negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells showed decreased accessibility of sites regulated by OL maturation genes. Glucose and lipid metabolism were implicated in abnormal cell maturation and PRKCE and Thiamine Pyrophosphokinase 1 were identified as central genes. High dose thiamine/biotin treatment of R6/1 HD mice to target thiamine metabolism not only restored OL maturation, but also rescued pathology in neurons. These findings reveal insights into HD OL pathology that spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.
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- 2022
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14. The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy
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Kevin F. Bieniek, Ann C. McKee, Jesse Mez, John F. Crary, Victor E. Alvarez, Thor D. Stein, Daniel P. Perl, C. Dirk Keene, Irene Litvan, Dennis W. Dickson, Nigel J. Cairns, Tbi, Michael L. Alosco, William Stewart, Rebecca D. Folkerth, Kristen Dams-O'Connor, Wayne A. Gordon, Yorghos Tripodis, and Jean-Paul Vonsattel
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0303 health sciences ,medicine.medical_specialty ,Traumatic brain injury ,business.industry ,Pathological staging ,General Medicine ,medicine.disease ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Chronic traumatic encephalopathy ,0302 clinical medicine ,Neurology ,Pathognomonic ,medicine ,Neurology (clinical) ,Radiology ,Stage (cooking) ,business ,Pathological ,Generalized estimating equation ,Brain trauma ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies.
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- 2021
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15. Early‐Onset Parkinsonism Is a Manifestation of the <scp> PPP2R5D </scp> p. <scp>E200K</scp> Mutation
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Jean Paul Vonsattel, Christine Tranchant, Jamel Chelly, Katrina Tatton-Brown, Wendy K. Chung, Thomas Wirth, Etty Cortes, Andrea H. Németh, Gabrielle Rudolf, Cécile Hubsch, Nathalie Drouot, Volkan Okur, Christine Y. Kim, Roy N. Alcalay, Mathieu Anheim, Cornelis Blauwendraat, Yale University [New Haven], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University College London Hospital, Les Hôpitaux Universitaires de Strasbourg (HUS), Fondation Ophtalmologique Adolphe de Rotschild, University of Oxford [Oxford], Columbia University [New York], Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Columbia University Medical Center (CUMC), and Icahn School of Medicine at Mount Sinai [New York] (MSSM)
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Adult ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Substantia nigra ,Early onset parkinsonism ,Article ,03 medical and health sciences ,0302 clinical medicine ,Neurodevelopmental disorder ,Parkinsonian Disorders ,medicine ,Humans ,Exome ,Protein Phosphatase 2 ,Age of Onset ,Exome sequencing ,business.industry ,Pars compacta ,Parkinsonism ,Brain ,DNA ,Middle Aged ,medicine.disease ,Pedigree ,030104 developmental biology ,nervous system ,Neurology ,Gliosis ,Mutation ,Mutation (genetic algorithm) ,Female ,Autopsy ,Neurology (clinical) ,medicine.symptom ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,030217 neurology & neurosurgery - Abstract
PPP2R5D-related neurodevelopmental disorder is characterized by a range of neurodevelopmental and behavioral manifestations. We report the association of early-onset parkinsonism with the PPP2R5D p.E200K mutation. Clinical characterization and exome sequencing were performed on three patients, with postmortem neuropathologic examination for one patient. All patients had mild developmental delay and developed levodopa-responsive parkinsonism between the ages of 25 and 40 years. The PPP2R5D c.598G>A (p.E200K) mutation was identified in all patients. Neuropathologic examination demonstrated uneven, focally severe neuronal loss and gliosis in the substantia nigra pars compacta, without Lewy bodies. Our findings suggest the PPP2R5D p.E200K mutation to be a possible new cause of early-onset parkinsonism. ANN NEUROL 2020;88:1028-1033.
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- 2020
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16. Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington’s Disease
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Christopher Medway, Vanessa C. Wheeler, Diane Lucente, Amelia Tee, Douglas Barker, Seung Kwak, Anka G Ehrhardt, Jean Paul Vonsattel, Kevin Correia, Michael J. Chao, Jacob M. Loupe, Darren G. Monckton, Alastair Maxwell, Jayalakshmi S. Mysore, Lesley Jones, Michael Orth, Richard H. Myers, Thomas Massey, Hugh Rickards, Ira Shoulson, Timothy Stone, Kyung Hee Kim, Marcy E. MacDonald, Marc Ciosi, Branduff McAllister, Erik van Duijn, Lynsey Hall, Tammy Gillis, Duncan McLauchlan, Jong-Min Lee, Ricardo Mouro Pinto, James F. Gusella, Eliana Marisa Ramos, Eun Pyo Hong, Jane S. Paulsen, Peter Holmans, G. Bernhard Landwehrmeyer, Cristina Sampaio, Afroditi Chatzi, Natalie Ellis, Kawther Abu Elneel, and Jeffrey D. Long
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0301 basic medicine ,medicine.medical_specialty ,Psychosis ,Population ,Disease ,Irritability ,Article ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Huntington's disease ,Risk Factors ,Genetic variation ,Humans ,Medicine ,Apathy ,Cognitive decline ,Psychiatry ,education ,Biological Psychiatry ,Depression (differential diagnoses) ,030304 developmental biology ,Genetic association ,0303 health sciences ,education.field_of_study ,Depression ,business.industry ,Polygenic risk ,medicine.disease ,3. Good health ,Huntington Disease ,030104 developmental biology ,Psychotic Disorders ,Schizophrenia ,Psychiatric ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Huntington’s disease - Abstract
Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. In general, polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.
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- 2020
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17. Abstract WP127: Cerebral Microbleeds, Cerebral Amyloid Angiopathy, And Their Relationships To Quantitative Markers Of Neurodegeneration
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Charles Beaman, Khrystyna Kozii, Saima Hilal, Minghua Liu, Antonio Spagnolo-Allende, Christopher Chen, Ching-Yu Cheng, Daniela Zambrano, Burak Arikan, Victor J Del Brutto, Clinton Wright, Xena E Flowers, Sandra P Leskinen, Tatjana Rundek, Amanda Mitchell, Jean Paul Vonsattel, Etty Cortes, Andrew F Teich, Ralph L Sacco, Mitchell S Elkind, David Roh, and Jose Gutierrez
- Subjects
Advanced and Specialized Nursing ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Age-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer’s disease. In the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA impact volumetric changed in the brain related to neurodegenerative disease remains unclear. Methods: We performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer’s Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between two related markers of cerebrovascular disease – MRI-based CMBs and autopsy-based CAA, as independent variables, and volumetric markers of neurodegeneration, as dependent variables. Results: We included 2657 participants with available MRI data and 82 autopsy cases from the BARS. In a meta-analysis of NOMAS, ADNI and EDIS, superficial CMBs were associated with larger gray (β=4.49 ± 1.13, P=0.04) and white (β=4.72 ± 2.1, P=0.03) matter volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with one CMB (B=5.17 ± 2.47, P=0.04) than in those with ≥ 2 CMBs (β=1.97 ± 3.41, P=0.56). In the BARS, CAA was associated with increased cortical thickness (β = 6.5 ± 2.3, P=0.016) but not with increased brain weight (β=1.54 ± 1.29, P=0.26). Discussion: Superficial CMBs are associated with larger morphometric brain measures. This association is strongest in brains with fewer CMBs, suggesting that the CMBs/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease.
- Published
- 2022
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18. Amyotrophic lateral sclerosis is over-represented in two Huntington’s disease brain bank cohorts: further evidence to support genetic pleiotropy of pathogenic HTT gene expansion
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Jean-Paul Vonsattel, Karen Marder, Ramita Dewan, Bryan J. Traynor, Richard A. Hickman, and Etty Cortes
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Genetics ,Cellular and Molecular Neuroscience ,Huntington's disease ,Htt gene ,medicine ,Genetic Pleiotropy ,Brain bank ,Neurology (clinical) ,Biology ,Amyotrophic lateral sclerosis ,medicine.disease ,Article ,Pathology and Forensic Medicine - Published
- 2021
19. Wolframin is a novel regulator of tau pathology and neurodegeneration
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Shuo Chen, Diana Acosta, Liangping Li, Jiawen Liang, Yuzhou Chang, Cankun Wang, Julie Fitzgerald, Cody Morrison, Chris N. Goulbourne, Yoshi Nakano, Nancy C. Hernandez Villegas, Lalitha Venkataraman, Cris Brown, Geidy E. Serrano, Erica Bell, Trina Wemlinger, Min Wu, Olga N. Kokiko-Cochran, Phillip Popovich, Xena E. Flowers, Lawrence S. Honig, Jean Paul Vonsattel, Douglas W. Scharre, Thomas G. Beach, Qin Ma, Jeff Kuret, Sulev Kõks, Fumihiko Urano, Karen E. Duff, and Hongjun Fu
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Neurons ,Cellular and Molecular Neuroscience ,Mice ,Protein Aggregates ,Tauopathies ,Alzheimer Disease ,Animals ,Mice, Transgenic ,Neurology (clinical) ,Lysosomes ,Pathology and Forensic Medicine - Abstract
Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD.
- Published
- 2021
20. Multiple System Atrophy With Predominant Striatonigral Degeneration and TAR DNA‐Binding Protein of 43 kDa Pathology: An Unusual Variant of Multiple System Atrophy
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Lynda Nwabuobi, Etty Cortes, Darya Tomishon, Jean Paul Vonsattel, Neil A. Shneider, and Stanley Fahn
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Striatonigral Degeneration ,Clinico‐pathological Case ,030105 genetics & heredity ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,mental disorders ,medicine ,business.industry ,Lenticular nucleus ,Putamen ,Neurodegeneration ,Frontotemporal lobar degeneration ,medicine.disease ,nervous system diseases ,Globus pallidus ,nervous system ,Neurology ,Gliosis ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Background The pathological hallmark in MSA is oligodendrocytic glial cytoplasmic inclusions (GCIs) containing α-synuclein, in addition to neuronal loss and astrogliosis especially involving the striatonigral and olivopontocerebellar systems. Rarely, TAR DNA-binding protein of 43 kDa (TDP-43), a component of ubiquitinated inclusions observed mainly in amyotrophic lateral sclerosis and frontotemporal lobar degeneration has been demonstrated in cases of MSA and, more recently, was shown to colocalize with α-synuclein pathology in GCIs in 2 patients. Methods A 66-year-old woman presented with a syndrome characterized by spasticity, dysautonomia, bulbar dysfunction, and parkinsonism. Symptoms progressed until her death at age 74. Neuropathological evaluation was performed at the New York Brain Bank at Columbia University. Results On gross examination, there was striking severe volume loss of the left striatum compared to mild involvement of the right striatum. Microscopically, neuronal loss and gliosis of the putamen and globus pallidus were severe on the left side, in contrast to mild involvement on the right side. Immunohistochemistry for α-synuclein revealed widespread GCIs. The sections subjected to TDP-43 antibodies showed a few GCIs with definite nucleocytoplasmic translocation of the labeling within the lenticular nucleus and within the paracentral cortex. Conclusions This report adds to the evidence that TDP-43 and α-synuclein colocalize in GCIs. Whether this coexistence contributes to the pathogenesis of a subset of MSA patients or is an age-related process is not known. More cases with these peculiar pathological hallmarks might help determine whether TDP-43 contributes to neurodegeneration in a subset of patients with MSA.
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- 2019
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21. Genome-wide association study and functional validation implicates JADE1 in tauopathy
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Kurt Farrell, SoongHo Kim, Natalia Han, Megan A. Iida, Elias Gonzalez, Marcos Otero-Garcia, Jamie Walker, Tim Richardson, Alan E. Renton, Shea J. Andrews, Brian Fulton-Howard, Jack Humphrey, Ricardo A. Vialle, Kathryn R. Bowles, Kristen Whitney, Diana K. Dangoor, Edoardo Marcora, Marco M. Hefti, Alicia Casella, Cheick Sissoko, Manav Kapoor, Gloriia Novikova, Evan Udine, Garrett Wong, Weijing Tang, Tushar Bhangale, Julie Hunkapiller, Gai Ayalon, Rob Graham, Jonathan D. Cherry, Etty Cortes, Valeriy Borukov, Ann C. McKee, Thor D. Stein, Jean-Paul Vonsattel, Andy F. Teich, Marla Gearing, Jonathan Glass, Juan C. Troncoso, Matthew P. Frosch, Bradley T. Hyman, Dennis W. Dickson, Melissa E. Murray, Johannes Attems, Margaret E. Flanagan, Qinwen Mao, M-Marsel Mesulam, Sandra Weintraub, Randy Woltjer, Thao Pham, Julia Kofler, Julie A. Schneider, Lei Yu, Dushyant P. Purohit, Vahram Haroutunian, Patrick R. Hof, Sam Gandy, Mary Sano, Thomas G. Beach, Wayne Poon, Claudia Kawas, María Corrada, Robert A. Rissman, Jeff Metcalf, Sara Shuldberg, Bahar Salehi, Peter T. Nelson, John Q. Trojanowski, Edward B. Lee, David A. Wolk, Corey T. McMillan, Dirk C. Keene, Thomas J. Montine, Gabor G. Kovacs, Mirjam I. Lutz, Peter Fischer, Richard J. Perrin, Nigel Cairns, Erin E. Franklin, Herbert T. Cohen, Maria Inmaculada Cobos Sillero, Bess Frost, Towfique Raj, Alison Goate, Charles L. White, and John F. Crary
- Subjects
medicine ,Neurofibrillary tangle ,Genome-wide association study ,Single-nucleotide polymorphism ,Tauopathy ,Alzheimer's disease ,Biology ,medicine.disease ,Molecular biology ,Phenotype ,Genetic association ,Progressive supranuclear palsy - Abstract
Primary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.
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- 2021
- Full Text
- View/download PDF
22. Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation
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Ryan G. Lim, Osama Al-Dalahmah, Jie Wu, Maxwell P. Gold, Jack C. Reidling, Guomei Tang, Miriam Adam, David K. Dansu, Hye-Jin Park, Patrizia Casaccia, Ricardo Miramontes, Andrea M. Reyes-Ortiz, Alice Lau, Richard A. Hickman, Fatima Khan, Fahad Paryani, Alice Tang, Kenneth Ofori, Emily Miyoshi, Neethu Michael, Nicolette McClure, Xena E. Flowers, Jean Paul Vonsattel, Shawn Davidson, Vilas Menon, Vivek Swarup, Ernest Fraenkel, James E. Goldman, and Leslie M. Thompson
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Huntington's Disease ,General Physics and Astronomy ,Biotin ,Mice, Transgenic ,Nerve Tissue Proteins ,Neurodegenerative ,General Biochemistry, Genetics and Molecular Biology ,Transgenic ,Mice ,Rare Diseases ,Genetics ,Solitary Nucleus ,2.1 Biological and endogenous factors ,Animals ,Humans ,Thiamine ,Aetiology ,Multidisciplinary ,Animal ,Neurosciences ,General Chemistry ,Stem Cell Research ,Brain Disorders ,Oligodendroglia ,Disease Models, Animal ,Huntington Disease ,Disease Models ,Neurological ,Dietary Supplements ,Stem Cell Research - Nonembryonic - Non-Human - Abstract
The complexity of affected brain regions and cell types is a challenge for Huntington’s disease (HD) treatment. Here we use single nucleus RNA sequencing to investigate molecular pathology in the cortex and striatum from R6/2 mice and human HD post-mortem tissue. We identify cell type-specific and -agnostic signatures suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) are arrested in intermediate maturation states. OL-lineage regulatorsOLIG1andOLIG2are negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells shows decreased accessibility regulated by OL maturation genes. The data implicates glucose and lipid metabolism in abnormal cell maturation and identifyPRKCEand Thiamine Pyrophosphokinase 1 (TPK1) as central genes. Thiamine/biotin treatment of R6/1 HD mice to compensate forTPK1dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.
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- 2021
23. Neuropathological correlation supports automated image-based differential diagnosis in parkinsonism
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David Eidelberg, Stanley Fahn, Katharina A Schindlbeck, Jean-Paul Vonsattel, Sarah A. O'Shea, Kathleen L. Poston, Chris C. Tang, Deepak K. Gupta, Vijay Dhawan, and Yoon Young Choi
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medicine.medical_specialty ,business.industry ,Parkinsonism ,Clinical Decision-Making ,Uncertainty ,Brain ,Autopsy ,General Medicine ,Gold standard (test) ,Neuropathology ,Multiple System Atrophy ,medicine.disease ,Article ,Progressive supranuclear palsy ,Correlation ,Diagnosis, Differential ,Atrophy ,Parkinsonian Disorders ,Fluorodeoxyglucose F18 ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Radiology ,Differential diagnosis ,business - Abstract
PURPOSE: Up to 25% of patients diagnosed as idiopathic Parkinson’s disease (IPD) have an atypical parkinsonian syndrome (APS). We had previously validated an automated image-based algorithm to discriminate between IPD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). While the algorithm was accurate with respect to the final clinical diagnosis after long term expert follow-up, its relationship to the initial referral diagnosis and to the neuropathological gold standard is not known. METHODS: Patients with an uncertain diagnosis of parkinsonism were referred for [(18)F]-fluorodeoxyglucose (FDG) PET to classify patients as IPD or as APS based on the automated algorithm. Patients were followed by a movement disorder specialist and subsequently underwent neuropathological examination. The image-based classification was compared to the neuropathological diagnosis in 15 patients with parkinsonism. RESULTS: At the time of referral to PET, the clinical impression was only 66.7% accurate. The algorithm correctly identified 80% of the cases as IPD or APS (p=0.02) and 87.5% of the APS cases as MSA or PSP (p=0.03). The final clinical diagnosis was 93.3% accurate (p
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- 2021
24. Single cell RNA sequencing of human microglia uncovers a subset that is associated with Alzheimer’s disease
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Jean Paul Vonsattel, David A. Bennett, Christina J. Yung, Naomi Habib, Julie A. Schneider, Mariko Taga, Marta Olah, Guillermo Coronas-Samano, Aviv Regev, Philip L. De Jager, Anthony Khairallah, Andrew F. Teich, Yiyi Ma, and Vilas Menon
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Microglia ,Epidemiology ,Health Policy ,Cell ,RNA ,Disease ,Biology ,Cell biology ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,Developmental Neuroscience ,medicine ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2020
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25. Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer's disease
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Andrew F. Teich, Danielle Dionne, Philip L. De Jager, Aviv Regev, Julie A. Schneider, Roman Sankowski, Jean Paul Vonsattel, Jeffrey Helgager, Jeffrey A. Golden, Marta Olah, Rani A. Sarkis, Dominic Grün, Vilas Menon, Wassim Elyaman, Naomi Habib, Elizabeth M. Bradshaw, Guillermo Coronas-Samano, Alexandra Kroshilina, Anthony Khairallah, Mariko Taga, David A. Bennett, Page B. Pennell, Christina J. Yung, Marco Prinz, Yiyi Ma, Garth Rees Cosgrove, and Maria Cimpean
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0301 basic medicine ,Male ,Cell type ,Science ,Cell ,Neuroimmunology ,General Physics and Astronomy ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Cortex (anatomy) ,medicine ,Humans ,Myeloid Cells ,Gene ,Cerebral Cortex ,Multidisciplinary ,Microglia ,Sequence Analysis, RNA ,RNA ,General Chemistry ,Alzheimer's disease ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Cerebral cortex ,Female ,Neuroscience ,Nucleus ,030217 neurology & neurosurgery - Abstract
The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer’s disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD., Imbalance of microglial phenotypes in the aging brain might underlie their involvement in late onset neurodegenerative diseases. Here we report the population structure of microglia in the aged human brain and the reduction of a particular microglia subset in individuals with Alzheimer’s disease .
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- 2020
26. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis
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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
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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.
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- 2020
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27. Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington's disease patients
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Jean Paul Vonsattel, X. William Yang, Judith Frydman, Matthew Stricos, Harry V. Vinters, Kristina H Cheon, Nancy S. Wexler, Peter Langfelder, Etty Cortes, C.Y. Daniel Lee, Robert Damoiseaux, Koning Shen, and Nan Wang
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Male ,Huntington's Disease ,Protein Folding ,Huntingtin ,Intravital Microscopy ,Mutant ,Cell ,lcsh:Medicine ,Diseases ,Protein aggregation ,Neurodegenerative ,Protein Engineering ,Genes, Reporter ,80 and over ,2.1 Biological and endogenous factors ,Aetiology ,lcsh:Science ,Cerebrospinal Fluid ,Aged, 80 and over ,Huntingtin Protein ,Multidisciplinary ,biology ,food and beverages ,Brain ,Huntington's disease ,Exons ,Middle Aged ,medicine.anatomical_structure ,Huntington Disease ,Neurology ,Neurological ,Female ,Antibody ,Adult ,Nerve Tissue Proteins ,Protein Aggregation, Pathological ,Article ,Cell Line ,Rare Diseases ,Protein Domains ,Pathological ,medicine ,Humans ,Reporter ,Aged ,lcsh:R ,Neurosciences ,Diagnostic markers ,HSP40 Heat-Shock Proteins ,medicine.disease ,Protein Aggregation ,Brain Disorders ,Genes ,Cell culture ,Chaperone (protein) ,Mutation ,biology.protein ,Cancer research ,lcsh:Q ,Molecular Chaperones - Abstract
In Huntington’s disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. It has been difficult to quantitatively detect such pathological seeding activities in patient biosamples, e.g. cerebrospinal fluids (CSF), and study their correlation with the disease manifestation. Here we developed a cell line expressing a domain-engineered mHTT-exon 1 reporter, which showed remarkably high sensitivity and specificity in detecting mHTT seeding species in HD patient biosamples. We showed that the seeding-competent mHTT species in HD CSF are significantly elevated upon disease onset and with the progression of neuropathological grades. Mechanistically, we showed that mHTT seeding activities in patient CSF could be ameliorated by the overexpression of chaperone DNAJB6 and by antibodies against the polyproline domain of mHTT. Together, our study developed a selective and scalable cell-based tool to investigate mHTT seeding activities in HD CSF, and demonstrated that the CSF mHTT seeding species are significantly associated with certain disease states. This seeding activity can be ameliorated by targeting specific domain or proteostatic pathway of mHTT, providing novel insights into such pathological activities.
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- 2020
28. Reply to 'PPP2R5D Genetic Mutations and Early Onset Parkinsonism'
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Christine Tranchant, Andrea H. Németh, Wendy K. Chung, Thomas Wirth, Mathieu Anheim, Volkan Okur, Roy N. Alcalay, Christine Y. Kim, Jean Paul Vonsattel, Etty Cortes, Cécile Hubsch, Nathalie Drouot, Katrina Tatton-Brown, Jamel Chelly, Gabrielle Rudolf, and Cornelis Blauwendraat
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Text mining ,Neurology ,Parkinsonian Disorders ,business.industry ,Mutation ,MEDLINE ,Medicine ,Humans ,Neurology (clinical) ,Protein Phosphatase 2 ,Early onset parkinsonism ,business ,Bioinformatics - Published
- 2020
29. Authors' replies to the comments of Koga et al. on 'Movement disorders rounds: A case of missing pathology in a patient with LRRK2 Parkinson's disease'
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Roy N. Alcalay, Karen Marder, Julian Agin-Liebes, Jean-Paul Vonsattel, and Richard A. Hickman
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Alpha-synuclein ,Pediatrics ,medicine.medical_specialty ,Parkinson's disease ,Movement disorders ,business.industry ,MEDLINE ,Parkinson Disease ,medicine.disease ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,LRRK2 ,chemistry.chemical_compound ,Neurology ,chemistry ,medicine ,alpha-Synuclein ,Humans ,Neurology (clinical) ,Geriatrics and Gerontology ,medicine.symptom ,business - Published
- 2020
30. Evidence for the spread of human-derived mutant huntingtin protein in mice and non-human primates
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Steve Lacroix, Benjamin Dehay, Chuan Qin, Giulia Cisbani, Ludivine S. Breger, Abid Oueslati, Zhang Ling, Melanie Alpaugh, Alexander Maxan, Zhu Tao, Jean-Paul Vonsattel, Philippe Gosset, Erwan Bezard, Nadia Fortin, Francesca Cicchetti, Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), China Academy of Medical Sciences [Beijing, China] (Institute of Laboratory Animal Sciences), University of Toronto, Columbia University [New York], Université Laval [Québec] (ULaval), and Dehay, Benjamin
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0301 basic medicine ,Huntingtin ,Pathological polyQ ,[SDV]Life Sciences [q-bio] ,Mutant ,Endogeny ,Disease ,Biology ,Protein Aggregation, Pathological ,lcsh:RC321-571 ,03 medical and health sciences ,0302 clinical medicine ,Huntington's disease ,medicine ,Huntingtin Protein ,Animals ,Humans ,BACHD ,Induced pluripotent stem cell ,Child ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Neurons ,Behavior, Animal ,Mechanism (biology) ,Neurodegenerative diseases ,Prion-like protein ,Brain ,Animal behaviour ,medicine.disease ,Macaca mulatta ,Cell biology ,Mice, Inbred C57BL ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Neurology ,Mutation ,Female ,030217 neurology & neurosurgery - Abstract
International audience; In recent years, substantial evidence has emerged to suggest that spreading of pathological proteins contributes to disease pathology in numerous neurodegenerative disorders. Work from our laboratory and others have shown that, despite its strictly genetic nature, Huntington's disease (HD) may be another condition in which this mechanism contributes to pathology. In this study, we set out to determine if the mutant huntingtin protein (mHTT) present in post-mortem brain tissue derived from HD patients can induce pathology in mice and/or non-human primates. For this, we performed three distinct sets of experiments where homogenates were injected into the brains of adult a) Wild-type (WT) and b) BACHD mice or c) non-human primates. Neuropathological assessments revealed that, while changes in the endogenous huntingtin were not apparent, mHTT could spread between cellular elements and brain structures. Furthermore, behavioural differences only occurred in the animal model of HD which already overexpressed mHTT. Taken together, our results indicate that mHTT derived from human brains has only a limited capacity to propagate between cells and does not depict prion-like characteristics. This contrasts with recent work demonstrating that other forms of mHTT - such as fibrils of a pathological polyQ length or fibroblasts and induced pluripotent stem cells derived from HD cases - can indeed disseminate disease throughout the brain in a prion-like fashion.
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- 2020
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31. Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in spinocerebellar ataxia type 1
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H. Brent Clark, Vanessa C. Wheeler, Jean Paul Vonsattel, Marissa A Andrew, Sarah Maria von Hein, Pedram Razghandi, Kevin Correia, Larissa Arning, Suman Jayadaev, Ricardo Mouro Pinto, Diane Lucente, Carsten Saft, Huu Phuc Nguyen, C. Dirk Keene, Constanze R. Parwez, Eckart Förster, Debora M. Grote Urtubey, Thomas D. Bird, James Victor Giordano, Harry T. Orr, Jayalakshmi S. Mysore, Elisabeth Petrasch-Parwez, Tammy Gillis, and Allison Beller
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Adult ,Central Nervous System ,Male ,AcademicSubjects/SCI01140 ,Spinocerebellar Ataxia Type 1 ,Cerebellum ,Cell type ,congenital, hereditary, and neonatal diseases and abnormalities ,Somatic cell ,Central nervous system ,Disease ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Huntington's disease ,Trinucleotide Repeats ,mental disorders ,Genetics ,medicine ,Humans ,Spinocerebellar Ataxias ,Child ,Molecular Biology ,Genetics (clinical) ,030304 developmental biology ,Aged ,0303 health sciences ,Huntingtin Protein ,General Medicine ,Middle Aged ,medicine.disease ,Neostriatum ,medicine.anatomical_structure ,Huntington Disease ,Female ,Autopsy ,General Article ,Trinucleotide repeat expansion ,Trinucleotide Repeat Expansion ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.
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- 2020
32. Genetic load determines atrophy in hand cortico-striatal pathways in presymptomatic Huntington's disease
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Fan Zhang, Demian Wassermann, Ofer Pasternak, Nikolaos Makris, Peter Savadjiev, Hans J. Johnson, Yi Hong, Lauren J. O'Donnell, Carl-Fredrik Westin, Jean-Paul Vonsattel, Yogesh Rathi, Jane S. Paulsen, Department of Computer Science [Athens GA], University of Georgia [USA], Departments of Psychiatry and Radiology [Boston], Brigham and Women's Hospital [Boston], Modelling brain structure, function and variability based on high-field MRI data (PARIETAL), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Computational Imaging of the Central Nervous System (ATHENA), Inria Sophia Antipolis - Méditerranée (CRISAM), University of Iowa [Iowa City], Columbia University [New York], Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], Laboratory of Mathematics in Imaging [Boston], Harvard Medical School [Boston] (HMS), Department of Computer Science, University of Georgia, Modelling brain structure, function and variability based on high-field MRI data ( PARIETAL ), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Service NEUROSPIN ( NEUROSPIN ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Computational Imaging of the Central Nervous System ( ATHENA ), Inria Sophia Antipolis - Méditerranée ( CRISAM ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), University of Iowa [Iowa], Harvard Medical School [Boston] ( HMS ), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Service NEUROSPIN (NEUROSPIN), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
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Male ,Striatum ,030218 nuclear medicine & medical imaging ,0302 clinical medicine ,Trinucleotide Repeats ,CAG-repeats ,Neural Pathways ,Isotropic volume fraction ,Longitudinal Studies ,Aged, 80 and over ,Cortico-striatal pathways ,Radiological and Ultrasound Technology ,Putamen ,Motor Cortex ,Middle Aged ,White Matter ,Diffusion Tensor Imaging ,Huntington Disease ,medicine.anatomical_structure ,Neurology ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Genetic Load ,Anatomy ,Tractography ,Adult ,Adolescent ,[PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph] ,Prodromal Symptoms ,Biology ,Article ,Diffusion MRI ,White matter ,Young Adult ,03 medical and health sciences ,Atrophy ,Huntington's disease ,[ PHYS.PHYS.PHYS-BIO-PH ] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph] ,Fractional anisotropy ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Equal contribution Keywords: Prodromal-HD ,Aged ,medicine.disease ,Prodromal-HD ,[ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,Caudate Nucleus ,Neuroscience ,030217 neurology & neurosurgery - Abstract
International audience; Huntington's disease (HD) is an inherited neurodegenerative disorder that causes progressive breakdown of striatal neurons. Standard white matter integrity measures like fractional anisotropy and mean diffusivity derived from diffusion tensor imaging were analyzed in prodromal-HD subjects; however, they studied either a whole brain or specific subcortical white matter structures with connections to cortical motor areas. In this work, we propose a novel analysis of a longitudinal cohort of 243 prodromal-HD individuals and 88 healthy controls who underwent two or more diffusion MRI scans as part of the PREDICT-HD study. We separately trace specific white matter fiber tracts connecting the striatum (caudate and putamen) with four cortical regions corresponding to the hand, face, trunk, and leg motor areas. A multi-tensor tractography algorithm with an isotropic volume fraction compartment allows Hong et al., Genetic load determines hand atrophy in preHD 2 estimating diffusion of fast-moving extra-cellular water in regions containing crossing fibers and provides quantification of a microstructural property related to tissue atrophy. The tissue atrophy rate is separately analyzed in eight cortico-striatal pathways as a function of CAG-repeats (genetic load) by statistically regressing out age effect from our cohort. The results demonstrate a statistically significant increase in isotropic volume fraction (atrophy) bilaterally in hand fiber connections to the putamen with increasing CAG-repeats, which connects the genetic abnormality (CAG-repeats) to an imaging-based microstructural marker of tissue integrity in specific white matter pathways in HD. Isotropic volume fraction measures in eight cortico-striatal pathways are also correlated significantly with total motor scores and diagnostic confidence levels, providing evidence of their relevance to HD clinical presentation.
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- 2018
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33. Clinical and neuropathological features of progressive supranuclear palsy in Leucine rich repeat kinase ( LRRK2 ) G2019S mutation carriers
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David Genís, Madeleine Sharp, Karen Marder, Roy N. Alcalay, Etty Cortes, Ellen Gelpi, Dolores Vilas, Jean-Paul Vonsattel, and Eduard Tolosa
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0301 basic medicine ,Kinase ,business.industry ,Leucine-rich repeat ,medicine.disease ,LRRK2 ,Molecular biology ,Progressive supranuclear palsy ,Serine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Neurology ,Glycine ,Mutation (genetic algorithm) ,medicine ,Locus coeruleus ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Published
- 2017
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34. Fulminant corticobasal degeneration: a distinct variant with predominant neuronal tau aggregates
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Lea R'Bibo, John C. Hedreen, Matthew Ellis, Gabor G. Kovacs, Kieren Allinson, Sebastian Brandner, Jean Paul Vonsattel, John Hardy, Thomas T. Warner, Eniko Veronika Kovari, Safa Al-Sarraj, David G. Mann, Glenda M. Halliday, Edwin Jabbari, Tamas Revesz, Johannes Attems, Helen Ling, Ellen Gelpi, James W. Ironside, Seth Love, Teisha Bradshaw, Roberto Simone, Rohan de Silva, Karen Davey, Núria Setó-Salvia, Kin Y. Mok, Daniela Hansen, Selina Wray, Janice L. Holton, Zane Jaunmuktane, Huw R. Morris, Ling, Helen [0000-0003-1532-3526], Revesz, Tamas [0000-0003-2501-0259], and Apollo - University of Cambridge Repository
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Male ,Neurofibrillary tangles ,Pathology ,medicine.medical_specialty ,Fulminant ,tau Proteins ,Disease ,Asymptomatic ,digestive system ,Pathology and Forensic Medicine ,Progressive supranuclear palsy ,ddc:616.89 ,Cellular and Molecular Neuroscience ,Basal Ganglia Diseases ,Humans ,Medicine ,Corticobasal degeneration ,Cognitive decline ,Pathological ,Aged ,Aged, 80 and over ,Cerebral Cortex ,Original Paper ,business.industry ,Astrocytic plaques ,Neurodegenerative Diseases ,Middle Aged ,medicine.disease ,digestive system diseases ,surgical procedures, operative ,Concomitant ,Disease Progression ,Female ,Neurology (clinical) ,medicine.symptom ,Tau ,business - Abstract
Corticobasal degeneration typically progresses gradually over 5–7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), corticobasal syndrome (N = 2) and Richardson’s syndrome (N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p p p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research.
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- 2020
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35. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes
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Bradley T. Hyman, Gerard D. Schellenberg, Jean Paul Vonsattel, Yinghua Chen, Matthew J. Huentelman, Thomas G. Beach, Julie A. Schneider, Walter A. Kukull, M. Ilyas Kamboh, Bernardino Ghetti, Richard J. Caselli, Kathryn L. Lunetta, Yi Su, John Q. Trojanowski, Eric B. Larson, Julia Kofler, John Hardy, John Gilbert, Amanda J. Myers, Margaret A. Pericak-Vance, Thomas J. Montine, Richard Mayeux, Paul K. Crane, Joseph D. Buxbaum, Yakeel T. Quiroz, Linda Duque, Steven G. Younkin, David A. Bennett, Matthew P. Frosch, Tatiana Foroud, Lindsay A. Farrer, Joseph F. Arboleda-Velasquez, Harry E. Gwirtsman, Philip L. De Jager, Jonathan L. Haines, C. Dirk Keene, Dennis W. Dickson, Eric M. Reiman, Gyungah Jun, Li-San Wang, and Gary W. Beecham
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Apolipoprotein E ,0303 health sciences ,medicine.medical_specialty ,business.industry ,Odds ratio ,Disease ,medicine.disease ,Lower risk ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,mental disorders ,medicine ,Dementia ,Alzheimer s dementia ,Allele ,business ,030217 neurology & neurosurgery ,Alzheimers dementia ,030304 developmental biology - Abstract
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, such that APOE4 homozygotes have a particularly high risk. While the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with exceptionally low Alzheimer’s dementia odds ratios compared to APOE2/3, 3/3 and 4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of this terrible disease.
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- 2019
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36. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study
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Eric M, Reiman, Joseph F, Arboleda-Velasquez, Yakeel T, Quiroz, Matthew J, Huentelman, Thomas G, Beach, Richard J, Caselli, Yinghua, Chen, Yi, Su, Amanda J, Myers, John, Hardy, Jean, Paul Vonsattel, Steven G, Younkin, David A, Bennett, Philip L, De Jager, Eric B, Larson, Paul K, Crane, C Dirk, Keene, M Ilyas, Kamboh, Julia K, Kofler, Linda, Duque, John R, Gilbert, Harry E, Gwirtsman, Joseph D, Buxbaum, Dennis W, Dickson, Matthew P, Frosch, Bernardino F, Ghetti, Kathryn L, Lunetta, Li-San, Wang, Bradley T, Hyman, Walter A, Kukull, Tatiana, Foroud, Jonathan L, Haines, Richard P, Mayeux, Margaret A, Pericak-Vance, Julie A, Schneider, John Q, Trojanowski, Lindsay A, Farrer, Gerard D, Schellenberg, Gary W, Beecham, Thomas J, Montine, Gyungah R, Jun, Yi, Zhao, Reiman, Eric M [0000-0002-0705-3696], Arboleda-Velasquez, Joseph F [0000-0002-3192-9117], Dickson, Dennis W [0000-0001-7189-7917], Ghetti, Bernardino F [0000-0002-1842-8019], Lunetta, Kathryn L [0000-0002-9268-810X], Hyman, Bradley T [0000-0002-7959-9401], Haines, Jonathan L [0000-0002-4351-4728], Pericak-Vance, Margaret A [0000-0001-7283-8804], Trojanowski, John Q [0000-0002-9239-8794], Jun, Gyungah R [0000-0002-3230-8697], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Oncology ,Apolipoprotein E ,Male ,Aging ,Apolipoprotein E2 ,Apolipoprotein E4 ,Apolipoprotein E3 ,General Physics and Astronomy ,Disease ,Neurodegenerative ,Alzheimer's Disease ,0302 clinical medicine ,Genotype ,Genetics research ,80 and over ,2.1 Biological and endogenous factors ,Aetiology ,lcsh:Science ,Neuropathology ,Aged, 80 and over ,Multidisciplinary ,Homozygote ,Brain ,Middle Aged ,Alzheimer's disease ,Neurological ,Female ,medicine.medical_specialty ,Science ,Lower risk ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Alzheimer Disease ,Internal medicine ,mental disorders ,medicine ,Acquired Cognitive Impairment ,Genetics ,Dementia ,Humans ,Genetic Predisposition to Disease ,Allele ,Alleles ,Genetic Association Studies ,Aged ,Probability ,business.industry ,Prevention ,Alzheimer’s Disease Genetics Consortium ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,General Chemistry ,Odds ratio ,medicine.disease ,Brain Disorders ,030104 developmental biology ,Good Health and Well Being ,lcsh:Q ,business ,030217 neurology & neurosurgery - Abstract
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, while the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with a low Alzheimer’s dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of the disease., APOE is the major genetic risk factor for Alzheimer’s disease. In a large number of neuropathologically confirmed cases and controls, the impact of different APOE genotypes on Alzheimer’s dementia risk was greater than previously thought and APOE2 homozygotes had an exceptionally low risk.
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- 2019
37. C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy
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Wan Yun Ho, Claire Troakes, Edward B. Lee, Hans A. Kretzschmar, Charles L. White, Virginia M.-Y. Lee, Helen Ling, Christopher P. Cali, Catriona McLean, Jean Paul Vonsattel, Bernardino Ghetti, Juan C. Troncoso, Gerard D. Schellenberg, Shuo-Chien Ling, Kin Y. Mok, Maribel Patino, John Q. Trojanowski, Sigrun Roeber, William W. Seeley, Dennis W. Dickson, Vivianna M. Van Deerlin, Bruce L. Miller, Marla Gearing, Carles Gaig, Yee Kit Tai, and Christopher Morris
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0301 basic medicine ,Aging ,Neurodegenerative ,0302 clinical medicine ,C9orf72 ,Corticobasal degeneration ,2.1 Biological and endogenous factors ,Aetiology ,Alzheimer's Disease Related Dementias (ADRD) ,biology ,Neurodegeneration ,Brain ,Neurodegenerative Diseases ,Parkinson Disease ,Frontotemporal Dementia (FTD) ,Frontotemporal Dementia ,Neurological ,Frontotemporal dementia ,Tau protein ,Clinical Sciences ,Parkinsonism ,Article ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Rare Diseases ,Basal Ganglia Diseases ,Parkinsonian Disorders ,Alzheimer Disease ,Microsatellite Repeat ,medicine ,Genetics ,Acquired Cognitive Impairment ,Autophagy ,Humans ,Neurology & Neurosurgery ,C9orf72 Protein ,Amyotrophic Lateral Sclerosis ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,C9orf72 repeat expansion ,medicine.disease ,Stem Cell Research ,Brain Disorders ,030104 developmental biology ,biology.protein ,Cancer research ,Dementia ,Neurology (clinical) ,ALS ,Trinucleotide repeat expansion ,030217 neurology & neurosurgery - Abstract
Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson's disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson's but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.
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- 2019
38. Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation
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Angela M. Christiano, Aulona Gaba, Charles F. Lang, Benjamin Tycko, Mary Pat Gallagher, Robin Goland, Catherine Do, John Lin, John G. Kral, Raphael Clynes, Catherine Monk, Andrew J. Dwork, Lynn Petukhova, Huferesh K. Darbary, Izabela Krupska, and Jean-Paul Vonsattel
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0301 basic medicine ,Placenta ,T-Lymphocytes ,Quantitative Trait Loci ,Genome-wide association study ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Article ,Genomic Imprinting ,03 medical and health sciences ,Species Specificity ,Pregnancy ,Genetics ,Animals ,Humans ,Genetics(clinical) ,Allele ,Alleles ,Genetics (clinical) ,Brain ,Methylation ,DNA Methylation ,Macaca mulatta ,Macaca radiata ,030104 developmental biology ,Differentially methylated regions ,Haplotypes ,Immune System Diseases ,CTCF ,DNA methylation ,Trans-Activators ,Female ,Nervous System Diseases ,Genomic imprinting ,Genome-Wide Association Study - Abstract
Haplotype-dependent allele-specific methylation (hap-ASM) can impact disease susceptibility, but maps of this phenomenon using stringent criteria in disease-relevant tissues remain sparse. Here we apply array-based and Methyl-Seq approaches to multiple human tissues and cell types, including brain, purified neurons and glia, T lymphocytes, and placenta, and identify 795 hap-ASM differentially methylated regions (DMRs) and 3,082 strong methylation quantitative trait loci (mQTLs), most not previously reported. More than half of these DMRs have cell type-restricted ASM, and among them are 188 hap-ASM DMRs and 933 mQTLs located near GWAS signals for immune and neurological disorders. Targeted bis-seq confirmed hap-ASM in 12/13 loci tested, including CCDC155, CD69 , FRMD1 , IRF1, KBTBD11 , and S100A ∗ -ILF2 , associated with immune phenotypes, MYT1L, PTPRN2, CMTM8 and CELF2 , associated with neurological disorders, NGFR and HLA-DRB6 , associated with both immunological and brain disorders, and ZFP57 , a trans -acting regulator of genomic imprinting. Polymorphic CTCF and transcription factor (TF) binding sites were over-represented among hap-ASM DMRs and mQTLs, and analysis of the human data, supplemented by cross-species comparisons to macaques, indicated that CTCF and TF binding likelihood predicts the strength and direction of the allelic methylation asymmetry. These results show that hap-ASM is highly tissue specific; an important trans -acting regulator of genomic imprinting is regulated by this phenomenon; and variation in CTCF and TF binding sites is an underlying mechanism, and maps of hap-ASM and mQTLs reveal regulatory sequences underlying supra- and sub-threshold GWAS peaks in immunological and neurological disorders.
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- 2016
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39. Huntington’s disease onset is determined by length of uninterrupted CAG, not encoded polyglutamine, and is modified by DNA maintenance mechanisms
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Diane Lucente, Douglas Barker, Michael J. Chao, Branduff McAllister, Georg Bernhard Landwehrmeyer, Abu Elneel K, Lynsey S. Hall, Jean-Paul Vonsattel, Jacob M. Loupe, Anka G Ehrhardt, J.S. Paulsen, Richard H. Myers, Vanessa C. Wheeler, Christopher W Medway, Jayalakshmi S. Mysore, Alastair Maxwell, Ira Shoulson, Tammy Gillis, Seung Kwak, Michael Orth, Peter Holmans, Timothy Stone, Lesley Jones, Eliana Marisa Ramos, J. F. Gusella, Cristina Sampaio, Eun Pyo Hong, Julianna Y. Lee, Dorsey Er, Mouro Pinto R, Kyuseok Kim, Kevin Correia, Jeffrey D. Long, Afroditi Chatzi, Tom Massey, Marcy E. MacDonald, Darren G. Monckton, and Marc Ciosi
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Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,Somatic cell ,Repeat sequence ,Genome-wide association study ,Biology ,medicine.disease ,Pathogenesis ,Huntington's disease ,DNA Maintenance ,mental disorders ,medicine ,Gene - Abstract
SUMMARYThe effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtin’s polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the “polyglutamine disorders”.
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- 2019
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40. The New York Brain Bank of Columbia University: practical highlights of 35 years of experience
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Etty Paola Cortes, Ramirez, Christian Ernst, Keller, and Jean Paul, Vonsattel
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Universities ,Academies and Institutes ,New York ,Brain ,Humans ,Tissue Banks ,History, 20th Century ,History, 21st Century ,Information Systems - Abstract
The New York Brain Bank processes brains and organs of clinically well-characterized patients with age-related neurodegenerative diseases, and for comparison, from individuals without neurologic or psychiatric impairments. The donors, either patients or individuals, were evaluated at healthcare facilities of the Columbia University of New York. Each source brain yields four categories of samples: fresh frozen blocks and crushed parenchyma, and formalin-fixed wet blocks and histology sections. A source brain is thoroughly evaluated to determine qualitatively and quantitatively any changes it might harbor using conventional neuropathologic techniques. The clinical and pathologic diagnoses are integrated to determine the distributive diagnosis assigned to the samples obtained from a source brain. The gradual standardization of the protocol was developed in 1981 in response to the evolving requirements of basic investigations on neurodegeneration. The methods assimilate long-standing experience from multiple centers. The resulting and current protocol includes a constant central core applied to all brains with conditional flexibility around it. The New York Brain Bank is an integral part of the department of pathology, where the expertise, teaching duties, and hardware are shared. Since details of the protocols are available online, this chapter focuses on practical issues in professionalizing brain banking.
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- 2018
41. Clinicopathological characteristics of freezing of gait in autopsy-confirmed Parkinson's disease
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Stanley Fahn, Jean-Paul Vonsattel, Carol Moskowitz, and Tuhin Virmani
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medicine.medical_specialty ,Levodopa ,Parkinson's disease ,Autopsy ,Substantia nigra ,Disease ,medicine.disease ,Gait (human) ,Physical medicine and rehabilitation ,Neurology ,Quality of life ,Cohort ,medicine ,Physical therapy ,Neurology (clinical) ,Psychology ,human activities ,medicine.drug - Abstract
Background Twenty-five percent to sixty percent of Parkinson's disease (PD) patients reportedly have freezing of gait, leading to impaired mobility, falls, and decreased quality of life. Several factors have been associated with gait freezing in PD patients. We analyze for these factors in autopsy-proven PD patients. Methods We performed a chart review of 58 patients with pathologically confirmed PD based on substantia nigra Lewy bodies. Freezing of gait was defined as a score of 1 or more on Item 14 of the Unified Parkinson's Disease Rating Scale or if documented on examination. Serial office notes and scales were used to determine onset and progression of motor and non-motor symptoms. Results Patients had been followed up for an average of 20 visits over 9 y. The mean onset of gait freezing was 9.3 y from initial motor symptoms. Patients with earlier gait freezing more commonly had initial gait difficulties and developed postural instability, dyskinesias, memory impairment, hallucinations, and vivid dreams earlier during the disease course. Early onset of hallucinations was correlated with more rapid progression of gait freezing. Maximal equivalent levodopa dose was not correlated with earlier onset or progression of gait freezing. Progressive and more severe gait freezing trended toward higher-severity Lewy body disease on postmortem examination. Conclusions Early onset and rapid progression of freezing of gait in this cohort were correlated with early cognitive impairment and hallucinations that are potential clinical hallmarks of cortical Lewy bodies. The gradual worsening and severity of gait freezing correlated with the density of cortical Lewy body–containing neurons. © 2015 International Parkinson and Movement Disorder Society
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- 2015
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42. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study
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David J. Irwin, Nilufer Ertekin-Taner, Sara Rollinson, Mads Kjolby, John Hardy, Julia Kofler, Robert A. Rissman, Bernardino Ghetti, Stuart Pickering-Brown, Jonathan Glass, Carlos Cruchaga, Jonathan D. Rohrer, Keith A. Josephs, Maura Gallo, Parastoo Momeni, Emilia J. Sitek, Matthis Synofzik, Sandro Sorbi, Carlo Wilke, Oscar L. Lopez, Nigel J. Cairns, Miren Zulaica, Peter Heutink, Leonard Petrucelli, Bret M. Evers, Luisa Benussi, Jeroen van Rooij, Olivier Piguet, Sandra E. Black, Bradley F. Boeve, Cyril Pottier, Eric M. Reiman, Melissa E. Murray, Ralph B. Perkerson, Daniela Galimberti, Thomas G. Beach, Giorgio G. Fumagalli, Giacomina Rossi, David M. A. Mann, John B.J. Kwok, Harro Seelaar, Edward B. Lee, Jean-Paul Vonsattel, Didier Hannequin, Rosa Rademakers, John R. Hodges, Nicole A. Finch, John Q. Trojanowski, David S. Knopman, Yingxue Ren, Albert Lladó, Anders Nykjaer, Claire Troakes, Linn Öijerstedt, EunRan Suh, Isabelle Le Ber, Juliane Winkelmann, Ian R. Mackenzie, Glenda M. Halliday, William W. Seeley, Salvatore Spina, Simon Mead, Elio Scarpini, Fabrizio Tagliavini, Bruce L. Miller, Mariely DeJesus-Hernandez, Dennis W. Dickson, Elizabeth Christopher, Mario Masellis, Florence Pasquier, Roberta Ghidoni, Janine Diehl-Schmid, Silvia Bagnoli, Barbara Borroni, Adam L. Boxer, Adrian L. Oblak, Elizabeth Finger, Carol F. Lippa, Giuliano Binetti, Eileen H. Bigio, Vivianna M. Van Deerlin, Anna Karydas, William S. Brooks, Julie S. Snowden, Anna Richardson, Lea T. Grinberg, Manuela Neumann, Jordan Grafman, Zbigniew K. Wszolek, Edward D. Huey, Caroline Graff, John C. van Swieten, Sandra Weintraub, Raffaele Maletta, Ekaterina Rogaeva, Fermin Moreno, Raffaele Ferrari, Charles L. White, Adolfo López de Munain, Neill R. Graff-Radford, Camilla Ferrari, Jill R. Murell, Marwan N. Sabbagh, Raquel Sánchez-Valle, Marka van Blitterswijk, Alessandro Padovani, Peter Johannsen, Daniel J. Serie, Francesca Frangipane, Safa Al-Sarraj, Anna Antonell, Kevin F. Bieniek, Tsz H. Wong, Ging-Yuek Robin Hsiung, Jarosław Sławek, Matthew B. Baker, Gregory D. Jenkins, Ronald C. Petersen, Murray Grossman, Benedetta Nacmias, Tammee M. Parsons, Lawrence S. Honig, Maria Anfossi, Richard J. Caselli, Changiz Geula, Marla Gearing, M.-Marsel Mesulam, Xiaolai Zhou, Joanna M. Biernacka, Joseph E. Parisi, Irene Piaceri, Jorgen E. Nielsen, Amalia C. Bruni, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Erasmus MC other, and Neurology
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0301 basic medicine ,Oncology ,Male ,RNA, Messenger/metabolism ,Genome-wide association study ,Disease ,Gene mutation ,genetics [Progranulins] ,0302 clinical medicine ,Progranulins ,Cerebellum ,GFRA2 protein, human ,Medicine ,Age of Onset ,genetics [Genetic Predisposition to Disease] ,Genetic Predisposition to Disease/genetics ,Frontotemporal lobar degeneration ,metabolism [Cerebellum] ,Middle Aged ,3. Good health ,Frontotemporal Dementia ,Female ,genetics [Frontotemporal Lobar Degeneration] ,Frontotemporal dementia ,medicine.medical_specialty ,Glial Cell Line-Derived Neurotrophic Factor Receptors ,Mutation/genetics ,Genetic counseling ,genetics [Mutation] ,Progranulins/genetics ,metabolism [RNA, Messenger] ,Article ,03 medical and health sciences ,Internal medicine ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,RNA, Messenger ,Cerebellum/metabolism ,Aged ,business.industry ,metabolism [Progranulins] ,Case-control study ,genetics [Glial Cell Line-Derived Neurotrophic Factor Receptors] ,Odds ratio ,medicine.disease ,metabolism [Frontotemporal Lobar Degeneration] ,metabolism [Glial Cell Line-Derived Neurotrophic Factor Receptors] ,030104 developmental biology ,Case-Control Studies ,Mutation ,GRN protein, human ,Frontotemporal Lobar Degeneration/genetics ,Neurology (clinical) ,Human medicine ,Frontotemporal Lobar Degeneration ,business ,Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.
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- 2018
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43. The New York Brain Bank of Columbia University: practical highlights of 35 years of experience
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Etty Paola Cortes Ramirez, Christian E. Keller, and Jean Paul Vonsattel
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0301 basic medicine ,Protocol (science) ,medicine.medical_specialty ,business.industry ,Columbia university ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Tissue bank ,Health care ,medicine ,Fresh frozen ,Medical physics ,Brain bank ,Medical diagnosis ,business ,Psychology ,030217 neurology & neurosurgery - Abstract
The New York Brain Bank processes brains and organs of clinically well-characterized patients with age-related neurodegenerative diseases, and for comparison, from individuals without neurologic or psychiatric impairments. The donors, either patients or individuals, were evaluated at healthcare facilities of the Columbia University of New York. Each source brain yields four categories of samples: fresh frozen blocks and crushed parenchyma, and formalin-fixed wet blocks and histology sections. A source brain is thoroughly evaluated to determine qualitatively and quantitatively any changes it might harbor using conventional neuropathologic techniques. The clinical and pathologic diagnoses are integrated to determine the distributive diagnosis assigned to the samples obtained from a source brain. The gradual standardization of the protocol was developed in 1981 in response to the evolving requirements of basic investigations on neurodegeneration. The methods assimilate long-standing experience from multiple centers. The resulting and current protocol includes a constant central core applied to all brains with conditional flexibility around it. The New York Brain Bank is an integral part of the department of pathology, where the expertise, teaching duties, and hardware are shared. Since details of the protocols are available online, this chapter focuses on practical issues in professionalizing brain banking.
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- 2018
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44. PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease
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Owen A. Ross, Jeffery M. Vance, James B. Leverenz, Margaret A. Pericak-Vance, Bernardino Ghetti, Joseph D. Buxbaum, John Q. Trojanowski, Zbigniew K. Wszolek, Eric B. Larson, William K. Scott, Eden R. Martin, Matthew P. Frosch, Howard I. Hurtig, Karen Nuytemans, Juan C. Troncoso, Derek M. Dykxhoorn, Samuel M. Goldman, Ted M. Dawson, Thomas G. Beach, Liyong Wang, Olga Pletnikova, Karen Marder, Harry V. Vinters, Gerard D. Schellenberg, Jean Paul Vonsattel, Lawrence S. Honig, Vivianna M. Van Deerlin, Deborah C. Mash, Tatiana Foroud, Thomas J. Montine, Dennis W. Dickson, and Gary W. Beecham
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Male ,Aging ,Linkage disequilibrium ,Candidate gene ,Clinical Sciences ,Single-nucleotide polymorphism ,Locus (genetics) ,Genome-wide association study ,Neurodegenerative ,Biology ,Polymorphism, Single Nucleotide ,Chromosomes ,Linkage Disequilibrium ,Genetic linkage ,80 and over ,Genetics ,2.1 Biological and endogenous factors ,Humans ,Polymorphism ,Aetiology ,Aged ,Genetic association ,Aged, 80 and over ,Parkinson's Disease ,Neurology & Neurosurgery ,Prevention ,Human Genome ,Haplotype ,Neurosciences ,Parkinson Disease ,Single Nucleotide ,Brain Disorders ,Chromosomes, Human, Pair 1 ,Genetic Loci ,Neurological ,Pair 1 ,Cognitive Sciences ,Female ,Neurology (clinical) ,Human ,Genome-Wide Association Study - Abstract
Objective: To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls. Methods: Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis. Results: A small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10 −8 ). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2 , TMEM59 , miR-4781 , and LDLRAD1 . Conclusions: We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.
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- 2015
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45. The Complexity of Clinical Huntington's Disease: Developments in Molecular Genetics, Neuropathology and Neuroimaging Biomarkers
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Lynette J, Tippett, Henry J, Waldvogel, Russell G, Snell, Jean-Paul, Vonsattel, Anne B, Young, and Richard L M, Faull
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Cerebral Cortex ,Huntingtin Protein ,Genes, Modifier ,Movement Disorders ,Mental Disorders ,Movement ,Neuroimaging ,Corpus Striatum ,Affect ,Cognition ,Huntington Disease ,Humans ,Molecular Targeted Therapy ,Cognition Disorders ,Molecular Biology - Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterised by extensive neuronal loss in the striatum and cerebral cortex, and a triad of clinical symptoms affecting motor, cognitive/behavioural and mood functioning. The mutation causing HD is an expansion of a CAG tract in exon 1 of the HTT gene. This chapter provides a multifaceted overview of the clinical complexity of HD. We explore recent directions in molecular genetics including the identification of loci that are genetic modifiers of HD that could potentially reveal therapeutic targets beyond the HTT gene transcript and protein. The variability of clinical symptomatology in HD is considered alongside recent findings of variability in cellular and neurochemical changes in the striatum and cerebral cortex in human brain. We review evidence from structural neuroimaging methods of progressive changes of striatum, cerebral cortex and white matter in pre-symptomatic and symptomatic HD, with a particular focus on the potential identification of neuroimaging biomarkers that could be used to test promising disease-specific and modifying treatments. Finally we provide an overview of completed clinical trials in HD and future therapeutic developments.
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- 2017
46. Polyglutamine expansion affects huntingtin conformation in multiple Huntington's disease models
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Marta Cherubini, Margherita Verani, Lucia Azzollini, Manuel Daldin, Paola Martufi, Cristina Cariulo, Hilal A. Lashuel, Ferdinando Squitieri, Valentina Fodale, Alberto Bresciani, Silvia Ginés, Douglas Macdonald, Andrea Caricasole, Iolanda Santimone, Jean Paul Vonsattel, J. Lawrence Marsh, Sean M. DeGuire, Massimo Marano, Andreas Weiss, Lara Petricca, Maria Carolina Spiezia, and Universitat de Barcelona
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0301 basic medicine ,Huntingtin ,Protein Conformation ,Science ,Biology ,Huntington's chorea ,medicine.disease_cause ,Article ,03 medical and health sciences ,Phosphoserine ,0302 clinical medicine ,Protein structure ,Huntington's disease ,Corea de Huntington ,medicine ,Huntingtin Protein ,Animals ,Humans ,Phosphorylation ,Genetics ,Mutation ,Multidisciplinary ,HEK 293 cells ,Malalties neurodegeneratives ,Mutació (Biologia) ,Brain ,Neurodegenerative Diseases ,Exons ,Mutation (Biology) ,Fibroblasts ,medicine.disease ,Cell biology ,Disease Models, Animal ,030104 developmental biology ,HEK293 Cells ,Huntington Disease ,Protein Fragment ,Medicine ,Drosophila ,Mutant Proteins ,Trinucleotide repeat expansion ,Peptides ,Trinucleotide Repeat Expansion ,030217 neurology & neurosurgery - Abstract
Conformational changes in disease-associated or mutant proteins represent a key pathological aspect of Huntington’s disease (HD) and other protein misfolding diseases. Using immunoassays and biophysical approaches, we and others have recently reported that polyglutamine expansion in purified or recombinantly expressed huntingtin (HTT) proteins affects their conformational properties in a manner dependent on both polyglutamine repeat length and temperature but independent of HTT protein fragment length. These findings are consistent with the HD mutation affecting structural aspects of the amino-terminal region of the protein, and support the concept that modulating mutant HTT conformation might provide novel therapeutic and diagnostic opportunities. We now report that the same conformational TR-FRET based immunoassay detects polyglutamine- and temperature-dependent changes on the endogenously expressed HTT protein in peripheral tissues and post-mortem HD brain tissue, as well as in tissues from HD animal models. We also find that these temperature- and polyglutamine-dependent conformational changes are sensitive to bona-fide phosphorylation on S13 and S16 within the N17 domain of HTT. These findings provide key clinical and preclinical relevance to the conformational immunoassay, and provide supportive evidence for its application in the development of therapeutics aimed at correcting the conformation of polyglutamine-expanded proteins as well as the pharmacodynamics readouts to monitor their efficacy in preclinical models and in HD patients.
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- 2017
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47. Cellular density in the cerebellar molecular layer in essential tremor, spinocerebellar ataxia, and controls
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Elan D. Louis, Sheng-Han Kuo, Ravi J. Louis, Jean Paul Vonsattel, Phyllis L. Faust, and Michelle Lee
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Male ,Cerebellum ,Essential Tremor ,Cell ,Purkinje cell ,Cell Count ,Biology ,Article ,Purkinje Cells ,medicine ,Humans ,Spinocerebellar Ataxias ,Aged ,Aged, 80 and over ,Cellular density ,Essential tremor ,Hereditary cerebellar ataxia ,Neurodegeneration ,medicine.disease ,medicine.anatomical_structure ,Neurology ,Spinocerebellar ataxia ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Neuroscience - Abstract
It would be useful to identify additional postmortem markers of Purkinje cell loss in essential tremor (ET). In hereditary cerebellar ataxia, Purkinje cell loss has been reported to result in a secondary increase in the density of the remaining cell populations in the cerebellar molecular layer. However, this phenomenon has not been studied in ET. We quantified cerebellar molecular layer cellular density in 15 ET cases, 15 controls, and 7 spinocerebellar ataxia (SCA) cases (2:2:1 ratio).A standard neocerebellar tissue block was stained with Luxol fast blue HematoxylinEosin. Within 5 selected fields, cell soma (e.g., stellate, basket, and glial cell bodies) were counted. Cellular density was the number of cells/cm(2).The Purkinje cell count differed across the three groups (p 0.001), with the highest counts in controls, intermediate counts in ET cases and lowest counts in SCA cases. ET cases and controls had similar molecular layer cellular density (p = 0.79) but SCA cases had higher values than both groups (p 0.01). A robust inverse correlation between Purkinje cell count and molecular layer cellular density (i.e., brains with more Purkinje cell loss had higher molecular layer cellular density), observed in SCA and controls (r = -0.55, p = 0.008), was not observed in ET cases.Although Purkinje cell counts were reduced in ET cases compared to controls, an increase in molecular layer cellular density was not evident in ET. The increase in molecular layer cellular density, observed in SCA cases, may require a more marked loss of PCs than occurs in ET.
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- 2014
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48. Neuropathologic Changes of Multiple System Atrophy and Diffuse Lewy Body Disease
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Etty Paola Cortes Ramirez and Jean Paul Vonsattel
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Lewy Body Disease ,Pathology ,medicine.medical_specialty ,Central nervous system ,Striatonigral Degeneration ,Neuropathology ,Atrophy ,Olivopontocerebellar atrophy ,stomatognathic system ,mental disorders ,medicine ,Humans ,Dementia ,Neurons ,Lewy body ,business.industry ,Parkinsonism ,Brain ,Multiple System Atrophy ,medicine.disease ,nervous system diseases ,medicine.anatomical_structure ,nervous system ,Neurology ,Neurology (clinical) ,business ,Neuroscience - Abstract
The accumulation of fibrillar α-synuclein protein is the pathological hallmark occurring in both multiple system atrophy (MSA) and diffuse Lewy body disease (DLBD). The oligodendrocytes are especially involved in MSA, while subtypes of neurons are the targets in DLBD. In both instances, the changes are widespread within the central nervous system, but with distinct and topistic vulnerability.Two diagnostic subtypes of MSA are currently applied: multiple system atrophy-cerebellar (MSA-C), formerly designated olivopontocerebellar atrophy, and multiple system atrophy-parkinsonian (MSA-P), formerly called striatonigral degeneration. However, overlaps exist between them, notably during the late stages of the illness. The brainstem and cerebellum are especially vulnerable and dysfunctional in MSA-C, but the striatum and mesencephalon in MSA-P, wherein parkinsonism usually prevails.In DLBD, Lewy-body-containing neurons (LBCN) involve the cerebral cortex in addition to the sites affected in Parkinson disease (PD). Thus, dementia and parkinsonism occur, often without brain atrophy. Then, two main pathological subtypes are used: the limbic or the cortical type. Possibly, DLBD, either the limbic or cortical-type, is the ultimate stage of PD, which corresponds to the brainstem type. The epidemiologic and genetic traits causing sporadic MSA and sporadic DLBD are not known.
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- 2014
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49. Corrigendum
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Keith A. Josephs, Thomas Wisniewski, Bernardino Ghetti, William Hu, Ian G. Mackenzie, Yuko Saito, Manuela Neumann, T Revesz, Jennifer L. Whitwell, Karl Herrup, Tammaryn Lashley, Matthew P. Frosch, Brittany N. Dugger, JL Holton, Kirsty E. McAleese, Eileen H. Bigio, Murray Grossman, Kurt Jellinger, Masato Hasegawa, Joseph E. Parisi, Tetsuaki Arai, and Jean Paul Vonsattel
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ddc:610 ,Neurology (clinical) - Abstract
Article NavigationLATE to the PART-y Keith A Josephs, Ian Mackenzie, Matthew P Frosch, Eileen H Bigio, Manuela Neumann, Tetsuaki Arai, Brittany N Dugger, Bernardino Ghetti, Murray Grossman, Masato Hasegawa ... Show moreBrain, Volume 142, Issue 9, September 2019, Page e47, https://doi.org/10.1093/brain/awz224Published: 29 July 2019A correction has been published:Brain, Volume 142, Issue 12, December 2019, Page e73, https://doi.org/10.1093/brain/awz263pdfPDF Split ViewCitePermissions Icon Permissions Share Issue Section: Letters to the EditorSir,We wish to address the recent proposal of a disease entity newly titled ‘limbic-predominant age-related TDP-43 encephalopathy (LATE)’ (Nelson et al., 2019) which, to our reading, is itself a derivative of the 2016 proposed term cerebral age-related TDP-43 with sclerosis (CART) (Nelson et al., 2016). The transactive response DNA binding protein of ∼43 kD (TDP-43) was first reported in 2006 to be a main component of ubiquitinated inclusions in autopsy-confirmed cases of frontotemporal lobar degeneration (FTLD) negative for tau immunoreactivity (Arai et al., 2006; Neumann et al., 2006). Over a decade of research into FTLD-TDP (and FTLD-U before it) has highlighted important phenotypic variability in TDP-43-immunoreactive lesions resulting in the identification of five different types of FTLD-TDP (Mackenzie et al., 2006, 2011; Sampathu et al., 2006; Josephs et al., 2009; Lee et al., 2011, 2017). There have also been important advances in the molecular and biochemical characterization of TDP-immunoreactive in FTLD-TDP (Sampathu et al., 2006; Hasegawa et al., 2008; Igaz et al., 2008; Zhang et al., 2009; Bigio et al., 2013; Laferriere et al., 2019). Soon after the initial characterization of TDP-immunoreactive lesions in FTLD and amyotrophic lateral sclerosis, TDP-immunoreactive lesions were identified in 25–33% of cases with pathologically confirmed Alzheimer’s disease (Amador-Ortiz et al., 2007; Higashi et al., 2007). TDP-immunoreactive lesions related to Alzheimer’s disease were initially thought to appear first in the hippocampus (Amador-Ortiz et al., 2007), but more detailed morphological studies involving multiple anatomical regions revealed the amygdala to be the earliest affected region (Higashi et al., 2007; Hu et al., 2008; Arai et al., 2009) followed by the entorhinal cortex and hippocampus, occipitotemporal cortex, insular and inferior temporal cortex, brainstem, and frontal neocortex and basal ganglia (Josephs et al., 2014, 2016); a scheme that has been independently validated (Tan et al., 2015). TDP-immunoreactive lesions have also been described in cognitively normal individuals (Wilson et al., 2011; Arnold et al., 2013; Uchino et al., 2015; Wennberg et al., 2019) including those with asymptomatic definite primary age related tauopathy (PART) (Josephs et al., 2017; Zhang et al., 2019), as well being associated with other well-defined clinic-pathological entities (Fig. 1) including Lewy body disease (with or without co-existing Alzheimer’s disease) (Arai et al., 2009; McAleese et al., 2017), the amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam (Hasegawa et al., 2007; Geser et al., 2008), Pick’s disease (Freeman et al., 2008), progressive supranuclear palsy (Yokota et al., 2010; Koga et al., 2017), corticobasal degeneration (Uryu et al., 2008; Koga et al., 2018), polyglutamine diseases such as Huntington’s disease (Schwab et al., 2008), Machado-Joseph disease (Tan et al., 2009) and spinocerebellar ataxia type 2 (Toyoshima et al., 2011), Perry syndrome (Wider et al., 2009), and chronic traumatic encephalopathy (McKee et al., 2010).
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- 2019
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50. The Complexity of Clinical Huntington’s Disease: Developments in Molecular Genetics, Neuropathology and Neuroimaging Biomarkers
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Anne B. Young, Russell G. Snell, Lynette J. Tippett, Richard L.M. Faull, Jean-Paul Vonsattel, and Henry J. Waldvogel
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0301 basic medicine ,medicine.medical_specialty ,Human brain ,Neuropathology ,medicine.disease ,White matter ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Neurochemical ,Huntington's disease ,Neuroimaging ,Cerebral cortex ,Molecular genetics ,medicine ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by extensive neuronal loss in the striatum and cerebral cortex, and a triad of clinical symptoms affecting motor, cognitive/behavioural and mood functioning. The mutation causing HD is an expansion of a CAG tract in exon 1 of the HTT gene. This chapter provides a multifaceted overview of the clinical complexity of HD. We explore recent directions in molecular genetics including the identification of loci that are genetic modifiers of HD that could potentially reveal therapeutic targets beyond the HTT gene transcript and protein. The variability of clinical symptomatology in HD is considered alongside recent findings of variability in cellular and neurochemical changes in the striatum and cerebral cortex in human brain. We review evidence from structural neuroimaging methods of progressive changes of striatum, cerebral cortex and white matter in pre-symptomatic and symptomatic HD, with a particular focus on the potential identification of neuroimaging biomarkers that could be used to test promising disease-specific and modifying treatments. Finally we provide an overview of completed clinical trials in HD and future therapeutic developments.
- Published
- 2017
- Full Text
- View/download PDF
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