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3. Neuroimaging biomarkers in the biological definition of Parkinson’s disease and dementia with Lewy bodies – EANM position on current state, unmet needs and future perspectives

Author

Brendel, Matthias, Guedj, Eric, Yakushev, Igor, Morbelli, Silvia, Höglinger, Günter U., Tolboom, Nelleke, Verger, Antoine, Albert, Nathalie L., Cecchin, Diego, Fernandez, Pablo Aguiar, Fraioli, Francesco, Traub-Weidinger, Tatjana, Van Weehaeghe, Donatienne, and Barthel, Henryk

Published
2024
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5. Diagnosing primary lateral sclerosis: a clinico-pathological study

Author

de Boer, Eva M. J., de Vries, Bálint S., Van Hecke, Wim, Mühlebner, Angelika, Vincken, Koen L., Mol, Christian P., van Rheenen, Wouter, Westeneng, Henk-Jan, Veldink, Jan H., Höglinger, Günter U., Morris, Huw R., Litvan, Irene, Raaphorst, Joost, Ticozzi, Nicola, Corcia, Philippe, Vandenberghe, Wim, Pijnenburg, Yolande A. L., Seelaar, Harro, Ingre, Caroline, Van Damme, Philip, van den Berg, Leonard H., van de Warrenburg, Bart P. C., and van Es, Michael A.

Published
2025
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6. Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

Author

Wang, Hui, Chang, Timothy S, Dombroski, Beth A, Cheng, Po-Liang, Patil, Vishakha, Valiente-Banuet, Leopoldo, Farrell, Kurt, Mclean, Catriona, Molina-Porcel, Laura, Rajput, Alex, De Deyn, Peter Paul, Le Bastard, Nathalie, Gearing, Marla, Kaat, Laura Donker, Van Swieten, John C, Dopper, Elise, Ghetti, Bernardino F, Newell, Kathy L, Troakes, Claire, de Yébenes, Justo G, Rábano-Gutierrez, Alberto, Meller, Tina, Oertel, Wolfgang H, Respondek, Gesine, Stamelou, Maria, Arzberger, Thomas, Roeber, Sigrun, Müller, Ulrich, Hopfner, Franziska, Pastor, Pau, Brice, Alexis, Durr, Alexandra, Le Ber, Isabelle, Beach, Thomas G, Serrano, Geidy E, Hazrati, Lili-Naz, Litvan, Irene, Rademakers, Rosa, Ross, Owen A, Galasko, Douglas, Boxer, Adam L, Miller, Bruce L, Seeley, Willian W, Van Deerlin, Vivanna M, Lee, Edward B, White, Charles L, Morris, Huw, de Silva, Rohan, Crary, John F, Goate, Alison M, Friedman, Jeffrey S, Leung, Yuk Yee, Coppola, Giovanni, Naj, Adam C, Wang, Li-San, Dalgard, Clifton, Dickson, Dennis W, Höglinger, Günter U, Schellenberg, Gerard D, Geschwind, Daniel H, and Lee, Wan-Ping

Subjects
Biological Sciences, Genetics, Biotechnology, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Frontotemporal Dementia (FTD), Dementia, Aging, Human Genome, Neurodegenerative, Alzheimer's Disease, Alzheimer's Disease Related Dementias (ADRD), Rare Diseases, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, Neurological, Humans, Supranuclear Palsy, Progressive, Genetic Predisposition to Disease, Whole Genome Sequencing, Male, Genome-Wide Association Study, Female, Aged, Polymorphism, Single Nucleotide, Middle Aged, Aged, 80 and over, Progressive Supranuclear Palsy, Whole-Genome Sequencing, Structural Variants, Apolipoprotein E, P. S. P. genetics study group, Clinical Sciences, Neurology & Neurosurgery, Biochemistry and cell biology
Abstract

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Published
2024

7. A quantitative Lewy-fold-specific alpha-synuclein seed amplification assay as a progression marker for Parkinson’s disease

Author

Bernhardt, Alexander M., Longen, Sebastian, Trossbach, Svenja V., Rossi, Marcello, Weckbecker, Daniel, Schmidt, Felix, Jäck, Alexander, Katzdobler, Sabrina, Fietzek, Urban M., Weidinger, Endy, Palleis, Carla, Ruf, Viktoria, Baiardi, Simone, Parchi, Piero, Höglinger, Günter U., Matthias, Torsten, Levin, Johannes, and Giese, Armin

Published
2025
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9. Neuronal and oligodendroglial, but not astroglial, tau translates to in vivo tau PET signals in individuals with primary tauopathies

Author

Slemann, Luna, Gnörich, Johannes, Hummel, Selina, Bartos, Laura M., Klaus, Carolin, Kling, Agnes, Kusche-Palenga, Julia, Kunte, Sebastian T., Kunze, Lea H., Englert, Amelie L., Li, Yunlei, Vogler, Letizia, Katzdobler, Sabrina, Palleis, Carla, Bernhardt, Alexander, Jäck, Alexander, Zwergal, Andreas, Hopfner, Franziska, Roemer-Cassiano, Sebastian N., Biechele, Gloria, Stöcklein, Sophia, Bischof, Gerard, van Eimeren, Thilo, Drzezga, Alexander, Sabri, Osama, Barthel, Henryk, Respondek, Gesine, Grimmer, Timo, Levin, Johannes, Herms, Jochen, Paeger, Lars, Willroider, Marie, Beyer, Leonie, Höglinger, Günter U., Roeber, Sigrun, Franzmeier, Nicolai, and Brendel, Matthias

Published
2024
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10. Author Correction: Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Author

Farrell, Kurt, Humphrey, Jack, Chang, Timothy, Zhao, Yi, Leung, Yuk Yee, Kuksa, Pavel P., Patil, Vishakha, Lee, Wan-Ping, Kuzma, Amanda B., Valladares, Otto, Cantwell, Laura B., Wang, Hui, Ravi, Ashvin, De Sanctis, Claudia, Han, Natalia, Christie, Thomas D., Afzal, Robina, Kandoi, Shrishtee, Whitney, Kristen, Krassner, Margaret M., Ressler, Hadley, Kim, SoongHo, Dangoor, Diana, Iida, Megan A., Casella, Alicia, Walker, Ruth H., Nirenberg, Melissa J., Renton, Alan E., Babrowicz, Bergan, Coppola, Giovanni, Raj, Towfique, Höglinger, Günter U., Müller, Ulrich, Golbe, Lawrence I., Morris, Huw R., Hardy, John, Revesz, Tamas, Warner, Tom T., Jaunmuktane, Zane, Mok, Kin Y., Rademakers, Rosa, Dickson, Dennis W., Ross, Owen A., Wang, Li-San, Goate, Alison, Schellenberg, Gerard, Geschwind, Daniel H., Crary, John F., and Naj, Adam

Published
2024
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11. Correction: Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

Author

Wang, Hui, Chang, Timothy S., Dombroski, Beth A., Cheng, Po-Liang, Patil, Vishakha, Valiente-Banuet, Leopoldo, Farrell, Kurt, Mclean, Catriona, Molina-Porcel, Laura, Rajput, Alex, De Deyn, Peter Paul, Le Bastard, Nathalie, Gearing, Marla, Kaat, Laura Donker, Van Swieten, John C., Dopper, Elise, Ghetti, Bernardino F., Newell, Kathy L., Troakes, Claire, de Yébenes, Justo G., Rábano-Gutierrez, Alberto, Meller, Tina, Oertel, Wolfgang H., Respondek, Gesine, Stamelou, Maria, Arzberger, Thomas, Roeber, Sigrun, Müller, Ulrich, Hopfner, Franziska, Pastor, Pau, Brice, Alexis, Durr, Alexandra, Le Ber, Isabelle, Beach, Thomas G., Serrano, Geidy E., Hazrati, Lili-Naz, Litvan, Irene, Rademakers, Rosa, Ross, Owen A., Galasko, Douglas, Boxer, Adam L., Miller, Bruce L., Seeley, Willian W., Van Deerlin, Vivanna M., Lee, Edward B., White, III, Charles L., Morris, Huw, de Silva, Rohan, Crary, John F., Goate, Alison M., Friedman, Jeffrey S., Leung, Yuk Yee, Coppola, Giovanni, Naj, Adam C., Wang, Li-San, Dalgard, Clifton, Dickson, Dennis W., Höglinger, Günter U., Schellenberg, Gerard D., Geschwind, Daniel H., and Lee, Wan-Ping

Published
2024
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12. Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Author

Farrell, Kurt, Humphrey, Jack, Chang, Timothy, Zhao, Yi, Leung, Yuk Yee, Kuksa, Pavel P., Patil, Vishakha, Lee, Wan-Ping, Kuzma, Amanda B., Valladares, Otto, Cantwell, Laura B., Wang, Hui, Ravi, Ashvin, De Sanctis, Claudia, Han, Natalia, Christie, Thomas D., Afzal, Robina, Kandoi, Shrishtee, Whitney, Kristen, Krassner, Margaret M., Ressler, Hadley, Kim, SoongHo, Dangoor, Diana, Iida, Megan A., Casella, Alicia, Walker, Ruth H., Nirenberg, Melissa J., Renton, Alan E., Babrowicz, Bergan, Coppola, Giovanni, Raj, Towfique, Höglinger, Günter U., Müller, Ulrich, Golbe, Lawrence I., Morris, Huw R., Hardy, John, Revesz, Tamas, Warner, Tom T., Jaunmuktane, Zane, Mok, Kin Y., Rademakers, Rosa, Dickson, Dennis W., Ross, Owen A., Wang, Li-San, Goate, Alison, Schellenberg, Gerard, Geschwind, Daniel H., Crary, John F., and Naj, Adam

Published
2024
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13. Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease

Author

Zatcepin, Artem, Gnörich, Johannes, Rauchmann, Boris-Stephan, Bartos, Laura M., Wagner, Stephan, Franzmeier, Nicolai, Malpetti, Maura, Xiang, Xianyuan, Shi, Yuan, Parhizkar, Samira, Grosch, Maximilian, Wind-Mark, Karin, Kunte, Sebastian T., Beyer, Leonie, Meyer, Carolin, Brösamle, Desirée, Wendeln, Ann-Christin, Osei-Sarpong, Collins, Heindl, Steffanie, Liesz, Arthur, Stoecklein, Sophia, Biechele, Gloria, Finze, Anika, Eckenweber, Florian, Lindner, Simon, Rominger, Axel, Bartenstein, Peter, Willem, Michael, Tahirovic, Sabina, Herms, Jochen, Buerger, Katharina, Simons, Mikael, Haass, Christian, Rupprecht, Rainer, Riemenschneider, Markus J., Albert, Nathalie L., Beyer, Marc, Neher, Jonas J., Paeger, Lars, Levin, Johannes, Höglinger, Günter U., Perneczky, Robert, Ziegler, Sibylle I., and Brendel, Matthias

Published
2024
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16. Associations between sex, body mass index and the individual microglial response in Alzheimer’s disease

Author

Biechele, Gloria, Rauchmann, Boris-Stephan, Janowitz, Daniel, Buerger, Katharina, Franzmeier, Nicolai, Weidinger, Endy, Guersel, Selim, Schuster, Sebastian, Finze, Anika, Harris, Stefanie, Lindner, Simon, Albert, Nathalie L., Wetzel, Christian, Rupprecht, Rainer, Rominger, Axel, Palleis, Carla, Katzdobler, Sabrina, Burow, Lena, Kurz, Carolin, Zaganjori, Mirlind, Trappmann, Lena-Katharina, Goldhardt, Oliver, Grimmer, Timo, Haeckert, Jan, Keeser, Daniel, Stoecklein, Sophia, Morenas-Rodriguez, Estrella, Bartenstein, Peter, Levin, Johannes, Höglinger, Günter U., Simons, Mikael, Perneczky, Robert, and Brendel, Matthias

Published
2024
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17. Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies

Author

Ferschmann, Christian, Messerschmidt, Konstantin, Gnörich, Johannes, Barthel, Henryk, Marek, Ken, Palleis, Carla, Katzdobler, Sabrina, Stockbauer, Anna, Fietzek, Urban, Finze, Anika, Biechele, Gloria, Rumpf, Jost-Julian, Saur, Dorothee, Schroeter, Matthias L., Rullmann, Michael, Beyer, Leonie, Eckenweber, Florian, Wall, Stephan, Schildan, Andreas, Patt, Marianne, Stephens, Andrew, Classen, Joseph, Bartenstein, Peter, Seibyl, John, Franzmeier, Nicolai, Levin, Johannes, Höglinger, Günter U., Sabri, Osama, Brendel, Matthias, and Scheifele, Maximilian

Published
2024
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18. The comorbidity profiles and medication issues of patients with multiple system atrophy: a systematic cross-sectional analysis

Author

Ye, Lan, Greten, Stephan, Wegner, Florian, Doll-Lee, Johanna, Krey, Lea, Heine, Johanne, Gandor, Florin, Vogel, Annemarie, Berger, Luise, Gruber, Doreen, Levin, Johannes, Katzdobler, Sabrina, Peters, Oliver, Dashti, Eman, Priller, Josef, Spruth, Eike Jakob, Kühn, Andrea A., Krause, Patricia, Spottke, Annika, Schneider, Anja, Beyle, Aline, Kimmich, Okka, Donix, Markus, Haussmann, Robert, Brandt, Moritz, Dinter, Elisabeth, Wiltfang, Jens, Schott, Björn H., Zerr, Inga, Bähr, Mathias, Buerger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris-Stephan, Weidinger, Endy, Düzel, Emrah, Glanz, Wenzel, Teipel, Stefan, Kilimann, Ingo, Wurster, Isabel, Brockmann, Kathrin, Hoffmann, Daniel C., Klockgether, Thomas, Krause, Olaf, Heck, Johannes, Höglinger, Günter U., and Klietz, Martin

Published
2024
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20. Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission

Author

Stockbauer, Anna, Beyer, Leonie, Huber, Maria, Kreuzer, Annika, Palleis, Carla, Katzdobler, Sabrina, Rauchmann, Boris-Stephan, Morbelli, Silvia, Chincarini, Andrea, Bruffaerts, Rose, Vandenberghe, Rik, Kramberger, Milica G., Trost, Maja, Garibotto, Valentina, Nicastro, Nicolas, Lathuilière, Aurélien, Lemstra, Afina W., van Berckel, Bart N. M., Pilotto, Andrea, Padovani, Alessandro, Ochoa-Figueroa, Miguel A., Davidsson, Anette, Camacho, Valle, Peira, Enrico, Bauckneht, Matteo, Pardini, Matteo, Sambuceti, Gianmario, Aarsland, Dag, Nobili, Flavio, Gross, Mattes, Vöglein, Jonathan, Perneczky, Robert, Pogarell, Oliver, Buerger, Katharina, Franzmeier, Nicolai, Danek, Adrian, Levin, Johannes, Höglinger, Günter U., Bartenstein, Peter, Cumming, Paul, Rominger, Axel, and Brendel, Matthias

Published
2024
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21. The comorbidity and co-medication profile of patients with progressive supranuclear palsy

Author

Greten, Stephan, Wegner, Florian, Jensen, Ida, Krey, Lea, Rogozinski, Sophia, Fehring, Meret, Heine, Johanne, Doll-Lee, Johanna, Pötter-Nerger, Monika, Zeitzschel, Molly, Hagena, Keno, Pedrosa, David J., Eggers, Carsten, Bürk, Katrin, Trenkwalder, Claudia, Claus, Inga, Warnecke, Tobias, Süß, Patrick, Winkler, Jürgen, Gruber, Doreen, Gandor, Florin, Berg, Daniela, Paschen, Steffen, Classen, Joseph, Pinkhardt, Elmar H., Kassubek, Jan, Jost, Wolfgang H., Tönges, Lars, Kühn, Andrea A., Schwarz, Johannes, Peters, Oliver, Dashti, Eman, Priller, Josef, Spruth, Eike J., Krause, Patricia, Spottke, Annika, Schneider, Anja, Beyle, Aline, Kimmich, Okka, Donix, Markus, Haussmann, Robert, Brandt, Moritz, Dinter, Elisabeth, Wiltfang, Jens, Schott, Björn H., Zerr, Inga, Bähr, Mathias, Buerger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris-Stephan, Weidinger, Endy, Levin, Johannes, Katzdobler, Sabrina, Düzel, Emrah, Glanz, Wenzel, Teipel, Stefan, Kilimann, Ingo, Prudlo, Johannes, Gasser, Thomas, Brockmann, Kathrin, Hoffmann, Daniel C., Klockgether, Thomas, Krause, Olaf, Heck, Johannes, Höglinger, Günter U., and Klietz, Martin

Published
2024
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22. Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

Author

Finze, Anika, Biechele, Gloria, Rauchmann, Boris-Stephan, Franzmeier, Nicolai, Palleis, Carla, Katzdobler, Sabrina, Weidinger, Endy, Guersel, Selim, Schuster, Sebastian, Harris, Stefanie, Schmitt, Julia, Beyer, Leonie, Gnörich, Johannes, Lindner, Simon, Albert, Nathalie L., Wetzel, Christian H., Rupprecht, Rainer, Rominger, Axel, Danek, Adrian, Burow, Lena, Kurz, Carolin, Tato, Maia, Utecht, Julia, Papazov, Boris, Zaganjori, Mirlind, Trappmann, Lena-Katharina, Goldhardt, Oliver, Grimmer, Timo, Haeckert, Jan, Janowitz, Daniel, Buerger, Katharina, Keeser, Daniel, Stoecklein, Sophia, Dietrich, Olaf, Morenas-Rodriguez, Estrella, Barthel, Henryk, Sabri, Osama, Bartenstein, Peter, Simons, Mikael, Haass, Christian, Höglinger, Günter U., Levin, Johannes, Perneczky, Robert, and Brendel, Matthias

Published
2023
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24. Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial.

Author

Dam, Tien, Boxer, Adam L, Golbe, Lawrence I, Höglinger, Günter U, Morris, Huw R, Litvan, Irene, Lang, Anthony E, Corvol, Jean-Christophe, Aiba, Ikuko, Grundman, Michael, Yang, Lili, Tidemann-Miller, Beth, Kupferman, Joseph, Harper, Kristine, Kamisoglu, Kubra, Wald, Michael J, Graham, Danielle L, Gedney, Liz, O'Gorman, John, Haeberlein, Samantha Budd, and PASSPORT Study Group

Subjects
PASSPORT Study Group, Humans, Pneumonia, Supranuclear Palsy, Progressive, tau Proteins, Treatment Outcome, Double-Blind Method, Aged, Female, Male, Antibodies, Monoclonal, Humanized, Brain Disorders, Clinical Research, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Immunology, Medical and Health Sciences
Abstract

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P

Published
2021

25. Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial

Author

Höglinger, Günter U, Litvan, Irene, Mendonca, Nuno, Wang, Deli, Zheng, Hui, Rendenbach-Mueller, Beatrice, Lon, Hoi-Kei, Jin, Ziyi, Fisseha, Nahome, Budur, Kumar, Gold, Michael, Ryman, Davis, Florian, Hana, Investigators, Arise, Ahmed, Anwar, Aiba, Ikuko, Albanese, Alberto, Bertram, Kelly, Bordelon, Yvette, Bower, James, Brosch, Jared, Claassen, Daniel, Colosimo, Carlo, Corvol, Jean-Christophe, Cudia, Paola, Daniele, Antonio, Defebvre, Luc, Driver-Dunckley, Erika, Duquette, Antoine, Eleopra, Roberto, Eusebio, Alexandre, Fung, Victor, Geldmacher, David, Golbe, Lawrence, Grandas, Francisco, Hall, Deborah, Hatano, Taku, Honig, Lawrence, Hui, Jennifer, Kerwin, Diana, Kikuchi, Akio, Kimber, Thomas, Kimura, Takashi, Kumar, Rajeev, Ljubenkov, Peter, Lorenzl, Stefan, Ludolph, Albert, Mari, Zoltan, McFarland, Nikolaus, Meissner, Wassilios, Rivera, Pablo Mir, Mochizuki, Hidek, Morgan, John, Munhoz, Renato, Nishikawa, Noriko, O`Sullivan, John, Oeda, Tomoko, Oizumi, Hideki, Onodera, Osamu, Ory-Magne, Fabienne, Peckham, Elizabeth, Postuma, Ronald, Quattrone, Aldo, Quinn, Joseph, Ruggieri, Stefano, Sarna, Justyna, Schulz, Paul E, Slevin, John, Tagliati, Michele, Wile, Daryl, Wszolek, Zbigniew, Xie, Tao, and Zesiewicz, Theresa

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Clinical Research, Clinical Trials and Supportive Activities, Patient Safety, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Neurological, Administration, Intravenous, Aged, Antibodies, Monoclonal, Humanized, Double-Blind Method, Female, Humans, Male, Middle Aged, Supranuclear Palsy, Progressive, Treatment Outcome, tau Proteins, Arise Investigators, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundProgressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy.MethodsWe did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics in Australia, Canada, France, Germany, Italy, Japan, Spain, and the USA. Participants (aged ≥40 years) diagnosed with possible or probable progressive supranuclear palsy who were symptomatic for less than 5 years, had a reliable study partner, and were able to walk five steps with minimal assistance, were randomly assigned (1:1:1) by interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or matching placebo administered intravenously on days 1, 15, and 29, then every 28 days through to the end of the 52-week treatment period. Randomisation was done by the randomisation specialist of the study sponsor, who did not otherwise participate in the study. The sponsor, investigators, and participants were unaware of treatment allocations. The primary endpoint was the change from baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score in the intention-to-treat population. Adverse events were monitored in participants who received at least one dose of study drug. Prespecified interim futility criteria were based on a model-based effect size of 0 or lower when 60 participants had completed the 52-week treatment period and 0·12 or lower when 120 participants had completed the 52-week treatment period. This study is registered at ClinicalTrials.gov, number NCT02985879.FindingsBetween Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised. The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis. A total of 377 participants received at least one dose of study drug and were included in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo, n=126). Least squares mean change from baseline to week 52 in PSPRS was similar in all groups (between-group difference vs placebo: 2000 mg, 0·0 [95% CI -2·6 to 2·6], effect size 0·000, p>0·99; 4000 mg, 1·0 [-1·6 to 3·6], -0·105, p=0·46). Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000 mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000 mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000 mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent serious adverse event (2000 mg, five [4%]; 4000 mg, six [5%]; placebo, six [5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine [7%]; placebo, eight [6%]) but none was drug related.InterpretationA similar safety profile was seen in all treatment groups. No beneficial treatment effects were recorded. Although this study did not provide evidence of efficacy in progressive supranuclear palsy, the findings provide potentially useful information for future investigations of passive immunisation using tau antibodies for progressive supranuclear palsy.FundingAbbVie Inc.

Published
2021

26. Clinical Features of Patients With Progressive Supranuclear Palsy in an US Insurance Claims Database

Author

Viscidi, Emma, Litvan, Irene, Dam, Tien, Juneja, Maneesh, Li, Li, Krzywy, Henry, Eaton, Susan, Hall, Susan, Kupferman, Joseph, and Höglinger, Günter U

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Pediatric, Clinical Research, Neurological, movement disorder, natural history, neurodegenerative disease, progressive supranuclear palsy, rare disease, Psychology, Clinical sciences, Biological psychology
Abstract

Background: Progressive supranuclear palsy is a rare neurodegenerative movement disorder and little is known about its epidemiology. Objective: Estimate age-adjusted prevalence of progressive supranuclear palsy and describe antecedent diagnoses and progressive supranuclear palsy patient features in the 5 years before first diagnostic code. Methods: In a nested case-control study in the IBM MarketScan Commercial and Medicare Supplemental Databases, a large set of US insurance databases containing medical service and prescription drug claims from employer-based commercial and Medicare supplemental health insurance plans, progressive supranuclear palsy cases (identified via International Statistical Classification of Diseases 9th/10th revision codes) and controls were included if enrollment was ≥1 month in the study period (October 1, 2015-October 31, 2017). Two controls with no diagnosis codes for PSP were matched to cases on birth year, sex, enrollment time in the database, and pharmacy benefit eligibility. Controls were assigned a randomly selected index date from their eligibility period. Prevalence of progressive supranuclear palsy was estimated in 2016 among patients with ≥1 month of continuous enrollment in that year. Prevalence ratios for comorbidities (claim/diagnosis codes) were examined in the ≤ 5 years before index date (first progressive supranuclear palsy claim date). Results: Age-adjusted progressive supranuclear palsy prevalence was 2.95/100,000 in 2016. The most common diagnosis codes in cases vs. controls in the 5 years pre-index were gait abnormalities (79.3 vs. 21.8%), pain in joint (54.9 vs. 36.0%), Parkinson's disease (54.6 vs. 1.0%), fatigue (49.8 vs. 21.6%), and cerebrovascular disease (45.6 vs. 16.4%). Conclusions: In this large database analysis, based on preliminary analyses, the prevalence of diagnosed progressive supranuclear palsy was 2.95/100,000, which is lower than many prior studies. Typical symptoms suggestive of progressive supranuclear palsy were present before index date, indicating a potential delay in time to diagnosis. The identification of diagnostic codes for clinical features of progressive supranuclear palsy that occurred before index date may be used to develop predictive models to identify potential progressive supranuclear palsy patients earlier in their disease course.

Published
2021

30. Distribution patterns of tau pathology in progressive supranuclear palsy

Author

Kovacs, Gabor G, Lukic, Milica Jecmenica, Irwin, David J, Arzberger, Thomas, Respondek, Gesine, Lee, Edward B, Coughlin, David, Giese, Armin, Grossman, Murray, Kurz, Carolin, McMillan, Corey T, Gelpi, Ellen, Compta, Yaroslau, van Swieten, John C, Laat, Laura Donker, Troakes, Claire, Al-Sarraj, Safa, Robinson, John L, Roeber, Sigrun, Xie, Sharon X, Lee, Virginia M-Y, Trojanowski, John Q, and Höglinger, Günter U

Subjects
Biomedical and Clinical Sciences, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Rare Diseases, Acquired Cognitive Impairment, Aging, Alzheimer's Disease, Frontotemporal Dementia (FTD), Dementia, Neurodegenerative, Brain Disorders, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Aged, Brain, Cohort Studies, Female, Humans, Male, Middle Aged, Supranuclear Palsy, Progressive, tau Proteins, Coiled body, Neurofibrillary tangle, Progressive supranuclear palsy, Propagation, Richardson syndrome, Sequential involvement, Stage, Tau, Tauopathy, Tufted astrocyte, Clinical Sciences, Neurology & Neurosurgery
Abstract

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.

Published
2020

31. The Progressive Supranuclear Palsy Clinical Deficits Scale

Author

Piot, Ines, Schweyer, Kerstin, Respondek, Gesine, Stamelou, Maria, Sckopke, Philipp, Schenk, Thomas, Goetz, Christopher G, Stebbins, Glenn T, Höglinger, Günter U, Gasser, Thomas, Hermann, Andreas, Höglinger, Günter, Höllerhage, Matthias, Kimmich, Okka, Klockgether, Thomas, Levin, Johannes, Machetanz, Gerrit, Osterrath, Antje, Palleis, Carla, Prudlo, Johannes, Spottke, Annika, Berg, Daniela, Bürk, Katrin, Claßen, Joseph, Eggers, Carsten, Greuel, Andrea, Grimm, Max‐Joseph, Hermann, Lennard, Iankova, Vassilena, Jahn, Klaus, Jost, Wolfgang, Klietz, Martin, Kühn, Andrea, Marxreiter, Franz, Paschen, Steffen, Poetter‐Nerger, Monika, Preisl, Marie‐Therese, Prilop, Lisa, Tönges, Lars, Trenkwalder, Claudia, Warnecke, Tobias, Wegner, Florian, Winkler, Jürgen, Antonini, Angelo, P, Kailash P, L, Adam L, Colosimo, Carlo, Compta, Yaroslau, Corvol, Jean‐Christophe, I, Lawrence I, E, Anthony E, Litvan, Irene, R, Huw R, Nilsson, Christer, and Pantelyat, Alexander

Subjects
Pediatric, Clinical Research, Perinatal Period - Conditions Originating in Perinatal Period, Neurosciences, Brain Disorders, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Neurological, Disease Progression, Female, Fingers, Humans, Male, Motor Skills, Reproducibility of Results, Supranuclear Palsy, Progressive, progressive supranuclear palsy, clinical rating scales, outcome measures, power calculation, DescribePSP study group, ProPSP study group, MDS-endorsed PSP study group, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundThere is currently no undisputed, validated, clinically meaningful measure for deficits in the broad spectrum of PSP phenotypes.ObjectiveTo develop a scale to monitor clinical deficits in patients with PSP across its broad phenotypes.MethodsThe Progressive Supranuclear Palsy Clinical Deficits Scale was conceptualized to cover seven clinical domains (Akinesia-rigidity, Bradyphrenia, Communication, Dysphagia, Eye movements, Finger dexterity, and Gait & balance), each scored from 0 to 3 (no, mild, moderate, or severe deficits). User guidelines were developed to standardize its application. Progressive Supranuclear Palsy Clinical Deficits Scale scores were collected in patients fulfilling the MDS-PSP diagnostic criteria in two independent, multicenter, observational studies, both cross-sectionally (exploratory DescribePSP cohort; confirmatory ProPSP cohort) and longitudinally (12-months' follow-up, both cohorts).ResultsCognitive pretesting demonstrated easy scale utility. In total, 164 patients were scored (70.4 ± 7.6 years; 62% males, 35% variant phenotypes). Mean Progressive Supranuclear Palsy Clinical Deficits Scale completion time was 4 minutes. The Progressive Supranuclear Palsy Clinical Deficits Scale total score correlated with existing scales (e.g., Progressive Supranuclear Palsy Rating Scale: R = 0.88; P

Published
2020

32. Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome

Author

Katzdobler, Sabrina, Nitschmann, Alexander, Barthel, Henryk, Bischof, Gerard, Beyer, Leonie, Marek, Ken, Song, Mengmeng, Wagemann, Olivia, Palleis, Carla, Weidinger, Endy, Nack, Anne, Fietzek, Urban, Kurz, Carolin, Häckert, Jan, Stapf, Theresa, Ferschmann, Christian, Scheifele, Maximilian, Eckenweber, Florian, Biechele, Gloria, Franzmeier, Nicolai, Dewenter, Anna, Schönecker, Sonja, Saur, Dorothee, Schroeter, Matthias L., Rumpf, Jost-Julian, Rullmann, Michael, Schildan, Andreas, Patt, Marianne, Stephens, Andrew W., van Eimeren, Thilo, Neumaier, Bernd, Drzezga, Alexander, Danek, Adrian, Classen, Joseph, Bürger, Katharina, Janowitz, Daniel, Rauchmann, Boris-Stephan, Stöcklein, Sophia, Perneczky, Robert, Schöberl, Florian, Zwergal, Andreas, Höglinger, Günter U., Bartenstein, Peter, Villemagne, Victor, Seibyl, John, Sabri, Osama, Levin, Johannes, and Brendel, Matthias

Published
2023
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35. Symptomatology in 4-repeat tauopathies is associated with data-driven topology of [18F]-PI-2620 tau-PET signal

Author

Schönecker, Sonja, Palleis, Carla, Franzmeier, Nicolai, Katzdobler, Sabrina, Ferschmann, Christian, Schuster, Sebastian, Finze, Anika, Scheifele, Maximilian, Prix, Catharina, Fietzek, Urban, Weidinger, Endy, Nübling, Georg, Vöglein, Jonathan, Patt, Marianne, Barthel, Henryk, Sabri, Osama, Danek, Adrian, Höglinger, Günter U., Brendel, Matthias, and Levin, Johannes

Published
2023
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36. Author Correction: Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial

Author

Dam, Tien, Boxer, Adam L., Golbe, Lawrence I., Höglinger, Günter U., Morris, Huw R., Litvan, Irene, Lang, Anthony E., Corvol, Jean-Christophe, Aiba, Ikuko, Grundman, Michael, Yang, Lili, Tidemann-Miller, Beth, Kupferman, Joseph, Harper, Kristine, Kamisoglu, Kubra, Wald, Michael J., Graham, Danielle L., Gedney, Liz, O’Gorman, John, and Haeberlein, Samantha Budd

Published
2023
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37. Validation of the movement disorder society criteria for the diagnosis of 4-repeat tauopathies.

Author

Respondek, Gesine, Grimm, Max-Joseph, Piot, Ines, Arzberger, Thomas, Compta, Yaroslau, Englund, Elisabet, Ferguson, Leslie W, Gelpi, Ellen, Roeber, Sigrun, Giese, Armin, Grossman, Murray, Irwin, David J, Meissner, Wassilios G, Nilsson, Christer, Pantelyat, Alexander, Rajput, Alex, van Swieten, John C, Troakes, Claire, Höglinger, Günter U, and Movement Disorder Society-Endorsed Progressive Supranuclear Palsy Study Group

Subjects
Movement Disorder Society-Endorsed Progressive Supranuclear Palsy Study Group, Brain, Humans, Multiple System Atrophy, Parkinsonian Disorders, Parkinson Disease, Supranuclear Palsy, Progressive, Tauopathies, Aged, Middle Aged, Female, Male, Four-repeat tauopathies, corticobasal degeneration, diagnostic criteria, progressive supranuclear palsy, Aging, Rare Diseases, Clinical Trials and Supportive Activities, Neurodegenerative, Neurosciences, Brain Disorders, Clinical Research, Pick's Disease, Acquired Cognitive Impairment, Dementia, Frontotemporal Dementia (FTD), 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Neurological, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundThe Movement Disorder Society criteria for progressive supranuclear palsy introduced the category "probable 4-repeat (4R)-tauopathy" for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration.ObjectivesTo validate the accuracy of these clinical criteria for "probable 4R-tauopathy" to predict underlying 4R-tauopathy pathology.MethodsDiagnostic accuracy for 4R-tauopathies according to the established criteria was estimated retrospectively in autopsy-confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R-tauopathies), and Parkinson's disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non-4R-tauopathies).ResultsWe identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non-4R-tauopathies (N = 161). Sensitivity and specificity of "probable 4R-tauopathy" was 10% and 99% in the first year and 59% and 88% at final record.ConclusionsThe new diagnostic category "probable 4R-tauopathy" showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R-tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society.

Published
2020

38. Towards a consensus on developmental regression.

Author

Zhang, Dajie, Bedogni, Francesco, Boterberg, Sofie, Camfield, Carol, Camfield, Peter, Charman, Tony, Curfs, Leopold, Einspieler, Christa, Esposito, Gianluca, De Filippis, Bianca, Goin-Kochel, Robin P, Höglinger, Günter U, Holzinger, Daniel, Iosif, Ana-Maria, Lancioni, Giulio E, Landsberger, Nicoletta, Laviola, Giovanni, Marco, Eva M, Müller, Michael, Neul, Jeffrey L, Nielsen-Saines, Karin, Nordahl-Hansen, Anders, O'Reilly, Mark F, Ozonoff, Sally, Poustka, Luise, Roeyers, Herbert, Rankovic, Marija, Sigafoos, Jeff, Tammimies, Kristiina, Townend, Gillian S, Zwaigenbaum, Lonnie, Zweckstetter, Markus, Bölte, Sven, and Marschik, Peter B

Subjects
Humans, Consensus, Regression, Psychology, Medical and Health Sciences, Psychology and Cognitive Sciences, Behavioral Science & Comparative Psychology
Published
2019

39. How to apply the movement disorder society criteria for diagnosis of progressive supranuclear palsy.

Author

Grimm, Max-Joseph, Respondek, Gesine, Stamelou, Maria, Arzberger, Thomas, Ferguson, Leslie, Gelpi, Ellen, Giese, Armin, Grossman, Murray, Irwin, David J, Pantelyat, Alexander, Rajput, Alex, Roeber, Sigrun, van Swieten, John C, Troakes, Claire, Antonini, Angelo, Bhatia, Kailash P, Colosimo, Carlo, van Eimeren, Thilo, Kassubek, Jan, Levin, Johannes, Meissner, Wassilios G, Nilsson, Christer, Oertel, Wolfgang H, Piot, Ines, Poewe, Werner, Wenning, Gregor K, Boxer, Adam, Golbe, Lawrence I, Josephs, Keith A, Litvan, Irene, Morris, Huw R, Whitwell, Jennifer L, Compta, Yaroslau, Corvol, Jean-Christophe, Lang, Anthony E, Rowe, James B, Höglinger, Günter U, and Movement Disorder Society-endorsed PSP Study Group

Subjects
Movement Disorder Society-endorsed PSP Study Group, Brain, Humans, Parkinsonian Disorders, Supranuclear Palsy, Progressive, Ocular Motility Disorders, Sensation Disorders, Autopsy, Retrospective Studies, Cohort Studies, Adult, Aged, Aged, 80 and over, Middle Aged, Societies, Medical, Female, Male, Postural Balance, Cognitive Dysfunction, autopsy, diversity, phenotype, progressive supranuclear palsy, Brain Disorders, Pediatric, Neurosciences, Rare Diseases, Clinical Research, Perinatal Period - Conditions Originating in Perinatal Period, 4.2 Evaluation of markers and technologies, Neurology & Neurosurgery, Clinical Sciences, Human Movement and Sports Sciences
Abstract

BackgroundThe Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them.MethodsWe retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations.ResultsComprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1.ConclusionsThe proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

41. Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease.

Author

Roemer-Cassiano, Sebastian N., Wagner, Fabian, Evangelista, Lisa, Rauchmann, Boris-Stephan, Dehsarvi, Amir, Steward, Anna, Dewenter, Anna, Biel, Davina, Zhu, Zeyu, Pescoller, Julia, Gross, Mattes, Perneczky, Robert, Malpetti, Maura, Ewers, Michael, Schöll, Michael, Dichgans, Martin, Höglinger, Günter U., Brendel, Matthias, Jäkel, Sarah, and Franzmeier, Nicolai

Subjects
FUNCTIONAL magnetic resonance imaging, POSITRON emission tomography, ALZHEIMER'S disease, TAU proteins, TEMPORAL lobe, NEUROFIBRILLARY tangles
Abstract

In Alzheimer's disease (AD), amyloid-β (Aβ) triggers the aggregation and spreading of tau pathology, which drives neurodegeneration and cognitive decline. However, the pathophysiological link between Aβ and tau remains unclear, which hinders therapeutic efforts to attenuate Aβ-related tau accumulation. Aβ has been found to trigger neuronal hyperactivity and hyperconnectivity, and preclinical research has shown that tau spreads across connected neurons in an activity-dependent manner. Here, we hypothesized that neuronal hyperactivity and hypersynchronicity, resulting in functional connectivity increases, constitute a crucial mechanism by which Aβ facilitates the spreading of tau pathology. By combining Aβ positron emission tomography (PET), resting-state functional magnetic resonance imaging, and longitudinal tau-PET in 69 cognitively normal amyloid-negative controls and 140 amyloid-positive patients covering the AD spectrum, we confirmed that Aβ induces hyperconnectivity of temporal lobe tau epicenters to posterior brain regions that are vulnerable to tau accumulation in AD. This was replicated in an independent sample of 55 controls and 345 individuals with preclinical AD and low cortical tau-PET uptake, suggesting that the emergence of Aβ-related hyperconnectivity precedes neocortical tau spreading. Last, using longitudinal tau-PET and mediation analysis, we confirmed that these Aβ-related connectivity increases in tau epicenters to typical tau-vulnerable brain regions in AD mediated the effect of Aβ on faster tau accumulation, unveiling increased connectivity as a potential causal link between the two AD hallmark pathologies. Together, these findings suggest that Aβ promotes tau spreading by eliciting neuronal hyperconnectivity and that targeting Aβ-related neuronal hyperconnectivity may attenuate tau spreading in AD. Editor's summary: The "amyloid cascade model" of Alzheimer's disease suggests that plaques of amyloid-β (Aβ) precede and trigger other pathological changes such as the spread of abnormal tau protein. How amyloid pathology influences tau pathology remains incompletely understood. Here, Roemer-Cassiano et al. analyzed Aβ positron emission tomography (PET), functional magnetic resonance imaging, and tau-PET data from the Alzheimer's Disease Neuroimaging Initiative and show that the spread of tau is in part mediated by Aβ-related increases in connectivity between tau epicenters and brain regions that are vulnerable to tau accumulation. These results highlight an intricate connection between amyloid and tau pathology. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Published
2025
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42. Diagnostic Efficacy of 123 Iodo-Metaiodobenzylguanidine SPECT/CT in Cardiac vs. Neurological Diseases: A Comparative Study of Arrhythmogenic Right Ventricular Cardiomyopathy and α-Synucleinopathies.

Author

Hagen, Johannes M., Scheifele, Maximilian, Zacherl, Mathias J., Katzdobler, Sabrina, Bernhardt, Alexander, Brendel, Matthias, Levin, Johannes, Höglinger, Günter U., Clauß, Sebastian, Kääb, Stefan, Todica, Andrei, Boening, Guido, and Fischer, Maximilian

Subjects
SINGLE-photon emission computed tomography, ARRHYTHMOGENIC right ventricular dysplasia, NEUROLOGICAL disorders, SYMPATHETIC nervous system, COMPUTED tomography
Abstract

Background/Objectives: 123Iodo-metaiodobenzylguanidine single photon emission computed tomography/computed tomography (123I-MIBG SPECT/CT) is used to evaluate the cardiac sympathetic nervous system in cardiac diseases such as arrhythmogenic right ventricular cardiomyopathy (ARVC) and α-synucleinopathies such as Parkinson's diseases. A common feature of these diseases is denervation. We aimed to compare quantitative and semi-quantitative cardiac sympathetic innervation using 123I-MIBG imaging of ARVC and α-synucleinopathies. Methods: Cardiac innervation was assessed using 123I-MIBG SPECT/CT in 20 patients diagnosed with definite ARVC and 8 patients with clinically diagnosed α-synucleinopathies. Heart-to-mediastinum-ratio (H/M-ratio), as semi-quantitative, was evaluated. Additionally, standardized uptake value (SUV), as quantitative, was measured as SUVmedian, SUVmax, and SUVpeak in the left ventricle (LV), the right ventricle (RV), and in the global heart, based on a CT scan following quantitative image reconstruction. Results: The quantification of 123I-MIBG uptake in the LV, the RV, and the global heart was feasible in patients suffering from α-synucleinopathies. SUVmedian, and SUVpeak demonstrated a significant difference between ARVC and α-synucleinopathies across all regions, with the α-synucleinopathy group showing a lower uptake. In addition, the H/M ratio showed significantly lower uptake in patients with α-synucleinopathies than in patients with ARVC. Conclusions: Patients with α-synucleinopathies demonstrate significantly lower cardiac innervation in semi-quantitative and quantitative examinations than ARVC patients. The comparison of semi-quantitative and quantitative examinations suggests that quantitative examination offers an advantage. Quantitative analysis can be performed separately for the LV, RV, and global heart. However, analyzing the LV or RV does not provide additional benefit over analyzing the global heart in distinguishing between α-synucleinopathies and ARVC. Considering the different clinical manifestations of these two diseases, the absolute SUV values should not be generalized across different pathologies, and disease-specific ranges should be used instead. [ABSTRACT FROM AUTHOR]

Published
2025
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44. Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations

Author

Brittain, Claire, McCarthy, Andrew, Irizarry, Michael C, McDermott, Dana, Biglan, Kevin, Höglinger, Günter U, Lorenzl, Stefan, del Ser, Teodoro, Boxer, Adam L, Group, The AL-108-231 Study, Williams, David, Lafontaine, Anne Louise, Marras, Connie, Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Stewart, Alistair J, Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Ludolph, Albert, Benecke, Reiner, Hoglinger, Gunter, Lipp, Axel, Reichmann, Heinz, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Miller, Bruce L, Lobach, Iryna V, Roberson, Erik, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Litvan, Irene, Knopman, David S, Schneider, Lon S, Doody, Rachelle S, Golbe, Lawrence I, Roberson, Erik D, Koestler, Mary, Jack, Clifford R, Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, Morimoto, Bruce H, investigators, The PROPSPERA, G, Georg Nuebling, Hensler, Mira, Paul, Sabine, Zwergal, Andreas, 4RNTI-1authors, Heuer, Hilary W, Tartaglia, Maria C, McGinnis, Scott M, Dickerson, Bradford C, Kornak, John, Schuff, Norbert, Rabinovici, Gil D, Rosen, Howard J, Investigators, Tau Restoration on PSP, Gómez, JC, Tijero, B, Berganzo, K, de Yebenes, J Garc'ıa, Sendón, JL Lopez, and Garcia, G

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Clinical Research, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Frontotemporal Dementia (FTD), Dementia, Aging, Neurodegenerative, Clinical Trials and Supportive Activities, Alzheimer's Disease Related Dementias (ADRD), Rare Diseases, Health Disparities, Brain Disorders, 4.2 Evaluation of markers and technologies, Neurological, Aged, Aged, 80 and over, Basal Ganglia Diseases, Data Visualization, Disease Progression, Female, Humans, Male, Middle Aged, Models, Neurological, Neurodegenerative Diseases, Prognosis, Severity of Illness Index, Supranuclear Palsy, Progressive, Syndrome, Corticobasal syndrome, Progressive supranuclear palsy, PSP rating scale, Interactive visualizations, Predictive models, AL-108-231 Study Group, PROPSPERA investigators, 4RNTI-1authors, Tau Restoration on PSP (TAUROS) Investigators, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

BackgroundProgressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP.ObjectivesTo determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS.MethodsMulticenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity.ResultsThe earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity.ConclusionThe PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.

Published
2019

45. Correction: Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.

Author

Broce, Iris, Karch, Celeste M, Wen, Natalie, Fan, Chun C, Wang, Yunpeng, Tan, Chin Hong, Kouri, Naomi, Ross, Owen A, Höglinger, Günter U, Muller, Ulrich, Hardy, John, International FTD-Genomics Consortium, Momeni, Parastoo, Hess, Christopher P, Dillon, William P, Miller, Zachary A, Bonham, Luke W, Rabinovici, Gil D, Rosen, Howard J, Schellenberg, Gerard D, Franke, Andre, Karlsen, Tom H, Veldink, Jan H, Ferrari, Raffaele, Yokoyama, Jennifer S, Miller, Bruce L, Andreassen, Ole A, Dale, Anders M, Desikan, Rahul S, and Sugrue, Leo P

Subjects
International FTD-Genomics Consortium, General & Internal Medicine, Medical and Health Sciences
Abstract

[This corrects the article DOI: 10.1371/journal.pmed.1002487.].

Published
2018

46. Recommendations of the Global Multiple System Atrophy Research Roadmap Meeting

Author

Walsh, Ryan R, Krismer, Florian, Galpern, Wendy R, Wenning, Gregor K, Low, Phillip A, Halliday, Glenda, Koroshetz, Walter J, Holton, Janice, Quinn, Niall P, Rascol, Olivier, Shaw, Leslie M, Eidelberg, David, Bower, Pam, Cummings, Jeffrey L, Abler, Victor, Biedenharn, Judy, Bitan, Gal, Brooks, David J, Brundin, Patrik, Fernandez, Hubert, Fortier, Philip, Freeman, Roy, Gasser, Thomas, Hewitt, Art, Höglinger, Günter U, Huentelman, Matt J, Jensen, Poul H, Jeromin, Andreas, Kang, Un Jung, Kaufmann, Horacio, Kellerman, Lawrence, Khurana, Vikram, Klockgether, Thomas, Kim, Woojin Scott, Langer, Carol, LeWitt, Peter, Masliah, Eliezer, Meissner, Wassilios, Melki, Ronald, Ostrowitzki, Susanne, Piantadosi, Steven, Poewe, Werner, Robertson, David, Roemer, Cyndi, Schenk, Dale, Schlossmacher, Michael, Schmahmann, Jeremy D, Seppi, Klaus, Shih, Lily, Siderowf, Andrew, Stebbins, Glenn T, Stefanova, Nadia, Tsuji, Shoji, Sutton, Sharon, and Zhang, Jing

Subjects
Rare Diseases, Humans, Multiple System Atrophy, Nevada, Patient Advocacy, Research Design, Clinical Sciences, Neurosciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided.

Published
2018

47. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Author

Broce, Iris, Karch, Celeste M, Wen, Natalie, Fan, Chun C, Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A, Höglinger, Günter U, Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P, Dillon, William P, Miller, Zachary A, Bonham, Luke W, Rabinovici, Gil D, Rosen, Howard J, Schellenberg, Gerard D, Franke, Andre, Karlsen, Tom H, Veldink, Jan H, Ferrari, Raffaele, Yokoyama, Jennifer S, Miller, Bruce L, Andreassen, Ole A, Dale, Anders M, Desikan, Rahul S, Sugrue, Leo P, Brayne, Carol, and International FTD-Genomics Consortium

Published
2018

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