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150 results on '"McCullough, Austin"'

1. CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease

Author

Noble, James M., Day, Gregory S., Graff-Radford, Neill R., Voglein, Jonathan, Allegri, Ricardo, Mendez, Patricio Chrem, Surace, Ezequiel, Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh, Lopera, Francisco, Ramirez, Laura, Aguillon, David, Leon, Yudy, Ramos, Claudia, Alzate, Diana, Baena, Ana, Londono, Natalia, Mathias Jucker, Sonia Moreno, Laske, Christoph, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Preische, Oliver, Hofmann, Anna, Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Ishii, Kenji, Senda, Michio, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Fox, Nick, Cash, Dave, Lee, Jae-Hong, Roh, Jee Hoon, Riddle, Meghan, Menard, William, Bodge, Courtney, Surti, Mustafa, Takada, Leonel Tadao, Farlow, Martin, Chhatwal, Jasmeer P., Sanchez-Gonzalez, V.J., Orozco-Barajas, Maribel, Goate, Alison, Renton, Alan, Esposito, Bianca, Karch, Celeste M., Marsh, Jacob, Cruchaga, Carlos, Fernandez, Victoria, Gordon, Brian A., Fagan, Anne M., Jerome, Gina, Herries, Elizabeth, Llibre-Guerra, Jorge, Levey, Allan I., Johnson, Erik C.B., Seyfried, Nicholas T., Schofield, Peter R., Brooks, William, Bechara, Jacob, Bateman, Randall J., McDade, Eric, Hassenstab, Jason, Perrin, Richard J., Franklin, Erin, Benzinger, Tammie L.S., Chen, Allison, Chen, Charles, Flores, Shaney, Friedrichsen, Nelly, Hantler, Nancy, Hornbeck, Russ, Jarman, Steve, Keefe, Sarah, Koudelis, Deborah, Massoumzadeh, Parinaz, McCullough, Austin, McKay, Nicole, Nicklaus, Joyce, Pulizos, Christine, Wang, Qing, Mishall, Sheetal, Sabaredzovic, Edita, Deng, Emily, Candela, Madison, Smith, Hunter, Hobbs, Diana, Scott, Jalen, Levin, Johannes, Xiong, Chengjie, Wang, Peter, Xu, Xiong, Li, Yan, Gremminger, Emily, Ma, Yinjiao, Bui, Ryan, Lu, Ruijin, Martins, Ralph, Sosa Ortiz, Ana Luisa, Daniels, Alisha, Courtney, Laura, Mori, Hiroshi, Supnet-Bell, Charlene, Xu, Jinbin, Ringman, John, Shen, Yuanyuan, Timsina, Jigyasha, Heo, Gyujin, Beric, Aleksandra, Ali, Muhammad, Wang, Ciyang, Yang, Chengran, Wang, Yueyao, Western, Daniel, Liu, Menghan, Gorijala, Priyanka, Budde, John, Do, Anh, Liu, Haiyan, Gordon, Brian, Llibre-Guerra, Jorge J., Joseph-Mathurin, Nelly, Maschi, Dario, Wyss-Coray, Tony, Pastor, Pau, Renton, Alan E., Surace, Ezequiel I., Alvarez, Ignacio, Ringman, John M., Allegri, Ricardo Francisco, Seyfried, Nicholas, Day, Gregg S., Wu, Qisi, Fernández, M. Victoria, Tarawneh, Rawan, Morris, John C., Ibanez, Laura, and Sung, Yun Ju

Published
2024
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2. γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Author

Aguillon, David, Allegri, Ricardo F., Aschenbrenner, Andrew J., Baker, Bryce, Barthelemy, Nicolas, Bechara, Jacob A., Berman, Sarah B., Brooks, William S., Cash, David M., Chen, Allison, Chrem Mendez, Patricio, Courtney, Laura, Cruchaga, Carlos, Daniels, Alisha J., Fagan, Anne M., Flores, Shaney, Fox, Nick C., Franklin, Erin, Goate, Alison M., Graber-Sultan, Susanne, Graff-Radford, Neill R., Gremminger, Emily, Herries, Elizabeth, Hofmann, Anna, Holtzman, David M., Hornbeck, Russ, Huey, Edward D., Ibanez, Laura, Ikeuchi, Takeshi, Ikonomovic, Snezana, Jackson, Kelley, Jarman, Steve, Jerome, Gina, Johnson, Erik C.B, Kasuga, Kensaku, Keefe, Sarah, Koudelis, Deborah, Kuder-Buletta, Elke, Laske, Christoph, Leon, Yudy Milena, Levey, Allan I., Li, Yan, Llibre-Guerra, Jorge J., Lopera, Francisco, Lu, Ruijin, Marsh, Jacob, Martins, Ralph, Massoumzadeh, Parinaz, Masters, Colin, McCullough, Austin, McKay, Nicole, Minton, Matthew, Mori, Hiroshi, Morris, John C., Nadkarni, Neelesh K., Nicklaus, Joyce, Niimi, Yoshiki, Noble, James M., Obermueller, Ulrike, Picarello, Danielle M., Pulizos, Christine, Ramirez, Laura, Renton, Alan E., Ringman, John, Rizzo, Jacqueline, Roedenbeck, Yvonne, Roh, Jee Hoon, Rosa-Neto, Pedro, Ryan, Natalie S., Sabaredzovic, Edita, Salloway, Stephen, Sanchez-Valle, Raquel, Scott, Jalen, Seyfried, Nicholas T., Simmons, Ashlee, Smith, Jennifer, Smith, Hunter, Stauber, Jennifer, Stout, Sarah, Supnet-Bell, Charlene, Surace, Ezequiel, Vazquez, Silvia, Vöglein, Jonathan, Wang, Guoqiao, Wang, Qing, Xu, Xiong, Xu, Jinbin, Schultz, Stephanie A, Liu, Lei, Schultz, Aaron P, Fitzpatrick, Colleen D, Levin, Raina, Bellier, Jean-Pierre, Shirzadi, Zahra, Joseph-Mathurin, Nelly, Chen, Charles D, Benzinger, Tammie L S, Day, Gregory S, Farlow, Martin R, Gordon, Brian A, Hassenstab, Jason J, Jack, Clifford R, Jr, Jucker, Mathias, Karch, Celeste M, Lee, Jae-Hong, Levin, Johannes, Perrin, Richard J, Schofield, Peter R, Xiong, Chengjie, Johnson, Keith A, McDade, Eric, Bateman, Randall J, Sperling, Reisa A, Selkoe, Dennis J, and Chhatwal, Jasmeer P

Published
2024
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3. Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN)

Author

McKay, Nicole S., Gordon, Brian A., Hornbeck, Russ C., Dincer, Aylin, Flores, Shaney, Keefe, Sarah J., Joseph-Mathurin, Nelly, Jack, Clifford R., Koeppe, Robert, Millar, Peter R., Ances, Beau M., Chen, Charles D., Daniels, Alisha, Hobbs, Diana A., Jackson, Kelley, Koudelis, Deborah, Massoumzadeh, Parinaz, McCullough, Austin, Nickels, Michael L., Rahmani, Farzaneh, Swisher, Laura, Wang, Qing, Allegri, Ricardo F., Berman, Sarah B., Brickman, Adam M., Brooks, William S., Cash, David M., Chhatwal, Jasmeer P., Day, Gregory S., Farlow, Martin R., la Fougère, Christian, Fox, Nick C., Fulham, Michael, Ghetti, Bernardino, Graff-Radford, Neill, Ikeuchi, Takeshi, Klunk, William, Lee, Jae-Hong, Levin, Johannes, Martins, Ralph, Masters, Colin L., McConathy, Jonathan, Mori, Hiroshi, Noble, James M., Reischl, Gerald, Rowe, Christopher, Salloway, Stephen, Sanchez-Valle, Raquel, Schofield, Peter R., Shimada, Hiroyuki, Shoji, Mikio, Su, Yi, Suzuki, Kazushi, Vöglein, Jonathan, Yakushev, Igor, Cruchaga, Carlos, Hassenstab, Jason, Karch, Celeste, McDade, Eric, Perrin, Richard J., Xiong, Chengjie, Morris, John C., Bateman, Randall J., and Benzinger, Tammie L. S.

Published
2023
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4. Longitudinal head-to-head comparison of 11C-PiB and 18F-florbetapir PET in a Phase 2/3 clinical trial of anti-amyloid-β monoclonal antibodies in dominantly inherited Alzheimer’s disease

Author

Chen, Charles D., McCullough, Austin, Gordon, Brian, Joseph-Mathurin, Nelly, Flores, Shaney, McKay, Nicole S., Hobbs, Diana A., Hornbeck, Russ, Fagan, Anne M., Cruchaga, Carlos, Goate, Alison M., Perrin, Richard J., Wang, Guoqiao, Li, Yan, Shi, Xinyu, Xiong, Chengjie, Pontecorvo, Michael J., Klein, Gregory, Su, Yi, Klunk, William E., Jack, Clifford, Koeppe, Robert, Snider, B. Joy, Berman, Sarah B., Roberson, Erik D., Brosch, Jared, Surti, Ghulam, Jiménez-Velázquez, Ivonne Z., Galasko, Douglas, Honig, Lawrence S., Brooks, William S., Clarnette, Roger, Wallon, David, Dubois, Bruno, Pariente, Jérémie, Pasquier, Florence, Sanchez-Valle, Raquel, Shcherbinin, Sergey, Higgins, Ixavier, Tunali, Ilke, Masters, Colin L., van Dyck, Christopher H., Masellis, Mario, Hsiung, Robin, Gauthier, Serge, Salloway, Steve, Clifford, David B., Mills, Susan, Supnet-Bell, Charlene, McDade, Eric, Bateman, Randall J., and Benzinger, Tammie L. S.

Published
2023
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5. Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging

Author

Noble, James M., Day, Gregory S., Graff-Radford, Neill R., Voglein, Jonathan, Levin, Johannes, Allegri, Ricardo F., Mendez, Patricio Chrem, Surace, Ezequiel, Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh K., Lopera, Francisco, Ramirez, Laura, Aguillon, David, Leon, Yudy, Ramos, Claudia, Alzate, Diana, Baena, Ana, Londono, Natalia, Moreno, Sonia, Jucker, Mathias, Laske, Christoph, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Preische, Oliver, Hofmann, Anna, Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Ishii, Kenji, Senda, Michio, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Fox, Nick C., Cash, Dave, Lee, Jae-Hong, Roh, Jee Hoon, Salloway, Stephen, Riddle, Meghan C., Menard, William, Bodge, Courtney, Surti, Mustafa, Takada, Leonel Tadao, Farlow, Martin, Chhatwal, Jasmeer P., Sanchez-Gonzalez, V.J., Orozco-Barajas, Maribel, Goate, Alison M., Renton, Alan E., Esposito, Bianca T., Karch, Celeste M., Marsh, Jacob, Cruchaga, Carlos, Fernanadez, Victoria, Gordon, Brian A., Fagan, Anne M., Jerome, Gina, Herries, Elizabeth, Llibre-Guerra, Jorge, Levey, Allan I., Johnson, Erik C.B., Seyfried, Nicholas T., Schofield, Peter R., Brooks, William S., Bechara, Jacob A., Bateman, Randall, McDade, Eric, Hassenstab, Jason, Perrin, Richard J., Franklin, Erin E., Benzinger, Tammie, Chen, Allison, Chen, Charles, Flores, Shaney, Friedrichsen, Nelly, Gordon, Brian, Hantler, Nancy, Hornbeck, Russ, Jarman, Steve, Keefe, Sarah, Koudelis, Deborah, Massoumzadeh, Parinaz, McCullough, Austin, McKay, Nicole, Nicklaus, Joyce, Pulizos, Christine, Wang, Qing, Mishall, Sheetal, Sabaredzovic, Edita, Deng, Emily, Candela, Madison, Smith, Hunter, Hobbs, Diana, Scott, Jalen, Xiong, Chengjie, Wang, Peter, Xu, Xiong, Li, Yan, Gremminger, Emily, Ma, Yinjiao, Bui, Ryan, Lu, Ruijin, Martins, Ralph, Sosa Ortiz, Ana Luisa, Daniels, Alisha, Courtney, Laura, Mori, Hiroshi, Supnet-Bell, Charlene, Xu, Jinbin, Ringman, John, Barthelemy, Nicolas, Morris, John, Smith, Jennifer, Doering, Stephanie, Chen, Charles D., Jarman, Stephen, Jackson, Kelley, Hornbeck, Russ C., Ances, Beau M., Aschenbrenner, Andrew J., Bateman, Randall J., Morris, John C., and Benzinger, Tammie L.S.

Published
2024
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6. Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study

Author

Aizenstein, Howard J, Andrews, Howard F, Bell, Karen, Birn, Rasmus M, Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Clark, Lorraine, Cohen, Ann D, Constantino, John N, Doran, Eric W, Feingold, Eleanor, Foroud, Tatiana M, Hartley, Sigan L, Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D, Johnson, Sterling C, Jordan, Courtney, Kamboh, M Ilyas, Keator, David, Klunk MD, William E, Kofler, Julia K, Kreisl, William C, Krinsky- McHale, Sharon J, Lao, Patrick, Laymon, Charles, Lott, Ira T, Lupson, Victoria, Mathis, Chester A, Minhas, Davneet S, Nadkarni, Neelesh, Pang, Deborah, Petersen, Melissa, Price, Julie C, Pulsifer, Margaret, Reiman, Eric, Rizvi, Batool, Sabbagh, Marwan N, Schupf, Nicole, Tudorascu, Dana L, Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A, Yassa, Michael A, Zaman, Shahid, Zhang, Fan, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Mendez, Patricio C, Chua, Jasmin, Chui, Helena, Courtney, Laura, Day, Gregory, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häslerc, Lisa, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Jucker, Mathias, Karch, Celeste, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Mason, Neal S, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, Mejia, Arlene, Morenas-Rodriguez, Estrella, Morris, John C, Mountz, James, Mummery, Catherine, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O'Connor, Antoinette, Patira, Riddhi, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xu, Jinbin, Xu, Xiong, Boerwinkle, Anna H, Gordon, Brian A, Wisch, Julie, Flores, Shaney, Henson, Rachel L, Butt, Omar H, McKay, Nicole, Chen, Charles D, Benzinger, Tammie L S, Fagan, Anne M, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O'Bryant, Sid, Lai, Florence, Rosas, H Diana, Lee, Joseph H, Silverman, Wayne, Brickman, Adam M, Chhatwal, Jasmeer P, Cruchaga, Carlos, Perrin, Richard J, Xiong, Chengjie, Hassenstab, Jason, McDade, Eric, Bateman, Randall J, and Ances, Beau M

Published
2023
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7. Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease

Author

Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bateman, Randall, Bechara, Jacob, Benzinger, Tammie, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William (Bill), Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Mendez, Patricio Chrem, Chua, Jasmin, Chui, Helena, Courtney, Laura, Cruchaga, Carlos, Day, Gregory S, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Fagan, Anne, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gordon, Brian, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häsler, Lisa, Hassenstab, Jason, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Jucker, Mathias, Karch, Celeste, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, McDade, Eric, Mejia, Arlene, Morenas-Rodriguez, Estrella, Morris, John, Mountz, James, Mummery, Cath, Nadkarni, N eelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O'Connor, Antoinette, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xiong, Chengjie, Xu, Jinbin, Xu, Xiong, Millar, Peter R., Luckett, Patrick H., Gordon, Brian A., Benzinger, Tammie L.S., Schindler, Suzanne E., Fagan, Anne M., Bateman, Randall J., Lee, Jae-Hong, Mori, Hiroshi, Salloway, Stephen P, Yakushev, Igor, Morris, John C., and Ances, Beau M.

Published
2022
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8. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study

Author

Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William (Bill), Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Chrem, Patricio, Chua, Jasmin, Chui, Helena, Cruchaga, Carlos, Day, Gregory S, De La Cruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Friedrichsen, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Häsler, Lisa, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William (Bill), Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Lopez, Oscar, Marsh, Jacob, Martinez, Rita, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, Mejia, Arlene, MountzMD, James, Mummery, Cath, Nadkarni, Neelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, O'Connor, Antoinette, Obermüller, Ulricke, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nick, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Wang, Peter, Wang, Qing, Weamer, Elise, Xu, Jinbin, Xu, Xiong, Morenas-Rodríguez, Estrella, Li, Yan, Franzmeier, Nicolai, Xiong, Chengjie, Suárez-Calvet, Marc, Fagan, Anne M, Schultz, Stephanie, Gordon, Brian A, Benzinger, Tammie L S, Hassenstab, Jason, McDade, Eric, Feederle, Regina, Karch, Celeste M, Schlepckow, Kai, Morris, John C, Kleinberger, Gernot, Nellgard, Bengt, Vöglein, Jonathan, Blennow, Kaj, Zetterberg, Henrik, Ewers, Michael, Jucker, Mathias, Levin, Johannes, Bateman, Randall J, and Haass, Christian

Published
2022
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9. Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging

Author

Doering, Stephanie, primary, McCullough, Austin, additional, Gordon, Brian A., additional, Chen, Charles D., additional, McKay, Nicole, additional, Hobbs, Diana, additional, Keefe, Sarah, additional, Flores, Shaney, additional, Scott, Jalen, additional, Smith, Hunter, additional, Jarman, Stephen, additional, Jackson, Kelley, additional, Hornbeck, Russ C., additional, Ances, Beau M., additional, Xiong, Chengjie, additional, Aschenbrenner, Andrew J., additional, Hassenstab, Jason, additional, Cruchaga, Carlos, additional, Daniels, Alisha, additional, Bateman, Randall J., additional, Noble, James M., additional, Day, Gregory S., additional, Graff-Radford, Neill R., additional, Voglein, Jonathan, additional, Levin, Johannes, additional, Allegri, Ricardo F., additional, Mendez, Patricio Chrem, additional, Surace, Ezequiel, additional, Berman, Sarah B., additional, Ikonomovic, Snezana, additional, Nadkarni, Neelesh K., additional, Lopera, Francisco, additional, Ramirez, Laura, additional, Aguillon, David, additional, Leon, Yudy, additional, Ramos, Claudia, additional, Alzate, Diana, additional, Baena, Ana, additional, Londono, Natalia, additional, Moreno, Sonia, additional, Jucker, Mathias, additional, Laske, Christoph, additional, Kuder-Buletta, Elke, additional, Graber-Sultan, Susanne, additional, Preische, Oliver, additional, Hofmann, Anna, additional, Ikeuchi, Takeshi, additional, Kasuga, Kensaku, additional, Niimi, Yoshiki, additional, Ishii, Kenji, additional, Senda, Michio, additional, Sanchez-Valle, Raquel, additional, Rosa-Neto, Pedro, additional, Fox, Nick C., additional, Cash, Dave, additional, Lee, Jae-Hong, additional, Roh, Jee Hoon, additional, Salloway, Stephen, additional, Riddle, Meghan C., additional, Menard, William, additional, Bodge, Courtney, additional, Surti, Mustafa, additional, Takada, Leonel Tadao, additional, Farlow, Martin, additional, Chhatwal, Jasmeer P., additional, Sanchez-Gonzalez, V.J., additional, Orozco-Barajas, Maribel, additional, Goate, Alison M., additional, Renton, Alan E., additional, Esposito, Bianca T., additional, Karch, Celeste M., additional, Marsh, Jacob, additional, Fernanadez, Victoria, additional, Fagan, Anne M., additional, Jerome, Gina, additional, Herries, Elizabeth, additional, Llibre-Guerra, Jorge, additional, Levey, Allan I., additional, Johnson, Erik C.B., additional, Seyfried, Nicholas T., additional, Schofield, Peter R., additional, Brooks, William S., additional, Bechara, Jacob A., additional, Bateman, Randall, additional, McDade, Eric, additional, Perrin, Richard J., additional, Franklin, Erin E., additional, Benzinger, Tammie, additional, Chen, Allison, additional, Chen, Charles, additional, Friedrichsen, Nelly, additional, Gordon, Brian, additional, Hantler, Nancy, additional, Hornbeck, Russ, additional, Jarman, Steve, additional, Koudelis, Deborah, additional, Massoumzadeh, Parinaz, additional, Nicklaus, Joyce, additional, Pulizos, Christine, additional, Wang, Qing, additional, Mishall, Sheetal, additional, Sabaredzovic, Edita, additional, Deng, Emily, additional, Candela, Madison, additional, Wang, Peter, additional, Xu, Xiong, additional, Li, Yan, additional, Gremminger, Emily, additional, Ma, Yinjiao, additional, Bui, Ryan, additional, Lu, Ruijin, additional, Martins, Ralph, additional, Sosa Ortiz, Ana Luisa, additional, Courtney, Laura, additional, Mori, Hiroshi, additional, Supnet-Bell, Charlene, additional, Xu, Jinbin, additional, Ringman, John, additional, Barthelemy, Nicolas, additional, Morris, John, additional, Smith, Jennifer, additional, Morris, John C., additional, and Benzinger, Tammie L.S., additional

Published
2024
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10. Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease

Author

Chen, Charles D., Joseph-Mathurin, Nelly, Sinha, Namita, Zhou, Aihong, Li, Yan, Friedrichsen, Karl, McCullough, Austin, Franklin, Erin E., Hornbeck, Russ, Gordon, Brian, Sharma, Vijay, Cruchaga, Carlos, Goate, Alison, Karch, Celeste, McDade, Eric, Xiong, Chengjie, Bateman, Randall J., Ghetti, Bernardino, Ringman, John M., Chhatwal, Jasmeer, Masters, Colin L., McLean, Catriona, Lashley, Tammaryn, Su, Yi, Koeppe, Robert, Jack, Clifford, Klunk, William E., Morris, John C., Perrin, Richard J., Cairns, Nigel J., and Benzinger, Tammie L. S.

Published
2021
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11. Investigating White Matter Neuroinflammation in Alzheimer Disease Using Diffusion-Based Neuroinflammation Imaging

Author

Wang, Qing, primary, Schindler, Suzanne E., additional, Chen, Gengsheng, additional, Mckay, Nicole S., additional, McCullough, Austin, additional, Flores, Shaney, additional, Liu, Jingxia, additional, Sun, Zhexian, additional, Wang, Sicheng, additional, Wang, Wenshang, additional, Hassenstab, Jason, additional, Cruchaga, Carlos, additional, Perrin, Richard J., additional, Fagan, Anne M., additional, Morris, John C., additional, Wang, Yong, additional, and Benzinger, Tammie L.S., additional

Published
2024
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12. White matter injury mediates the effects of PS1 mutation position on clinical measures in late disease stage

Author

Joseph‐Mathurin, Nelly, primary, Lu, Ruijin, additional, Shirzadi, Zahra, additional, Strain, Jeremy F., additional, Clair, Junie Saint, additional, Feldman, Rebecca L., additional, McKay, Nicole S., additional, Keefe, Sarah J., additional, Massoumzadeh, Parinaz, additional, Chen, Gengsheng, additional, Gordon, Brian A., additional, McCullough, Austin A., additional, Chen, Charles D., additional, Schultz, Stephanie A., additional, Llibre‐Guerra, Jorge J, additional, Cruchaga, Carlos, additional, Morris, John C, additional, Bateman, Randall J., additional, McDade, Eric, additional, Chhatwal, Jasmeer P., additional, Xiong, Chengjie, additional, and Benzinger, Tammie L.S., additional

Published
2023
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14. Presenilin‐1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

Author

Joseph‐Mathurin, Nelly, Feldman, Rebecca L., Lu, Ruijin, Shirzadi, Zahra, Toomer, Carmen, Saint Clair, Junie R., Ma, Yinjiao, McKay, Nicole S., Strain, Jeremy F., Kilgore, Collin, Friedrichsen, Karl A., Chen, Charles D., Gordon, Brian A., Chen, Gengsheng, Hornbeck, Russ C., Massoumzadeh, Parinaz, McCullough, Austin A., Wang, Qing, Li, Yan, and Wang, Guoqiao

Abstract

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin‐1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre‐/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross‐sectionally evaluated regional Pittsburgh compound B‐positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging‐based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. Highlights: Mutation position influences Aβ burden, SVD, and dementia.PSEN1 pre‐200 group had stronger associations between Aβ burden and disease stage.PSEN1 post‐200 group had stronger associations between SVD markers and disease stage.PSEN1 post‐200 group had worse dementia score than pre‐200 in late disease stage.Diffusion tensor imaging‐based SVD markers mediated mutation position effects on dementia in the late stage. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study

Author

Morenas-Rodríguez, Estrella, Li, Yan, Hassenstab, Jason, Laske, Christoph, Levey, Allan, Lopez, Oscar, Marsh, Jacob, Martinez, Rita, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, McDade, Eric, Mejia, Arlene, MountzMD, James, Mummery, Cath, Nadkarni, Neelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Feederle, Regina, O'Connor, Antoinette, Obermüller, Ulricke, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Karch, Celeste M, Senda, Michio, Seyfried, Nick, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Schlepckow, Kai, Taddei, Kevin, Thompson, Sarah, Wang, Peter, Wang, Qing, Weamer, Elise, Xu, Jinbin, Xu, Xiong, Morris, John C, Kleinberger, Gernot, Nellgard, Bengt, Vöglein, Jonathan, Blennow, Kaj, Zetterberg, Henrik, Ewers, Michael, Jucker, Mathias, Levin, Johannes, Bateman, Randall J, Haass, Christian, Network, Dominantly Inherited Alzheimer, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Franzmeier, Nicolai, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William Bill, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Xiong, Chengjie, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Chrem, Patricio, Chua, Jasmin, Chui, Helena, Cruchaga, Carlos, Day, Gregory S, De La Cruz, Chrismary, Denner, Darcy, Suarez-Calvet, Marc, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Fagan, Anne M, Flores, Shaney, Fox, Nick, Franklin, Erin, Friedrichsen, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Schultz, Stephanie, Gonzalez, Alyssa, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Häsler, Lisa, Hellm, Cortaiga, Gordon, Brian A, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Benzinger, Tammie L S, Jack, Clifford, Jerome, Gina, Johnson, Erik, Kaeser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William Bill, Koeppe, Robert, Koudelis, Deb, and Kuder-Buletta, Elke

Subjects
Adult, Amyloid beta-Peptides, Membrane Glycoproteins, TREM2 protein, human, physiology [Cognition], diagnostic imaging [Cognitive Dysfunction], genetics [Cognitive Dysfunction], genetics [Alzheimer Disease], Middle Aged, United States, Cognition, genetics [Membrane Glycoproteins], Alzheimer Disease, Humans, genetics [Receptors, Immunologic], Cognitive Dysfunction, ddc:610, Neurology (clinical), cerebrospinal fluid [Membrane Glycoproteins], Receptors, Immunologic, diagnostic imaging [Alzheimer Disease], Biomarkers
Abstract

Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease.We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models.In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=-4·28 × 10-2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=-5·51 × 10-3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=-0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020).Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing.German Research Foundation, US National Institutes of Health.

Published
2022
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18. Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study

Author

Boerwinkle, Anna H, primary, Gordon, Brian A, additional, Wisch, Julie, additional, Flores, Shaney, additional, Henson, Rachel L, additional, Butt, Omar H, additional, McKay, Nicole, additional, Chen, Charles D, additional, Benzinger, Tammie L S, additional, Fagan, Anne M, additional, Handen, Benjamin L, additional, Christian, Bradley T, additional, Head, Elizabeth, additional, Mapstone, Mark, additional, Rafii, Michael S, additional, O'Bryant, Sid, additional, Lai, Florence, additional, Rosas, H Diana, additional, Lee, Joseph H, additional, Silverman, Wayne, additional, Brickman, Adam M, additional, Chhatwal, Jasmeer P, additional, Cruchaga, Carlos, additional, Perrin, Richard J, additional, Xiong, Chengjie, additional, Hassenstab, Jason, additional, McDade, Eric, additional, Bateman, Randall J, additional, Ances, Beau M, additional, Aizenstein, Howard J, additional, Andrews, Howard F, additional, Bell, Karen, additional, Birn, Rasmus M, additional, Bulova, Peter, additional, Cheema, Amrita, additional, Chen, Kewei, additional, Clare, Isabel, additional, Clark, Lorraine, additional, Cohen, Ann D, additional, Constantino, John N, additional, Doran, Eric W, additional, Feingold, Eleanor, additional, Foroud, Tatiana M, additional, Hartley, Sigan L, additional, Hom, Christy, additional, Honig, Lawrence, additional, Ikonomovic, Milos D, additional, Johnson, Sterling C, additional, Jordan, Courtney, additional, Kamboh, M Ilyas, additional, Keator, David, additional, Klunk MD, William E, additional, Kofler, Julia K, additional, Kreisl, William C, additional, Krinsky- McHale, Sharon J, additional, Lao, Patrick, additional, Laymon, Charles, additional, Lott, Ira T, additional, Lupson, Victoria, additional, Mathis, Chester A, additional, Minhas, Davneet S, additional, Nadkarni, Neelesh, additional, Pang, Deborah, additional, Petersen, Melissa, additional, Price, Julie C, additional, Pulsifer, Margaret, additional, Reiman, Eric, additional, Rizvi, Batool, additional, Sabbagh, Marwan N, additional, Schupf, Nicole, additional, Tudorascu, Dana L, additional, Tumuluru, Rameshwari, additional, Tycko, Benjamin, additional, Varadarajan, Badri, additional, White, Desiree A, additional, Yassa, Michael A, additional, Zaman, Shahid, additional, Zhang, Fan, additional, Adams, Sarah, additional, Allegri, Ricardo, additional, Araki, Aki, additional, Barthelemy, Nicolas, additional, Bechara, Jacob, additional, Berman, Sarah, additional, Bodge, Courtney, additional, Brandon, Susan, additional, Brooks, William, additional, Brosch, Jared, additional, Buck, Jill, additional, Buckles, Virginia, additional, Carter, Kathleen, additional, Cash, Lisa, additional, Mendez, Patricio C, additional, Chua, Jasmin, additional, Chui, Helena, additional, Courtney, Laura, additional, Day, Gregory, additional, DeLaCruz, Chrismary, additional, Denner, Darcy, additional, Diffenbacher, Anna, additional, Dincer, Aylin, additional, Donahue, Tamara, additional, Douglas, Jane, additional, Duong, Duc, additional, Egido, Noelia, additional, Esposito, Bianca, additional, Farlow, Marty, additional, Feldman, Becca, additional, Fitzpatrick, Colleen, additional, Fox, Nick, additional, Franklin, Erin, additional, Joseph-Mathurin, Nelly, additional, Fujii, Hisako, additional, Gardener, Samantha, additional, Ghetti, Bernardino, additional, Goate, Alison, additional, Goldberg, Sarah, additional, Goldman, Jill, additional, Gonzalez, Alyssa, additional, Gräber-Sultan, Susanne, additional, Graff-Radford, Neill, additional, Graham, Morgan, additional, Gray, Julia, additional, Gremminger, Emily, additional, Grilo, Miguel, additional, Groves, Alex, additional, Haass, Christian, additional, Häslerc, Lisa, additional, Hellm, Cortaiga, additional, Herries, Elizabeth, additional, Hoechst-Swisher, Laura, additional, Hofmann, Anna, additional, Holtzman, David, additional, Hornbeck, Russ, additional, Igor, Yakushev, additional, Ihara, Ryoko, additional, Ikeuchi, Takeshi, additional, Ikonomovic, Snezana, additional, Ishii, Kenji, additional, Jack, Clifford, additional, Jerome, Gina, additional, Johnson, Erik, additional, Jucker, Mathias, additional, Karch, Celeste, additional, Käser, Stephan, additional, Kasuga, Kensaku, additional, Keefe, Sarah, additional, Klunk, William, additional, Koeppe, Robert, additional, Koudelis, Deb, additional, Kuder-Buletta, Elke, additional, Laske, Christoph, additional, Levey, Allan, additional, Levin, Johannes, additional, Li, Yan, additional, Lopez, Oscar, additional, Marsh, Jacob, additional, Martins, Ralph, additional, Mason, Neal S, additional, Masters, Colin, additional, Mawuenyega, Kwasi, additional, McCullough, Austin, additional, Mejia, Arlene, additional, Morenas-Rodriguez, Estrella, additional, Morris, John C, additional, Mountz, James, additional, Mummery, Catherine, additional, Nagamatsu, Akemi, additional, Neimeyer, Katie, additional, Niimi, Yoshiki, additional, Noble, James, additional, Norton, Joanne, additional, Nuscher, Brigitte, additional, Obermüller, Ulricke, additional, O'Connor, Antoinette, additional, Patira, Riddhi, additional, Ping, Lingyan, additional, Preische, Oliver, additional, Renton, Alan, additional, Ringman, John, additional, Salloway, Stephen, additional, Schofield, Peter, additional, Senda, Michio, additional, Seyfried, Nicholas T, additional, Shady, Kristine, additional, Shimada, Hiroyuki, additional, Sigurdson, Wendy, additional, Smith, Jennifer, additional, Smith, Lori, additional, Snitz, Beth, additional, Sohrabi, Hamid, additional, Stephens, Sochenda, additional, Taddei, Kevin, additional, Thompson, Sarah, additional, Vöglein, Jonathan, additional, Wang, Peter, additional, Wang, Qing, additional, Weamer, Elise, additional, Xu, Jinbin, additional, and Xu, Xiong, additional

Published
2023
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19. Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease

Author

Joseph-Mathurin, Nelly, Llibre-Guerra, Jorge J, Gordon, Brian A, Chen, Charles D, Flores, Shaney, Aggarwal, Neelum T, Berman, Sarah B, Bird, Thomas D, Black, Sandra E, Borowski, Bret, Brooks, William S, Chhatwal, Jasmeer P, Li, Yan, Clarnette, Roger, Cruchaga, Carlos, Fagan, Anne M, Farlow, Martin, Fox, Nick C, Gauthier, Serge, Hassenstab, Jason, Hobbs, Diana A, Holdridge, Karen C, Honig, Lawrence S, McCullough, Austin A, Hornbeck, Russ C, Hsiung, Ging-Yuek R, Jack, Clifford R, Jimenez-Velazquez, Ivonne Z, Jucker, Mathias, Klein, Gregory, Levin, Johannes, Mancini, Michele, Masellis, Mario, McKay, Nicole S, Hofmann, Carsten, Mummery, Catherine J, Ringman, John M, Shimada, Hiroyuki, Snider, B Joy, Suzuki, Kazushi, Wallon, David, Xiong, Chengjie, Yaari, Roy, McDade, Eric, Perrin, Richard J, Wojtowicz, Jakub, Bateman, Randall J, Salloway, Stephen P, Benzinger, Tammie L S, Clifford, David B, Dominantly Inherited Alzheimer Network Trials Unit., Park, Ethan, Wang, Guoqiao, Preboske, Gregory M, and Wang, Qing

Subjects
Amyloid, Amyloid beta-Peptides, gantenerumab, genetics [Alzheimer Disease], Cross-Sectional Studies, Apolipoproteins E, Neurology, Alzheimer Disease, drug therapy [Alzheimer Disease], Humans, ddc:610, Neurology (clinical), diagnostic imaging [Alzheimer Disease], Biomarkers
Abstract

To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD).142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors.Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR 0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E.In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Published
2022
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20. APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression

Author

Dincer, Aylin, primary, Chen, Charles D., additional, McKay, Nicole S., additional, Koenig, Lauren N., additional, McCullough, Austin, additional, Flores, Shaney, additional, Keefe, Sarah J., additional, Schultz, Stephanie A., additional, Feldman, Rebecca L., additional, Joseph-Mathurin, Nelly, additional, Hornbeck, Russ C., additional, Cruchaga, Carlos, additional, Schindler, Suzanne E., additional, Holtzman, David M., additional, Morris, John C., additional, Fagan, Anne M., additional, Benzinger, Tammie L.S., additional, and Gordon, Brian A., additional

Published
2022
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21. Generation of a gene-corrected human isogenic iPSC line from an Alzheimer’s disease iPSC line carrying the PSEN1 H163R mutation

Author

Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bateman, Randall, Bechara, Jacob, Benzinger, Tammie, Berman, Sarah, Bodge, Courtney, Brandon, Sus, (Bill) Brooks, William, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Chrem Mendez, Patricio, Chua, Jasmin, Chui, Helena, Courtney, Laura, Cruchaga, Carlos, Day, Gregory S, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Fagan, Anne, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gordon, Brian, Gr¨aber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, H¨asler, Lisa, Hassenstab, Jason, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Jucker, Mathias, Karch, Celeste, K¨aser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Scott Mason, Neal, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, McDade, Eric, Mejia, Arlene, Morenas-Rodriguez, Estrella, Morris, John, Mountz, James, Mummery, Cath, Nadkarni, Neelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O’Connor, Antoinette, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, V¨oglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xiong, Chengjie, Xu, Jinbin, Xu, Xiong, Hernández, Damián, Morgan Schlicht, Stephanie, Elli Clarke, Jordan, Daniszewski, Maciej, Karch, Celeste M., Goate, Alison M., and Pébay, Alice

Published
2024
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22. Longitudinal head-to-head comparison of 11C-PiB and 18F-florbetapir PET in a Phase 2/3 clinical trial of anti-amyloid-β monoclonal antibodies in dominantly inherited Alzheimer's disease.

Author

Chen, Charles D., McCullough, Austin, Gordon, Brian, Joseph-Mathurin, Nelly, Flores, Shaney, McKay, Nicole S., Hobbs, Diana A., Hornbeck, Russ, Fagan, Anne M., Cruchaga, Carlos, Goate, Alison M., Perrin, Richard J., Wang, Guoqiao, Li, Yan, Shi, Xinyu, Xiong, Chengjie, Pontecorvo, Michael J., Klein, Gregory, Su, Yi, and Klunk, William E.

Subjects
*ALZHEIMER'S disease, *MONOCLONAL antibodies, *CLINICAL trials, *FALSE positive error, *POSITRON emission tomography, *RADIOACTIVE tracers
Abstract

Purpose : Pittsburgh Compound-B (11C-PiB) and 18F-florbetapir are amyloid-β (Aβ) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer's disease (AD) clinical trials to evaluate the efficacy of anti-Aβ monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aβ radiotracers were used. To study the consequences of using different Aβ radiotracers to measure Aβ clearance, we performed a head-to-head comparison of 11C-PiB and 18F-florbetapir in a Phase 2/3 clinical trial of anti-Aβ monoclonal antibodies. Methods: Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both 11C-PiB and 18F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using 11C-PiB while other sites use 18F-florbetapir for Aβ PET imaging. Results: In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11C-PiB SUVRs did not differ from that of global cortical 18F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11C-PiB SUVRs decreased more rapidly than global cortical 18F-florbetapir SUVRs. Drug effects were statistically significant across both Aβ radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aβ radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aβ radiotracers were used versus trials where only one Aβ radiotracer was used. Power was lower in trials where 18F-florbetapir was primarily used versus trials where 11C-PiB was primarily used. Conclusion: Gantenerumab treatment induces longitudinal changes in Aβ PET, and the absolute rates of these longitudinal changes differ significantly between Aβ radiotracers. These differences were not seen in the placebo arm, suggesting that Aβ-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aβ radiotracers. Our results suggest converting Aβ PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aβ PET biomarker data and, if feasible, use a single radiotracer for the best results. Trial registration: ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered. [ABSTRACT FROM AUTHOR]

Published
2023
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23. Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease

Author

Millar, Peter R., primary, Luckett, Patrick H., additional, Gordon, Brian A., additional, Benzinger, Tammie L.S., additional, Schindler, Suzanne E., additional, Fagan, Anne M., additional, Cruchaga, Carlos, additional, Bateman, Randall J., additional, Allegri, Ricardo, additional, Jucker, Mathias, additional, Lee, Jae-Hong, additional, Mori, Hiroshi, additional, Salloway, Stephen P, additional, Yakushev, Igor, additional, Morris, John C., additional, Ances, Beau M., additional, Adams, Sarah, additional, Araki, Aki, additional, Barthelemy, Nicolas, additional, Bateman, Randall, additional, Bechara, Jacob, additional, Benzinger, Tammie, additional, Berman, Sarah, additional, Bodge, Courtney, additional, Brandon, Susan, additional, Brooks, William (Bill), additional, Brosch, Jared, additional, Buck, Jill, additional, Buckles, Virginia, additional, Carter, Kathleen, additional, Cash, Lisa, additional, Chen, Charlie, additional, Chhatwal, Jasmeer, additional, Mendez, Patricio Chrem, additional, Chua, Jasmin, additional, Chui, Helena, additional, Courtney, Laura, additional, Day, Gregory S, additional, DeLaCruz, Chrismary, additional, Denner, Darcy, additional, Diffenbacher, Anna, additional, Dincer, Aylin, additional, Donahue, Tamara, additional, Douglas, Jane, additional, Duong, Duc, additional, Egido, Noelia, additional, Esposito, Bianca, additional, Fagan, Anne, additional, Farlow, Marty, additional, Feldman, Becca, additional, Fitzpatrick, Colleen, additional, Flores, Shaney, additional, Fox, Nick, additional, Franklin, Erin, additional, Joseph-Mathurin, Nelly, additional, Fujii, Hisako, additional, Gardener, Samantha, additional, Ghetti, Bernardino, additional, Goate, Alison, additional, Goldberg, Sarah, additional, Goldman, Jill, additional, Gonzalez, Alyssa, additional, Gordon, Brian, additional, Gräber-Sultan, Susanne, additional, Graff-Radford, Neill, additional, Graham, Morgan, additional, Gray, Julia, additional, Gremminger, Emily, additional, Grilo, Miguel, additional, Groves, Alex, additional, Haass, Christian, additional, Häsler, Lisa, additional, Hassenstab, Jason, additional, Hellm, Cortaiga, additional, Herries, Elizabeth, additional, Hoechst-Swisher, Laura, additional, Hofmann, Anna, additional, Holtzman, David, additional, Hornbeck, Russ, additional, Igor, Yakushev, additional, Ihara, Ryoko, additional, Ikeuchi, Takeshi, additional, Ikonomovic, Snezana, additional, Ishii, Kenji, additional, Jack, Clifford, additional, Jerome, Gina, additional, Johnson, Erik, additional, Karch, Celeste, additional, Käser, Stephan, additional, Kasuga, Kensaku, additional, Keefe, Sarah, additional, Klunk, William, additional, Koeppe, Robert, additional, Koudelis, Deb, additional, Kuder-Buletta, Elke, additional, Laske, Christoph, additional, Levey, Allan, additional, Levin, Johannes, additional, Li, Yan, additional, Lopez, Oscar, additional, Marsh, Jacob, additional, Martins, Ralph, additional, Mason, Neal Scott, additional, Masters, Colin, additional, Mawuenyega, Kwasi, additional, McCullough, Austin, additional, McDade, Eric, additional, Mejia, Arlene, additional, Morenas-Rodriguez, Estrella, additional, Morris, John, additional, Mountz, James, additional, Mummery, Cath, additional, Nadkarni, N eelesh, additional, Nagamatsu, Akemi, additional, Neimeyer, Katie, additional, Niimi, Yoshiki, additional, Noble, James, additional, Norton, Joanne, additional, Nuscher, Brigitte, additional, Obermüller, Ulricke, additional, O'Connor, Antoinette, additional, Patira, Riddhi, additional, Perrin, Richard, additional, Ping, Lingyan, additional, Preische, Oliver, additional, Renton, Alan, additional, Ringman, John, additional, Salloway, Stephen, additional, Schofield, Peter, additional, Senda, Michio, additional, Seyfried, Nicholas T, additional, Shady, Kristine, additional, Shimada, Hiroyuki, additional, Sigurdson, Wendy, additional, Smith, Jennifer, additional, Smith, Lori, additional, Snitz, Beth, additional, Sohrabi, Hamid, additional, Stephens, Sochenda, additional, Taddei, Kevin, additional, Thompson, Sarah, additional, Vöglein, Jonathan, additional, Wang, Peter, additional, Wang, Qing, additional, Weamer, Elise, additional, Xiong, Chengjie, additional, Xu, Jinbin, additional, and Xu, Xiong, additional

Published
2022
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24. Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease

Author

Millar, Peter R, Luckett, Patrick H, Lee, Jaehyun, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, Mori, Hiroshi, McCullough, Austin, McDade, Eric, Mejia, Arlene, Morenas Rodriguez, Estrella, Morris, John, Mountz, James, Mummery, Cath, Nadkarni, N Eelesh, Nagamatsu, Akemi, Neimeyer, Katie, Salloway, Stephen P, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O'Connor, Antoinette, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Yakushev, Igor, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Morris, John C, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Ances, Beau M, Xiong, Chengjie, Xu, Jinbin, Xu, Xiong, Network, Dominantly Inherited Alzheimer, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Gordon, Brian A, Barthelemy, Nicolas, Bateman, Randall, Bechara, Jacob, Benzinger, Tammie, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William Bill, Brosch, Jared, Buck, Jill, Benzinger, Tammie L S, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Mendez, Patricio Chrem, Chua, Jasmin, Chui, Helena, Courtney, Laura, Cruchaga, Carlos, Schindler, Suzanne E, Day, Gregory S, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Fagan, Anne M, Fagan, Anne, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gordon, Brian, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Bateman, Randall J, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häsler, Lisa, Hassenstab, Jason, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Jucker, Mathias, Johnson, Erik, Karch, Celeste, Kaeser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, and Kuder-Buletta, Elke

Subjects
Adult, Aged, 80 and over, Adolescent, Resting-state functional connectivity, Cognitive Neuroscience, fMRI, Brain, Neuroimaging, Middle Aged, Magnetic Resonance Imaging, pathology [Alzheimer Disease], Young Adult, physiology [Brain], methods [Magnetic Resonance Imaging], Neurology, Brain aging, Alzheimer Disease, Machine learning, Humans, ddc:610, Alzheimer disease, Biomarkers, Aged
Abstract

"Brain-predicted age" quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18-89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker.

Published
2022
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26. The interaction of APOE genotype and amyloid‐β PET predicts PET but not CSF measures of tauopathy in regions of high APOE mRNA expression

Author

Dincer, Aylin, primary, Chen, Charles D., additional, McKay, Nicole S., additional, McCullough, Austin A., additional, Flores, Shaney E., additional, Keefe, Sarah J., additional, Schultz, Stephanie A., additional, Feldman, Rebecca L., additional, Hornbeck, Russ C., additional, Cruchaga, Carlos, additional, Holtzman, David M., additional, Morris, John C., additional, Benzinger, Tammie L.S., additional, and Gordon, Brian A., additional

Published
2021
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27. [11C]PiB and [18F]AV45 PET radiotracers show different rates of amyloid‐β clearance

Author

Chen, Charles D., primary, McCullough, Austin A., additional, Gordon, Brian A., additional, Joseph‐Mathurin, Nelly, additional, Wang, Guoqiao, additional, Li, Yan, additional, Xiong, Chengjie, additional, Pontecorvo, Michael J., additional, Klein, Gregory, additional, Shcherbinin, Sergey, additional, Higgins, Ixavier A., additional, Masters, Colin L, additional, Clifford, David B., additional, van Dyck, Christopher H, additional, Masellis, Mario, additional, Hsiung, Ging‐Yuek Robin, additional, Gauthier, Serge, additional, Bateman, Randall J., additional, McDade, Eric, additional, Salloway, Stephen P., additional, and Benzinger, Tammie L.S., additional

Published
2021
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28. Association ofBDNFVal66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease

Author

Lim, Yen Ying, Maruff, Paul, Levin, Johannes, Snitz, Beth, Thompson, Sarah, Weamer, Elise, Mason, Neal Scott, Chui, Helena, Ringman, John, Adams, Sarah, Barthelemy, Nicolas, Bateman, Randall, Benzinger, Tammie, Farlow, Martin R, Brandon, Susan, Buckles, Virginia, Cash, Lisa, Chen, Charlie, Chua, Jasmin, Cruchaga, Carlos, Denner, Darcy, Dincer, Aylin, Donahue, Tamara, Fagan, Anne, Graff-Radford, Neill R, Feldman, Becca, Flores, Shaney, Franklin, Erin, Friedrichsen, Nelly, Gonzalez, Alyssa, Gordon, Brian, Gray, Julia, Gremminger, Emily, Groves, Alex, Hassenstab, Jason, Laske, Christoph, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Holtzman, David, Hornbeck, Russ, Jerome, Gina, Karch, Celeste, Keefe, Sarah, Koudelis, Deb, Li, Yan, Masters, Colin L, Marsh, Jacob, Martinez, Rita, Mawuenyega, Kwasi, McCullough, Austin, McDade, Eric, Morris, John, Norton, Joanne, Perrin, Richard, Shady, Kristine, Sigurdson, Wendy, Salloway, Stephen, Smith, Jennifer, Wang, Peter, Wang, Qing, Xiong, Chengjie, Xu, Jinbin, Xu, Xiong, Schofield, Peter R, Morris, John C, Bateman, Randall J, Barthélemy, Nicolas R, Network, Dominantly Inherited Alzheimer, Chhatwal, Jasmeer, Fitzpatrick, Colleen, Bodge, Courtney, De La Cruz, Chrismary, Goldman, Jill, Mejia, Arlene, Neimeyer, Katie, Noble, James, Goate, Alison, Gardener, Samantha, Martins, Ralph, Sohrabi, Hamid, Taddei, Kevin, Carter, Kathleen, Duong, Duc, Johnson, Erik, Levey, Allan, Ping, Lingyan, Seyfried, Nick, Gräber-Sultan, Susanne, Häsler, Lisa, Hofmann, Anna, Jucker, Mathias, Kaeser, Stephan, Kuder-Buletta, Elke, Preische, Oliver, Diffenbacher, Anna, Igor, Yakushev, Sato, Chihiro, Vöglein, Jonathan, Obermüller, Ulricke, Esposito, Bianca, Renton, Alan, Brosch, Jared, Buck, Jill, Farlow, Marty, Ghetti, Bernardino, Fagan, Anne M, Allegri, Ricardo, Chrem, Patricio, Egido, Noelia, Haass, Christian, Morenas Rodriguez, Estrella, Nuscher, Brigitte, Day, Gregory S, Graff-Radford, Neill, Graham, Morgan, Stephens, Sochenda, Benzinger, Tammie L S, Jack, Clifford, Bechara, Jacob, Brooks, William Bill, Schofield, Peter, Araki, Aki, Ikeuchi, Takeshi, Kasuga, Kensaku, Ishii, Kenji, Fujii, Hisako, Senda, Michio, Shimada, Hiroyuki, Ihara, Ryoko, Nagamatsu, Akemi, Niimi, Yoshiki, Douglas, Jane, Fox, Nick, Grilo, Miguel, Mummery, Cath, O'Connor, Antoinette, Masters, Colin, Koeppe, Robert, Berman, Sarah, Goldberg, Sarah, Ikonomovic, Snezana, Klunk, William Bill, Lopez, Oscar, Mountz, James, Nadkarni, Neelesh, Patira, Riddhi, and Smith, Lori

Subjects
Adult, Male, Threonine, Memory Disorders, methods [Positron-Emission Tomography], cerebrospinal fluid [Amyloid beta-Peptides], Middle Aged, genetics [Brain-Derived Neurotrophic Factor], cerebrospinal fluid [Alzheimer Disease], Cognition, Cross-Sectional Studies, cerebrospinal fluid [tau Proteins], Humans, Female, ddc:610, Neurology (clinical), Biomarkers, Aged
Abstract

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism moderates increases in cerebrospinal fluid (CSF) levels of tau and phosphorylated tau 181 (p-tau181), measured using immunoassay, and cognitive decline in presymptomatic dominantly inherited Alzheimer disease (DIAD). Advances in mass spectrometry show that CSF tau phosphorylation occupancy at threonine 181 and 217 (p-tau181/tau181, p-tau217/tau217) increases with initial β-amyloid (Aβ) aggregation, while phosphorylation occupancy at threonine 205 (p-tau205/tau205) and level of total tau increase when brain atrophy and clinical symptoms become evident.To determine whether site-specific tau phosphorylation occupancy (ratio of phosphorylated to unphosphorylated tau) is associated with BDNF Val66Met in presymptomatic and symptomatic DIAD.This cross-sectional cohort study included participants from the Dominantly Inherited Alzheimer Network (DIAN) and Aβ-positive cognitively normal older adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data were collected from 2009 through 2018 at multicenter clinical sites in the United States, United Kingdom, and Australia, with no follow-up. DIAN participants provided a CSF sample and completed clinical and cognitive assessments. Data analysis was conducted between March 2020 and March 2021.Mass spectrometry analysis was used to determine site-specific tau phosphorylation level; tau levels were also measured using immunoassay. Episodic memory and global cognitive composites were computed.Of 374 study participants, 144 were mutation noncarriers, 156 were presymptomatic mutation carriers, and 74 were symptomatic carriers. Of the 527 participants in the network, 153 were excluded because their CSF sample, BDNF status, or both were unavailable. Also included were 125 Aβ-positive cognitively normal older adults in the ADNI. The mean (SD) age of DIAD participants was 38.7 (10.9) years; 43% were women. The mean (SD) age of participants with preclinical sporadic AD was 74.8 (5.6) years; 52% were women. In presymptomatic mutation carriers, compared with Val66 homozygotes, Met66 carriers showed significantly poorer episodic memory (d = 0.62; 95% CI, 0.28-0.95), lower hippocampal volume (d = 0.40; 95% CI, 0.09-0.71), and higher p-tau217/tau217 (d = 0.64; 95% CI, 0.30-0.97), p-tau181/tau181 (d = 0.65; 95% CI, 0.32-0.99), and mass spectrometry total tau (d = 0.43; 95% CI, 0.10-0.76). In symptomatic mutation carriers, Met66 carriers showed significantly poorer global cognition (d = 1.17; 95% CI, 0.65-1.66) and higher p-tau217/tau217 (d = 0.53; 95% CI, 0.05-1.01), mass spectrometry total tau (d = 0.78; 95% CI, 0.28-1.25), and p-tau205/tau205 (d = 0.97; 95% CI, 0.46-1.45), when compared with Val66 homozygotes. In preclinical sporadic AD, Met66 carriers showed poorer episodic memory (d = 0.39; 95% CI, 0.00-0.77) and higher total tau (d = 0.45; 95% CI, 0.07-0.84) and p-tau181 (d = 0.46; 95% CI, 0.07-0.85).In DIAD, clinical disease stage and BDNF Met66 were associated with cognitive impairment and levels of site-specific tau phosphorylation. This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial.

Published
2022
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31. Evaluation of dose‐dependent treatment effects after mid‐trial dose escalation in biomarker, clinical, and cognitive outcomes for gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Author

Wang, Guoqiao, Li, Yan, Xiong, Chengjie, McDade, Eric, Clifford, David B., Mills, Susan L., Santacruz, Anna M., Aschenbrenner, Andrew J., Hassenstab, Jason, Benzinger, Tammie L.S., Gordon, Brian A., Fagan, Anne M., Coalier, Kelley A., Libre‐Guerra, Jorge J., McCullough, Austin, Joseph‐Mathurin, Nelly, Chen, Charles D., Mummery, Catherine, Wendelberger, Barbara A., and Gauthier, Serge

Subjects
ALZHEIMER'S disease, TREATMENT effectiveness, POSITRON emission tomography, CEREBROSPINAL fluid, BIOMARKERS
Abstract

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5‐fold, and solanezumab was increased 4‐fold. We evaluated to what extent mid‐trial dose increases produced a dose‐dependent treatment effect. Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low‐ and high‐dose treatment effects in clinical, cognitive, and biomarker outcomes. Results: Both gantenerumab and solanezumab demonstrated dose‐dependent treatment effects (significant for gantenerumab, non‐significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose‐dependent treatment effects were observed in clinical or cognitive outcomes. Conclusions: Mid‐trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. Highlights: We evaluated the dose‐dependent treatment effect of two different amyloid‐specific immunotherapies.Dose‐dependent treatment effects were observed in some biomarkers.No dose‐dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations. [ABSTRACT FROM AUTHOR]

Published
2022
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32. Evaluating Regional Importance for Tau Spatial Spread in Predicting Cognitive Impairment with Machine Learning.

Author

Doering, Stephanie, McCullough, Austin A., Gordon, Brian A., Chen, Charles D., McKay, Nicole S., Hobbs, Diana A., Keefe, Sarah J., Flores, Shaney, Hornbeck, Russ C., Xiong, Chengjie, Hassenstab, Jason J., Bateman, Randall J., Ances, Beau, Morris, John C, and Benzinger, Tammie L.S.

Abstract

Background: Cognitive decline in Alzheimer Disease (AD) is strongly correlated to the spatiotemporal pattern of tau‐protein neurofibrillary tangles (NFTs). Evidence suggests tau seeding spreads transneuronally in a prion‐like manner, a biological process distinct from NFT aggregation in previously‐affected regions. We previously proposed a method for quantifying global tau spatial spread (TSS) using tau positron emission tomography (PET) which found TSS is particularly informative in preclinical AD. The spread of tau pathology into specific regions may therefore be key to the onset of cognitive decline. Methods: 445 older adult and 21 younger control participants were recruited. Cognition was assessed with the Knight ADRC‐PACC and Tau‐PET images were parcellated using the Schaeffer400 atlas. For each region, TSS was calculated as the proportion of voxels with significant levels of tau. Abnormal voxels were identified by z‐scoring tau‐PET voxel‐wise relative to corresponding voxels in younger controls and then thresholded at z>1.96 for significance. This study predicted participant PACC from regional TSS using random forest regression (trained with 100 repeated 10‐folds). Feature importance (FI) was calculated with Mean Decrease in Impurity to identify regions in which tau spread is most significant to cognitive impairment. Results: Regional TSS demonstrated highly saturated regions in the limbic and temporal lobes with progressively lower levels in peripheral regions, largely sparing the frontal lobe (Figure 1). However, the importance of regional spread in predicting cognition did not reflect the same spatial pattern (Figure 2). Four regions emerged with the highest FI in the limbic and default networks, indicating the spread of tau within these brain regions is key to predicting cognitive impairment (Table 1). Conclusion: Our results suggest that tau pathology has spread extensively within medial and temporal regions early in AD. Regional TSS can be used to identify peripheral regions in which tau pathology is currently spreading into. As expected, limbic regions in the temporal lobe were critical to predicting participant cognitive impairment. However, regions in the temporal and parietal lobes belonging to the default network were additionally informative. Spread of tau pathology into new peripheral brain regions should therefore be evaluated when predicting future AD‐related cognitive decline. [ABSTRACT FROM AUTHOR]

Published
2023
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33. Modeling autosomal dominant Alzheimer's disease with machine learning.

Author

Luckett, Patrick H., McCullough, Austin, Gordon, Brian A., Strain, Jeremy, Flores, Shaney, Dincer, Aylin, McCarthy, John, Kuffner, Todd, Stern, Ari, Meeker, Karin L., Berman, Sarah B., Chhatwal, Jasmeer P., Cruchaga, Carlos, Fagan, Anne M., Farlow, Martin R., Fox, Nick C., Jucker, Mathias, Levin, Johannes, Masters, Colin L., and Mori, Hiroshi

Abstract

Introduction: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease. Methods: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non‐carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status. Results: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R2 = 0.95), fluorodeoxyglucose (R2 = 0.93), and atrophy (R2 = 0.95) in mutation carriers compared to non‐carriers. Discussion: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions. [ABSTRACT FROM AUTHOR]

Published
2021
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34. P2-412: PRECLINICAL AD PATHOLOGY PARTIALLY MEDIATES THE RELATIONSHIP BETWEEN CORTICAL THICKNESS AND ATTENTIONAL CONTROL

Author

Dincer, Aylin, primary, Mehrotra, Vidushri, additional, Aschenbrenner, Andrew J., additional, McCullough, Austin A., additional, Duchek, Janet M., additional, Balota, David A., additional, Chen, Gengsheng, additional, Hornbeck, Russ C., additional, Morris, John C., additional, Benzinger, Tammie L.S., additional, and Gordon, Brian A., additional

Published
2019
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35. IC-P-090: COMPARISON OF ALZHEIMER'S DISEASE BIOMARKER MEASURES AS PREDICTORS OF COGNITION

Author

Dincer, Aylin, primary, Gordon, Brian A., additional, Vlassenko, Andrei G., additional, Goyal, Manu S., additional, Aschenbrenner, Andrew J., additional, McCullough, Austin A., additional, Adedokun, Adedamola, additional, Marple, Laura M., additional, Flores, Shaney, additional, Keefe, Sarah, additional, Chen, Gengsheng, additional, Hornbeck, Russ C., additional, Morris, John C., additional, and Benzinger, Tammie L.S., additional

Published
2019
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42. Reduced non–rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease

Author

Lucey, Brendan P., primary, McCullough, Austin, additional, Landsness, Eric C., additional, Toedebusch, Cristina D., additional, McLeland, Jennifer S., additional, Zaza, Aiad M., additional, Fagan, Anne M., additional, McCue, Lena, additional, Xiong, Chengjie, additional, Morris, John C., additional, Benzinger, Tammie L. S., additional, and Holtzman, David M., additional

Published
2019
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45. A time‐embedding network model captures dynamic longitudinal pathology changes in a dominantly inherited Alzheimer disease population: Neuroimaging / New imaging methods.

Author

McCullough, Austin A, Gordon, Brian A, McDade, Eric, Bateman, Randall J, Morris, John C, and Benzinger, Tammie LS

Abstract

Background: Population‐level analyses of autosomal dominant Alzheimer disease (ADAD) cohorts have revealed a roadmap of neuropathological and volumetric changes that increase over disease‐time and culminate in severe cognitive impairment. Traditional statistical analysis approaches struggle to integrate these cohort‐level dynamics with patient data to inform disease trajectory predictions at the individual level. Current machine learning approaches excel at this integration of population and individual level information, but require much larger sample sizes than current Alzheimer disease research cohorts can provide. The current work introduces a time‐embedding neural network in order to accurately represent known disease‐time dependent patterns among neuroimaging variables. The network is trained to predict ADAD carrier status to demonstrate the ability of this framework to make actionable predictions within ADAD populations. Method: 468 participants from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer Network (DIAN) were selected for analysis. Structural MRI, [11C] Pittsburgh Compound B (PiB) PET, and [18F] Fluorodeoxyglucose (FDG) PET region of interest imaging data was utilized (Table 1). DIAN estimated years to symptom onset (EYO) was used as disease‐time. The time‐embedding network learns EYO‐dependent representations of all imaging data in both mutation carrier and non‐carrier groups. These representations are combined with control variables and passed to a decoder network trained to output carrier status predictions (Figure 1). Result: The time‐embedding network captures three main longitudinal pathology dynamics that correspond to known longitudinal PiB PET, FDG PET, and volumetric pathology changes in ADAD populations (Figure 2A). The network was successfully trained to predict ADAD carrier status in individual participants (Figure 2B). Prediction accuracy increases as the time of prediction moves closer to onset of clinical symptoms (Figure 2C). Conclusion: The time‐embedding network model is able to accurately represent nonlinear time‐dependent processes in a low‐dimensional, sparsely sampled embedding. This embedding provides an interpretable framework that is consistent with known longitudinal pathology changes when applied to an ADAD population, and can be trained to make accurate longitudinal predictions with currently available data sets. [ABSTRACT FROM AUTHOR]

Published
2020
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46. P3‐401: EXAMINING THE ABILITY OF A TAU SPATIAL SPREAD METRIC TO INDICATE DISEASE PROGRESSION COMPARED TO AN INTENSITY‐BASED APPROACH

Author

McCullough, Austin A., primary, Gordon, Brian A., additional, Christensen, Jon, additional, Dincer, Aylin, additional, Keefe, Sarah, additional, Flores, Shaney, additional, Hornbeck, Russ C., additional, Bateman, Randall J., additional, Morris, John C., additional, Ances, Beau M., additional, and Benzinger, Tammie L.S., additional

Published
2018
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47. IC‐P‐207: EXAMINING THE ABILITY OF A TAU SPATIAL SPREAD METRIC TO INDICATE DISEASE PROGRESSION COMPARED TO AN INTENSITY‐BASED APPROACH

Author

McCullough, Austin A., primary, Gordon, Brian A., additional, Christensen, Jon, additional, Dincer, Aylin, additional, Keefe, Sarah, additional, Flores, Shaney, additional, Hornbeck, Russ C., additional, Bateman, Randall J., additional, Morris, John C., additional, Ances, Beau M., additional, and Benzinger, Tammie L.S., additional

Published
2018
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49. Ultrasound‐Guided Fine‐Needle Aspiration With Optional Core Needle Biopsy of Head and Neck Lymph Nodes and Masses: Comparison of Diagnostic Performance in Treated Squamous Cell Cancer Versus All Other Lesions.

Author

Wagner, Jason M., Monfore, Natosha, McCullough, Austin J., Zhao, Lichao, Conrad, Rachel D., Krempl, Greg A., and Alleman, Anthony M.

Subjects
CORE needle biopsy, SQUAMOUS cell carcinoma, LYMPH nodes, NEEDLE biopsy, DIAGNOSTIC ultrasonic imaging
Abstract

Objectives: To evaluate the diagnostic performance of ultrasound (US)‐guided fine‐needle aspiration with optional core needle biopsy of head and neck lymph nodes and masses, with attention to differences between biopsy of treated squamous cell carcinoma (SCC) and biopsy of other lesions. Methods: Institutional Review Board approval was obtained, and the need for consent was waived for this retrospective study. All 861 US‐guided biopsies of head and neck lymph nodes and masses performed between March 1, 2012, and May 16, 2016, were reviewed. Results: Of the 861 biopsies, 53 targeted SCC with residual masses after treatment. The biopsy procedures yielded benign or malignant pathologic results in 71.7% (38 of 53) of treated SCC and 90.7% (733 of 808) of all other lesions (P < .001). A reference standard based on subsequent pathologic results or clinical and imaging follow‐up was established in 68.4% of procedures. In cases with benign or malignant biopsy results and a subsequent reference standard, the sensitivity values for malignancy were 87.5% (95% confidence interval, 64.0%–96.5%) in treated SCC and 98.3% (95% confidence interval, 96.0%–99.3%) in all other cases (P = .047), and the specificity values were 63.6% (95% confidence interval, 35.4%–84.8%) in treated SCC and 99.5% (95% confidence interval, 97.3%–99.9%) in all other cases (P < .001). There were no major complications related to the biopsy procedures. Conclusions: Excluding treated SCC, US‐guided fine‐needle aspiration with optional core needle biopsy of head and neck lymph nodes and masses has excellent diagnostic performance. Needle biopsy of head and neck SCC with a residual mass after therapy has a high rate of nondiagnostic samples, suboptimal sensitivity, and poor specificity. [ABSTRACT FROM AUTHOR]

Published
2019
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