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204 results on '"Vöglein, Jonathan"'

1. 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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2. Biomarker clustering in autosomal dominant Alzheimers disease.

Author

Luckett, Patrick, Chen, Charlie, Gordon, Brian, Wisch, Julie, Berman, Sarah, Chhatwal, Jasmeer, Cruchaga, Carlos, Fagan, Anne, Farlow, Martin, Fox, Nick, Jucker, Mathias, Levin, Johannes, Masters, Colin, Mori, Hiroshi, Noble, James, Salloway, Stephen, Schofield, Peter, Brickman, Adam, Brooks, William, Cash, David, Fulham, Michael, Ghetti, Bernardino, Jack, Clifford, Vöglein, Jonathan, Klunk, William, Koeppe, Robert, Su, Yi, Weiner, Michael, Wang, Qing, Marcus, Daniel, Koudelis, Deborah, Joseph-Mathurin, Nelly, Cash, Lisa, Hornbeck, Russ, Xiong, Chengjie, Perrin, Richard, Karch, Celeste, Hassenstab, Jason, McDade, Eric, Morris, John, Benzinger, Tammie, Bateman, Randall, and Ances, Beau

Subjects
Autosomal dominant Alzheimers disease, biomarkers, machine learning, Humans, Alzheimer Disease, Amyloid beta-Peptides, Amyloidogenic Proteins, Biomarkers, Cross-Sectional Studies, Inflammation, tau Proteins
Abstract

INTRODUCTION: As the number of biomarkers used to study Alzheimers disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.

Published
2023

3. Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology

Author

Morris, John C, Weiner, Michael, Xiong, Chengjie, Beckett, Laurel, Coble, Dean, Saito, Naomi, Aisen, Paul S, Allegri, Ricardo, Benzinger, Tammie LS, Berman, Sarah B, Cairns, Nigel J, Carrillo, Maria C, Chui, Helena C, Chhatwal, Jasmeer P, Cruchaga, Carlos, Fagan, Anne M, Farlow, Martin, Fox, Nick C, Ghetti, Bernardino, Goate, Alison M, Gordon, Brian A, Graff-Radford, Neill, Day, Gregory S, Hassenstab, Jason, Ikeuchi, Takeshi, Jack, Clifford R, Jagust, William J, Jucker, Mathias, Levin, Johannes, Massoumzadeh, Parinaz, Masters, Colin L, Martins, Ralph, McDade, Eric, Mori, Hiroshi, Noble, James M, Petersen, Ronald C, Ringman, John M, Salloway, Stephen, Saykin, Andrew J, Schofield, Peter R, Shaw, Leslie M, Toga, Arthur W, Trojanowski, John Q, Vöglein, Jonathan, Weninger, Stacie, Bateman, Randall J, and Buckles, Virginia D

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Brain Disorders, Clinical Trials and Supportive Activities, Alzheimer's Disease, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biomedical Imaging, Genetics, Aging, Acquired Cognitive Impairment, Neurosciences, Neurodegenerative, Dementia, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Alzheimer Disease, Amyloid beta-Peptides, Magnetic Resonance Imaging, Amyloidosis, Biomarkers, Alzheimer pathophysiology, biomarkers, rates of change, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.

Published
2022

4. 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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6. 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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7. Comparison of tau spread in people 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, 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, Bateman, Randall, Daniels, Alisha J., Courtney, Laura, McDade, Eric, Llibre-Guerra, Jorge J., Supnet-Bell, Charlene, Xiong, Chengie, Xu, Xiong, Lu, Ruijin, Wang, Guoqiao, Li, Yan, Gremminger, Emily, Perrin, Richard J., Franklin, Erin, Ibanez, Laura, Jerome, Gina, Herries, Elizabeth, Stauber, Jennifer, Baker, Bryce, Minton, Matthew, Cruchaga, Carlos, Goate, Alison M., Renton, Alan E., Picarello, Danielle M., Benzinger, Tammie, Gordon, Brian A., Hornbeck, Russall, Hassenstab, Jason, Smith, Jennifer, Stout, Sarah, Aschenbrenner, Andrew J., Karch, Celeste M., Marsh, Jacob, Morris, John C., Holtzman, David M., Barthelemy, Nicolas, Xu, Jinbin, Noble, James M., Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh K., Day, Gregory, Graff-Radford, Neill R., Farlow, Martin, Chhatwal, Jasmeer P., Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Huey, Edward D., Salloway, Stephen, Schofield, Peter R., Brooks, William S., Bechara, Jacob A., Martins, Ralph, Fox, Nick C., Cash, David M., Ryan, Natalie S., Jucker, Mathias, Laske, Christoph, Hofmann, Anna, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Obermueller, Ulrike, Levin, Johannes, Roedenbeck, Yvonne, Vöglein, Jonathan, Lee, Jae-Hong, Roh, Jee Hoon, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Allegri, Ricardo F., Chrem Mendez, Patricio, Surace, Ezequiel, Vazquez, Silvia, Lopera, Francisco, Leon, Yudy Milena, Ramirez, Laura, Aguillon, David, Levey, Allan I., Johnson, Erik C.B, Seyfried, Nicholas T., Ringman, John, Mori, Hiroshi, Wisch, Julie K, McKay, Nicole S, Boerwinkle, Anna H, Kennedy, James, Flores, Shaney, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O’Bryant, Sid E, Price, Julie C, Laymon, Charles M, Krinsky-McHale, Sharon J, Lai, Florence, Rosas, H Diana, Hartley, Sigan L, Lott, Ira T, Tudorascu, Dana, Zammit, Matthew, Brickman, Adam M, Lee, Joseph H, Bird, Thomas D, Cohen, Annie, Chrem, Patricio, Daniels, Alisha, Chhatwal, Jasmeer P, Karch, Celeste M, Day, Gregory S, Llibre-Guerra, Jorge, Ringman, John M, van Dyck, Christopher H, Xiong, Chengjie, Morris, John C, Bateman, Randall J, Benzinger, Tammie L S, Gordon, Brian A, and Ances, Beau M

Published
2024
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8. Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

Author

Millar, Peter R, Gordon, Brian A, Wisch, Julie K, Schultz, Stephanie A, Benzinger, Tammie LS, Cruchaga, Carlos, Hassenstab, Jason J, Ibanez, Laura, Karch, Celeste, Llibre-Guerra, Jorge J, Morris, John C, Perrin, Richard J, Supnet-Bell, Charlene, Xiong, Chengjie, Allegri, Ricardo F, Berman, Sarah B, Chhatwal, Jasmeer P, Chrem Mendez, Patricio A, Day, Gregory S, Hofmann, Anna, Ikeuchi, Takeshi, Jucker, Mathias, Lee, Jae-Hong, Levin, Johannes, Lopera, Francisco, Niimi, Yoshiki, Sánchez-González, Victor J, Schofield, Peter R, Sosa-Ortiz, Ana Luisa, Vöglein, Jonathan, Bateman, Randall J, Ances, Beau M, and McDade, Eric M

Published
2023
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9. Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort

Author

Kommaddi, Reddy Peera, Verma, Aditi, Muniz-Terrera, Graciela, Tiwari, Vivek, Chithanathan, Keerthana, Diwakar, Latha, Gowaikar, Ruturaj, Karunakaran, Smitha, Malo, Palash Kumar, Graff-Radford, Neill R., Day, Gregory S., Laske, Christoph, Vöglein, Jonathan, Nübling, Georg, Ikeuchi, Takeshi, Kasuga, Kensaku, and Ravindranath, Vijayalakshmi

Published
2023
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10. Deep Learning in current Neuroimaging: a multivariate approach with power and type I error control but arguable generalization ability

Author

Jiménez-Mesa, Carmen, Ramírez, Javier, Suckling, John, Vöglein, Jonathan, Levin, Johannes, Górriz, Juan Manuel, ADNI, Alzheimer's Disease Neuroimaging Initiative, and DIAN, Dominantly Inherited Alzheimer Network

Subjects
Statistics - Machine Learning, Computer Science - Machine Learning, Electrical Engineering and Systems Science - Image and Video Processing, Statistics - Applications
Abstract

Discriminative analysis in neuroimaging by means of deep/machine learning techniques is usually tested with validation techniques, whereas the associated statistical significance remains largely under-developed due to their computational complexity. In this work, a non-parametric framework is proposed that estimates the statistical significance of classifications using deep learning architectures. In particular, a combination of autoencoders (AE) and support vector machines (SVM) is applied to: (i) a one-condition, within-group designs often of normal controls (NC) and; (ii) a two-condition, between-group designs which contrast, for example, Alzheimer's disease (AD) patients with NC (the extension to multi-class analyses is also included). A random-effects inference based on a label permutation test is proposed in both studies using cross-validation (CV) and resubstitution with upper bound correction (RUB) as validation methods. This allows both false positives and classifier overfitting to be detected as well as estimating the statistical power of the test. Several experiments were carried out using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, the Dominantly Inherited Alzheimer Network (DIAN) dataset, and a MCI prediction dataset. We found in the permutation test that CV and RUB methods offer a false positive rate close to the significance level and an acceptable statistical power (although lower using cross-validation). A large separation between training and test accuracies using CV was observed, especially in one-condition designs. This implies a low generalization ability as the model fitted in training is not informative with respect to the test set. We propose as solution by applying RUB, whereby similar results are obtained to those of the CV test set, but considering the whole set and with a lower computational cost per iteration., Comment: 26 pages, 10 figures, 13 tables

Published
2021

11. Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease

Author

Keret, Ophir, Staffaroni, Adam M, Ringman, John M, Cobigo, Yann, Goh, Sheng‐Yang M, Wolf, Amy, Allen, Isabel Elaine, Salloway, Stephen, Chhatwal, Jasmeer, Brickman, Adam M, Reyes‐Dumeyer, Dolly, Bateman, Randal J, Benzinger, Tammie LS, Morris, John C, Ances, Beau M, Joseph‐Mathurin, Nelly, Perrin, Richard J, Gordon, Brian A, Levin, Johannes, Vöglein, Jonathan, Jucker, Mathias, la Fougère, Christian, Martins, Ralph N, Sohrabi, Hamid R, Taddei, Kevin, Villemagne, Victor L, Schofield, Peter R, Brooks, William S, Fulham, Michael, Masters, Colin L, Ghetti, Bernardino, Saykin, Andrew J, Jack, Clifford R, Graff‐Radford, Neill R, Weiner, Michael, Cash, David M, Allegri, Ricardo F, Chrem, Patricio, Yi, Su, Miller, Bruce L, Rabinovici, Gil D, Rosen, Howard J, and Network, Dominantly Inherited Alzheimer

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Aging, Prevention, Neurodegenerative, Alzheimer's Disease, Dementia, Brain Disorders, Acquired Cognitive Impairment, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Patient Safety, Neurological, Good Health and Well Being, autosomal dominant Alzheimer's disease, brain atrophy, Dominantly Inherited Alzheimer Network, preclinical Alzheimer's disease, Biological psychology
Abstract

IntroductionAsymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.MethodsWe created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.ResultsOur risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset.DiscussionIndividualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.

Published
2021

13. 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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14. 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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15. Covariance-based vs. correlation-based functional connectivity dissociates healthy aging from Alzheimer disease

Author

Strain, Jeremy F., Brier, Matthew R., Tanenbaum, Aaron, Gordon, Brian A., McCarthy, John E., Dincer, Aylin, Marcus, Daniel S., Chhatwal, Jasmeer P., Graff-Radford, Neill R., Day, Gregory S., la Fougère, Christian, Perrin, Richard J., Salloway, Stephen, Schofield, Peter R., Yakushev, Igor, Ikeuchi, Takeshi, Vöglein, Jonathan, Morris, John C., Benzinger, Tammie L.S., Bateman, Randall J., Ances, Beau M., and Snyder, Abraham Z.

Published
2022
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16. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease

Author

Preische, Oliver, Schultz, Stephanie A, Apel, Anja, Kuhle, Jens, Kaeser, Stephan A, Barro, Christian, Gräber, Susanne, Kuder-Buletta, Elke, LaFougere, Christian, Laske, Christoph, Vöglein, Jonathan, Levin, Johannes, Masters, Colin L, Martins, Ralph, Schofield, Peter R, Rossor, Martin N, Graff-Radford, Neill R, Salloway, Stephen, Ghetti, Bernardino, Ringman, John M, Noble, James M, Chhatwal, Jasmeer, Goate, Alison M, Benzinger, Tammie LS, Morris, John C, Bateman, Randall J, Wang, Guoqiao, Fagan, Anne M, McDade, Eric M, Gordon, Brian A, and Jucker, Mathias

Subjects
Dementia, Alzheimer's Disease, Aging, Acquired Cognitive Impairment, Neurosciences, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Clinical Research, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Neurological, Good Health and Well Being, Alzheimer Disease, Disease Progression, Humans, Mutation, Nerve Degeneration, Neurofilament Proteins, Dominantly Inherited Alzheimer Network, Medical and Health Sciences, Immunology
Abstract

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.

Published
2019

17. 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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18. 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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19. Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer's disease

Author

Brown, Belinda M, Sohrabi, Hamid R, Taddei, Kevin, Gardener, Samantha L, Rainey‐Smith, Stephanie R, Peiffer, Jeremiah J, Xiong, Chengjie, Fagan, Anne M, Benzinger, Tammie, Buckles, Virginia, Erickson, Kirk I, Clarnette, Roger, Shah, Tejal, Masters, Colin L, Weiner, Michael, Cairns, Nigel, Rossor, Martin, Graff‐Radford, Neill R, Salloway, Stephen, Vöglein, Jonathan, Laske, Christoph, Noble, James, Schofield, Peter R, Bateman, Randall J, Morris, John C, and Martins, Ralph N

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Aging, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Alzheimer Disease, Amyloid, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Aniline Compounds, Apolipoproteins E, Brain, Cohort Studies, Cross-Sectional Studies, Exercise, Female, Genotype, Humans, Linear Models, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Peptide Fragments, Positron-Emission Tomography, Presenilin-1, Presenilin-2, Surveys and Questionnaires, Thiazoles, tau Proteins, Physical activity, Amyloid beta, Genetics, Tau, Alzheimer's disease, Dominantly Inherited Alzheimer Network, Amyloid β, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionThe objective of this study was to evaluate the relationship between self-reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers.MethodsIn 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self-reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ42, and CSF tau levels was evaluated using linear regression.ResultsNo differences in brain amyloid load, CSF Aβ42, or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels.DiscussionOur findings indicate a relationship exists between self-reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers.

Published
2017

20. Measurement properties of the German version of the Cambridge examination for mental disorders of older people with Down syndrome and others with intellectual disabilities (CAMDEX-DS)

Author

Loosli, Sandra V., primary, Neumann, Lennart C., additional, Wlasich, Elisabeth, additional, Prix, Catharina, additional, Koll, Laura, additional, Weidinger, Endy, additional, Vöglein, Jonathan, additional, Wagemann, Olivia, additional, Danek, Adrian, additional, Nübling, Georg, additional, and Levin, Johannes, additional

Published
2024
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22. α‐Synuclein seed amplification assay detects Lewy body co‐pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden.

Author

Levin, Johannes, Baiardi, Simone, Quadalti, Corinne, Rossi, Marcello, Mammana, Angela, Vöglein, Jonathan, Bernhardt, Alexander, Perrin, Richard J., Jucker, Mathias, Preische, Oliver, Hofmann, Anna, Höglinger, Günter U., Cairns, Nigel J., Franklin, Erin E., Chrem, Patricio, Cruchaga, Carlos, Berman, Sarah B., Chhatwal, Jasmeer P., Daniels, Alisha, and Day, Gregory S.

Abstract

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α‐synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α‐synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala‐ or olfactory‐predominant LBP, for which CSF α‐synuclein SAA has low sensitivity. Highlights: Cerebrospinal fluid (CSF) real‐time quaking‐induced conversion (RT‐QuIC) detects misfolded α‐synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients.CSF RT‐QuIC does not detect α‐synuclein seeding activity in asymptomatic mutation carriers.Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala‐predominant variants.LBP develops late in the disease course in ADAD.CSF α‐synuclein RT‐QuIC has low sensitivity for focal, low‐burden LBP. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Refinement of Neurofilament light Dynamics in CSF and Blood for familial Alzheimer’s Disease

Author

Hofmann, Anna, primary, Haesler, Lisa M., additional, Preische, Oliver, additional, Gräber‐Sultan, Susanne, additional, Obermüller, Ulrike, additional, Vöglein, Jonathan, additional, Levin, Johannes, additional, Laske, Christoph, additional, Fitzpatrick, Colleen D, additional, Levin, Raina, additional, Joseph‐Mathurin, Nelly, additional, Chen, Charles D., additional, Cruchaga, Carlos, additional, Goate, Alison, additional, Allegri, Ricardo Francisco, additional, Benzinger, Tammie L.S., additional, Berman, Sarah, additional, Chui, Helena C, additional, Fagan, Anne M., additional, Farlow, Martin R., additional, Fox, Nick C, additional, Day, Gregory S., additional, Hassenstab, Jason J., additional, Jack, Clifford R., additional, Lee, Jae‐Hong, additional, Levey, Allan I., additional, Martins, Ralph N, additional, Mori, Hiroshi, additional, Noble, James M, additional, Perrin, Richard J., additional, Sperling, Reisa A., additional, Rosa‐Neto, Pedro, additional, Salloway, Stephen, additional, Sanchez‐Valle, Raquel, additional, Schofield, Peter R, additional, Xiong, Chengjie, additional, Karch, Celeste M., additional, Graff‐Radford, Neill R, additional, Gordon, Brian A., additional, Morris, John C, additional, McDade, Eric, additional, Bateman, Randall J., additional, Chhatwal, Jasmeer P., additional, Jucker, Mathias, additional, and Schultz, Stephanie A., additional

Published
2023
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26. Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission

Author

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

Published
2023
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28. Seizures as an early symptom of autosomal dominant Alzheimer's disease

Author

Vöglein, Jonathan, Noachtar, Soheyl, McDade, Eric, Quaid, Kimberly A., Salloway, Stephen, Ghetti, Bernardino, Noble, James, Berman, Sarah, Chhatwal, Jasmeer, Mori, Hiroshi, Fox, Nick, Allegri, Ricardo, Masters, Colin L., Buckles, Virginia, Ringman, John M., Rossor, Martin, Schofield, Peter R., Sperling, Reisa, Jucker, Mathias, Laske, Christoph, Paumier, Katrina, Morris, John C., Bateman, Randall J., Levin, Johannes, and Danek, Adrian

Published
2019
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29. Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer's disease

Author

Müller, Stephan, Preische, Oliver, Sohrabi, Hamid R., Gräber, Susanne, Jucker, Mathias, Ringman, John M., Martins, Ralph N., McDade, Eric, Schofield, Peter R., Ghetti, Bernardino, Rossor, Martin, Fox, Nick N., Graff-Radford, Neill R., Levin, Johannes, Danek, Adrian, Vöglein, Jonathan, Salloway, Stephen, Xiong, Chengjie, Benzinger, Tammie, Buckles, Virginia, Masters, Colin L., Sperling, Reisa, Bateman, Randall J., Morris, John C., and Laske, Christoph

Published
2018
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30. Sequence of Alzheimer disease biomarker changes in cognitively normal adults: A cross-sectional study

Author

Luo, Jingqin, Agboola, Folasade, Grant, Elizabeth, Masters, Colin L., Albert, Marilyn S., Johnson, Sterling C., McDade, Eric M., Vöglein, Jonathan, Fagan, Anne M., Benzinger, Tammie, Massoumzadeh, Parinaz, Hassenstab, Jason, Bateman, Randall J., Morris, John C., Perrin, Richard J., Chhatwal, Jasmeer, Jucker, Mathias, Ghetti, Bernardino, Cruchaga, Carlos, Graff-Radford, Neill R., Schofield, Peter R., Mori, Hiroshi, and Xiong, Chengjie

Published
2020
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31. Accelerated longitudinal changes and ordering of Alzheimer disease biomarkers across the adult lifespan

Author

Luo, Jingqin, Agboola, Folasade, Hassenstab, Jason, Bateman, Randall J, Perrin, Richard J, Wang, Guoqiao, Li, Yan, Gordon, Brian, Cruchaga, Carlos, Day, Gregory S, Levin, Johannes, Vöglein, Jonathan, Grant, Elizabeth, Ikeuchi, Takeshi, Suzuki, Kazushi, Allegri, Ricardo F, Xiong, Chengjie, Network, Dominantly Inherited Alzheimer, Morris, John C, Masters, Colin L, Albert, Marilyn S, Johnson, Sterling C, McDade, Eric M, Fagan, Anne M, and Benzinger, Tammie L S

Subjects
Adult, Adolescent, Longevity, genetics [Alzheimer Disease], tau Proteins, temporal evolution and ordering, Young Adult, Apolipoproteins E, Alzheimer Disease, Humans, ddc:610, Longitudinal Studies, Aged, Aged, 80 and over, Amyloid beta-Peptides, accelerated rates of longitudinal change, biomarkers, Middle Aged, Peptide Fragments, Positron-Emission Tomography, genetics [Apolipoproteins E], Original Article, Neurology (clinical), Alzheimer disease, Biomarkers
Abstract

The temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-β42 (Aβ42), Aβ40, total tau (Tau) and phosphorylated tau181 (pTau181), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-β with PET using the 11C-Pittsburgh Compound-B (PiB), MRI-based hippocampal volume and cortical thickness and cognition have been hypothesized but not yet fully tested with longitudinal data for all major biomarker modalities among cognitively normal individuals across the adult lifespan starting from 18 years. By leveraging a large harmonized database from 8 biomarker studies with longitudinal data from 2609 participants in cognition, 873 in MRI biomarkers, 519 in PET PiB imaging and 475 in CSF biomarkers for a median follow-up of 5–6 years, we estimated the longitudinal trajectories of all major Alzheimer disease biomarkers as functions of baseline age that spanned from 18 to 103 years, located the baseline age window at which the longitudinal rates of change accelerated and further examined possible modifying effects of apolipoprotein E (APOE) genotype. We observed that participants 18–45 years at baseline exhibited learning effects on cognition and unexpected directions of change on CSF and PiB biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio (with an increase) and for Tau, and pTau181 (with a decrease) at the next baseline age interval of 45–50 years, followed by an accelerated increase for PiB SUVR at the baseline age of 50–55 years and an accelerated decrease for hippocampal volume at the baseline age of 55–60 years and finally by an accelerated decline for cortical thickness and cognition at the baseline age of 65–70 years. Another acceleration in the rate of change occurred at the baseline age of 65–70 years for Aβ42/Aβ40 ratio, Tau, pTau181, PiB SUVR and hippocampal volume. Accelerated declines in hippocampal volume and cognition continued after 70 years. For participants 18–45 years at baseline, significant increases in Aβ42 and Aβ42/Aβ40 ratio and decreases in PiB SUVR occurred in APOE ɛ4 non-carriers but not carriers. After age 45 years, APOE ɛ4 carriers had greater magnitudes than non-carriers in the rates of change for all CSF biomarkers, PiB SUVR and cognition. Our results characterize the temporal evolutions and relative orderings of Alzheimer disease biomarkers across the adult lifespan and the modification effect of APOE ɛ4. These findings may better inform the design of prevention trials on Alzheimer disease.

Published
2022

32. Pattern and implications of neurological examination findings in autosomal dominant Alzheimer disease

Author

Vöglein, Jonathan, Franzmeier, Nicolai, Fagan, Anne, Noble, James M, Berman, Sarah B, Graff-Radford, Neill R, Ghetti, Bernardino, Farlow, Martin R, Chhatwal, Jasmeer P, Salloway, Stephen, Xiong, Chengjie, Karch, Celeste M, Morris, John C, Cairns, Nigel, Perrin, Richard J, Day, Gregory, Martins, Ralph, Sanchez-Valle, Raquel, Mori, Hiroshi, Shimada, Hiroyuki, Ikeuchi, Takeshi, Suzuki, Kazushi, Schofield, Peter R, Dieterich, Marianne, Masters, Colin L, Goate, Alison, Buckles, Virginia, Fox, Nick C, Chrem, Patricio, Allegri, Ricardo, Ringman, John M, Yakushev, Igor, Laske, Christoph, Jucker, Mathias, McDade, Eric, Höglinger, Günter, Bateman, Randall J, Danek, Adrian, Levin, Johannes, Network, Dominantly Inherited Alzheimer, Simons, Mikael, Preische, Oliver, Hofmann, Anna, Hassenstab, Jason, and Benzinger, Tammie L

Subjects
Arthrogryposis, Neurologic Examination, predictive value, Epidemiology, Health Policy, genetics [Cognitive Dysfunction], ddc, FEATURED ARTICLE, FEATURED ARTICLES, Alzheimer disease, autosomal dominant Alzheimer disease, differential diagnosis, neurological examination, neurological examination findings, prognosis, pathology [Alzheimer Disease], Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Humans, ddc:610, Neurology (clinical), Geriatrics and Gerontology
Abstract

As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD.Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers.AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time.ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.

Published
2022

33. Patterns and implications of neurological examination findings in autosomal dominant Alzheimer disease

Author

Vöglein, Jonathan, Franzmeier, Nicolai, Morris, John C., Dieterich, Marianne, McDade, Eric, Simons, Mikael, Preische, Oliver, Hofmann, Anna, Hassenstab, Jason, Benzinger, Tammie L., Fagan, Anne, Noble, James M., Berman, Sarah B., Graff-Radford, Neill R., Ghetti, Bernardino, Farlow, Martin R., Chhatwal, Jasmeer P., Salloway, Stephen, Xiong, Chengjie, Karch, Celeste M., Cairns, Nigel, Perrin, Richard J., Day, Gregory, Martins, Ralph, Sanchez-Valle, Raquel, Mori, Hiroshi, Shimada, Hiroyuki, Ikeuchi, Takeshi, Suzuki, Kazushi, Schofield, Peter R., Masters, Colin L., Goate, Alison, Buckles, Virginia, Fox, Nick C., Chrem, Patricio, Allegri, Ricardo, Ringman, John M., Yakushev, Igor, Laske, Christoph, Jucker, Mathias, Höglinger, Günter, Bateman, Randall L., Danek, Adrian, Levin, Johannes, Dominantly Inherited Alzheimer Network, Vöglein, Jonathan, Franzmeier, Nicolai, Morris, John C., Dieterich, Marianne, McDade, Eric, Simons, Mikael, Preische, Oliver, Hofmann, Anna, Hassenstab, Jason, Benzinger, Tammie L., Fagan, Anne, Noble, James M., Berman, Sarah B., Graff-Radford, Neill R., Ghetti, Bernardino, Farlow, Martin R., Chhatwal, Jasmeer P., Salloway, Stephen, Xiong, Chengjie, Karch, Celeste M., Cairns, Nigel, Perrin, Richard J., Day, Gregory, Martins, Ralph, Sanchez-Valle, Raquel, Mori, Hiroshi, Shimada, Hiroyuki, Ikeuchi, Takeshi, Suzuki, Kazushi, Schofield, Peter R., Masters, Colin L., Goate, Alison, Buckles, Virginia, Fox, Nick C., Chrem, Patricio, Allegri, Ricardo, Ringman, John M., Yakushev, Igor, Laske, Christoph, Jucker, Mathias, Höglinger, Günter, Bateman, Randall L., Danek, Adrian, Levin, Johannes, and Dominantly Inherited Alzheimer Network

Abstract

Introduction: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. Methods: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. Results: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1 %. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. Discussion: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.

Published
2023

34. 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

35. 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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36. Clinical and genetic features of Lewy body pathology in autosomal dominant and sporadic Alzheimer disease

Author

Vöglein, Jonathan, primary, Ryan, Natalie S, additional, Bateman, Randall J., additional, Paumier, Katrina L., additional, Cairns, Nigel J, additional, Franklin, Erin E., additional, Perrin, Richard J., additional, Xiong, Chengjie, additional, Jucker, Mathias, additional, Lashley, Tammaryn, additional, Arzberger, Thomas, additional, Herms, Jochen, additional, Dieterich, Marianne, additional, Höglinger, Günter, additional, Danek, Adrian, additional, Morris, John C., additional, Fox, Nick C, additional, and Levin, Johannes, additional

Published
2022
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37. Cross-sectional and longitudinal comparisons of biomarkers and cognition among asymptomatic middle-aged individuals with a parental history of either autosomal dominant or late-onset Alzheimer's disease

Author

Xiong, Chengjie, McCue, Lena M, Schindler, Suzanne E, McDade, Eric, Moulder, Krista, Gordon, Brian A, Cruchaga, Carlos, Day, Gregory S, Ikeuchi, Takeshi, Suzuki, Kazushi, Allegri, Ricardo F, Vöglein, Jonathan, Buckles, Virginia, Levin, Johannes, Morris, John C, Network, and Dominantly Inherited Alzheimer, Grant, Elizabeth, Agboola, Folasade, Coble, Dean, Bateman, Randall J, Fagan, Anne M, Benzinger, Tammie L S, and Hassenstab, Jason

Subjects
Pittsburgh compound-B (PiB), autosomal dominant Alzheimer's disease (ADAD), cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), Alzheimer's disease (AD), ddc:610, positron emission tomography (PET)
Abstract

Comparisons of late-onset Alzheimer's disease (LOAD) and autosomal dominant AD (ADAD) are confounded by age.We compared biomarkers from cerebrospinal fluid (CSF), magnetic resonance imaging, and amyloid imaging with Pittsburgh Compound-B (PiB) across four groups of 387 cognitively normal participants, 42 to 65 years of age, in the Dominantly Inherited Alzheimer Network (DIAN) and the Adult Children Study (ACS) of LOAD: DIAN mutation carriers (MCs) and non-carriers (NON-MCs), and ACS participants with a positive (FH+) and negative (FH-) family history of LOAD.At baseline, MCs had the lowest age-adjusted level of CSF Aβ42 and the highest levels of total and phosphorylated tau-181, and PiB uptake. Longitudinally, MC had similar increase in PiB uptake to FH+, but drastically faster decline in hippocampal volume than others, and was the only group showing cognitive decline.Preclinical ADAD and LOAD share many biomarker signatures, but cross-sectional and longitudinal differences may exist.

Published
2023

38. Biomarker clustering in autosomal dominant Alzheimer's disease

Author

Luckett, Patrick H., Chen, Charlie, Jucker, Mathias, Levin, Johannes, Masters, Colin L., Mori, Hiroshi, Noble, James M., Salloway, Stephen, Schofield, Peter R., Brickman, Adam M., Brooks, William S., Cash, David M., Gordon, Brian A., Fulham, Michael J., Ghetti, Bernardino, Jack, Clifford R., Vöglein, Jonathan, Klunk, William E., Koeppe, Robert, Su, Yi, Weiner, Michael, Wang, Qing, Marcus, Daniel, Wisch, Julie, Koudelis, Deborah, Joseph-Mathurin, Nelly, Cash, Lisa, Hornbeck, Russ, Xiong, Chengjie, Perrin, Richard J., Karch, Celeste M., Hassenstab, Jason, McDade, Eric, Morris, John C., Berman, Sarah B., Benzinger, Tammie L. S., Bateman, Randall J., Ances, Beau M., Chhatwal, Jasmeer P., Cruchaga, Carlos, Fagan, Anne M., Farlow, Martin R., and Fox, Nick C.

Subjects
Inflammation, Amyloid beta-Peptides, Epidemiology, Health Policy, diagnosis [Alzheimer Disease], biomarkers, Amyloidogenic Proteins, tau Proteins, cerebrospinal fluid [Amyloid beta-Peptides], Psychiatry and Mental health, Cellular and Molecular Neuroscience, genetics [tau Proteins], Cross-Sectional Studies, machine learning, Developmental Neuroscience, cerebrospinal fluid [Biomarkers], cerebrospinal fluid [tau Proteins], Humans, Neurology (clinical), ddc:610, Geriatrics and Gerontology, Autosomal dominant Alzheimer's disease
Abstract

INTRODUCTIONAs the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others.METHODSWe used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation.RESULTSThree primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors.DISCUSSIONThese results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.

Published
2023

39. Different rates of cognitive decline in autosomal dominant and late‐onset Alzheimer disease

Author

Buckles, Virginia D, Xiong, Chengjie, Goate, Alison, Graff-Radford, Neill, Jucker, Mathias, Levin, Johannes, Marcus, Daniel S, Masters, Colin L, McCue, Lena, McDade, Eric, Mori, Hiroshi, Moulder, Krista L, Bateman, Randall J, Noble, James M, Paumier, Katrina, Preische, Oliver, Ringman, John M, Fox, Nick C, Salloway, Stephen, Schofield, Peter R, Martins, Ralph, Vöglein, Jonathan, Morris, John C, Hassenstab, Jason, Network, Dominantly Inherited Alzheimer's, Allegri, Ricardo, Berman, Sarah B, Chhatwal, Jasmeer P, Danek, Adrian, Fagan, Anne M, and Ghetti, Bernardino

Subjects
Pediatrics, medicine.medical_specialty, physiopathology [Cognitive Dysfunction], Epidemiology, late-onset Alzheimer disease, comorbidities, physiopathology [Alzheimer Disease], cognitive, pathology [Alzheimer Disease], Cellular and Molecular Neuroscience, Developmental Neuroscience, Alzheimer Disease, Humans, Medicine, Cognitive Dysfunction, ddc:610, Symptom onset, Cognitive decline, business.industry, Health Policy, Late Onset Alzheimer Disease, Cognition, medicine.disease, Psychiatry and Mental health, Neurology (clinical), Alzheimer disease, autosomal dominant Alzheimer disease, Geriatrics and Gerontology, Alzheimer's disease, Prevention trials, business
Abstract

As prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and "sporadic" late-onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy-confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy-confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences.

Published
2021

41. 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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44. 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

45. Comparative analysis of Alzheimer’s disease Cerebrospinal fluid biomarkers measurement by multiplex SOMAscan platform and immunoassay-based approach

Author

Timsina, Jigyasha, Gomez-Fonseca, Duber, Xiong, Chengjie, Schindler, Suzanne E, Fagan, Anne M, Bateman, Randall J, Farlow, Martin, Morris, John C, Perrin, Richard J, Moulder, Krista, Hassenstab, Jason, Vöglein, Jonathan, Wang, Lihua, Chhatwal, Jasmeer, Mori, Hiroshi, Initiative, Alzheimer’s Disease Neuroimaging, Consortia, Dominantly Inherited Alzheimer Network, Sung, Yun Ju, Cruchaga, Carlos, Do, Anh, Western, Dan, Alvarez, Ignacio, Aguilar, Miquel, Pastor, Pau, Henson, Rachel L, and Herries, Elizabeth

Subjects
Immunoassay, Amyloid beta-Peptides, assays, diagnosis [Alzheimer Disease], tau Proteins, cerebrospinal fluid [Amyloid beta-Peptides], Article, cerebrospinal fluid [Alzheimer Disease], cerebrospinal fluid [Biomarkers], cerebrospinal fluid [tau Proteins], ROC Curve, Alzheimer Disease, correlation, Humans, Neurogranin, ddc:610, cerebrospinal fluid [Neurogranin], SOMAscan, cerebrospinal fluid biomarkers, Alzheimer’s disease, Biomarkers
Abstract

BACKGROUND: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. OBJECTIVE: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer’s disease (AD) and neurodegeration: NfL, Neurogranin, sTREM2, VILIP-1 and SNAP-25. METHODS: We compared biomarkers measured in ADNI (N=689), Knight-ADRC (N=870), DIAN (N=115), and Barcelona-1 (N=92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson’s correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. RESULTS: Neurogranin, VILIP-1 and NfL showed high correlation between SOMAscan and immunoassay measures (r > 0.9). sTREM2 had a fair correlation (r > 0.6), whereas SNAP-25 showed weak correlation (r = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. CONCLUSION: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1 and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers.

Published
2022

46. Neurodegenerative diseases and lifetime seizure risk: A study of autopsy proven cases

Author

Vöglein, Jonathan, primary, Kostova, Irena, additional, Arzberger, Thomas, additional, Noachtar, Soheyl, additional, Dieterich, Marianne, additional, Herms, Jochen, additional, Schmitz, Peer, additional, Ruf, Viktoria, additional, Windl, Otto, additional, Roeber, Sigrun, additional, Simons, Mikael, additional, Höglinger, Günter, additional, Danek, Adrian, additional, Giese, Armin, additional, and Levin, Johannes, additional

Published
2021
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47. Seizure prevalence in neurodegenerative diseases—a study of autopsy proven cases

Author

Vöglein, Jonathan, primary, Kostova, Irena, additional, Arzberger, Thomas, additional, Noachtar, Soheyl, additional, Dieterich, Marianne, additional, Herms, Jochen, additional, Schmitz, Peer, additional, Ruf, Viktoria, additional, Windl, Otto, additional, Roeber, Sigrun, additional, Simons, Mikael, additional, Höglinger, Günter U., additional, Danek, Adrian, additional, Giese, Armin, additional, and Levin, Johannes, additional

Published
2021
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48. Longitudinal increase of CSF soluble TREM2 is driven by early aggregation of Aβ42 and associates with slower amyloid deposition and clinical decline in autosomal-dominant Alzheimer’s disease

Author

Haass, Christian, primary, Morenas-Rodriguez, Estrella, additional, Li, Yan, additional, Nuscher, Brigitte, additional, Franzmeier, Nicolai, additional, Xiong, Chengjie, additional, Suárez-Calvet, Marc, additional, Fagan, Anne, additional, Schultz, Stephanie, additional, Gordon, Brian, additional, Benzinger, Tammie, additional, Hassenstab, Jason, additional, McDade, Eric, additional, Feederle, Regina, additional, Karch, Celeste, additional, Schlepckow, Kai, additional, Morris, John, additional, Kleinberger, Gernot, additional, Nellgård, Bengt, additional, Vöglein, Jonathan, additional, Blennow, Kaj, additional, Zetterberg, Henrik, additional, Ewers, Michael, additional, Jucker, Mathias, additional, Levin, Johannes, additional, and Bateman, Randall, additional

Published
2021
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49. Low-degree trisomy 21 mosaicism promotes early-onset Alzheimer disease

Author

Nuebling, Georg S., primary, Prix, Catharina, additional, Brendel, Matthias, additional, Beyer, Leonie, additional, Wlasich, Elisabeth, additional, Loosli, Sandra V., additional, Barthel, Henryk, additional, Sabri, Osama, additional, Bartenstein, Peter, additional, Vöglein, Jonathan, additional, Danek, Adrian, additional, Rominger, Axel, additional, Edbauer, Dieter, additional, Haass, Christian, additional, and Levin, Johannes, additional

Published
2021
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50. 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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