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1. Molecular neuroimaging in dominantly inherited versus sporadic early-onset Alzheimer’s disease

Author

Iaccarino, Leonardo, Llibre-Guerra, Jorge J, McDade, Eric, Edwards, Lauren, Gordon, Brian, Benzinger, Tammie, Hassenstab, Jason, Kramer, Joel H, Li, Yan, Miller, Bruce L, Miller, Zachary, Morris, John C, Mundada, Nidhi, Perrin, Richard J, Rosen, Howard J, Soleimani-Meigooni, David, Strom, Amelia, Tsoy, Elena, Wang, Guoqiao, Xiong, Chengjie, Allegri, Ricardo, Chrem, Patricio, Vazquez, Silvia, Berman, Sarah B, Chhatwal, Jasmeer, Masters, Colin L, Farlow, Martin R, Jucker, Mathias, Levin, Johannes, Salloway, Stephen, Fox, Nick C, Day, Gregory S, Gorno-Tempini, Maria Luisa, Boxer, Adam L, La Joie, Renaud, Bateman, Randall, and Rabinovici, Gil D

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Acquired Cognitive Impairment, Brain Disorders, Dementia, Biomedical Imaging, Clinical Research, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Alzheimer's Disease, 2.1 Biological and endogenous factors, Aetiology, Neurological, Good Health and Well Being, Alzheimer's disease, amyloid-PET, brain glucose metabolism, FDG-PET, Alzheimer’s disease, Clinical sciences, Biological psychology
Abstract

Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50-70 cerebellar grey reference and FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease.

Published
2024

2. Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease

Author

Llibre-Guerra, Jorge J, Iaccarino, Leonardo, Coble, Dean, Edwards, Lauren, Li, Yan, McDade, Eric, Strom, Amelia, Gordon, Brian, Mundada, Nidhi, Schindler, Suzanne E, Tsoy, Elena, Ma, Yinjiao, Lu, Ruijin, Fagan, Anne M, Benzinger, Tammie LS, Soleimani-Meigooni, David, Aschenbrenner, Andrew J, Miller, Zachary, Wang, Guoqiao, Kramer, Joel H, Hassenstab, Jason, Rosen, Howard J, Morris, John C, Miller, Bruce L, Xiong, Chengjie, Perrin, Richard J, Allegri, Ricardo, Chrem, Patricio, Surace, Ezequiel, Berman, Sarah B, Chhatwal, Jasmeer, Masters, Colin L, Farlow, Martin R, Jucker, Mathias, Levin, Johannes, Fox, Nick C, Day, Gregory, Gorno-Tempini, Maria Luisa, Boxer, Adam L, La Joie, Renaud, Rabinovici, Gil D, and Bateman, Randall

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Acquired Cognitive Impairment, Clinical Research, Clinical Trials and Supportive Activities, Alzheimer's Disease, Neurodegenerative, Genetics, Aging, Dementia, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Aetiology, Neurological, early-onset Alzheimer's disease, sporadic, dominantly inherited, early-onset Alzheimer’s disease, Clinical sciences, Biological psychology
Abstract

Approximately 5% of Alzheimer's disease cases have an early age at onset (

Published
2023

4. 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

5. 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

6. 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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7. Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Author

Johnson, Erik C. B., Bian, Shijia, Haque, Rafi U., Carter, E. Kathleen, Watson, Caroline M., Gordon, Brian A., Ping, Lingyan, Duong, Duc M., Epstein, Michael P., McDade, Eric, Barthélemy, Nicolas R., Karch, Celeste M., Xiong, Chengjie, Cruchaga, Carlos, Perrin, Richard J., Wingo, Aliza P., Wingo, Thomas S., Chhatwal, Jasmeer P., Day, Gregory S., Noble, James M., Berman, Sarah B., Martins, Ralph, Graff-Radford, Neill R., Schofield, Peter R., Ikeuchi, Takeshi, Mori, Hiroshi, Levin, Johannes, Farlow, Martin, Lah, James J., Haass, Christian, Jucker, Mathias, Morris, John C., Benzinger, Tammie L. S., Roberts, Blaine R., Bateman, Randall J., Fagan, Anne M., Seyfried, Nicholas T., and Levey, Allan I.

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

Author

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

Published
2024
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11. 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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12. Serum IL-6, sAXL, and YKL-40 as systemic correlates of reduced brain structure and function in Alzheimer’s disease: results from the DELCODE study

Author

Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, Kolbe, Carl-Christian, Wolfsgruber, Steffen, Santarelli, Francesco, Häsler, Lisa M., McManus, Róisín, Ising, Christina, Röske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Schneider, Luisa-Sophie, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn H., Buerger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Görß, Doreen, Laske, Christoph, Munk, Matthias H., Düzel, Emrah, Yakupow, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Spottke, Annika, Ramirez, Alfredo, Mengel, David, Synofzik, Matthis, Jucker, Mathias, Latz, Eicke, Jessen, Frank, Wagner, Michael, and Heneka, Michael T.

Published
2023
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13. Accelerated functional brain aging in pre-clinical familial Alzheimer’s disease

Author

Gonneaud, Julie, Baria, Alex T, Pichet Binette, Alexa, Gordon, Brian A, Chhatwal, Jasmeer P, Cruchaga, Carlos, Jucker, Mathias, Levin, Johannes, Salloway, Stephen, Farlow, Martin, Gauthier, Serge, Benzinger, Tammie LS, Morris, John C, Bateman, Randall J, Breitner, John CS, Poirier, Judes, Vachon-Presseau, Etienne, and Villeneuve, Sylvia

Subjects
Biological Psychology, Psychology, Clinical Research, Neurodegenerative, Aging, Brain Disorders, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Alzheimer's Disease, Dementia, Neurological, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Brain, Brain Mapping, Cognitive Dysfunction, Female, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Positron-Emission Tomography, Young Adult, Alzheimer’s Disease Neuroimaging Initiative, Dominantly Inherited Alzheimer Network (DIAN) Study Group, Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT-AD) Research Group
Abstract

Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer's disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18-94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology.

Published
2021

15. 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

16. Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Author

Wagner, Jessica, Degenhardt, Karoline, Veit, Marleen, Louros, Nikolaos, Konstantoulea, Katerina, Skodras, Angelos, Wild, Katleen, Liu, Ping, Obermüller, Ulrike, Bansal, Vikas, Dalmia, Anupriya, Häsler, Lisa M., Lambert, Marius, De Vleeschouwer, Matthias, Davies, Hannah A., Madine, Jillian, Kronenberg-Versteeg, Deborah, Feederle, Regina, Del Turco, Domenico, Nilsson, K. Peter R., Lashley, Tammaryn, Deller, Thomas, Gearing, Marla, Walker, Lary C., Heutink, Peter, Rousseau, Frederic, Schymkowitz, Joost, Jucker, Mathias, and Neher, Jonas J.

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

Author

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

Published
2024
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19. 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

20. CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM2, neurodegeneration and cognitive decline

Author

Suárez‐Calvet, Marc, Capell, Anja, Caballero, Miguel Ángel Araque, Morenas‐Rodríguez, Estrella, Fellerer, Katrin, Franzmeier, Nicolai, Kleinberger, Gernot, Eren, Erden, Deming, Yuetiva, Piccio, Laura, Karch, Celeste M, Cruchaga, Carlos, Paumier, Katrina, Bateman, Randall J, Fagan, Anne M, Morris, John C, Levin, Johannes, Danek, Adrian, Jucker, Mathias, Masters, Colin L, Rossor, Martin N, Ringman, John M, Shaw, Leslie M, Trojanowski, John Q, Weiner, Michael, Ewers, Michael, Haass, Christian, Network, the Dominantly Inherited Alzheimer, and Initiative, the Alzheimer's Disease Neuroimaging

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Neurodegenerative, Aging, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Alzheimer Disease, Cognitive Dysfunction, Cross-Sectional Studies, Female, Humans, Male, Membrane Glycoproteins, Microglia, Middle Aged, Progranulins, Receptors, Immunologic, Dominantly Inherited Alzheimer Network, Alzheimer's Disease Neuroimaging Initiative, Alzheimer's disease, TREM2, biomarker, microglia, progranulin, Medical and Health Sciences, Biochemistry and cell biology
Abstract

Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity-specific manner in AD We measured PGRN in cerebrospinal fluid (CSF) in two of the best-characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross-sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non-carriers 10 years before the expected symptom onset. In late-onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.

Published
2018

21. 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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23. Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

Author

Rother, Christine, Uhlmann, Ruth E., Müller, Stephan A., Schelle, Juliane, Skodras, Angelos, Obermüller, Ulrike, Häsler, Lisa M., Lambert, Marius, Baumann, Frank, Xu, Ying, Bergmann, Carina, Salvadori, Giulia, Loos, Maarten, Brzak, Irena, Shimshek, Derya, Neumann, Ulf, Walker, Lary C., Schultz, Stephanie A., Chhatwal, Jasmeer P., Kaeser, Stephan A., Lichtenthaler, Stefan F., Staufenbiel, Matthias, and Jucker, Mathias

Published
2022
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24. 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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25. White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease

Author

Caballero, Miguel Ángel Araque, Suárez-Calvet, Marc, Duering, Marco, Franzmeier, Nicolai, Benzinger, Tammie, Fagan, Anne M, Bateman, Randall J, Jack, Clifford R, Levin, Johannes, Dichgans, Martin, Jucker, Mathias, Karch, Celeste, Masters, Colin L, Morris, John C, Weiner, Michael, Rossor, Martin, Fox, Nick C, Lee, Jae-Hong, Salloway, Stephen, Danek, Adrian, Goate, Alison, Yakushev, Igor, Hassenstab, Jason, Schofield, Peter R, Haass, Christian, and Ewers, Michael

Subjects
Health Services and Systems, Health Sciences, Neurosciences, Dementia, Biomedical Imaging, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Brain Disorders, Alzheimer's Disease, Neurodegenerative, Aging, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Alzheimer Disease, Brain, Diffusion Tensor Imaging, Female, Humans, Male, Middle Aged, White Matter, Alzheimer's disease, autosomal dominant, white matter, diffusion tensor imaging, TREM2, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.

Published
2018

26. Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer’s disease

Author

Franzmeier, Nicolai, Düzel, Emrah, Jessen, Frank, Buerger, Katharina, Levin, Johannes, Duering, Marco, Dichgans, Martin, Haass, Christian, Suárez-Calvet, Marc, Fagan, Anne M, Paumier, Katrina, Benzinger, Tammie, Masters, Colin L, Morris, John C, Perneczky, Robert, Janowitz, Daniel, Catak, Cihan, Wolfsgruber, Steffen, Wagner, Michael, Teipel, Stefan, Kilimann, Ingo, Ramirez, Alfredo, Rossor, Martin, Jucker, Mathias, Chhatwal, Jasmeer, Spottke, Annika, Boecker, Henning, Brosseron, Frederic, Falkai, Peter, Fliessbach, Klaus, Heneka, Michael T, Laske, Christoph, Nestor, Peter, Peters, Oliver, Fuentes, Manuel, Menne, Felix, Priller, Josef, Spruth, Eike J, Franke, Christiana, Schneider, Anja, Kofler, Barbara, Westerteicher, Christine, Speck, Oliver, Wiltfang, Jens, Bartels, Claudia, Caballero, Miguel Ángel Araque, Metzger, Coraline, Bittner, Daniel, Weiner, Michael, Lee, Jae-Hong, Salloway, Stephen, Danek, Adrian, Goate, Alison, Schofield, Peter R, Bateman, Randall J, and Ewers, Michael

Subjects
Clinical Trials and Supportive Activities, Brain Disorders, Aging, Basic Behavioral and Social Science, Dementia, Neurosciences, Behavioral and Social Science, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease, Neurodegenerative, Biomedical Imaging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Alzheimer Disease, Amyloid beta-Protein Precursor, Brain Mapping, Cognitive Dysfunction, Female, Frontal Lobe, Functional Laterality, Humans, Imaging, Three-Dimensional, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Nerve Net, Presenilin-1, Presenilin-2, Alzheimer's disease, cognitive reserve, resting state connectivity, memory, dementia biomarkers, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Published
2018

28. Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice

Author

Degenhardt, Karoline, Wagner, Jessica, Skodras, Angelos, Candlish, Michael, Koppelmann, Anna Julia, Wild, Katleen, Maxwell, Rusheka, Rotermund, Carola, von Zweydorf, Felix, Gloeckner, Christian Johannes, Davies, Hannah A., Madine, Jillian, Del Turco, Domenico, Feederle, Regina, Lashley, Tammaryn, Deller, Thomas, Kahle, Philipp, Hefendehl, Jasmin K., Jucker, Mathias, and Neher, Jonas J.

Published
2020

29. Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study

Author

Fagan, Anne M, Henson, Rachel L, Li, Yan, Boerwinkle, Anna H, Xiong, Chengjie, Bateman, Randall J, Goate, Alison, Ances, Beau M, Doran, Eric, Christian, Bradley T, Lai, Florence, Rosas, H Diana, Schupf, Nicole, Krinsky-McHale, Sharon, Silverman, Wayne, Lee, Joseph H, Klunk, William E, Handen, Benjamin L, Allegri, Ricardo F, Chhatwal, Jasmeer P, Day, Gregory S, Graff-Radford, Neill R, Jucker, Mathias, Levin, Johannes, Martins, Ralph N, Masters, Colin L, Mori, Hiroshi, Mummery, Catherine J, Niimi, Yoshiki, Ringman, John M, Salloway, Stephen, Schofield, Peter R, Shoji, Mikio, and Lott, Ira T

Published
2021
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32. 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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34. Potential human transmission of amyloid β pathology: surveillance and risks

Author

Lauwers, Elsa, Lalli, Giovanna, Brandner, Sebastian, Collinge, John, Compernolle, Veerle, Duyckaerts, Charles, Edgren, Gustaf, Haïk, Stéphane, Hardy, John, Helmy, Adel, Ivinson, Adrian J, Jaunmuktane, Zane, Jucker, Mathias, Knight, Richard, Lemmens, Robin, Lin, I-Chun, Love, Seth, Mead, Simon, Perry, V Hugh, Pickett, James, Poppy, Guy, Radford, Sheena E, Rousseau, Frederic, Routledge, Carol, Schiavo, Giampietro, Schymkowitz, Joost, Selkoe, Dennis J, Smith, Colin, Thal, Dietmar R, Theys, Tom, Tiberghien, Pierre, van den Burg, Peter, Vandekerckhove, Philippe, Walton, Clare, Zaaijer, Hans L, Zetterberg, Henrik, and De Strooper, Bart

Published
2020
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35. Autosomal dominantly inherited alzheimer disease: Analysis of genetic subgroups by machine learning

Author

Castillo-Barnes, Diego, Su, Li, Ramírez, Javier, Salas-Gonzalez, Diego, Martinez-Murcia, Francisco J., Illan, Ignacio A., Segovia, Fermin, Ortiz, Andres, Cruchaga, Carlos, Farlow, Martin R., Xiong, Chengjie, Graff-Radford, Neil R., Schofield, Peter R., Masters, Colin L., Salloway, Stephen, Jucker, Mathias, Mori, Hiroshi, Levin, Johannes, Gorriz, Juan M., and (DIAN), Dominantly Inherited Alzheimer Network

Published
2020
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36. 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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37. New in vitro tools to investigate the role of microglia in neurodegeneration

Author

Erlebach, Lena, primary, Welzer, Marc, additional, Bühler, Anika, additional, Miely, Daniela, additional, Schwarz, Niklas, additional, Panagiotakopoulou, Vasiliki, additional, Haesler, Lisa M., additional, Lambert, Marius, additional, Obermüller, Ulrike, additional, Beschorner, Natalie, additional, Koch, Henner, additional, Neher, Jonas J., additional, Wuttke, Thomas, additional, Hedrich‐Klimosch, Ulrike, additional, Jucker, Mathias, additional, and Kronenberg‐Versteeg, Deborah, additional

Published
2023
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38. Polyglucosan body density in the aged mouse hippocampus is controlled by a novel modifier locus on chromosome 1

Author

Gomez-Pascual, Alicia, primary, Glikman, Dow M., additional, Ng, Hui X., additional, Tomkins, James E., additional, Lu, Lu, additional, Xu, Ying, additional, Ashbrook, David G., additional, Kaczorowski, Catherine, additional, Kempermann, Gerd, additional, Killmar, John, additional, Mozhui, Khyobeni, additional, Aebersold, Rudolf, additional, Williams, Evan G., additional, Williams, Robert W., additional, Overall, Rupert W., additional, Jucker, Mathias, additional, and de Bakker, Dennis Eduard Maria, additional

Published
2023
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39. Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life

Author

Uhlmann, Ruth E., Rother, Christine, Rasmussen, Jay, Schelle, Juliane, Bergmann, Carina, Ullrich Gavilanes, Emily M., Fritschi, Sarah K., Buehler, Anika, Baumann, Frank, Skodras, Angelos, Al-Shaana, Rawaa, Beschorner, Natalie, Ye, Lan, Kaeser, Stephan A., Obermüller, Ulrike, Christensen, Søren, Kartberg, Fredrik, Stavenhagen, Jeffrey B., Rahfeld, Jens-Ulrich, Cynis, Holger, Qian, Fang, Weinreb, Paul H., Bussiere, Thierry, Walker, Lary C., Staufenbiel, Matthias, and Jucker, Mathias

Published
2020
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40. Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

Author

Barth, Melanie, Bacioglu, Mehtap, Schwarz, Niklas, Novotny, Renata, Brandes, Janine, Welzer, Marc, Mazzitelli, Sonia, Häsler, Lisa M., Schweighauser, Manuel, Wuttke, Thomas V., Kronenberg-Versteeg, Deborah, Fog, Karina, Ambjørn, Malene, Alik, Ania, Melki, Ronald, Kahle, Philipp J., Shimshek, Derya R., Koch, Henner, Jucker, Mathias, and Tanriöver, Gaye

Published
2021
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41. Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease

Author

Schindler, Suzanne E., Li, Yan, Todd, Kaitlin W., Herries, Elizabeth M., Henson, Rachel L., Gray, Julia D., Wang, Guoqiao, Graham, Danielle L., Shaw, Leslie M., Trojanowski, John Q., Hassenstab, Jason J., Benzinger, Tammie L.S., Cruchaga, Carlos, Jucker, Mathias, Levin, Johannes, Chhatwal, Jasmeer P., Noble, James M., Ringman, John M., Graff-Radford, Neill R., Holtzman, David M., Ladenson, Jack H., Morris, John C., Bateman, Randall J., Xiong, Chengjie, and Fagan, Anne M.

Published
2019
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42. 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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44. Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial

Author

Wagemann, Olivia, Liu, Haiyan, Wang, Guoqiao, Shi, Xinyu, Bittner, Tobias, Scelsi, Marzia A., Farlow, Martin R., Clifford, David B., Supnet-Bell, Charlene, Santacruz, Anna M., Aschenbrenner, Andrew J., Hassenstab, Jason J., Benzinger, Tammie L. S., Gordon, Brian A., Coalier, Kelley A., Cruchaga, Carlos, Ibanez, Laura, Perrin, Richard J., Xiong, Chengjie, Li, Yan, Morris, John C., Lah, James J., Berman, Sarah B., Roberson, Erik D., van Dyck, Christopher H., Galasko, Douglas, Gauthier, Serge, Hsiung, Ging-Yuek R., Brooks, William S., Pariente, Jérémie, Mummery, Catherine J., Day, Gregory S., Ringman, John M., Mendez, Patricio Chrem, St. George-Hyslop, Peter, Fox, Nick C., Suzuki, Kazushi, Okhravi, Hamid R., Chhatwal, Jasmeer, Levin, Johannes, Jucker, Mathias, Sims, John R., Holdridge, Karen C., Proctor, Nicholas K., Yaari, Roy, Andersen, Scott W., Mancini, Michele, Llibre-Guerra, Jorge, Bateman, Randall J., and McDade, Eric

Abstract

IMPORTANCE: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). OBJECTIVE: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. DESIGN, SETTING, AND PARTICIPANTS: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. INTERVENTIONS: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. MAIN OUTCOMES AND MEASURES: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. RESULTS: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. CONCLUSIONS AND RELEVANCE: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04623242

Published
2024
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45. 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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47. Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer’s disease

Author

Rasmussen, Jay, Mahler, Jasmin, Beschorner, Natalie, Kaeser, Stephan A., Häsler, Lisa M., Baumann, Frank, Nyström, Sofie, Portelius, Erik, Blennow, Kaj, Lashley, Tammaryn, Fox, Nick C., Sepulveda-Falla, Diego, Glatzel, Markus, Oblak, Adrian L., Ghetti, Bernardino, Nilsson, K. Peter R., Hammarström, Per, Staufenbiel, Matthias, Walker, Lary C., and Jucker, Mathias

Published
2017

48. Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells

Author

Varvel, Nicholas H, Grathwohl, Stefan A, Baumann, Frank, Liebig, Christian, Bosch, Andrea, Brawek, Bianca, Thal, Dietmar R, Charo, Israel F, Heppner, Frank L, Aguzzi, Adriano, Garaschuk, Olga, Ransohoff, Richard M, and Jucker, Mathias

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Neurosciences, Stem Cell Research - Nonembryonic - Non-Human, Bioengineering, Stem Cell Research, Hematology, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adenosine Triphosphate, Animals, Central Nervous System, Homeostasis, Mice, Microglia, Thymidine Kinase, chemokines, myeloid cell heterogeneity, neuroinflammation, in vivo calcium imaging
Abstract

Under most physiological circumstances, monocytes are excluded from parenchymal CNS tissues. When widespread monocyte entry occurs, their numbers decrease shortly after engraftment in the presence of microglia. However, some disease processes lead to focal and selective loss, or dysfunction, of microglia, and microglial senescence typifies the aged brain. In this regard, the long-term engraftment of monocytes in the microglia-depleted brain remains unknown. Here, we report a model in which a niche for myeloid cells was created through microglia depletion. We show that microglia-depleted brain regions of CD11b-HSVTK transgenic mice are repopulated with new Iba-1-positive cells within 2 wk. The engrafted cells expressed high levels of CD45 and CCR2 and appeared in a wave-like pattern frequently associated with blood vessels, suggesting the engrafted cells were peripheral monocytes. Although two times more numerous and morphologically distinct from resident microglia up to 27 wk after initial engraftment, the overall distribution of the engrafted cells was remarkably similar to that of microglia. Two-photon in vivo imaging revealed that the engrafted myeloid cells extended their processes toward an ATP source and displayed intracellular calcium transients. Moreover, the engrafted cells migrated toward areas of kainic acid-induced neuronal death. These data provide evidence that circulating monocytes have the potential to occupy the adult CNS myeloid niche normally inhabited by microglia and identify a strong homeostatic drive to maintain the myeloid component in the mature brain.

Published
2012

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