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Cited by 440Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsMedical Imaging Techniques and Applications

The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.

In vivo staging of regional amyloid deposition

Open access
Grothe, Michel J., Barthel, Henryk, Sepulcre, Jorge, Dyrba, Martin, Sabri, Osama, Teipel, Stefan J., For the Alzheimer's Disease Neuroimaging Initiative, Alzheimer's Disease Neuroimaging Initiative, Weiner, Michael, Aisen, Paul, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R., Jagust, William, Trojanowki, John Q., Toga, Arthur W., Beckett, Laurel, Green, Robert C., Saykin, Andrew J., Morris, John, Liu, Enchi, Green, Robert C., Montine, Tom, Petersen, Ronald, Aisen, Paul, Gamst, Anthony, Thomas, Ronald G., Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Beckett, Laurel, Harvey, Danielle, Gamst, Anthony, Donohue, Michael, Kornak, John, Jack, Clifford R., Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Jagust, William, Bandy, Dan, Koeppe, Robert A., Foster, Norm, Reiman, Eric M., Chen, Kewei, Mathis, Chet, Morris, John, Cairns, Nigel J., Taylor-Reinwald, Lisa, Trojanowki, J.Q., Shaw, Les, Lee, Virginia M.Y., Korecka, Magdalena, Toga, Arthur W., Crawford, Karen, Neu, Scott, Saykin, Andrew J., Foroud, Tatiana M., Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J., Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S., Pawluczyk, Sonia, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Heidebrink, Judith L., Lord, Joanne L., Petersen, Ronald, Johnson, Kris, Doody, Rachelle S., Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S., Bell, Karen L., Morris, John C., Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A., Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Shah, Raj C., Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P. Murali, Petrella, Jeffrey R., Coleman, R. Edward, Arnold, Steven E., Karlawish, Jason H., Wolk, David, Smith, Charles D., Jicha, Greg, Hardy, Peter, Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Porsteinsson, Anton P., Goldstein, Bonnie S., Martin, Kim, Makino, Kelly M., Ismail, M. Saleem, Brand, Connie, Mulnard, Ruth A., Thai, Gaby, Mc-Adams-Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I., Lah, James J., Cellar, Janet S., Burns, Jeffrey M., Anderson, Heather S., Swerdlow, Russell H., Apostolova, Liana, Lu, Po H., Bartzokis, George, Silverman, Daniel H.S., Parfitt, Francine, Johnson, Heather, Farlow, Martin R., Hake, Ann Marie, Matthews, Brandy R., Herring, Scott, van Dyck, Christopher H., Carson, Richard E., MacAvoy, Martha G., Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Robin Hsiung, Ging-Yuek, Feldman, Howard, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A., Johnson, Keith A., Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L., Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Kowall, Neil, Killiany, Ronald, Budson, Andrew E., Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O., Wolday, Saba, Bwayo, Salome K., Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Olichney, John, DeCarli, Charles, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Potkin, Steven G., Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W., Kataki, Maria, Zimmerman, Earl A., Celmins, Dzintra, Brown, Alice D., Pearlson, Godfrey D., Blank, Karen, Anderson, Karen, Saykin, Andrew J., Santulli, Robert B., Schwartz, Eben S., Sink, Kaycee M., Williamson, Jeff D., Garg, Pradeep, Watkins, Franklin, Ott, Brian R., Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J., Miller, Bruce L., Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Finger, Elizabether, Rachinsky, Irina, Rogers, John, Kertesz, Andrew, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K., Boles Ponto, Laura L., Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok·2017·Neurology
DOI 10.1212/wnl.0000000000004643PMC PMC5711511
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Abstract

OBJECTIVES: To estimate a regional progression pattern of amyloid deposition from cross-sectional amyloid-sensitive PET data and evaluate its potential for in vivo staging of an individual's amyloid pathology. METHODS: F-AV45)-PET data was used to determine individual amyloid distribution profiles in a sample of 667 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including cognitively normal older individuals (CN) as well as patients with mild cognitive impairment and Alzheimer disease (AD) dementia. The frequency of regional amyloid positivity across CN individuals was used to construct a 4-stage model of progressing amyloid pathology, and individual distribution profiles were used to evaluate the consistency of this hierarchical stage model across the full cohort. RESULTS: According to a 4-stage model, amyloid deposition begins in temporobasal and frontomedial areas, and successively affects the remaining associative neocortex, primary sensory-motor areas and the medial temporal lobe, and finally the striatum. Amyloid deposition in these brain regions showed a highly consistent hierarchical nesting across participants, where only 2% exhibited distribution profiles that deviated from the staging scheme. The earliest in vivo amyloid stages were mostly missed by conventional dichotomous classification approaches based on global florbetapir-PET signal, but were associated with significantly reduced CSF Aβ42 levels. Advanced in vivo amyloid stages were most frequent in patients with AD and correlated with cognitive impairment in individuals without dementia. CONCLUSIONS: The highly consistent regional hierarchy of PET-evidenced amyloid deposition across participants resembles neuropathologic observations and suggests a predictable regional sequence that may be used to stage an individual's progress of amyloid pathology in vivo.

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Figure 1 Model of regional amyloid progression and staging scheme Brain renderings on the left illustrate the frequency of regional amyloid positivity across individuals on a color scale from black/blue (lowest) to yellow/red (highest). The 52 brain regions are merged into 4 larger anatomic divisions based on equal partitions of the frequency range (1–4). In the resulting 4-stage model of regional amyloid progression (I–IV), incremental stages are defined by involvement of higher numbered anatomic divisions (in red), in addition to the affected areas of the previous stage (blue).
Figure 1 Model of regional amyloid progression and staging scheme Brain renderings on the left illustrate the frequency of regional amyloid positivity across individuals on a color scale from black/blue (lowest) to yellow/red (highest). The 52 brain regions are merged into 4 larger anatomic divisions based on equal partitions of the frequency range (1–4). In the resulting 4-stage model of regional amyloid progression (I–IV), incremental stages are defined by involvement of higher numbered anatomic divisions (in red), in addition to the affected areas of the previous stage (blue).CC BY-NC-ND · PubMed Central
Figure 2 Staging of individual amyloid burden Each row of the matrix corresponds to a study participant and each column to one of the 4 anatomic divisions (1–4). Absence or presence of amyloid is denoted by gray and red, respectively. Amyloid deposition in the 4 anatomic divisions shows a consistent hierarchical nesting across participants, allowing us to stage 98% of the participants with detectable regional amyloid deposits into one of the 4 amyloid stages predicted by the regional progression model (blue boxes, I–IV). Only 8 participants showed distribution profiles that did not conform to the model (yellow arrows; 2 individuals [1 cognitively normal (CN), 1 Alzheimer disease] with deposition profiles of 1-1-0-1; 5 individuals [2 CN, 3 mild cognitive impairment (MCI)] with 0-1-0-0; and 1 individual [MCI] with 0-0-0-1).
Figure 2 Staging of individual amyloid burden Each row of the matrix corresponds to a study participant and each column to one of the 4 anatomic divisions (1–4). Absence or presence of amyloid is denoted by gray and red, respectively. Amyloid deposition in the 4 anatomic divisions shows a consistent hierarchical nesting across participants, allowing us to stage 98% of the participants with detectable regional amyloid deposits into one of the 4 amyloid stages predicted by the regional progression model (blue boxes, I–IV). Only 8 participants showed distribution profiles that did not conform to the model (yellow arrows; 2 individuals [1 cognitively normal (CN), 1 Alzheimer disease] with deposition profiles of 1-1-0-1; 5 individuals [2 CN, 3 mild cognitive impairment (MCI)] with 0-1-0-0; and 1 individual [MCI] with 0-0-0-1).CC BY-NC-ND · PubMed Central
Figure 3 Proportions of in vivo amyloid stages by clinical diagnosis The relative proportions of in vivo amyloid stages were plotted for each diagnostic group separately and across all participants. Among participants exhibiting stageable amyloid deposition, there is a shift from lower to higher in vivo amyloid stages across the cognitively normal (CN) over the mild cognitive impairment (MCI) to the Alzheimer disease (AD) group. Unstageable cases were relatively rare across all diagnostic categories.
Figure 3 Proportions of in vivo amyloid stages by clinical diagnosis The relative proportions of in vivo amyloid stages were plotted for each diagnostic group separately and across all participants. Among participants exhibiting stageable amyloid deposition, there is a shift from lower to higher in vivo amyloid stages across the cognitively normal (CN) over the mild cognitive impairment (MCI) to the Alzheimer disease (AD) group. Unstageable cases were relatively rare across all diagnostic categories.CC BY-NC-ND · PubMed Central

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Authors
Grothe, M. J., Barthel, H., Sepulcre, J., Dyrba, M., Sabri, O., Teipel, S. J., Initiative, F. T. A. D. N., Initiative, A. D. N., Weiner, M., Aisen, P., Weiner, M., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J., Liu, E., Green, R. C., Montine, T., Petersen, R., Aisen, P., Gamst, A., Thomas, R. G., Donohue, M., Walter, S., Gessert, D., Sather, T., Beckett, L., Harvey, D., Gamst, A., Donohue, M., Kornak, J., Jack, C. R., Dale, A., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., Alexander, G., DeCarli, C., Jagust, W., Bandy, D., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Mathis, C., Morris, J., Cairns, N. J., Taylor-Reinwald, L., Trojanowki, J. Q., Shaw, L., Lee, V. M. Y., Korecka, M., Toga, A. W., Crawford, K., Neu, S., Saykin, A. J., Foroud, T. M., Potkin, S., Shen, L., Kachaturian, Z., Frank, R., Snyder, P. J., Molchan, S., Kaye, J., Quinn, J., Lind, B., Dolen, S., Schneider, L. S., Pawluczyk, S., Spann, B. M., Brewer, J., Vanderswag, H., Heidebrink, J. L., Lord, J. L., Petersen, R., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Stern, Y., Honig, L. S., Bell, K. L., Morris, J. C., Ances, B., Carroll, M., Leon, S., Mintun, M. A., Schneider, S., Marson, D., Griffith, R., Clark, D., Grossman, H., Mitsis, E., Romirowsky, A., deToledo-Morrell, L., Shah, R. C., Duara, R., Varon, D., Roberts, P., Albert, M., Onyike, C., Kielb, S., Rusinek, H., de Leon, M. J., Glodzik, L., De Santi, S., Doraiswamy, P. M., Petrella, J. R., Coleman, R. E., Arnold, S. E., Karlawish, J. H., Wolk, D., Smith, C. D., Jicha, G., Hardy, P., Lopez, O. L., Oakley, M., Simpson, D. M., Porsteinsson, A. P., Goldstein, B. S., Martin, K., Makino, K. M., Ismail, M. S., Brand, C., Mulnard, R. A., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Weiner, M., Martin-Cook, K., DeVous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Swerdlow, R. H., Apostolova, L., Lu, P. H., Bartzokis, G., Silverman, D. H. S., Parfitt, F., Johnson, H., Farlow, M. R., Hake, A. M., Matthews, B. R., Herring, S., van Dyck, C. H., Carson, R. E., MacAvoy, M. G., Chertkow, H., Bergman, H., Hosein, C., Black, S., Stefanovic, B., Caldwell, C., Robin Hsiung, G.-Y., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Munic, D., Kerwin, D., Mesulam, M.-M., Lipowski, K., Wu, C.-K., Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, R. S., Johnson, K., Reynolds, B., Sperling, R. A., Johnson, K. A., Marshall, G., Frey, M., Yesavage, J., Taylor, J. L., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M., Belden, C., Jacobson, S., Kowall, N., Killiany, R., Budson, A. E., Norbash, A., Johnson, P. L., Obisesan, T. O., Wolday, S., Bwayo, S. K., Lerner, A., Hudson, L., Ogrocki, P., Fletcher, E., Carmichael, O., Olichney, J., DeCarli, C., Kittur, S., Borrie, M., Lee, T.-Y., Bartha, R., Johnson, S., Asthana, S., Carlsson, C. M., Potkin, S. G., Preda, A., Nguyen, D., Tariot, P., Fleisher, A., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, D. W., Kataki, M., Zimmerman, E. A., Celmins, D., Brown, A. D., Pearlson, G. D., Blank, K., Anderson, K., Saykin, A. J., Santulli, R. B., Schwartz, E. S., Sink, K. M., Williamson, J. D., Garg, P., Watkins, F., Ott, B. R., Querfurth, H., Tremont, G., Salloway, S., Malloy, P., Correia, S., Rosen, H. J., Miller, B. L., Mintzer, J., Longmire, C. F., Spicer, K., Finger, E., Rachinsky, I., Rogers, J., Kertesz, A., Drost, D., Pomara, N., Hernando, R., Sarrael, A., Schultz, S. K., Boles Ponto, L. L., Shim, H., Smith, K. E., Relkin, N., Chaing, G., Raudin, L., Smith, A., Fargher, K., & Raj, B. A.
Affiliations
German Center for Neurodegenerative Diseases (DE)
Corresponding author
Grothe, Michel J.
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2017-11-14
Volume
89
Issue
20
Pages
2031-2038
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0000000000004643
PMC
PMC5711511
OpenAlex
W2766782573
Cited by
440
References
40
Citations by year
2026: 39 · 2025: 42 · 2024: 53 · 2023: 61 · 2022: 56 · 2021: 62 · 2020: 52 · 2019: 40 · 2018: 31 · 2017: 3
FWCI
28.31
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Neurology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH1220012, AG024904)
  • Foundation for the National Institutes of Health (W81XWH-12-2-0012, U01AG024904, AG024904)
  • Alzheimer's Association (U01 AG024904, W81XWH-12-2-0012)
  • Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • University of Southern California (W81XWH-12-2-0012, U01 AG024904)
  • F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, Department of Defense award number W81XWH-12-2-0012)
  • BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
  • Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
  • Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Deutsches Zentrum für Neurodegenerative Erkrankungen
  • Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, U01-AG024904, AG024904)
  • Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • University of California, San Diego
  • Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012)
  • National Institute on Aging (U01-AG-024904, P30AG010129, W81XWH-12-2–0012, AG 024904)
  • National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, P41EB015922, AG024904)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
Keywords
amyloid deposition, florbetapir PET, Alzheimer's disease, mild cognitive impairment, CSF amyloid-beta 42, medial temporal lobe, striatum, cognitive impairment without dementia, Alzheimer's Disease Neuroimaging Initiative
MeSH terms
Aged, Aged, 80 and over, Aging, Alzheimer Disease, Aniline Compounds, Cerebral Cortex, Cross-Sectional Studies, Ethylene Glycols, Female, Humans, Male, Peptide Fragments, Biomarkers, Amyloid beta-Peptides, Neostriatum, Disease Progression, Positron-Emission Tomography, Cognitive Dysfunction

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Grothe, M. J., Barthel, H., Sepulcre, J., Dyrba, M., Sabri, O., Teipel, S. J., Initiative, F. T. A. D. N., Initiative, A. D. N., Weiner, M., Aisen, P., Weiner, M., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., . . . Raj, B. A. (2017). In vivo staging of regional amyloid deposition. Neurology. https://doi.org/10.1212/wnl.0000000000004643