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1. Sex Modulates the Pathological Aging Effect on Caudate Functional Connectivity in Mild Cognitive Impairment

Author: Zhengshi Yang, Jessica Z. K. Caldwell, Jeffrey L. Cummings, Aaron Ritter, Jefferson W. Kinney, Dietmar Cordes, The Alzheimer's Disease Neuroimaging Initiative (ADNI), Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Enchi Liu, Tom Montine, Anthony Gamst, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Danielle Harvey, John Kornak, Anders Dale, Matthew Bernstein, Joel Felmlee, Nick Fox, Paul Thompson, Norbert Schuff, Gene Alexander, Charles DeCArli, Dan Bandy, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Nigel J. Cairns, Lisa Taylor-Reinwald, J. Q. Trojanowki, Les Shaw, Virginia M.Y. Lee, Magdalena Korecka, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Zaven Khachaturian, Richard Frank, Peter J. Snyder, Susan Molchan, Jeffrey Kaye, Joseph Quinn, Betty Lind, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Bryan M. Spann, James Brewer, Helen Vanderswag, Judith L. Heidebrink, Joanne L. Lord, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Munir Chowdhury, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, John C. Morris, Beau Ances, Maria Carroll, Sue Leon, Mark A. Mintun, Stacy Schneider, Daniel Marson, Randall Griffith, David Clark, Hillel Grossman, Effie Mitsis, Aliza Romirowsky, Leyla deToledo-Morrell, Raj C. Shah, Ranjan Duara, Daniel Varon, Peggy Roberts, Marilyn Albert, Chiadi Onyike, Stephanie Kielb, Henry Rusinek, Mony J de Leon, Lidia Glodzik, P. Murali Doraiswamy, Jeffrey R. Petrella, Edward R. Coleman, Steven E. Arnold, Jason H. Karlawish, David Wolk, Charles D. Smith, Greg Jicha, Peter Hardy, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Ruth A. Mulnard, Gaby Thai, Catherine Mc-Adams-Ortiz, Ramon Diaz-Arrastia, Kristen Martin-Cook, Michael DeVous, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Heather S Anderson, Russell H. Swerdlow, Liana Apostolova, Po H. Lu, George Bartzokis, Daniel H.S. Silverman, Neill R Graff-Radford, Francine Parfitt, Heather Johnson, Martin Farlow, Scott Herring, Ann M. Hake, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Howard Feldman, Michele Assaly, Andrew KertesZ, John Rogers, Dick Trost, Charles Bernick, Donna Munic, Diana Kerwin, Marek-Marsel Mesulam, Kristine Lipowski, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Walter Martinez, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Meghan Frey, Allyson Rosen, Jared Tinklenberg, Marwan Sabbagh, Christine Belden, Sandra Jacobson, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Salome K. Bwayo, Alan Lerner, Leon Hudson, Paula Ogrocki, Evan Fletcher, Owen Carmichael, John Olichney, Charles DeCarli, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Steven G. Potkin, Adrian Preda, Dana Nguyen, Pierre Tariot, Adam Fleisher, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Barry A. Hendin, Douglas W. Scharre, Maria Kataki, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Robert B. Santulli, Eben S. Schwartz, Kaycee M. Sink, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Henry Querfurth, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, Jacobo Mintzer, Crystal Flynn Longmire, and Kenneth Spicer
Subjects: aging effect, caudate, mild cognitive impairment, functional connectivity, Alzheimer's Disease, sex difference, Psychiatry, RC435-571
Abstract: PurposeTo assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process.Materials and MethodsTwo hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI.ResultsThe MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10−7, right: P = 3.37 × 10−8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI.ConclusionSex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.
Published: 2022
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2. Feasibility study for detection of retinal amyloid in clinical trials: The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial

Author: Jennifer Ngolab, Michael Donohue, Alison Belsha, Jennifer Salazar, Paula Cohen, Sandhya Jaiswal, Veasna Tan, Devon Gessert, Shaina Korouri, Neelum T. Aggarwal, Jessica Alber, Ken Johnson, Gregory Jicha, Christopher vanDyck, James Lah, Stephen Salloway, Reisa A. Sperling, Paul S. Aisen, Michael S. Rafii, and Robert A. Rissman
Subjects: Alzheimer's disease, amyloid, NeuroVision, positron emission tomography, retina, retinopathy, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract: Abstract Introduction The retina and brain exhibit similar pathologies in patients diagnosed with neurodegenerative diseases. The ability to access the retina through imaging techniques opens the possibility for non‐invasive evaluation of Alzheimer's disease (AD) pathology. While retinal amyloid deposits are detected in individuals clinically diagnosed with AD, studies including preclinical individuals are lacking, limiting assessment of the feasibility of retinal imaging as a biomarker for early‐stage AD risk detection. Methods In this small cross‐sectional study we compare retinal and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial as well as a companion cohort of individuals who exhibited low levels of amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin‐positive fluorescent retinal spots from a small subset of participants from both studies to determine retinal amyloid deposition at baseline. Results The four participants from the A4 trial showed a greater number of retinal spots compared to the four participants from the LEARN study. We observed a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr). Discussion The results of this small pilot study support the use of retinal fundus imaging for detecting amyloid deposition that is correlated with brain amyloid PET SUVr. A larger sample size will be necessary to fully ascertain the relationship between amyloid PET and retinal amyloid both cross‐sectionally and longitudinally.
Published: 2021
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3. Prediction and Classification of Alzheimer’s Disease Based on Combined Features From Apolipoprotein-E Genotype, Cerebrospinal Fluid, MR, and FDG-PET Imaging Biomarkers

Author: Yubraj Gupta, Ramesh Kumar Lama, Goo-Rak Kwon, Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, Steven Chao, Scott Mackin, Rema Raman, Erin Drake, Mike Donohue, Gustavo Jimenez, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Lindsey Hergesheimer, Elizabeth Shaffer, Craig Nelson, David Bickford, Meryl Butters, Michelle Zmuda, Denise Reyes, Kelley M. Faber, Kelly N. Nudelman, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, and Dariella Fernandez
Subjects: Alzheimer's disease, MCIs (MCI stable), MCIc (MCI converted), sMRI, FDG-PET, CSF, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Alzheimer's disease (AD), including its mild cognitive impairment (MCI) phase that may or may not progress into the AD, is the most ordinary form of dementia. It is extremely important to correctly identify patients during the MCI stage because this is the phase where AD may or may not develop. Thus, it is crucial to predict outcomes during this phase. Thus far, many researchers have worked on only using a single modality of a biomarker for the diagnosis of AD or MCI. Although recent studies show that a combination of one or more different biomarkers may provide complementary information for the diagnosis, it also increases the classification accuracy distinguishing between different groups. In this paper, we propose a novel machine learning-based framework to discriminate subjects with AD or MCI utilizing a combination of four different biomarkers: fluorodeoxyglucose positron emission tomography (FDG-PET), structural magnetic resonance imaging (sMRI), cerebrospinal fluid (CSF) protein levels, and Apolipoprotein-E (APOE) genotype. The Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline dataset was used in this study. In total, there were 158 subjects for whom all four modalities of biomarker were available. Of the 158 subjects, 38 subjects were in the AD group, 82 subjects were in MCI groups (including 46 in MCIc [MCI converted; conversion to AD within 24 months of time period], and 36 in MCIs [MCI stable; no conversion to AD within 24 months of time period]), and the remaining 38 subjects were in the healthy control (HC) group. For each image, we extracted 246 regions of interest (as features) using the Brainnetome template image and NiftyReg toolbox, and later we combined these features with three CSF and two APOE genotype features obtained from the ADNI website for each subject using early fusion technique. Here, a different kernel-based multiclass support vector machine (SVM) classifier with a grid-search method was applied. Before passing the obtained features to the classifier, we have used truncated singular value decomposition (Truncated SVD) dimensionality reduction technique to reduce high dimensional features into a lower-dimensional feature. As a result, our combined method achieved an area under the receiver operating characteristic (AU-ROC) curve of 98.33, 93.59, 96.83, 94.64, 96.43, and 95.24% for AD vs. HC, MCIs vs. MCIc, AD vs. MCIs, AD vs. MCIc, HC vs. MCIc, and HC vs. MCIs subjects which are high relative to single modality results and other state-of-the-art approaches. Moreover, combined multimodal methods have improved the classification performance over the unimodal classification.
Published: 2019
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4. The Influence of Cerebrospinal Fluid Abnormalities and APOE 4 on PHF-Tau Protein: Evidence From Voxel Analysis and Graph Theory

Author: Yuan Li, Zhijun Yao, Yue Yu, Yu Fu, Ying Zou, Bin Hu, for the Alzheimer’s Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Tom Montine, Gustavo Jimenez, Michael Donohue, Devon Gessert, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Sarah Walter, Lindsey Hergesheimer, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Joseph Quinn, Lisa C. Silbert, Betty Lind, Jeffrey A. Kaye, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Jaimie Ziolkowski, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Javier Villanueva-Meyer, Valory Pavlik, Nathaniel Pacini, Ashley Lamb, Joseph S. Kass, Rachelle S. Doody, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Randy Yeh, Beau Ances, David Winkfield, Maria Carroll, Angela Oliver, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Hillel Grossman, Effie Mitsis, Raj C. Shah, Melissa Lamar, Patricia Samuels, Ranjan Duara, Maria T. Greig-Custo, Rosemarie Rodriguez, Chiadi Onyike, Daniel D’Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Jamika Singleton-Garvin, Anaztasia Ulysse, Mrunalini Gaikwad, P. Murali Doraiswamy, Jeffrey R. Petrella, Olga James, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Jason H. Karlawish, David A. Wolk, Sanjeev Vaishnavi, Christopher M. Clark, Steven E. Arnold, Charles D. Smith, Greg Jicha, Peter Hardy, Riham El Khouli, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Kim Martin, Nancy Kowalksi, Melanie Keltz, Bonnie S. Goldstein, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Gaby Thai, Aimee Pierce, Beatriz Yanez, Elizabeth Sosa, Megan Witbracht, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Ellen Woo, Daniel H.S. Silverman, Edmond Teng, Sarah Kremen, Liana Apostolova, Kathleen Tingus, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Chris (Chinthaka) Heyn, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, William Pavlosky, Irina Rachinsky, Dick Drost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall, Jerome Yesavage, Joy L. Taylor, Steven Chao, Barton Lane, Allyson Rosen, Jared Tinklenberg, Edward Zamrini, Christine M. Belden, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Ntekim E. Oyonumo, Joanne Allard, Olu Ogunlana, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Joel Hetelle, Kathryn DeMarco, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Rawan Tarawneh, Earl A. Zimmerman, Dzintra Celmins, David Hart, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Mia Yang, Akiva Mintz, Rhode Island, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Courtney Bodge, Stephen Salloway, Paul Malloy, Stephen Correia, Athena Lee, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, John Rogers, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Delwyn D. Miller, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Susan K. Schultz, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Christi Leach, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Lindsey Hergesheimen, Jacqueline Hayes, Shannon Finley, Susan Landau, Erin Householder, Karl Friedl, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Bonnie Goldstein, Kimberly S. Martin, Steven G. Potkin, Adrian Preda, Dana Nguyen, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Gad Marshall, Marwan N. Sabbagh, Sandra A. Jacobson, Saba Wolday, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, Scott Mackin, Rema Raman, Erin Drake, Mike Donohue, Elizabeth Shaffer, Craig Nelson, David Bickford, Meryl Butters, Michelle Zmuda, Denise Reyes, Kelley M. Faber, Kelly N. Nudelman, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, and Dariella Fernandez
Subjects: PHF-Tau, graph theory, network properties, APOE 4, CSF-Tau, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Mild cognitive impairment (MCI) is a transitional state between the cognitive changes in normal aging and Alzheimer’s disease (AD), which induces abnormalities in specific brain regions. Previous studies showed that paired helical filaments Tau (PHF-Tau) protein is a potential pathogenic protein which may cause abnormal brain function and structure in MCI and AD patients. However, the understanding of the PHF-Tau protein network in MCI patients is limited. In this study, 225 subjects with PHF-Tau Positron Emission Tomography (PET) images were divided into four groups based on whether they carried Apolipoprotein E ε4 (APOE 4) or abnormal cerebrospinal fluid Total-Tau (CSF T-Tau). They are two important pathogenic factors that might cause cognitive function impairment. The four groups were: individuals harboring CSF T-Tau pathology but no APOE 4 (APOE 4−T+); APOE 4 carriers with normal CSF T-Tau (APOE 4+T−); APOE 4 carriers with abnormal CSF T-Tau (APOE 4+T+); and APOE 4 noncarriers with abnormal CSF T-Tau (APOE 4−T−). We explored the topological organization of PHF-Tau networks in these four groups and calculated five kinds of network properties: clustering coefficient, shortest path length, Q value of modularity, nodal centrality and degree. Our findings showed that compared with APOE 4−T− group, the other three groups showed different alterations in the clustering coefficient, shortest path length, Q value of modularity, nodal centrality and degree. Simultaneously, voxel-level analysis was conducted and the results showed that compared with APOE 4−T− group, the other three groups were found increased PHF-Tau distribution in some brain regions. For APOE 4+T+ group, positive correlation was found between the value of PHF-Tau distribution in altered regions and Functional Assessment Questionnaire (FAQ) score. Our results indicated that the effects of APOE 4 and abnormal CSF T-Tau may induce abnormalities of PHF-Tau protein and APOE 4 has a greater impact on PHF-Tau than abnormal CSF T-Tau. Our results may be particularly helpful in uncovering the pathophysiology underlying the cognitive dysfunction in MCI patients.
Published: 2019
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5. New Perspective for Non-invasive Brain Stimulation Site Selection in Mild Cognitive Impairment: Based on Meta- and Functional Connectivity Analyses

Author: Jiao Liu, Binlong Zhang, Georgia Wilson, Jian Kong, the Alzheimer’s Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, and Steven Chao
Subjects: mild cognitive impairment, non-invasive brain stimulation, stimulation site, meta-analysis, resting state functional connectivity, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: BackgroundNon-invasive brain stimulation (NIBS) has been widely used to treat mild cognitive impairment (MCI). However, there exists no consensus on the best stimulation sites.ObjectiveTo explore potential stimulation locations for NIBS treatment in patients with MCI, combining meta- and resting state functional connectivity (rsFC) analyses.MethodsThe meta-analysis was conducted to identify brain regions associated with MCI. Regions of interest (ROIs) were extracted based on this meta-analysis. The rsFC analysis was applied to 45 MCI patients to determine brain surface regions that are functionally connected with the above ROIs.ResultsWe found that the dorsolateral prefrontal cortex (DLPFC) and inferior frontal gyrus (IFG) were the overlapping brain regions between our results and those of previous studies. In addition, we recommend that the temporoparietal junction (including the angular gyrus), which was found in both the meta- and rsFC analysis, should be considered in NIBS treatment of MCI. Furthermore, the bilateral orbital prefrontal gyrus, inferior temporal gyrus, medial superior frontal gyrus, and right inferior occipital gyrus may be potential brain stimulation sites for NIBS treatment of MCI.ConclusionOur results provide several potential sites for NIBS, such as the DLFPC and IFG, and may shed light on the locations of NIBS sites in the treatment of patients with MCI.
Published: 2019
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6. Performing Sparse Regularization and Dimension Reduction Simultaneously in Multimodal Data Fusion

Author: Zhengshi Yang, Xiaowei Zhuang, Christopher Bird, Karthik Sreenivasan, Virendra Mishra, Sarah Banks, Dietmar Cordes, the Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, Steven Chao, Scott Mackin, Rema Raman, Erin Drake, Mike Donohue, Gustavo Jimenez, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Lindsey Hergesheimer, Elizabeth Shaffer, Craig Nelson, David Bickford, Meryl Butters, Michelle Zmuda, Denise Reyes, Kelley M. Faber, Kelly N. Nudelman, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, and Dariella Fernandez
Subjects: sparse principal component analysis, PCA, canonical correlation analysis, CCA, data fusion, mild cognitive impairment, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Collecting multiple modalities of neuroimaging data on the same subject is increasingly becoming the norm in clinical practice and research. Fusing multiple modalities to find related patterns is a challenge in neuroimaging analysis. Canonical correlation analysis (CCA) is commonly used as a symmetric data fusion technique to find related patterns among multiple modalities. In CCA-based data fusion, principal component analysis (PCA) is frequently applied as a preprocessing step to reduce data dimension followed by CCA on dimension-reduced data. PCA, however, does not differentiate between informative voxels from non-informative voxels in the dimension reduction step. Sparse PCA (sPCA) extends traditional PCA by adding sparse regularization that assigns zero weights to non-informative voxels. In this study, sPCA is incorporated into CCA-based fusion analysis and applied on neuroimaging data. A cross-validation method is developed and validated to optimize the parameters in sPCA. Different simulations are carried out to evaluate the improvement by introducing sparsity constraint to PCA. Four fusion methods including sPCA+CCA, PCA+CCA, parallel ICA and sparse CCA were applied on structural and functional magnetic resonance imaging data of mild cognitive impairment subjects and normal controls. Our results indicate that sPCA significantly can reduce the impact of non-informative voxels and lead to improved statistical power in uncovering disease-related patterns by a fusion analysis.
Published: 2019
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7. Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients

Author: Qian Zhao, Min Liu, Lingxia Ha, Yun Zhou, Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, Steven Chao, Scott Mackin, Rema Raman, Erin Drake, Mike Donohue, Gustavo Jimenez, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Lindsey Hergesheimer, Elizabeth Shaffer, Craig Nelson, David Bickford, Meryl Butters, Michelle Zmuda, Denise Reyes, Kelley M. Faber, Kelly N. Nudelman, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, and Dariella Fernandez
Subjects: 18F-AV1451, Tau PET, cognitively normal, mild cognition impairment, Alzheimer's disease, Neurology. Diseases of the nervous system, RC346-429
Abstract: Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification.
Published: 2019
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8. Corrigendum: Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images

Author: Shengwen Guo, Chunren Lai, Congling Wu, Guiyin Cen, The Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, and Steven Chao
Subjects: mild cognitive impairment, conversion, cortical feature, sparse-constrained regression, feature reduction, classification, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published: 2017
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9. Time to Amyloid Positivity and Preclinical Changes in Brain Metabolism, Atrophy, and Cognition: Evidence for Emerging Amyloid Pathology in Alzheimer's Disease

Author: Philip S. Insel, Rik Ossenkoppele, Devon Gessert, William Jagust, Susan Landau, Oskar Hansson, Michael W. Weiner, Niklas Mattsson, and for the Alzheimer's Disease Neuroimaging Initiative
Subjects: Alzheimer's disease, β-amyloid, atrophy, metabolism, cognition, preclinical, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Background: Aβ pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Aβ information is usually measured cross-sectionally and dichotomized to classify subjects as Aβ-positive or Aβ-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Aβ pathology. In this study, we use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition.Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we estimated the points at which rates of fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to the time to Aβ-positivity. Points of initial acceleration in rates of decline were estimated using mixed-effects models with penalized regression splines.Results: Acceleration of rates of FDG PET were observed to occur 20+ years before the conventional threshold for Aβ-positivity. Subtle signs of cognitive dysfunction were observed 10+ years before Aβ-positivity.Conclusions: Aβ may have subtle associations with other hallmarks of Alzheimer's disease before Aβ biomarkers reach conventional thresholds for Aβ-positivity. Therefore, we propose that emerging Aβ pathology occurs many years before cognitively healthy elders reach the current threshold for Aβ positivity (preclinical AD). To allow prevention in the earliest disease stages, AD clinical trials may be designed to also include subjects with Aβ biomarkers in the sub-threshold range.
Published: 2017
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10. Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images

Author: Shengwen Guo, Chunren Lai, Congling Wu, Guiyin Cen, The Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, and Steven Chao
Subjects: mild cognitive impairment, conversion, cortical feature, sparse-constrained regression, feature reduction, classification, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Neuroimaging measurements derived from magnetic resonance imaging provide important information required for detecting changes related to the progression of mild cognitive impairment (MCI). Cortical features and changes play a crucial role in revealing unique anatomical patterns of brain regions, and further differentiate MCI patients from normal states. Four cortical features, namely, gray matter volume, cortical thickness, surface area, and mean curvature, were explored for discriminative analysis among three groups including the stable MCI (sMCI), the converted MCI (cMCI), and the normal control (NC) groups. In this study, 158 subjects (72 NC, 46 sMCI, and 40 cMCI) were selected from the Alzheimer's Disease Neuroimaging Initiative. A sparse-constrained regression model based on the l2-1-norm was introduced to reduce the feature dimensionality and retrieve essential features for the discrimination of the three groups by using a support vector machine (SVM). An optimized strategy of feature addition based on the weight of each feature was adopted for the SVM classifier in order to achieve the best classification performance. The baseline cortical features combined with the longitudinal measurements for 2 years of follow-up data yielded prominent classification results. In particular, the cortical thickness produced a classification with 98.84% accuracy, 97.5% sensitivity, and 100% specificity for the sMCI–cMCI comparison; 92.37% accuracy, 84.78% sensitivity, and 97.22% specificity for the cMCI–NC comparison; and 93.75% accuracy, 92.5% sensitivity, and 94.44% specificity for the sMCI–NC comparison. The best performances obtained by the SVM classifier using the essential features were 5–40% more than those using all of the retained features. The feasibility of the cortical features for the recognition of anatomical patterns was certified; thus, the proposed method has the potential to improve the clinical diagnosis of sub-types of MCI and predict the risk of its conversion to Alzheimer's disease.
Published: 2017
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11. The Impact of Amyloid Burden and APOE on Rates of Cognitive Impairment in Late Life Depression

Author: Arthur W. Toga, Philip S. Insel, Craig Nelson, Howie Rosen, R. Scott Mackin, Susan M. Landau, Paul S. Aisen, Duygu Tosun, Ruth T. Morin, Alzheimer’s Disease Neuroimaging Initiative, Adni Depression, Andrew J. Saykin, Meryl A. Butters, Devon Gessert, Michael W. Weiner, Emma Rhodes, Rema Raman, David Bickford, and Clifford R. Jack
Subjects: Male, medicine.medical_specialty, Neurology, Trail Making Test, Apolipoprotein E4, Disease, Audiology, Verbal learning, Article, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Memory impairment, Humans, Cognitive Dysfunction, Depression (differential diagnoses), Aged, Depressive Disorder, Major, Amyloid beta-Peptides, business.industry, General Neuroscience, Cognition, General Medicine, Late life depression, Middle Aged, 030227 psychiatry, Psychiatry and Mental health, Clinical Psychology, Female, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract: Background: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. Objective: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-β (Aβ) burden. Methods: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aβ burden. Results: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls (H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aβ positivity was associated with worse performance on Logical Memory I (p = 0.044), Logical Memory II (p = 0.011), and Trail Making Test –B (p = 0.032), and APOE ɛ4 genotype was associated with worse performance on Logical Memory I (p = 0.022); these relationships did not differ between LLD and ND. Conclusion: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer’s disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.
Published: 2021

12. Feasibility study for detection of retinal amyloid in clinical trials: The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial

Author: Devon Gessert, Gregory A. Jicha, Veasna Tan, Jessica Alber, Jennifer Salazar, Alison Belsha, Robert A. Rissman, James J. Lah, Christopher H. van Dyck, Stephen Salloway, Michael S. Rafii, Paul S. Aisen, Michael C. Donohue, Sandhya Jaiswal, Paula Cohen, Kenneth O. Johnson, Neelum T. Aggarwal, Shaina Korouri, Jennifer Ngolab, and Reisa A. Sperling
Subjects: Retinal Imaging, Pathology, medicine.medical_specialty, retina, positron emission tomography, Amyloid, Standardized uptake value, Asymptomatic, chemistry.chemical_compound, mental disorders, retinopathy, medicine, RC346-429, Retina, medicine.diagnostic_test, business.industry, Neurodegeneration, NeuroVision, RC952-954.6, amyloid, Retinal, Alzheimer's disease, medicine.disease, Psychiatry and Mental health, medicine.anatomical_structure, chemistry, Positron emission tomography, Geriatrics, Biomarker (medicine), Neurology (clinical), Neurology. Diseases of the nervous system, medicine.symptom, business, Research Article
Abstract: Introduction The retina and brain exhibit similar pathologies in patients diagnosed with neurodegenerative diseases. The ability to access the retina through imaging techniques opens the possibility for non‐invasive evaluation of Alzheimer's disease (AD) pathology. While retinal amyloid deposits are detected in individuals clinically diagnosed with AD, studies including preclinical individuals are lacking, limiting assessment of the feasibility of retinal imaging as a biomarker for early‐stage AD risk detection. Methods In this small cross‐sectional study we compare retinal and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial as well as a companion cohort of individuals who exhibited low levels of amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin‐positive fluorescent retinal spots from a small subset of participants from both studies to determine retinal amyloid deposition at baseline. Results The four participants from the A4 trial showed a greater number of retinal spots compared to the four participants from the LEARN study. We observed a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr). Discussion The results of this small pilot study support the use of retinal fundus imaging for detecting amyloid deposition that is correlated with brain amyloid PET SUVr. A larger sample size will be necessary to fully ascertain the relationship between amyloid PET and retinal amyloid both cross‐sectionally and longitudinally.
Published: 2021

13. KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease

Author: the Alzheimer's Disease Neuroimaging Initiative, J. (Julia) Neitzel, Nicolai Franzmeier, Anna Rubinski, Martin Dichgans, Matthias Brendel, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John A. Morris, Leslie M. Shaw, Enchi Liu, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J. Cairns, Erin Householder, Lisa Taylor Reinwald, Virginia Lee, Magdalena Korecka, L.S. (Li Shen) Ho, the Alzheimer's Disease Neuroimaging Initiative, J. (Julia) Neitzel, Nicolai Franzmeier, Anna Rubinski, Martin Dichgans, Matthias Brendel, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John A. Morris, Leslie M. Shaw, Enchi Liu, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J. Cairns, Erin Householder, Lisa Taylor Reinwald, Virginia Lee, Magdalena Korecka, and L.S. (Li Shen) Ho
Abstract: Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer’s disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that o
Published: 2021
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14. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial

Author: Cecily Jenkins, Tiffany W. Chow, Michael C. Donohue, Devon Gessert, James B. Brewer, Suzanne Craft, Chung-Kai Sun, Robert A. Rissman, Kelly Harless, Rema Raman, Michael S. Rafii, and Paul S. Aisen
Subjects: Male, medicine.medical_specialty, Clinical Dementia Rating, Population, Neuropsychological Tests, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, Alzheimer Disease, Internal medicine, Outcome Assessment, Health Care, Medicine, Dementia, Humans, Hypoglycemic Agents, Insulin, Cognitive Dysfunction, 030212 general & internal medicine, education, Administration, Intranasal, Original Investigation, Aged, Aged, 80 and over, education.field_of_study, business.industry, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical trial, Cohort, Feasibility Studies, Female, Neurology (clinical), Alzheimer's disease, business, 030217 neurology & neurosurgery
Abstract: Importance Insulin modulates aspects of brain function relevant to Alzheimer disease and can be delivered to the brain using intranasal devices. To date, the use of intranasal insulin to treat persons with mild cognitive impairment and Alzheimer’s disease dementia remains to be examined in a multi-site trial. Objective To examine the feasibility, safety, and efficacy of intranasal insulin for the treatment of persons with mild cognitive impairment and Alzheimer disease dementia in a phase 2/3 multisite clinical trial. Design, Setting, and Participants A randomized (1:1) double-blind clinical trial was conducted between 2014 and 2018. Participants received 40 IU of insulin or placebo for 12 months during the blinded phase, which was followed by a 6-month open-label extension phase. The clinical trial was conducted at 27 sites of the Alzheimer’s Therapeutic Research Institute. A total of 432 adults were screened, and 144 adults were excluded. Inclusion criteria included adults aged 55 to 85 years with a diagnosis of amnestic mild cognitive impairment or Alzheimer disease (based on National Institute on Aging–Alzheimer Association criteria), a score of 20 or higher on the Mini-Mental State Examination, a clinical dementia rating of 0.5 or 1.0, and a delayed logical memory score within a specified range. A total of 289 participants were randomized. Among the first 49 participants, the first device (device 1) used to administer intranasal insulin treatment had inconsistent reliability. A new device (device 2) was used for the remaining 240 participants, who were designated the primary intention-to-treat population. Data were analyzed from August 2018 to March 2019. Interventions Participants received 40 IU of insulin (Humulin-RU-100; Lilly) or placebo (diluent) daily for 12 months (blinded phase) followed by a 6-month open-label extension phase. Insulin was administered with 2 intranasal delivery devices. Main Outcomes and Measures The primary outcome (mean score change on the Alzheimer Disease Assessment Scale–cognitive subscale 12) was evaluated at 3-month intervals. Secondary clinical outcomes were assessed at 6-month intervals. Cerebrospinal fluid collection and magnetic resonance imaging scans occurred at baseline and 12 months. Results A total of 289 participants (155 men [54.6%]; mean [SD] age, 70.9 [7.1] years) were randomized. Of those, 260 participants completed the blinded phase, and 240 participants completed the open-label extension phase. For the first 49 participants, the first device used to administer treatment had inconsistent reliability. A second device was used for the remaining 240 participants (123 men [51.3%]; mean [SD] age, 70.8 [7.1] years), who were designated the primary intention-to-treat population. No differences were observed between treatment arms for the primary outcome (mean score change on ADAS-cog-12 from baseline to month 12) in the device 2 ITT cohort (0.0258 points; 95% CI, −1.771 to 1.822 points;P = .98) or for the other clinical or cerebrospinal fluid outcomes in the primary (second device) intention-to-treat analysis. No clinically important adverse events were associated with treatment. Conclusions and Relevance In this study, no cognitive or functional benefits were observed with intranasal insulin treatment over a 12-month period among the primary intention-to-treat cohort. Trial Registration ClinicalTrials.gov Identifier:NCT01767909
Published: 2020

15. Type 2 diabetes mellitus, brain atrophy, and cognitive decline

Author: Paul S. Aisen, Sarah Walter, Kenneth M. Spicer, Stephanie Reeder, Nick C. Fox, Heather Anderson, Chuang Kuo Wu, Teresa Villena, Cynthia M. Carlsson, Paul Malloy, Bonnie S. Goldstein, Stacy Schneider, Po H. Lu, Jeffrey M. Burns, Balebail Ashok Raj, Stephanie Kielb, Adrian Preda, Pierre N. Tariot, Chet Mathis, Christopher H. van Dyck, Maria Carroll, Karen E. Smith, Lon S. Schneider, Velandai Srikanth, Daniel Varon, Nunzio Pomara, Michael Borrie, Eben S. Schwartz, Gaby Thai, Susan De Santi, Dana Nguyen, Daniel C. Marson, Gene E. Alexander, Thomas O. Obisesan, Steven Potkin, Kris A. Johnson, Henry Rusinek, Nigel J. Cairns, Gad A. Marshall, Scott C. Neu, Benita Mudge, Leyla deToledo-Morrell, Jeff D. Williamson, Helen Vanderswag, Howard Chertkow, Sandra W. Jacobson, Dana Mathews, Arthur W. Toga, Saba Wolday, Douglas W. Scharre, Lidia Glodzik, Rob Bartha, Anders M. Dale, Norbert Schuff, Ging-Yuek Robin Hsiung, Rachelle S. Doody, Richard D. King, Vernice Bates, Li Shen, Barton Lane, Kristin Fargher, Chris Moran, Greg Jicha, Dan Bandy, Sara Dolen, Andrew E. Budson, Martha G. MacAvoy, Daniel H.S. Silverman, Anton P. Porsteinsson, Kathleen R. Johnson, Michele L. Callisaya, Betty Lind, Michael D. Devous, Robert C. Green, P. Murali Doraiswamy, Andrew J. Saykin, Joseph F. Quinn, Kristina Lipowski, Raymundo Hernando, Catherine Mc-Adams-Ortiz, Ronald G. Thomas, Jeffrey Kaye, Irina Rachinsky, Donna Munic, Munir Chowdhury, Bruce L. Miller, Les Shaw, Brian R. Ott, Randall Griffith, Kristen Martin-Cook, Marwan N. Sabbagh, Crystal V. Flynn Longmire, Raymond Scott Turner, Karen Blank, Effie M. Mitsis, Charles Bernick, Marilyn S. Albert, John M Olichney, Earl A. Zimmerman, Jared R. Tinklenberg, Robert A. Koeppe, Dick Trost, Howard Feldman, Laura L. Boles Ponto, M. Saleem Ismail, Alan J. Lerner, Kelly M. Makino, Pradeep Garg, Jeffrey R. Petrella, Peter J. Snyder, Norman R. Relkin, Laurel A. Beckett, Allyson C. Rosen, Devon Gessert, MaryAnn Oakley, J. Q. Trojanowki, Lisa Raudin, Stephen Salloway, Paula Ogrocki, Bryan M. Spann, Susan K. Schultz, Adam S. Fleisher, Brigid Reynolds, Jason Karlawish, Michele Assaly, John Q. Trojanowki, Kewei Chen, Enchi Liu, Mary Quiceno, Kaycee M. Sink, Jerome A. Yesavage, Sterling C. Johnson, Curtis B. Caldwell, Heather E. Johnson, Neill R. Graff-Radford, Karen S. Anderson, Richard Frank, John C. Morris, Donna M. Simpson, Tatiana Foroud, Joel P. Felmlee, Zaven Kachaturian, Magdalena Korecka, George Bartzokis, Francine Parfitt, Henry W. Querfurth, Patricia Lynn Johnson, Raj C. Shah, M.-Marsel Mesulam, Howard J. Rosen, Ann Marie Hake, Danielle J Harvey, Hyungsub Shim, Dick J. Drost, Yaakov Stern, Charles DeCarli, Brandy R. Matthews, Geoffrey Tremont, Kim Martin, Robert B. Santulli, Aliza Romirowsky, Joy L. Taylor, Ramon Diaz-Arrastia, Godfrey D. Pearlson, Mark A. Mintun, James J. Lah, Norm Foster, Matt A. Bernstein, Diana R. Kerwin, Virginia M.-Y. Lee, Bojana Stefanovic, Joanne L. Lord, Chris Hosein, Susan E. Molchan, David J. Clark, Leon Hudson, Janet S. Cellar, Karen Crawford, Richard Beare, Franklin Watkins, T. J. Montine, Ronald C. Petersen, Carl H. Sadowsky, David A. Wolk, Steven E. Arnold, Nancy Collins Johnson, Ruth A. Mulnard, Antero Sarrael, John Kornak, Amanda Smith, Owen Carmichael, Beau M. Ances, Clifford R. Jack, Meghan Frey, Martin R. Farlow, William J. Jagust, Ronald J. Killiany, Mony J. de Leon, Sandra E. Black, Javier Villanueva-Meyer, Smita Kittur, Walter Martinez, Sue Leon, Anthony Gamst, James B. Brewer, Hillel Grossman, Eric M. Reiman, Jacobo Mintzer, Stephen Correia, Kyle B. Womack, Maria Kataki, Lawrence S. Honig, Liana G. Apostolova, Peggy Roberts, Christine Belden, Michelle Rainka, Alexander Norbash, R. Edward Coleman, Richard E. Carson, Dzintra Celmins, Lisa Taylor-Reinwald, Scott Herring, Oscar L. Lopez, Michael W. Weiner, Ranjan Duara, Elizabether Finger, Peter A. Hardy, Myron F. Weiner, Horacio Capote, Keith A. Johnson, Karen L. Bell, Allan I. Levey, Steven G. Potkin, Howard Bergman, John A. Rogers, Wei Wang, Connie Brand, Chiadi U. Onyike, Paul M. Thompson, Russell H. Swerdlow, Gloria Chaing, Judith L. Heidebrink, Salome K. Bwayo, Reisa A. Sperling, Michael C. Donohue, Sanjay Asthana, Alice D. Brown, Charles D. Smith, Neil W. Kowall, Andrew Kertesz, Tamie Sather, Evan Fletcher, and Sonia Pawluczyk
Subjects: Blood Glucose, Male, Pediatrics, medicine.medical_specialty, endocrine system diseases, Article, Alzheimer Disease, medicine, Dementia, Humans, Cognitive Dysfunction, Longitudinal Studies, Cognitive decline, Cognitive reserve, Aged, Aged, 80 and over, Cerebral Cortex, business.industry, Type 2 Diabetes Mellitus, nutritional and metabolic diseases, Brain, Cognition, Organ Size, medicine.disease, Magnetic Resonance Imaging, Cognitive test, Diabetes Mellitus, Type 2, Cohort, Female, Neurology (clinical), Alzheimer's disease, Atrophy, business, Factor Analysis, Statistical
Abstract: ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.
Published: 2018

16. [P4–197]: EMERGING AMYLOID PATHOLOGY

Author: Susan M. Landau, William J. Jagust, Philip S. Insel, Oskar Hansson, Michael W. Weiner, Rik Ossenkoppele, Devon Gessert, and Niklas Mattsson
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Amyloid pathology, Pathology, medicine.medical_specialty, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2017

17. Pattern Discovery in Brain Imaging Genetics via SCCA Modeling with a Generic Non-convex Penalty

Author: Arthur W. Toga, Leslie M. Shaw, Kristin Fargher, Mary L. Creech, Richard Frank, Po H. Lu, Daniel C. Marson, Karen Blank, Kristine Lipowski, Charles DeCarli, Vernice Bates, Marc Seltzer, Norm Foster, Matt A. Bernstein, Janet S. Cellar, David G. Clark, Sonia Pawluczyk, David A. Wolk, Charles D. Smith, Neill R. Graff-Radford, Stephen Pasternack, Warren Barker, Paul Malloy, Chris Hosein, Steven E. Arnold, Paul S. Aisen, Adam Schwartz, Kenneth M. Spicer, Marissa Natelson Love, Iris Sim, Brendan J Kelly, Danielle J Harvey, Howard Feldman, David Bachman, Clifford R. Jack, Scott Herring, David C. Perry, Pierre N. Tariot, Chiadi U. Onyike, Paul M. Thompson, Gloria Chaing, Stephanie Reeder, David T.W. Jones, Anton P. Porsteinsson, Joanne L. Lord, Pauline Maillard, Lori A. Daiello, Kris Johnson, Steven G. Potkin, Reisa A. Sperling, Carl H. Sadowsky, Stephanie Kielb, Mohammed O. Sheikh, Jason Karlawish, Kim Martin, Allyson C. Rosen, Susan M. Landau, Dana Nguyen, Oscar L. Lopez, Kejal Kantarci, Neil Buckholtz, Christopher M. Clark, Laurel A. Beckett, Jingwen Yan, Michael Borrie, Greg Sorensen, Amanda Smith, Chad Ward, Bret J. Borowski, Stephen Salloway, Mary Quiceno, Kwangsik Nho, Marilyn S. Albert, Ann Marie Hake, Kaycee M. Sink, Howard Bergman, Lei Guo, Terence Z. Wong, Michael W. Weiner, William Z. Potter, David S. Knopman, M. Saleem Ismail, Alan J. Lerner, Pradeep Garg, Susan Rountree, Michal J. Figurski, Michelle Rainka, Kim Poki-Walker, Irina Rachisky, Chet Mathis, Elizabeth Finger, Jeff D. Williamson, Jeffrey R. Petrella, Prashanthi Vemuri, Gus Jiminez, Keith A. Johnson, Sara Dolen, Curtis Tatsuoka, Nadira Trncic, Pradeep Varma, Raj C. Shah, Karen L. Bell, Elizabeth Oates, Robert A. Koeppe, Adam S. Fleisher, Daniel D'Agostino, Joanne S. Allard, Jeffrey Kaye, Jared R. Tinklenberg, Saba Wolday, Leon J. Thal, Allan I. Levey, Douglas W. Scharre, James B. Brewer, Randall Griffith, Cynthia M. Carlsson, Nunzio Pomara, Howard Chertkow, Charles Bernick, Kefei Liu, Howard J. Rosen, Ranjan Duara, Howard Fillit, T. Y. Lee, Alexander Norbash, Bonnie S. Goldstein, Benita Mudge, John A. Rogers, John M Olichney, Leyla deToledo-Morrell, John C. Brockington, Nick C. Fox, Greg Jicha, Lei Du, Erik D. Roberson, Effie M. Mitsis, Kathleen Johnson, Vesna Sossi, Munir Chowdhury, Bruce L. Miller, Dana Mathews, Jeffrey M. Burns, Steven M. Paul, Balebail Ashok Raj, Chuang Kuo Wu, Karen Ekstam Smith, Xiaohui Yao, Hyungsub Shim, Ging-Yuek Robin Hsiung, Anna Burke, Sherye A. Sirrel, Teresa Villena, Geoffrey Tremont, Susan K. Schultz, Barton Lane, Sandra Jacobson, Tatiana Foroud, Michele Assaly, Sara S. Mason, Zaven S. Khachaturian, Archana B. Balasubramanian, James J. Lah, George Bartzokis, Parianne Fatica, Michael Lin, Laura A. Flashman, M. Marcel Mesulam, Dzintra Celmins, Brandy R. Matthews, Brian R. Ott, Gad A. Marshall, Lisa D. Ravdin, Sandra Weintraub, Sterling C. Johnson, Liberty Teodoro, Lisa Taylor-Reinwald, Karen Crawford, Christine M. Belden, Connie Brand, Bryan M. Spann, Marc Raichle, Ki Won Nam, Joy L. Taylor, Virginia M.-Y. Lee, Victoria Shibley, Franklin Watkins, T. J. Montine, Russell H. Swerdlow, Martin J. Sadowski, Hristina Koleva, Peter A. Hardy, Judith L. Heidebrink, Diana R. Kerwin, Antero Sarrael, Curtis Caldwell, Beau M. Ances, John K. Hsiao, Javier Villanueva-Meyer, Sandra E. Black, Horacio Capote, Eric M. Reiman, Jacobo Mintzer, Richard E. Carson, Stephen Correia, Valory N. Pavlik, Jeff Gunter, Anaztasia Ulysse, Lon S. Schneider, Brigid Reynolds, Patricia Lynn Johnson, Bojana Stefanovic, Kathleen Tingus, John Q. Trojanowki, Ronald J. Killiany, Mimi Dang, Raina Carter, Franz Hefti, Andrew E. Budson, Martha G. MacAvoy, Daniel H.S. Silverman, Smita Kittur, John C. Morris, Donna M. Simpson, Norbert Schuff, Peter Davies, Lawrence S. Honig, Joseph F. Quinn, Ronald G. Thomas, Raymond Scott Turner, Salvador Borges-Neto, Kyle B. Womack, Maria Kataki, Emily Rogalski, Angela Oliver, Maria C. Carrillo, Betty Lind, Lew Kuller, P. Murali Doraiswamy, William J. Jagust, Mary Ann Oakley, Donna Munic, Liana G. Apostolova, David M. Holtzman, Adrian Preda, Robert B. Santulli, Marwan N. Sabbagh, Godfrey D. Pearlson, Mark A. Mintun, Mary L. Hynes, Borna Bonakdarpour, Colleen S. Albers, Ronald C. Petersen, Devon Gessert, Scott C. Neu, Hillel Grossman, Gary R. Conrad, Kelley Faber, Edward Coleman, Karen E. Anderson, Owen Carmichael, Jared R. Brosch, William Brooks, Partha Sinha, Leslie Gordineer, Martin R. Farlow, Thomas O. Obisesan, Jennifer Mason, Kelly M. Makino, Li Shen, Shannon L. Risacher, Sungeun Kim, Lisa C. Silbert, Junwei Han, Ellen Woo, Dick Trost, Francine Parfitt, Michael C. Donohue, Sanjay Asthana, Alice D. Brown, Neil W. Kowall, Andrew Kertesz, Earl A. Zimmerman, Paula Ogrocki, Kewei Chen, Magdalena Korecka, Mrunalini Gaikwad, Nigel J. Cairns, Peter J. Snyder, Norman R. Relkin, Nancy Johnson, Mauricio Beccera, M. L. Senjem, Helen Vanderswag, Erin E. Franklin, Robert C. Green, Jerome A. Yesavage, Ann Marie Milliken, Maria T. Greig-Custo, David S. Geldmacher, Yaakov Stern, Tamie Sather, Evan Fletcher, Sarah Walter, Stacy Schneider, Rob Bartha, Rachelle S. Doody, Andrew J. Saykin, Raymundo Hernando, Christopher H. van Dyck, and Maria Carroll
Subjects: 0301 basic medicine, Male, lcsh:Medicine, Feature selection, Neuroimaging, Biology, Polymorphism, Single Nucleotide, Article, Pattern Recognition, Automated, Correlation, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Feature (machine learning), Image Processing, Computer-Assisted, Humans, lcsh:Science, Aged, Genetics, Computational model, Multidisciplinary, Models, Statistical, lcsh:R, Alzheimer’s Disease Neuroimaging Initiative, Regression, body regions, 030104 developmental biology, Phenotype, Pattern recognition (psychology), Multivariate Analysis, lcsh:Q, Female, Canonical correlation, 030217 neurology & neurosurgery, Algorithms, Alzheimer's Disease Neuroimaging Initiative
Abstract: Brain imaging genetics intends to uncover associations between genetic markers and neuroimaging quantitative traits. Sparse canonical correlation analysis (SCCA) can discover bi-multivariate associations and select relevant features, and is becoming popular in imaging genetic studies. The L1-norm function is not only convex, but also singular at the origin, which is a necessary condition for sparsity. Thus most SCCA methods impose $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm onto the individual feature or the structure level of features to pursuit corresponding sparsity. However, the $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm penalty over-penalizes large coefficients and may incurs estimation bias. A number of non-convex penalties are proposed to reduce the estimation bias in regression tasks. But using them in SCCA remains largely unexplored. In this paper, we design a unified non-convex SCCA model, based on seven non-convex functions, for unbiased estimation and stable feature selection simultaneously. We also propose an efficient optimization algorithm. The proposed method obtains both higher correlation coefficients and better canonical loading patterns. Specifically, these SCCA methods with non-convex penalties discover a strong association between the APOE e4 rs429358 SNP and the hippocampus region of the brain. They both are Alzheimer’s disease related biomarkers, indicating the potential and power of the non-convex methods in brain imaging genetics.
Published: 2017

18. Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease

Author: Christopher H. van Dyck, Robert A. Rissman, Rema Raman, Stephen M. Strittmatter, Michael S. Rafii, Paul S. Aisen, Jeffrey Kaye, Jiyoon Choi, Devon Gessert, Haakon B. Nygaard, Robert A. Koeppe, R. Scott Turner, James B. Brewer, Eric M. Reiman, Kewei Chen, Tiffany W. Chow, Michael C. Donohue, and Seth A. Gale
Subjects: education.field_of_study, medicine.medical_specialty, Clinical Dementia Rating, business.industry, Population, Placebo, medicine.disease, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Biomarker (medicine), 030212 general & internal medicine, Neurology (clinical), Tauopathy, Alzheimer's disease, education, business, Adverse effect, 030217 neurology & neurosurgery
Abstract: Importance Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease. Objective To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated. Design, Setting, and Participants This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-β peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018. Interventions AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks. Main Outcomes and Measures Primary outcome was the reduction in relative CMRgl, as measured by18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease–associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers. Results Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: −0.006 units/y; 95% CI, −0.017 to 0.006;P = .34). The treatment groups also did not differ in the rate of change in Alzheimer’s Disease Assessment Scale–Cognitive Subscale, Alzheimer’s Disease Cooperative Study–Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness. Conclusions and Relevance Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease–associated region of interest or on secondary clinical or biomarker measures. Trial Registration ClinicalTrials.gov identifier:NCT02167256
Published: 2019

19. DT-02-03: OPEN LABEL EXTENSION RESULTS FROM A PHASE II/III TRIAL OF INTRANASAL INSULIN

Author: Chung-Kai Sun, Tiffany W. Chow, Michael C. Donohue, James B. Brewer, Kelly Harless, Robert A. Rissman, Rema Raman, Devon Gessert, Michael S. Rafii, Paul S. Aisen, and Suzanne Craft
Subjects: PHASE II/III TRIAL, Epidemiology, business.industry, Health Policy, Insulin, medicine.medical_treatment, Extension (predicate logic), Pharmacology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Nasal administration, Neurology (clinical), Geriatrics and Gerontology, Open label, business
Published: 2019

20. Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology

Author: Howard Feldman, Anton P. Porsteinsson, Lon S. Schneider, Eben S. Schwartz, Earl A. Zimmerman, Richard V. King, Nunzio Pomara, James E. Galvin, M. Marcel Mesulam, Paula Ogrocki, Howard Chertkow, Gail Li, Gad A. Marshall, Kewei Chen, Norbert Schuff, Magdalena Korecka, MaryAnn Oakley, Elaine R. Peskind, Stephen Salloway, Kristine Lipowski, Clifford R. Jack, Charles DeCarli, Greg Jicha, Kathleen Tingus, Tatiana Foroud, Andrew E. Budson, Martha G. MacAvoy, Daniel H.S. Silverman, Sonia Pawluczyk, Mary Quiceno, Kaycee M. Sink, Paul S. Aisen, Peter Davies, Chris Hosein, Erin Householder, Adam Schwartz, Munir Chowdhury, Bruce L. Miller, James J. Lah, Steven E. Arnold, Kenneth M. Spicer, Keith A. Johnson, Karen L. Bell, Laura L. Boles Ponto, Olga James, Stephanie Reeder, Catherine Mc-Adams-Ortiz, Michele Assaly, Melissa J. Davis, Zaven Khachaturian, Leon J. Thal, Allan I. Levey, Betty Lind, Michael D. Devous, P. Murali Doraiswamy, John Q. Trojanowki, Jason Karlawish, Karen S. Anderson, Kejal Kantarci, Raina Carter, Gaby Thai, Tracy Kendall, Bojana Stefanovic, George Bartzokis, M.S. Albert, Donna Munic, Kelly M. Makino, Anahita Adeli, Franz Hefti, Dzintra Celmins, Marwan N. Sabbagh, Nigel J. Cairns, John C. Morris, Donna M. Simpson, Brandy R. Matthews, Marilyn S. Albert, Sterling C. Johnson, Curtis B. Caldwell, Greg Sorensen, Geoffrey Tremont, Charles Bernick, Susan De Santi, Jeffrey R. Petrella, Scott C. Neu, Jeffrey Kaye, Randall Griffith, Helen Vanderswag, Mauricio Beccera, M. L. Senjem, Charles D. Smith, David S. Knopman, Lisa Taylor-Reinwald, Chet Mathis, Susan M. Landau, Dana Nguyen, Nick C. Fox, Adrian Preda, Robert A. Koeppe, Cynthia Hunt, Benita Mudge, Lisa Raudin, Dick J. Drost, Steven M. Paul, Heather Anderson, Michal J. Figurski, Davie Holtzman, Scott Herring, Robert B. Santulli, Chad Ward, Godfrey D. Pearlson, Mark A. Mintun, Joseph F. Quinn, Thomas C. Neylan, M. Saleem Ismail, Alan J. Lerner, Sherye A. Sirrel, Henry W. Querfurth, Rosemary H Morrison, Ronald G. Thomas, Peter A. Hardy, Bryan M. Spann, Kristen Martin-Cook, Robert C. Green, John M Olichney, Lidia Glodzik, Pradeep Garg, Oscar L. Lopez, Annmarie Hake, Douglas W. Scharre, Raymond Scott Turner, Michael Borrie, Sara Dolen, Marc Raichle, Leyla de Toledo-Morrell, Jeffrey M. Burns, Joy L. Taylor, Balebail Ashok Raj, Irina Rachinsky, David Bachman, Horacio Capote, Erik D. Roberson, Effie M. Mitsis, Richard Frank, Michael W. Weiner, Michael C. Donohue, Ansgar J. Furst, Adam S. Fleisher, David S. Geldmacher, Joanne S. Allard, Gus Jiminez, Jared R. Tinklenberg, Teresa Villena, Ranjan Duara, Elizabether Finger, T. Y. Lee, Sanjay Asthana, Dino Massoglia, Alice D. Brown, Neil W. Kowall, Kim Martin, Angela Oliver, Ellen Woo, Susan Rountree, Peggy Roberts, Terence Z. Wong, Meghan Frey, Sandra Harding, Virginia M.-Y. Lee, Taylor W. Schmitz, William J. Jagust, Daniel Varon, Michelle Rainka, Norm Foster, Matt A. Bernstein, Colleen S. Albers, Elizabeth Oates, Myron F. Weiner, Eric C. Petrie, Andrew Kertesz, Janet S. Cellar, Karen Crawford, Christine M. Belden, Chuang-Kuo Wu, Jordan Grafman, Walter Martinez, Devon Gessert, John C. Brockington, David J. Clark, David A. Wolk, Heather E. Johnson, Alexander Norbash, Hillel Grossman, Gary R. Conrad, Kelley Faber, Jacqueline Hayes, Sandra Jacobson, Diana R. Kerwin, Franklin Watkins, T. J. Montine, Ramon Diaz-Arrastia, Hyungsub Shim, Leon Hudson, Jeff Gunter, Partha Sinha, Peter J. Snyder, Norman R. Relkin, Ruth A. Mulnard, Francine Parfitt, David Jones, Nancy Collins Johnson, Tamie Sather, Evan Fletcher, Sarah Walter, Jerome A. Yesavage, Antero Sarrael, Sungeun Kim, Brigid Reynolds, Maria T. Greig, Patricia Lynn Johnson, Stacy Schneider, Yaakov Stern, Beau M. Ances, Steven G. Potkin, Ronald J. Killiany, Mimi Dang, Smita Kittur, James B. Brewer, Chiadi U. Onyike, Paul M. Thompson, Mony J. de Leon, Sandra E. Black, Lawrence S. Honig, Rob Bartha, Gloria Chaing, R. Nathan Spreng, Rachelle S. Doody, Shannon Finley, Stephen H. Pasternak, Brian R. Ott, Reisa A. Sperling, Tamar J. Kitzmiller, John K. Hsiao, Kwangsik Nho, Richard E. Carson, Howard Bergman, Cynthia M. Carlsson, Bonnie S. Goldstein, Kyle B. Womack, Maria Kataki, Lew Kuller, Liana G. Apostolova, J. Jay Fruehling, Daniel D'Agostino, Christina A. Michel, Susan K. Schultz, Howard Fillit, Konstantinos Arfanakis, John A. Rogers, Dana Mathews, Ging-Yuek Robin Hsiung, Barton Lane, Brittany Cerbone, Sara S. Mason, Stephanie Kielb, Kris A. Johnson, Henry Rusinek, Liberty Teodoro, Connie Brand, Jeff D. Williamson, Prashanthi Vemuri, Russell H. Swerdlow, Judith L. Heidebrink, Paul Malloy, Pierre N. Tariot, Bret J. Borowski, Karl E. Friedl, Debra A. Fleischman, Martin R. Farlow, Javier Villanueva-Meyer, Eric M. Reiman, Jacobo Mintzer, Stephen Correia, Po H. Lu, Daniel C. Marson, Steven Potkin, Vernice Bates, Li Shen, Kathleen R. Johnson, Allyson C. Rosen, Neil Buckholtz, Andrew J. Saykin, Raymundo Hernando, Raj C. Shah, M.-Marsel Mesulam, Christopher H. van Dyck, Maria Carroll, Howard J. Rosen, Karen E. Smith, Arthur W. Toga, Leslie M. Shaw, Kristin Fargher, Karen Blank, Ronald C. Petersen, Amanda Smith, Owen Carmichael, Laurel A. Beckett, Sue Leon, William Z. Potter, Neill R. Graff-Radford, Danielle J Harvey, Joanne L. Lord, and Carl H. Sadowsky
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, Amyloid, Basal Forebrain, Science, General Physics and Astronomy, Degeneration (medical), Grey matter, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Entorhinal Cortex, Humans, Aged, Aged, 80 and over, Basal forebrain, Multidisciplinary, Amyloid beta-Peptides, business.industry, General Chemistry, medicine.disease, Entorhinal cortex, Prognosis, Magnetic Resonance Imaging, 030104 developmental biology, medicine.anatomical_structure, Biomarker (medicine), Female, Alzheimer's disease, business, 030217 neurology & neurosurgery, Biomarkers, Alzheimer's Disease Neuroimaging Initiative
Abstract: There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin., Whether Alzheimer's disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.
Published: 2016

21. P1‐338: Assessing Risk for Preclinical β‐Amyloid Pathology with APOE , Cognitive and Demographic Information

Author: Scott Mackin, Devon Gessert, Niklas Mattsson, Michael W. Weiner, Philip S. Insel, Sebastian Palmqvist, Oskar Hansson, and Rachel L. Nosheny
Subjects: 0301 basic medicine, Apolipoprotein E, Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Cognition, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 030104 developmental biology, 0302 clinical medicine, Developmental Neuroscience, β amyloid, medicine, Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience, 030217 neurology & neurosurgery
Published: 2016

22. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Author: Sandra Harding, Allyson Rosen, Paul Malloy, Anton P. Porsteinsson, Ramon Diaz-Arrastia, Richard V. King, James E. Galvin, Ruth A. Mulnard, Maria T. Greig, Nunzio Pomara, James B. Brewer, Gus Jiminez, Susan De Santi, Pierre N. Tariot, Bret J. Borowski, Dick J. Drost, Howard Chertkow, Gail Li, Eric C. Petrie, Amanda Smith, Steven G. Potkin, Stephen Salloway, Jared R. Tinklenberg, Jacqueline Hayes, John C. Brockington, Robert B. Santulli, John K. Hsiao, Kwangsik Nho, Mary Quiceno, Kaycee M. Sink, Richard E. Carson, Keith A. Johnson, Daniel Varon, Michal J. Figurski, Christine M. Belden, Godfrey D. Pearlson, Mark A. Mintun, Elaine R. Peskind, Shannon Finley, Howard Bergman, Charles D. Smith, Helen Vanderswag, David Glenn Clark, Michael Borrie, Peggy Roberts, Terence Z. Wong, David S. Knopman, Michelle Rainka, Greg Jicha, Tamar J. Kitzmiller, Michael C. Donohue, Davie Holtzman, Hyungsub Shim, Gaby Thai, Bojana Stefanovic, Cynthia M. Carlsson, Elizabeth Oates, Kelley Faber, Kristen Martin-Cook, John M Olichney, Bonnie S. Goldstein, Robert C. Green, Kyle B. Womack, Maria Kataki, Robert A. Koeppe, Alexander Norbash, Sonia Pawluczyk, Neil Buckholtz, Chet Mathis, Betty Lind, Michael D. Devous, Leon J. Thal, Allan I. Levey, Munir Chowdhury, Bruce L. Miller, P. Murali Doraiswamy, Sanjay Asthana, Dino Massoglia, Alice D. Brown, Donna Munic, J. Jay Fruehling, Angela Oliver, Paul S. Aisen, Adam Schwartz, Antero Sarrael, Christina A. Michel, Susan K. Schultz, Thomas C. Neylan, Kenneth M. Spicer, Scott Herring, Jeff Gunter, Daniel D'Agostino, Neil W. Kowall, Karen L. Bell, José María Mateos-Pérez, MaryAnn Oakley, Richard Frank, Beau M. Ances, Lew Kuller, Liana G. Apostolova, Marwan N. Sabbagh, Sterling C. Johnson, Charles Bernick, Scott C. Neu, Susan M. Landau, William J. Jagust, Dana Nguyen, Olga James, Stephanie Reeder, David Bachman, Karl E. Friedl, John Rogers, Karen Crawford, Debra A. Fleischman, Martin R. Farlow, Javier Villanueva-Meyer, Raj C. Shah, Jeffrey Kaye, Randall Griffith, Laura L. Boles Ponto, Ellen Woo, Michele Assaly, Cynthia Hunt, Andrew Kertesz, Lidia Glodzik, Ansgar J. Furst, Eric M. Reiman, Jacobo Mintzer, Mony J. de Leon, Chiadi U. Onyike, Paul M. Thompson, Gloria Chaing, David S. Geldmacher, Tamie Sather, Evan Fletcher, M.-Marsel Mesulam, Howard J. Rosen, Lawrence S. Honig, Stephen Correia, Steven Potkin, Howard Feldman, Greg Sorensen, Yaakov Stern, Karen Elizabeth Smith, Norm Foster, Matt A. Bernstein, Meghan Frey, Roberto C. Sotero, Sandra E. Black, Tatiana Foroud, Janet S. Cellar, David A. Wolk, Sarah Walter, Oscar L. Lopez, Nick C. Fox, Po H. Lu, Daniel C. Marson, Li Shen, Heather Johnson, Joy L. Taylor, Heather Anderson, Yasser Iturria-Medina, George Bartzokis, M.S. Albert, Brigid Reynolds, Geoffrey Tremont, Patricia Lynn Johnson, Earl A. Zimmerman, Sara Dolen, Virginia M.-Y. Lee, Stacy Schneider, Kris Johnson, Irina Rachinsky, Reisa A. Sperling, Walter Martinez, Vernice Bates, John Q. Trojanowki, David T.W. Jones, Chuang Kuo Wu, Michael W. Weiner, Brandy R. Matthews, Peter J. Snyder, James J. Lah, Raina Carter, Franz Hefti, Hillel Grossman, Gary R. Conrad, Norman R. Relkin, Steven M. Paul, Ronald J. Killiany, Mimi Dang, Francine Parfitt, Franklin Watkins, T. J. Montine, Teresa Villena, Ranjan Duara, Smita Kittur, Paula Ogrocki, Andrew J. Saykin, Raymundo Hernando, Paule-Joanne Toussaint, John C. Morris, Elizabether Finger, T. Y. Lee, Donna M. Simpson, Stephen H. Pasternak, Kewei Chen, Rob Bartha, Dzintra Celmins, Chad Ward, Zaven S. Khachaturian, Brian R. Ott, M. Marcel Mesulam, Lisa Taylor-Reinwald, Magdalena Korecka, Lon S. Schneider, Eben S. Schwartz, Liberty Teodoro, Rachelle S. Doody, Myron F. Weiner, Jerome A. Yesavage, Peter A. Hardy, M. Saleem Ismail, Connie Brand, Alan J. Lerner, Gad A. Marshall, Clifford R. Jack, Ronald C. Petersen, Pradeep Garg, Alan C. Evans, Russell H. Swerdlow, Bryan M. Spann, Horacio Capote, Karen E. Anderson, Adrian Preda, Judith L. Heidebrink, Sandra Jacobson, Catherine Mc-Adams-Ortiz, Marc Raichle, Owen Carmichael, Joseph F. Quinn, Adam S. Fleisher, Curtis Caldwell, Joanne S. Allard, Ronald G. Thomas, Kathleen Tingus, Barton Lane, Sue Leon, Raymond Scott Turner, Leyla de Toledo-Morrell, Andrew E. Budson, Martha G. MacAvoy, Daniel H.S. Silverman, Annmarie Hake, Peter Davies, Nigel J. Cairns, Kelly M. Makino, Jason Karlawish, Douglas W. Scharre, Nancy Johnson, Anahita Adeli, Diana R. Kerwin, Leon Hudson, Mauricio Beccera, M. L. Senjem, Sherye A. Sirrel, Henry W. Querfurth, Rosemary H Morrison, Tracy Kendall, Neill R. Graff-Radford, Danielle J Harvey, Joanne L. Lord, Carl H. Sadowsky, Kim Martin, Laurel A. Beckett, William Z. Potter, Christopher H. van Dyck, Maria Carroll, Arthur W. Toga, Leslie M. Shaw, Kristin Fargher, Melissa Davis, Karen Blank, Benita Mudge, Erik D. Roberson, Effie M. Mitsis, Kathleen Johnson, Partha Sinha, Sungeun Kim, Colleen S. Albers, Jordan Grafman, Devon Gessert, Kristine Lipowski, Charles DeCarli, Chris Hosein, Erin Householder, Steven E. Arnold, Kejal Kantarci, Marilyn S. Albert, Jeffrey R. Petrella, Lisa Raudin, Norbert Schuff, Jeffrey M. Burns, Balebail Ashok Raj, Susan Rountree, Dana Mathews, Ging-Yuek Robin Hsiung, Brittany Cerbone, Sara S. Mason, Howard Fillit, Konstantinos Arfanakis, Stephanie Kielb, Henry Rusinek, Jeff D. Williamson, and Prashanthi Vemuri
Subjects: 0301 basic medicine, Male, Aging, General Physics and Astronomy, Disease, Neurodegenerative, Alzheimer's Disease, Brain mapping, Diagnostic Radiology, Computer-Assisted, 0302 clinical medicine, Models, 2.1 Biological and endogenous factors, Alzheimer's Disease including Alzheimer's Disease Related Dementias, Aetiology, Cognitive decline, Brain Mapping, Multidisciplinary, Brain, Cognition, Blood Proteins, Statistical, Middle Aged, Magnetic Resonance Imaging, Cerebrovascular Circulation, Neurological, Disease Progression, Biomedical Imaging, Female, Alzheimer's disease, Alzheimer's Disease Neuroimaging Initiative, Science, Neuroimaging, tau Proteins, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Alzheimer Disease, Image Interpretation, Computer-Assisted, Acquired Cognitive Impairment, medicine, Humans, Cognitive Dysfunction, Image Interpretation, Pathological, Aged, Amyloid beta-Peptides, Models, Statistical, business.industry, Prevention, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer’s Disease Neuroimaging Initiative, General Chemistry, medicine.disease, Brain Disorders, 030104 developmental biology, Glucose, Positron-Emission Tomography, Multivariate Analysis, Dementia, business, Neuroscience, 030217 neurology & neurosurgery, Biomarkers
Abstract: Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions., Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.
Published: 2015

23. O3‐13‐05: The Gammaglobulin Alzheimer Partnership Study (GAP): Design, screening, enrollment and futility analysis results

Author: Leock Y. Ngo, Basia Adamiak, Karen T. Stokes, Ronald G. Thomas, Norman R. Relkin, David Gelmont, Paul S. Aisen, and Devon Gessert
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Alternative medicine, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Family medicine, General partnership, medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2012

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23 results on '"Devon Gessert"'

1. Sex Modulates the Pathological Aging Effect on Caudate Functional Connectivity in Mild Cognitive Impairment

2. Feasibility study for detection of retinal amyloid in clinical trials: The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial

3. Prediction and Classification of Alzheimer’s Disease Based on Combined Features From Apolipoprotein-E Genotype, Cerebrospinal Fluid, MR, and FDG-PET Imaging Biomarkers

4. The Influence of Cerebrospinal Fluid Abnormalities and APOE 4 on PHF-Tau Protein: Evidence From Voxel Analysis and Graph Theory

5. New Perspective for Non-invasive Brain Stimulation Site Selection in Mild Cognitive Impairment: Based on Meta- and Functional Connectivity Analyses

6. Performing Sparse Regularization and Dimension Reduction Simultaneously in Multimodal Data Fusion

7. Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients

8. Corrigendum: Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images

9. Time to Amyloid Positivity and Preclinical Changes in Brain Metabolism, Atrophy, and Cognition: Evidence for Emerging Amyloid Pathology in Alzheimer's Disease

10. Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images

11. The Impact of Amyloid Burden and APOE on Rates of Cognitive Impairment in Late Life Depression

12. Feasibility study for detection of retinal amyloid in clinical trials: The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial

13. KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease

14. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial

15. Type 2 diabetes mellitus, brain atrophy, and cognitive decline

16. [P4–197]: EMERGING AMYLOID PATHOLOGY

17. Pattern Discovery in Brain Imaging Genetics via SCCA Modeling with a Generic Non-convex Penalty

18. Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease

19. DT-02-03: OPEN LABEL EXTENSION RESULTS FROM A PHASE II/III TRIAL OF INTRANASAL INSULIN

20. Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology

21. P1‐338: Assessing Risk for Preclinical β‐Amyloid Pathology with APOE , Cognitive and Demographic Information

22. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

23. O3‐13‐05: The Gammaglobulin Alzheimer Partnership Study (GAP): Design, screening, enrollment and futility analysis results

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23 results on '"Devon Gessert"'

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