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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. 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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3. 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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4. 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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5. 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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6. 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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7. 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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8. 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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10. Evaluating outcomes of a clinical pharmacist medication management program in a multidisciplinary practice for outpatient buprenorphine treatment of opioid use disorder

Author

Michelle Rainka, Horacio Capote, Anna G. Mattle, Traci Aladeen, and Richard D. Blondell

Subjects
medicine.medical_specialty, business.industry, Addiction, media_common.quotation_subject, Pharmacist, Pharmaceutical Science, Opioid use disorder, Pharmacy, medicine.disease, Clinical pharmacy, Multidisciplinary approach, Family medicine, medicine, Pharmacology (medical), business, media_common, Buprenorphine, medicine.drug
Published
2021

11. Pharmacist intervention and <scp>anti‐platelet</scp> medication monitoring in patients following stroke and transient ischemic attack

Author

Michelle Rainka, Vernice Bates, Francis M. Gengo, Traci Aladeen, Rachael Wojcik, Erica Westphal, Kaitlin Landolf, Samantha Boyce, and Jessica Greger

Subjects
medicine.medical_specialty, Aspirin, business.industry, Pharmacist, Pharmaceutical Science, Pharmacy, Clopidogrel, medicine.disease, Anti platelet, Internal medicine, Medicine, Pharmacology (medical), In patient, Medication monitoring, business, Stroke, Pharmacist intervention, medicine.drug
Published
2020

12. Comparison of the Metabolic Characteristics of Newer Second Generation Antipsychotics

Author

Rachael Wojcik, Erica Westphal, Michelle Rainka, Jessica Greger, Emily Lewandowski, Traci Aladeen, and Horacio Capote

Subjects
Adult, Male, Olanzapine, medicine.medical_specialty, Bipolar Disorder, Blood Pressure, Cariprazine, Dibenzocycloheptenes, Thiophenes, Quinolones, Weight Gain, Piperazines, Lurasidone Hydrochloride, 03 medical and health sciences, Iloperidone, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, Internal medicine, medicine, Humans, Asenapine, Pharmacology (medical), Aged, Retrospective Studies, Lurasidone, Brexpiprazole, business.industry, Isoxazoles, Middle Aged, 030227 psychiatry, Psychiatry and Mental health, chemistry, Female, medicine.symptom, business, Weight gain, Body mass index, 030217 neurology & neurosurgery, Antipsychotic Agents, medicine.drug
Abstract

PURPOSE/BACKGROUND Extensive research has been conducted comparing the metabolic characteristics of older second-generation antipsychotics (SGAs); minimal data exist comparing the long-term metabolic effects of SGAs approved in the last 10 years. METHODS/PROCEDURES A retrospective chart review of patients treated with brexpiprazole, lurasidone, asenapine, cariprazine, and iloperidone (newer SGAs) for at least 6 weeks at an outpatient psychiatric practice was conducted. Patients treated with olanzapine, an older SGA, were included as a comparator. Metabolic characteristics were collected at baseline, approximately 6 weeks, 12 weeks, and for up to 12 months. FINDINGS/RESULTS Of the newer SGAs, there were statistically significant increases in patients' average weight at 12 weeks and 1 year or less with brexpiprazole (2.48 lb, P = 0.02; 5.97 lb, P = 0.01) and iloperidone (4.54 lb, P < 0.01; 5.13 lb, P = 0.02). Brexpiprazole and iloperidone resulted in significant increases in body mass index, up to a 0.90-kg/m2 average increase in patients taking brexpiprazole at 1 year or less. Minimal weight gain was seen with cariprazine (4.25 lb, P = 0.42) and asenapine (1.80 lb, P = 0.62) at 1 year or less after treatment initiation. Although not statistically significant, lurasidone showed an average weight loss of up to 0.60 lb at 1 year or less (P = 0.56). IMPLICATIONS/CONCLUSIONS Although some weight gain was seen with the newer SGAs, all demonstrated significantly favorable metabolic characteristics compared with olanzapine. Monitoring of weight and metabolic parameters remain important in patients treated with SGAs.

Published
2020

13. Generic Clopidogrel: Has Substitution for Brand Name Plavix® Been Effective?

Author

Francis M. Gengo, Kaitlin McCadden, Vernice Bates, Traci Aladeen, Denis Vanini, Erica Westphal, and Michelle Rainka

Subjects
Ticlopidine, Brand names, Platelet Aggregation, business.industry, Clopidogrel Bisulfate, Substitution (logic), Advertising, 030204 cardiovascular system & hematology, Clopidogrel, 03 medical and health sciences, 0302 clinical medicine, Medicine, Drugs, Generic, Humans, Pharmacology (medical), Female, cardiovascular diseases, business, 030217 neurology & neurosurgery, Platelet Aggregation Inhibitors, circulatory and respiratory physiology, medicine.drug
Abstract

Background: Following the expiration of brand name exclusivity of Plavix® in 2012, generic clopidogrel bisulfate was approved. As a widely prescribed medication with significant inter-patient pharmacokinetic and pharmacodynamic variability, data regarding the impact of switching to generic clopidogrel bisulfate on patients is needed. Objective: The objective of this study was to determine whether generic clopidogrel bisulfate is as efficacious as Plavix® for the inhibition of platelet aggregation. Methods: Patients treated with Plavix® monotherapy (n = 254) or generic clopidogrel bisulfate monotherapy (n = 185) were included in this retrospective review. Confounding factors previously found to affect clopidogrel responsiveness (diabetes, female sex, and smoking) were assessed, as well as medications classified as substrates, inducers, and inhibitors of enzymes involved in clopidogrel metabolism. Whole blood impedance aggregometry was used to measure platelet aggregation in response to adenosine diphosphate. Patients were tested after ≥2 weeks of treatment and designated as non-responders if aggregation response exceeded sensitivity thresholds of 6 ohms of impedance. Results: The introduction of generic clopidogrel bisulfate was associated with a decrease in antiplatelet resistance (44% to 31%, p < 0.01) and decreased mean ohms of resistance (5.06 ± 4.55 to 3.32 ± 4.03, p < 0.01). Prior to analysis of secondary outcomes, 217 patients were eliminated due to antiplatelet usage for longer than 3 years (n = 123 for Plavix® and n = 118 for clopidogrel). There was no statistically significant finding in prevalence of secondary events. Conclusion: Resistance rates to the antiplatelet, clopidogrel are significantly lower since the switch to generic formulations. Further investigation into the impact of variability between clopidogrel bisulfate formulations is needed.

Published
2021

14. Evaluating rates of reporting symptoms of Parkinson's disease psychosis: provider versus targeted questionnaire

Author

Jessica Greger, Anupama Kale, Traci Aladeen, Michelle Rainka, and Horacio Capote

Subjects
0301 basic medicine, Psychosis, medicine.medical_specialty, Parkinson's disease, business.industry, General Neuroscience, Parkinson Disease, General Medicine, Disease, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Cross-Sectional Studies, Psychotic Disorders, Surveys and Questionnaires, medicine, Humans, Screening tool, Psychiatry, business, 030217 neurology & neurosurgery
Abstract

A targeted questionnaire may help increase rates of reporting Parkinson's disease psychosis (PDP) symptoms. Despite the need for a rapid patient- and/or caregiver-administered screening tool for PDP symptoms, an appropriate tool is not yet available. This study developed a targeted PDP questionnaire and examined rates of reporting psychosis symptoms in response to the questionnaire compared to rates of reporting symptoms to healthcare providers during a routine visit.This was a single-center, cross-sectional observational study of patients at an outpatient neurology practice. Medical charts were screened for eligibility, and patients were contacted by telephone for informed consent.A total of 25 patients (24%,A targeted questionnaire increases rates of reporting PDP symptoms, and based on frequency, severity, and distress ratings, may allow for capture of PDP symptoms earlier in the course of the disease. By using a questionnaire, patients reported symptom onset an average of 1.4 years earlier than patients who reported symptoms to their providers according to patient medical records.

Published
2020

15. Evaluating the Effect of Six Proton Pump Inhibitors on the Antiplatelet Effects of Clopidogrel

Author

Michelle Rainka, Vernice Bates, Erica Westphal, Nicholas M. Smith, Francis M. Gengo, and Eugene R. Przespolewski

Subjects
Adult, Male, Time Factors, Platelet Aggregation, Platelet Function Tests, Population, New York, Lansoprazole, Rabeprazole, 030204 cardiovascular system & hematology, Pharmacology, Esomeprazole, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Drug Interactions, Dexlansoprazole, cardiovascular diseases, 030212 general & internal medicine, education, Omeprazole, Pantoprazole, education.field_of_study, Cross-Over Studies, business.industry, Rehabilitation, Proton Pump Inhibitors, Clopidogrel, Healthy Volunteers, Surgery, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Platelet Aggregation Inhibitors, circulatory and respiratory physiology, medicine.drug
Abstract

Background and Goal Cytochrome P450 (CYP) enzymes are responsible for the conversion of clopidogrel into its active metabolite and the metabolism of proton pump inhibitors (PPIs), which may also inhibit CYP enzymes. A current Food and Drug Administration advisory suggests avoiding esomeprazole and omeprazole while taking clopidogrel because of concerns that PPIs may compromise clopidogrel's antiplatelet effects. The objective of the present study was to examine the robustness of this interaction using a well-controlled study design in a population of participants free of confounders. Materials and Methods Twenty-eight healthy male participants, with a mean age 24.2 ± 3.2, were randomized to an incomplete crossover design schedule. Participants underwent platelet aggregation testing after clopidogrel alone, while on clopidogrel in combination with 1 of 3 PPIs (40 mg of pantoprazole, 20 mg of omeprazole, 20 mg of rabeprazole, 40 mg of esomeprazole, 30 mg of lansoprazole, or 30 mg of dexlansoprazole), and during 1 week of clopidogrel-only washout periods. Findings The median platelet aggregation to adenosine diphosphate during a drug-free baseline was 10Ω (2.5 interquartile range) of impedance and decreased to 0Ω on clopidogrel alone. Aggregation did not significantly change with concomitant use of PPIs and clopidogrel. Conclusion These data do not demonstrate a significant interaction between common individual PPIs and clopidogrel in healthy volunteers who respond to clopidogrel alone. This adds data to a growing body of evidence indicating that the addition of a PPI may have a weak effect on clopidogrel's antiplatelet properties, and may only be relevant in specific clinical circumstances.

Published
2018

16. Cascaded Multi-view Canonical Correlation (CaMCCo) for Early Diagnosis of Alzheimer’s Disease via Fusion of Clinical, Imaging and Omic Features

Author

Sterling C. Johnson, Paul Malloy, Joy L. Taylor, Alan J. Lerner, Pradeep Garg, Pierre N. Tariot, David G. Clark, Steven G. Potkin, Franklin Watkins, Howard Bergman, Dana M. Pogorelec, Charles D. Smith, Pradeep Varma, Stephen Pasternack, Betty Lind, Saba Wolday, Douglas W. Scharre, Donna Munic, Marwan N. Sabbagh, Adam S. Fleisher, Joanne S. Allard, Cynthia Hunt, Lidia Glodzik, Charles Bernick, Daniel D'Agostino, Owen T. Carmichael, Geoffrey Tremont, Christopher H. van Dyck, Maria Carroll, Po Lu, Leslie Gordineer, Catherine Mc-Adams-Ortiz, Irina Rachisky, Antero Sarrael, Clifford R. Jack, David Bachman, Dick Trost, Scott Herring, Arthur W. Toga, Evan Fletcher, Christina A. Michel, Lon S. Schneider, Francine Parfitt, Kelly M. Makino, Anahita Adeli, Daniel Varon, Christine M. Belden, Nunzio Pomara, Thomas O. Obisesan, Howard Feldman, Howard Chertkow, Sandra W. Jacobson, Haibo Wang, Greg Jicha, Laura A. Flashman, George Bartzokis, Beau M. Ances, Stacy Schneider, Earl A. Zimmerman, Munir Chowdhury, Bruce L. Miller, Javier Villanueva-Meyer, Kristin Fargher, Michael W. Weiner, Dana Nguyen, Ranjan Duara, T. Y. Lee, Lisa C. Silbert, Benita Mudge, Marilyn S. Albert, James J. Lah, Janet S. Cellar, Gad A. Marshall, Michael Lin, Marc Seltzer, Leslie Shaw, Bojana Stefanovic, Daniel C. Marson, Kyle B. Womack, Liberty Teodoro, Connie Brand, Nadira Trncic, Maria Kataki, Russell H. Swerdlow, Paul S. Aisen, Brigid Reynolds, Mony J. de Leon, Sandra E. Black, Rachelle S. Doody, Paula Ogrocki, Andrew J. Saykin, Raymundo Hernando, Leyla deToledo-Morrell, Anna Burke, Sherye A. Sirrel, Henry W. Querfurth, Jeffrey R. Petrella, Norman R. Relkin, Judith L. Heidebrink, Vernice Bates, Mary L. Creech, David C. Perry, Curtis Caldwell, Sara Dolen, Anton P. Porsteinsson, Patricia Lynn Johnson, Erik D. Roberson, Effie M. Mitsis, Kathleen Johnson, John Q. Trojanowki, Raina Carter, James E. Galvin, Karen Blank, John C. Morris, Bryan M. Spann, Keith A. Johnson, Jared R. Tinklenberg, Stephen Salloway, Ronald J. Killiany, Mimi Dang, Smita Kittur, Mary Quiceno, Kaycee M. Sink, Helen Vanderswag, Erin E. Franklin, Robbartha, Kim Martin, Gaby Thai, Allyson C. Rosen, Karen L. Bell, Tracy Kendall, P. M. Doraiswamy, Kathleen Tingus, Angela Oliver, Adrian Preda, Mary L. Hynes, Laurel A. Beckett, William J. Jagust, Jeffrey M. Burns, Ronald C. Petersen, Allan I. Levey, Balebail Ashok Raj, Lawrence S. Honig, Martin R. Farlow, Richard E. Carson, Dana Mathews, David S. Knopman, Robert C. Green, Jerome A. Yesavage, Elizabeth Finger, Ann Marie Hake, David S. Geldmacher, Yaakov Stern, Raj C. Shah, M.-Marsel Mesulam, Ruth A. Mulnard, Jacobo Mintzer, Howard J. Rosen, Peggy Roberts, Joseph F. Quinn, Raymond Scott Turner, Maria T. Greig, Salvador Borges-Neto, Jeffrey Kaye, Randall Griffith, Diana R. Kerwin, Neill R. Graff-Radford, James B. Brewer, John C. Brockington, Ging-Yuek Robin Hsiung, Anant Madabhushi, Andrew E. Budson, Martha G. MacAvoy, Stephen Correia, Terence Z. Wong, Michelle Rainka, Elizabeth Oates, Alexander Norbash, Chiadi U. Onyike, Gloria Chaing, Kris Johnson, Hillel Grossman, Gary R. Conrad, Nancy Johnson, Lisa D. Ravdin, Mauricio Beccera, Reisa A. Sperling, Heather Johnson, Kristine Lipowski, Charles DeCarli, Barton Lane, Joanne L. Lord, Carl H. Sadowsky, Chris Hosein, Marissa Natelson Love, M. Ismail, Liana G. Apostolova, Dzintra Celmins, Brian R. Ott, Brittany Cerbone, Sanjay Asthana, Alice D. Brown, Neil W. Kowall, Peter A. Hardy, Andrew Kertesz, Sara S. Mason, Horacio Capote, Pauline Maillard, Stephanie Kielb, Henry Rusinek, Ellen Woo, Jeff D. Williamson, Susan De Santi, Amanda Smith, John M Olichney, Michele Assaly, Karen S. Anderson, Parianne Fatica, Brandy R. Matthews, Michael Borrie, Susan Rountree, Chuang Kuo Wu, Curtis Tatsuoka, Teresa Villena, Asha Singanamalli, Borna Bonakdarpour, Colleen S. Albers, Cynthia M. Carlsson, Bonnie S. Goldstein, Sonia Pawluczyk, Edward Coleman, Kenneth M. Spicer, Jared R. Brosch, William Brooks, Partha Sinha, Stephanie Reeder, Daniel Silverman, Robert B. Santulli, Godfrey D. Pearlson, Mark A. Mintun, and Sandra Weintraub

Subjects
0301 basic medicine, Male, Proteomics, Science, Neuroimaging, Disease, Sensitivity and Specificity, Article, 03 medical and health sciences, 0302 clinical medicine, Text mining, Alzheimer Disease, medicine, Humans, Cognitive Dysfunction, Set (psychology), Aged, Aged, 80 and over, Multidisciplinary, Modalities, business.industry, Pattern recognition, Alzheimer’s Disease Neuroimaging Initiative, Genomics, Models, Theoretical, medicine.disease, 030104 developmental biology, Categorization, Case-Control Studies, Medicine, Female, Artificial intelligence, Alzheimer's disease, business, Canonical correlation, 030217 neurology & neurosurgery, Algorithms, Biomarkers
Abstract

The introduction of mild cognitive impairment (MCI) as a diagnostic category adds to the challenges of diagnosing Alzheimer’s Disease (AD). No single marker has been proven to accurately categorize patients into their respective diagnostic groups. Thus, previous studies have attempted to develop fused predictors of AD and MCI. These studies have two main limitations. Most do not simultaneously consider all diagnostic categories and provide suboptimal fused representations using the same set of modalities for prediction of all classes. In this work, we present a combined framework, cascaded multiview canonical correlation (CaMCCo), for fusion and cascaded classification that incorporates all diagnostic categories and optimizes classification by selectively combining a subset of modalities at each level of the cascade. CaMCCo is evaluated on a data cohort comprising 149 patients for whom neurophysiological, neuroimaging, proteomic and genomic data were available. Results suggest that fusion of select modalities for each classification task outperforms (mean AUC = 0.92) fusion of all modalities (mean AUC = 0.54) and individual modalities (mean AUC = 0.90, 0.53, 0.71, 0.73, 0.62, 0.68). In addition, CaMCCo outperforms all other multi-class classification methods for MCI prediction (PPV: 0.80 vs. 0.67, 0.63).

Published
2017

17. L-Methylfolate Calcium Supplementation in Adolescents and Children: A Retrospective Analysis

Author

Traci Aladeen, Michelle Rainka, Horacio Capote, Jacqueline Meaney, Francis M. Gengo, Jessica Greger, and Erica Westphal

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, MEDLINE, chemistry.chemical_element, Calcium, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pharmacotherapy, Patient experience, medicine, Humans, Young adult, Child, Tetrahydrofolates, Retrospective Studies, business.industry, Mood Disorders, Mental Disorders, Retrospective cohort study, medicine.disease, Anxiety Disorders, Antidepressive Agents, 030227 psychiatry, chemistry, Schizophrenia, Major depressive disorder, Anticonvulsants, Drug Therapy, Combination, Female, business, 030217 neurology & neurosurgery
Abstract

Previous studies have shown l-methylfolate to be a safe and beneficial therapy for neuropsychiatric conditions, including major depressive disorder and schizophrenia in adults. The purpose of this study was to assess safety and describe patient experience using l-methylfolate calcium in a real-world pediatric and adolescent population. A retrospective chart review of patients (7 to 20 y of age, mean age 16 y) prescribed l-methylfolate calcium at a psychiatry clinic in Amherst, NY, between January 1, 2010 and November 10, 2015 was conducted. Patients to whom l-methylfolate calcium 15 mg/d (n=139) or 7.5 mg/d (n=7) was administered were identified; 44 patients who were prescribed but to whom l-methylfolate calcium was not administered were included as a comparator population. Common neuropsychiatric diagnoses included anxiety disorders (68% in the treatment population vs. 50% in the comparator population) and mood disorders (57% in the treatment population vs. 52% in the comparator population). Antidepressants (69% vs. 55%) and mood stabilizers or antiepileptic drugs (63% vs. 57%) were frequently prescribed in combination with l-methylfolate calcium. Adverse events occurred less frequently in the treated population, possibly due to the addition of l-methylfolate calcium (10% vs. 25%, P=0.02). The most common adverse events in the treated population were impaired sleep (5 patients) and increased anxiety (3 patients). Rates of laboratory abnormalities did not differ significantly between the treated and comparator populations (P=0.13). Positive subjective treatment experiences were reported by 22.5% of treated patients and negative subjective treatment experiences were reported by 5.4% of treated patients. L-methylfolate calcium was well-tolerated in a pediatric/adolescent population and may provide benefits for patients with a range of neuropsychiatric conditions.

Published
2019

18. 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

19. Brain multiplexes reveal morphological connectional biomarkers fingerprinting late brain dementia states

Author

Jerome A. Yesavage, Thomas O. Obisesan, Ann Marie Hake, Yaakov Stern, Betty Lind, Daniel D'Agostino, Daniel Varon, Christine M. Belden, Evan Fletcher, Jef Williamson, Howard Feldman, Pauline Maillard, Stephanie Kielb, Dana Mathews, Henry Rusinek, Sonia Pawluczyk, Donna Munic, Michele Assaly, Ines Mahjoub, Barton Lane, Andrew J. Saykin, Raymundo Hernando, Randall Grifth, Paul S. Aisen, Brittany Cerbone, Saba Wolday, Douglas W. Scharre, Karen S. Anderson, Sara S. Mason, Marwan N. Sabbagh, Geofrey Tremont, Stacy Schneider, Marilyn S. Albert, Tracy Kendall, P. M. Doraiswamy, Antero Sarrael, Kenneth M. Spicer, George Bartzokis, Parianne Fatica, Christopher H. van Dyck, Maria Carroll, Benita Mudge, Beau M. Ances, Brandy R. Matthews, Allyson C. Rosen, Chiadi U. Onyike, Gloria Chaing, Helen Vanderswag, Javier Villanueva-Meyer, Stephanie Reeder, Erin E. Franklin, Sandra Weintraub, Liberty Teodoro, Connie Brand, Arthur W. Toga, Mony J. de Leon, Sandra E. Black, Robert C. Green, Russell H. Swerdlow, Leyla deToledo-Morrell, Bryan M. Spann, Judith L. Heidebrink, Leslie Shaw, Ruth A. Mulnard, Rob Bartha, Sterling C. Johnson, Kristin Fargher, Susan De Santi, Curtis Caldwell, Rachelle S. Doody, Erik D. Roberson, Norman R. Relkin, Kathleen Johnson, Raj C. Shah, Kris Johnson, Diana Kerwin, M.-Marsel Mesulam, Howard J. Rosen, Peggy Roberts, Michael Borrie, Martin R. Farlow, Steven G. Potkin, Reisa A. Sperling, John Q. Trojanowki, Amanda Smith, James J. Lah, Mary L. Creech, Janet S. Cellar, Michael Lin, Terence Z. Wong, Howard Bergman, Dana M. Pogorelec, Gaby Thai, Jacobo Mintzer, Raina Carter, Heather Johnson, Francine Parftt, Karen Blank, Daniel C. Marson, Nancy Johnson, Susan Rountree, Michelle Rainka, Elizabeth Oates, Stephen Correia, John C. Morris, Alan J. Lerner, Pradeep Garg, Mauricio Beccera, Mary L. Hynes, Chuang Kuo Wu, Curtis Tatsuoka, Brian R. Ott, Joy L. Taylor, Mohamed Ali Mahjoub, Adrian Preda, Islem Rekik, Ronald C. Petersen, Kathleen Tingus, Vernice Bates, Irina Rachisky, Neill Graf-Radford, Alexander Norbash, Teresa Villena, Paul Malloy, Cliford Jack, Pierre N. Tariot, Anton P. Porsteinsson, Jefrey Burns, Owen Carmichael, Maria T. Greig, Marc Seltzer, Pradeep Varma, Jefrey Petrella, James E. Galvin, Joseph F. Quinn, Franklin Watkins, John M Olichney, Joanne L. Lord, Raymond Scott Turner, Adam S. Fleisher, Salvador Borges-Neto, James B. Brewer, Carl H. Sadowsky, Andrew E. Budson, Martha G. MacAvoy, Joanne S. Allard, L. Schneider, Stephen Salloway, Kim Martin, Mary Quiceno, Kaycee M. Sink, Sanjay Asthana, Laurel A. Beckett, Alice D. Brown, David S. Knopman, Neil W. Kowall, Efe Mitsis, Elizabeth Finger, David C. Perry, Bojana Stefanovic, David S. Geldmacher, Andrew Kertesz, Cynthia M. Carlsson, Charles Bernick, Earl A. Zimmerman, Bonnie S. Goldstein, Dzintra Celmins, Paula Ogrocki, Daniel H.S. Silverman, David G. Clark, Charles D. Smith, Nunzio Pomara, Stephen Pasternack, Howard Chertkow, Christina A. Michel, Sandra W. Jacobson, Po Lu, Peter A. Hardy, Greg Jicha, David Bachman, Laura A. Flashman, Munir Chowdhury, Bruce L. Miller, Ging Yuek Robin Hsiung, Horacio Capote, Gad A. Marshall, Brigid Reynolds, Jefrey Kaye, Patricia Lynn Johnson, Ronald J. Killiany, Mimi Dang, Smita Kittur, Lawrence S. Honig, Ranjan Duara, T. Y. Lee, Keith A. Johnson, Karen L. Bell, Allan I. Levey, Scott Herring, Michael W. Weiner, Ellen Woo, Dana Nguyen, Robert B. Santulli, Godfrey D. Pearlson, Mark A. Mintun, Sara Dolen, Jared R. Tinklenberg, Edward Coleman, Jared R. Brosch, John C. Brockington, William Brooks, Partha Sinha, M. Ismail, Balebail Ashok Raj, Lisa D. Ravdin, Kristine Lipowski, Charles DeCarli, Borna Bonakdarpour, Colleen S. Albers, Chris Hosein, Marissa Natelson Love, Kyle B. Womack, Maria Kataki, Nadira Trncic, Anna Burke, Sherye A. Sirrel, Henry W. Querfurth, Liana G. Apostolova, Angela Oliver, William J. Jagust, Richard E. Carson, Cynthia Hunt, Lidia Glodzik, Hillel Grossman, Gary R. Conrad, Leslie Gordineer, Catherine Mc-Adams-Ortiz, Dick Trost, Kelly M. Makino, Anahita Adeli, and Lisa C. Silbert

Subjects
Right entorhinal cortex, Models, Neurological, lcsh:Medicine, Biology, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Humans, Middle frontal gyrus, Dementia, Patient treatment, lcsh:Science, Cognitive impairment, Multidisciplinary, Extramural, lcsh:R, Brain, Diagnostic marker, Alzheimer’s Disease Neuroimaging Initiative, medicine.disease, Magnetic Resonance Imaging, Brain region, lcsh:Q, Cognition Disorders, Neuroscience, Biomarkers, 030217 neurology & neurosurgery
Abstract

Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer’s disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, ‘shape connections’ between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus.

Published
2018

20. The Development of an In Vitro Assay for the Prospective Determination of Aspirin Sensitivity

Author

Nicholas M. Smith, Francis M. Gengo, Vernice Bates, Michelle Rainka, Caitlin Wisniewski, and Erica Westphal

Subjects
Adult, Blood Platelets, Male, Platelet Aggregation, Platelet Function Tests, 030204 cardiovascular system & hematology, Pharmacology, 030226 pharmacology & pharmacy, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, In vivo, medicine, Humans, Pharmacology (medical), Stroke, Aspirin, Dimethyl sulfoxide, medicine.disease, Aspirin sensitivity, In vitro, Collagen, type I, alpha 1, chemistry, Female, Ex vivo, Platelet Aggregation Inhibitors, medicine.drug
Abstract

Aspirin remains the standard for stroke prophylaxis. However, as many as 20%-25% of patients may fail to show a full response to aspirin. Ideally, patients who are resistant to aspirin could be identified, then receive an increased dose of aspirin or be changed to an alternative therapy more efficiently. We have developed an in vitro assay that may make this possible. Healthy volunteers (n = 13) between 18 and 50 years of age were tested for both ex vivo and in vivo responses to aspirin. Dimethyl sulfoxide (DMSO) was selected as the solvent for aspirin in the assay. DMSO can exhibit antiplatelet effects, necessitating the use of a concentration low enough to avoid such antiplatelet effects. Blood samples were tested against DMSO 0%, 0.05%, 0.5%, and 1% w/v with and without aspirin 0, 50, and 100 μM. The effects of both agents were measured via whole-blood aggregometry. A 3-dimensional response model described the data well, quantifying the combinatorial effect of DMSO and aspirin on platelet aggregation. Across all participants, baseline aggregation stimulated with collagen 1 μM or arachidonate 0.5 mM was approximately 18 and 13 Ω, respectively. The response model showed that 0.05% DMSO with 100 μM aspirin would provide platelet aggregation of 3.4 Ω. A DMSO concentration of 0.05% in the absence of aspirin would result in no discernable effects on platelet aggregation (17.7 Ω). Overall, the use of 100 μM of aspirin in 0.05% DMSO provides a robust method to test for ex vivo inhibition of platelet aggregation.

Published
2018

21. Topical diclofenac does not affect the antiplatelet properties of aspirin as compared to the intermediate effects of oral diclofenac: A prospective, randomized, complete crossover study

Author

M. Rowcliffe, B. Nezami, Vernice Bates, Francis M. Gengo, Monika Janda, Erica Westphal, and Michelle Rainka

Subjects
Adult, Blood Platelets, Male, Diclofenac, Adolescent, Platelet Function Tests, Administration, Topical, Administration, Oral, 030204 cardiovascular system & hematology, Pharmacology, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diclofenac Potassium, Humans, Medicine, Drug Interactions, Pharmacology (medical), Platelet, Prospective Studies, 030212 general & internal medicine, Aspirin, Cross-Over Studies, Nonsteroidal, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Topical diclofenac, Middle Aged, Crossover study, stomatognathic diseases, Increased risk, chemistry, Female, Collagen, business, Platelet Aggregation Inhibitors, medicine.drug
Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) adversely interact with aspirin, diminishing its antiplatelet effect and potentially placing patients at an increased risk for recurrent thrombotic events. This crossover study aimed to determine whether the topical NSAID diclofenac epolamine 1.3% patch or oral diclofenac 50 mg interfered with the antiplatelet effects of aspirin 325 mg. Twelve healthy men and women aged 18-50 were included. Participants were randomized into 5 treatment arms: aspirin, diclofenac potassium 50 mg, diclofenac patch, diclofenac potassium plus ASA 325 mg, and diclofenac patch plus aspirin. Platelet responsiveness was determined using whole-blood impedance aggregation (WBA) to collagen 1 μg/mL and arachidonic acid (AA) 0.5 mM and was sampled every 2 hours. No significant difference in platelet function was observed following the diclofenac patch and aspirin vs aspirin alone. Oral diclofenac produced a mixed effect with significant reduction in platelet inhibition at hour 2 and hour 8 following aspirin administration. Topical diclofenac does not significantly interfere with the antiplatelet effects of aspirin and may be a safer alternative to the oral formulation.

Published
2015

22. 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

23. The use of brexpiprazole amongst individuals with insufficient outcomes with aripiprazole or bupropion: A case series

Author

Horacio Capote, Carola Rong, Erica Westphal, Yena Lee, Traci Aladeen, Roger S. McIntyre, and Michelle Rainka

Subjects
Adult, Male, medicine.medical_specialty, Aripiprazole, New York, Thiophenes, Quinolones, law.invention, Preliminary analysis, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Randomized controlled trial, law, Medicine, Humans, Bipolar disorder, Psychiatry, Bupropion, Brexpiprazole, Retrospective Studies, Psychiatric Status Rating Scales, Depressive Disorder, Major, business.industry, General Medicine, Middle Aged, medicine.disease, 030227 psychiatry, Treatment Outcome, chemistry, Tolerability, Major depressive disorder, Female, Pshychiatric Mental Health, business, 030217 neurology & neurosurgery, medicine.drug, Antipsychotic Agents
Abstract

Purpose We sought to characterize the clinical experience of outpatients treated with brexpiprazole after achieving suboptimal outcomes with aripiprazole or bupropion as determined by the treating psychiatric provider. Design and methods Case series; inefficacy, intolerability, or other unsatisfactory outcome to previous trial with aripiprazole or bupropion. Findings The majority of individuals in our sample exhibited tolerability of brexpiprazole. In addition, reduction in mean PHQ-9 scores was observed with brexpiprazole treatment. Implications The results of our preliminary analysis suggest that a subpopulation of adults who have insufficient outcomes on aripiprazole or bupropion due to intolerability, inefficacy or other unsatisfactory outcome may benefit by switching to brexpiprazole treatment. Larger randomized controlled trials are needed, as well as sophisticated network analysis to further understand efficacy and tolerability differences between atypical antipsychotics.

Published
2017

24. Abstract TP412: Predicting Pharmacokinetic versus Pharmacodynamic Aspirin Resistance in Patients

Author

Traci Aladeen, Michelle Rainka, Vernice Bates, Michelle Amsler, Francis M. Gengo, Erica Westphal, and Caitlin Snyder

Subjects
Advanced and Specialized Nursing, Aspirin, medicine.medical_specialty, business.industry, medicine.medical_treatment, medicine.disease, Gastroenterology, Pharmacokinetics, Internal medicine, Pharmacodynamics, medicine, In patient, Neurology (clinical), Myocardial infarction, Cardiology and Cardiovascular Medicine, Stroke recovery, business, ASPIRIN RESISTANCE, Stroke, medicine.drug
Abstract

20%-40% of patients being treated with aspirin for secondary prophylaxis of stroke or myocardial infarction may derive no antiplatelet effects. Early identification of patients as pharmacokinetically or pharmacodynamically resistant to aspirin has the potential to become an invaluable clinical tool, reducing delays to optimal treatment, cardiovascular events, and healthcare costs. This study tested the capability of an assay that was previously developed in healthy volunteers, to differentiate between these two types of resistance in patients. Patients who needed aspirin treatment in the course of normal medical care were included. Dose escalation of chewable aspirin from 81 mg, to 162 mg, to a maximum 325 mg daily occurred every 10-14 days based on the results of whole blood impedance aggregation testing to the agonists, collagen (1 ug/mL, 5 ug/mL) and arachidonate (0.5 mM). The in vitro test was conducted in triplicate by performing the same aggregometry test on blood samples spiked to a concentration of 10 uM of aspirin in 0.05% dimethyl sulfoxide. Resistance was defined as a response to collagen 1 ug/mL >10 ohms, and/or response to arachidonate >6 ohms, and/or the ratio of collagen 1 to 5 ug/mL >0.5. Patients were excluded if they had any disorders affecting platelet function, an abnormal CBC, alcohol use within 24 hours of a test, NSAID use, or had any conditions that would affect absorption. Of the 36 patients included who were compliant with their 81 mg aspirin regimen based on pill count, 16 were found to be resistant to 81 mg of aspirin. Nine of these patients were predicted to stay resistant despite dose increase. Once tested at higher doses, ten actually remained resistant. Seven of the 16 patients were predicted to become sensitive to a higher dose of aspirin while six actually did. No statistical difference was found between predicted aspirin response and actual aspirin response (p=0.61). Sensitivity was 83% and specificity was 80%. In conclusion, results are promising and indicate that it is possible to predict, with reasonable accuracy, if a patient will have an adequate platelet response to aspirin or if the patient will never respond to aspirin therapy necessitating an alternative antiplatelet regimen. Larger, multi-site studies are inevitably needed.

Published
2017

25. Longitudinal measurement and hierarchical classification framework for the prediction of Alzheimer's disease

Author

Mary L. Hynes, Liberty Teodoro, John C. Brockington, Connie Brand, Paul Malloy, Russell H. Swerdlow, Ronald C. Petersen, Judith L. Heidebrink, Pierre N. Tariot, Curtis Caldwell, Clifford R. Jack, David G. Clark, Neill R. Graff-Radford, Charles D. Smith, Geoffrey Tremont, Ranjan Duara, Stephen Pasternack, T. Y. Lee, Owen Carmichael, Nadira Trncic, Irina Rachisky, Daniel D'Agostino, James J. Lah, Steven G. Potkin, Howard Bergman, Dana M. Pogorelec, Lon S. Schneider, Anna Burke, Sherye A. Sirrel, Henry W. Querfurth, Michael Lin, David Bachman, Edward Coleman, Michele Assaly, Allyson C. Rosen, Jeffrey M. Burns, Balebail Ashok Raj, Jared R. Brosch, Joanne L. Lord, William Brooks, Brigid Reynolds, Karen S. Anderson, Sandra Jacobson, Nunzio Pomara, Patricia Lynn Johnson, George Bartzokis, Parianne Fatica, Benita Mudge, Dana Nguyen, Carl H. Sadowsky, Michael Borrie, Qianjin Feng, Chiadi U. Onyike, Partha Sinha, Gloria Chaing, Howard Chertkow, Leyla deToledo-Morrell, Bojana Stefanovic, Richard E. Carson, Wufan Chen, Ronald J. Killiany, Mimi Dang, Thomas O. Obisesan, Christopher H. van Dyck, Maria Carroll, Gaby Thai, Arthur W. Toga, Chuang Kuo Wu, Erik D. Roberson, Effie M. Mitsis, Smita Kittur, Keith A. Johnson, Dana Mathews, Sara Dolen, Raj C. Shah, M.-Marsel Mesulam, Howard J. Rosen, Karen L. Bell, Ging-Yuek Robin Hsiung, Teresa Villena, Kris Johnson, Saba Wolday, Douglas W. Scharre, Kyle B. Womack, Maria Kataki, Barton Lane, Angela Oliver, Greg Jicha, Reisa A. Sperling, Wei Yang, David S. Geldmacher, Lawrence S. Honig, Sanjay Asthana, Janet S. Cellar, William J. Jagust, Dzintra Celmins, Susan Rountree, Christina A. Michel, Allan I. Levey, Tracy Kendall, Lisa D. Ravdin, Jared R. Tinklenberg, Brittany Cerbone, Alice D. Brown, Marilyn S. Albert, Andrew J. Saykin, Raymundo Hernando, Sandra Weintraub, John Q. Trojanowki, Raina Carter, Betty Lind, Kristin Fargher, Sterling C. Johnson, P. Murali Doraiswamy, Jeffrey R. Petrella, Neil W. Kowall, Sara S. Mason, Heather Johnson, Mary L. Creech, Stacy Schneider, Donna Munic, Liana G. Apostolova, Peter A. Hardy, Munir Chowdhury, Bruce L. Miller, Ruth A. Mulnard, Curtis Tatsuoka, Po H. Lu, Daniel C. Marson, Pauline Maillard, John C. Morris, Marwan N. Sabbagh, Jeffrey Kaye, Hillel Grossman, Gary R. Conrad, Karen Blank, Meiyan Huang, Stephanie Kielb, Andrew Kertesz, Jerome A. Yesavage, Leslie Shaw, Martin R. Farlow, Maria T. Greig, Jacobo Mintzer, Susan De Santi, David S. Knopman, Marc Seltzer, Scott Herring, Joy L. Taylor, Vernice Bates, Rob Bartha, Cynthia Hunt, Henry Rusinek, Randall Griffith, Cynthia M. Carlsson, Charles Bernick, Bonnie S. Goldstein, Rachelle S. Doody, Leslie Gordineer, Catherine Mc-Adams-Ortiz, Kim Martin, Howard Feldman, David C. Perry, Horacio Capote, Lidia Glodzik, Stephen Correia, James B. Brewer, Elizabeth Finger, Jeff D. Williamson, Franklin Watkins, Borna Bonakdarpour, Colleen S. Albers, M. Saleem Ismail, Alan J. Lerner, Daniel Varon, Christine M. Belden, Sonia Pawluczyk, Paul S. Aisen, Pradeep Garg, Kelly M. Makino, Laurel A. Beckett, Peggy Roberts, Nancy Johnson, Anahita Adeli, Terence Z. Wong, Michelle Rainka, Elizabeth Oates, Amanda Smith, Kenneth M. Spicer, Laura A. Flashman, Kristine Lipowski, Charles DeCarli, Stephanie Reeder, Mauricio Beccera, Dick Trost, Alexander Norbash, Lisa C. Silbert, Michael W. Weiner, Gad A. Marshall, Ann Marie Hake, Pradeep Varma, Francine Parfitt, Chris Hosein, Adam S. Fleisher, Marissa Natelson Love, Joanne S. Allard, Earl A. Zimmerman, Kathleen Tingus, Brian R. Ott, Joseph F. Quinn, Anton P. Porsteinsson, Paula Ogrocki, Raymond Scott Turner, Salvador Borges-Neto, James E. Galvin, Yaakov Stern, Andrew E. Budson, Martha G. MacAvoy, Daniel H.S. Silverman, Robert B. Santulli, Adrian Preda, Godfrey D. Pearlson, Mark A. Mintun, Stephen Salloway, Mary Quiceno, Kaycee M. Sink, John M Olichney, Antero Sarrael, Beau M. Ances, Javier Villanueva-Meyer, Mony J. de Leon, Sandra E. Black, Bryan M. Spann, Diana R. Kerwin, Ellen Woo, Helen Vanderswag, Erin E. Franklin, Robert C. Green, and Norman R. Relkin

Subjects
Male, Computer science, Neuroimaging, Disease, computer.software_genre, Sensitivity and Specificity, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Predictive Value of Tests, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, Longitudinal Studies, Cognitive impairment, Aged, Aged, 80 and over, Multidisciplinary, medicine.diagnostic_test, business.industry, Brain, Pattern recognition, Magnetic resonance imaging, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Early Diagnosis, Disease Progression, Female, Data mining, Artificial intelligence, business, computer, 030217 neurology & neurosurgery, Alzheimer's Disease Neuroimaging Initiative, Follow-Up Studies
Abstract

Accurate prediction of Alzheimer’s disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important information on the longitudinal changes, which can be used to classify MCI subjects as either MCI conversion (MCIc) or MCI non-conversion (MCInc) individuals. Moreover, a hierarchical framework was introduced to the classifier to manage high feature dimensionality issues and incorporate spatial information for improving the prediction accuracy. The proposed method was evaluated using 131 patients with MCI (70 MCIc and 61 MCInc) based on MRI scans taken at different time points. Results showed that the proposed method achieved 79.4% accuracy for the classification of MCIc versus MCInc, thereby demonstrating very promising performance for AD prediction.

Published
2017

26. A Phase 2a, Randomized, Crossover Trial of Gabapentin Enacarbil for the Treatment of Postherpetic Neuralgia in Gabapentin Inadequate Responders

Author

Carrie McClung, Setrina Hunter, R. Norman Harden, Michelle Rainka, Alienor Berges, Sarah Kavanagh, Christopher F. Bell, Roy Freeman, Kathleen Harding, Lixin Zhang, Chao Chen, Ole Graff, Samantha Warren, and Caryl Schwartzbach

Subjects
Adult, Male, Gabapentin, Population, Neuralgia, Postherpetic, Double-Blind Method, medicine, Humans, Prodrugs, education, Adverse effect, gamma-Aminobutyric Acid, Aged, Pain Measurement, Aged, 80 and over, Analgesics, education.field_of_study, Cross-Over Studies, Dose-Response Relationship, Drug, Postherpetic neuralgia, business.industry, General Medicine, Middle Aged, medicine.disease, Crossover study, Treatment period, Confidence interval, Treatment Outcome, Anesthesiology and Pain Medicine, Anesthesia, Female, Carbamates, Neurology (clinical), business, Gabapentin enacarbil, medicine.drug
Abstract

Objective To compare the efficacy of high-dose (3,600 mg/day) vs low-dose (1,200 mg/day) oral gabapentin enacarbil (GEn) on pain intensity in adults with postherpetic neuralgia (PHN) and a history of inadequate response to ≥1,800 mg/day gabapentin. Design Multicenter, randomized, double-blind, crossover study ([NCT00617461][1]). Setting Thirty-five outpatient centers in Germany and the United States. Subjects Subjects aged ≥18 years with a diagnosis of PHN. Methods During a 2-week baseline period, subjects received open-label treatment with 1,800 mg/day gabapentin. Subjects who had a mean 24-hour average pain intensity score ≥4 during the last 7 days of the baseline period were randomized to receive GEn (1,200 or 3,600 mg/day) for treatment period 1 (28 days), followed by GEn 2,400 mg/day (4 days), and the alternate GEn dose for treatment period 2 (28 days). Results There was a modest but significant improvement in pain intensity scores with GEn 3,600 mg vs 1,200 mg (adjusted mean [90% confidence interval] treatment difference, −0.29 [−0.48 to −0.10]; P = 0.013). The difference in efficacy between doses was observed primarily in subjects who received the higher dose during treatment period 2; certain aspects of the study design may have contributed to this outcome. Plasma steady-state gabapentin exposure during GEn treatment was as expected and consistent between treatment periods. No new safety signals or adverse event trends relating to GEn exposure were identified. Conclusions While the overall results demonstrated efficacy in a PHN population, the differences between treatment periods confound the interpretation. These findings could provide insight into future trial designs. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00617461&atom=%2Fpainmedicine%2F14%2F12%2F1918.atom

Published
2013

27. A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Efficacy and Safety of Gabapentin Enacarbil in Subjects With Neuropathic Pain Associated With Postherpetic Neuralgia (PXN110748)

Author

Kathleen Harding, Bart Laurijssens, Setrina Hunter, Lixin Zhang, Christopher F. Bell, Michelle Rainka, R. Norman Harden, Chao Chen, Ole Graff, Roy Freeman, Carrie McClung, Samantha Warren, Caryl Schwartzbach, and Sarah Kavanagh

Subjects
Adult, Male, Time Factors, Adolescent, Gabapentin, Population, Placebo-controlled study, Neuralgia, Postherpetic, Placebo, Young Adult, Double-Blind Method, medicine, Humans, education, gamma-Aminobutyric Acid, Aged, Anesthetics, Pain Measurement, Aged, 80 and over, education.field_of_study, Dose-Response Relationship, Drug, Postherpetic neuralgia, business.industry, Middle Aged, medicine.disease, Treatment Outcome, Anesthesiology and Pain Medicine, Neurology, Anesthesia, Neuropathic pain, Neuralgia, Female, Carbamates, Neurology (clinical), Gabapentin enacarbil, business, medicine.drug
Abstract

Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained, dose-proportional exposure to gabapentin. This randomized, double-blind, parallel-group, placebo-controlled study evaluated the safety and efficacy of 3 different maintenance doses of oral GEn in subjects with postherpetic neuralgia. Adults with a 24-hour average pain intensity score of ≥4.0 received GEn 1,200 mg, 2,400 mg, 3,600 mg, or placebo for 14 weeks (including a 1-week up-titration, 12-week maintenance, and 1-week taper). The primary endpoint was change from baseline to end of maintenance treatment in mean 24-hour average pain intensity score. The intent-to-treat population consisted of 371 subjects (GEn 1,200 mg = 107, 2,400 mg = 82, 3,600 mg = 87, placebo = 95). With regard to the primary endpoint, all 3 GEn treatment groups demonstrated a statistically significant difference relative to placebo. The adjusted mean change from baseline for the treatment groups ranged from −2.36 to −2.72 versus −1.66 for the placebo group. Exposure-response modeling suggested an ED50 around 1,200 mg/day, which was consistent with historical findings reported for gabapentin. The most commonly reported adverse events were dizziness and somnolence. All studied doses of GEn significantly improved pain associated with postherpetic neuralgia as compared to placebo and were well tolerated. Perspective GEn provides clinically important pain relief with doses from 1,200 mg to 3,600 mg and is generally well tolerated and efficacious. As an actively transported prodrug of gabapentin, it provides dose-proportional and extended exposure to gabapentin.

Published
2013

28. 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

29. Attenuation of risperidone-induced hyperprolactinemia with the addition of aripiprazole

Author

C. A. Ross, Michelle Rainka, H. A. Capote, and Francis M. Gengo

Subjects
Male, medicine.medical_specialty, Impulse control disorder, medicine.drug_class, medicine.medical_treatment, Aripiprazole, Atypical antipsychotic, Quinolones, Partial agonist, Piperazines, Internal medicine, medicine, Humans, Pharmacology (medical), Antipsychotic, Pharmacology, Risperidone, Receptors, Dopamine D2, business.industry, fungi, Dopamine antagonist, food and beverages, Middle Aged, medicine.disease, Hyperprolactinemia, Developmental disorder, Endocrinology, business, medicine.drug
Abstract

Hyperprolactinemia can be a complication of conventional neurolepics as well as risperidone. We report the third case of attenuation of risperidone-induced hyperprolactinemia by aripiprazole.

Published
2009

30. Effects of Ibuprofen on the Magnitude and Duration of Aspirin's Inhibition of Platelet Aggregation: Clinical Consequences in Stroke Prophylaxis

Author

Michelle Rainka, Vernice Bates, Donald E. Mager, Michael F. Gengo, Lisa M. Rubin, Francis M. Gengo, and Matthew J. Robson

Subjects
Male, Naproxen, Time Factors, Platelet Aggregation, Ibuprofen, Cohort Studies, medicine, Humans, Single-Blind Method, Pharmacology (medical), Volunteer, Stroke, Pharmacology, Analysis of Variance, Aspirin, Cross-Over Studies, Dose-Response Relationship, Drug, business.industry, Anti-Inflammatory Agents, Non-Steroidal, medicine.disease, Crossover study, Discontinuation, Treatment Outcome, Anesthesia, Pharmacodynamics, Drug Therapy, Combination, Female, business, Platelet Aggregation Inhibitors, Follow-Up Studies, medicine.drug
Abstract

This study was designed to measure the magnitude and duration of inhibition of platelet aggregation following doses of aspirin or ibuprofen alone or taken in combination in a group of healthy volunteers. Ten normal volunteer subjects underwent 3 randomized treatment sessions: aspirin 325 mg alone, ibuprofen 400 mg alone, and ibuprofen 400 mg, followed by dosing with aspirin 325 mg 2 hours thereafter. In addition, a confirmatory study was performed in patients. Over 27 months, a cohort of patients treated with aspirin for secondary stroke prophylaxis while concomitantly taking a nonsteroidal anti-inflammatory drug (NSAID) was identified. A significant reduction was found in both the magnitude and duration of aspirin's inhibitory effect on platelet aggregation when ibuprofen was given prior to aspirin administration in normal volunteer subjects. During a 27-month period, a cohort of 28 patients took regular daily doses of ibuprofen or naproxen. Of these 28 patients, 18 returned for follow-up testing in the absence of this pharmacodynamic interaction. None of these 18 patients demonstrated inhibition of platelet aggregation while on both NSAID and aspirin; however, all showed inhibition of aggregation following discontinuation of the NSAID. Notably, 13 of these 18 patients (72%) had experienced a recurrent ischemic episode while taking aspirin and NSAIDs concomitantly. These data suggest that ibuprofen prevents the irreversible inhibition of platelet aggregation produced by aspirin needed for secondary stroke prophylaxis, and this interaction can have clinical consequences for patients taking aspirin.

Published
2008

31. 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

32. Platelet response to increased aspirin dose in patients with persistent platelet aggregation while treated with aspirin 81 mg

Author

J. Maurice Hourihane, Erica Westphal, Michelle Rainka, Vernice Bates, Francis M. Gengo, Maria Janda, and Matthew J. Robson

Subjects
Blood Platelets, Male, medicine.medical_specialty, Platelet aggregation, Platelet Aggregation, Platelet Function Tests, Drug Resistance, Drug resistance, 030204 cardiovascular system & hematology, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Pharmacology (medical), Platelet, 030212 general & internal medicine, Stroke, Whole blood, Blood coagulation test, Pharmacology, Aspirin, business.industry, Middle Aged, medicine.disease, Surgery, Platelet aggregation inhibitor, Female, Blood Coagulation Tests, Collagen, business, Platelet Aggregation Inhibitors, medicine.drug
Abstract

This study demonstrates that patients who are taking 81 mg of aspirin and are nonresponsive benefit from a dose of 162 mg or greater vs a different antiplatelet therapy. We identified 100 patients who were nonresponsive to aspirin 81 mg via whole blood aggregometry and observed how many patients became responsive at a dose of 162 mg or greater. Platelet nonresponsiveness was defined as >10 Ω of resistance to collagen 1 µg/mL and/or an ohms ratio of collagen 1 µg/mL to collagen 5 µg/mL >0.5 and/or >6 Ω to arachidonate. Borderline response was defined as an improvement in 1 but not both of the above criteria. Of the initial 100 patients who were nonresponsive to an aspirin dose of 81 mg, 79% became responsive at a dose of 162 mg or >162 mg. Only 6% did not respond to any increase in dose. We believe that patients treated with low-dose aspirin who have significant risk for secondary vascular events should be individually assessed to determine their antiplatelet response. Those found to have persistent platelet aggregation despite treatment with 81 mg of aspirin have a higher likelihood of obtaining an adequate antiplatelet response at a higher aspirin dose.

Published
2015

33. Abstract T P386: The Clinical Implications of Assessing Platelet Responsiveness to Aspirin Using Whole Blood Platelet Aggregation versus Urinary 11-Dehydrothromboxane Testing

Author

Erica S Westphal, Francis Gengo, Patrick Galdun, Michelle Rainka, and Vernice Bates

Subjects
Advanced and Specialized Nursing, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Background: Whole blood aggregometry (WBA) is a direct measure of the effects of aspirin (ASA) on platelet aggregation while the measurement of urinary thromboxane B2 (TXB2) quantitates the metabolite produced by the ASA inhibited COX-1 enzyme. The objectives of this study were to a) compare indirect urine testing to a direct measure of platelet activity, b) determine the impact on clinical decision making if only TXB2 were measured, and c) compare time to obtain results from both procedures. Methods: Patients ages 18 to 90 who were on a stable dose of ASA for at least 14 days and had a confirmed stroke/TIA in the past 90 days were included. Patients were excluded if they used any medication that altered platelet function. Once consented, as per standard of care, blood was collected for WBA as well as a urine sample for a salicylate test for compliance. As per protocol, urine was sent out to have TXB2 levels measured in pg/mg of CR. Non-responsiveness was defined as aggregation to collagen 1 ug/mL >10 ohms of impedance, ohms ratio of collagen 1 to 5 ug/mL >.5, or arachidonic acid (AA) >6 ohms. Borderline patients were classified as either responsive or non-responsive for analysis according to the treatment decisions that were made based on clinical judgment. ABCD 2 scores were calculated and TXB2 test turnaround time was noted. Results: In 58 patients TXB2 reported only 11 as non-responsive to ASA while WBA found 18 as non-responsive and 4 as borderline. Chi square analysis found significantly different proportions of participants to be responsive or non-responsive to ASA (p=.024) through each test. ASA therapy was adjusted based on WBA results typically the next day while mean turnaround time for TXB2 was 7.29 days. ABCD 2 scores based on risk factors predicted 10.5 ischemic events while only two actually occurred. Conclusions: WBA testing reported significantly more patients to be ASA non-responsive, allowing therapy changes to be made immediately. TBX2 testing failed to identify many patients that were ASA non-responsive and results did not become available for 1 to 2 weeks.

Published
2015

34. Abstract T MP108: A Concentration Response Relationship Between the Active Metabolite of Clopidogrel and its Antiplatelet Activity

Author

Stephen Wolff, Francis Gengo, Erica S Westphal, Michelle Rainka, and Vernice Bates

Subjects
Advanced and Specialized Nursing, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Background: Variability in antiplatelet response to clopidogrel is reported to be due, in part, to the reduced ability to metabolize clopidogrel to its active form. This can be a result of a genetic difference in metabolizer status or to drug interactions which can cause inhibition of either the CYP2C19 or CYP3A4 P450 isoenzymes. Although up to this point it has remained unclear whether there is a concentration dependent relationship between clopidogrel's active thiol metabolite and its antiplatelet effects and whether there is a threshold concentration of the active metabolite (AM) needed to produce an adequate antiplatelet effect, this 3-arm, complete crossover study demonstrates a statistical relationship between AM concentrations and antiplatelet response. Methods: Fourteen healthy male volunteers took clopidogrel doses of 25 mg, 50 mg, and 75 mg. Participants were excluded for tobacco, illicit substance, and alcohol use. AM concentrations were measured using liquid chromatography-mass spectrometry over a 4 hour period and an area under the curve (AUC) was calculated. Results: The median baseline whole blood platelet aggregation value was 8 Ω (IQR=7-8.5 Ω) and responsiveness to clopidogrel was defined as 0-4 was found to be 784ng*min/mL. Sensitivity was 92.0% (95% CI: 48.0-100.0%) and specificity was 71.4% (95% CI: 46.4-85.7%). Area under the ROC curve was 84.0% (95% CI: 73.0-95.0%, p=1.867e-5) demonstrating statistical validity of the estimates of the AM threshold concentration needed to inhibit platelet aggregation. A Bayesian breakpoint analysis found the optimal threshold AUC to be in a range from 732-882 ng*min/mL. Conclusions: These findings could make it possible for clinicians to immediately tailor antiplatelet therapy to individual patients by measuring AM levels after the first dose of clopidogrel, conceivably preventing a secondary event at a time when risk is the highest. Additionally, research is ongoing to explore whether disease states commonly seen in stroke patients, such as diabetes, change the amount of the AM produced or whether they may actually result in a shift of the concentration response curve.

Published
2014

35. Pharmacokinetic simulation of fatal carbamazepine intoxication in 23-month old child following phenytoin discontinuation

Author

Jineane V. Venci, Francis M. Gengo, Meghan M. Rowcliffe, Michelle Rainka, and Lance Wollenberg

Subjects
Phenytoin, Male, Poison control, Models, Biological, Drug Administration Schedule, Pathology and Forensic Medicine, Forensic Toxicology, Pharmacotherapy, Fatal Outcome, Pharmacokinetics, Seizures, otorhinolaryngologic diseases, Medicine, Humans, Computer Simulation, Drug Interactions, Biotransformation, business.industry, Maintenance dose, Poisoning, Infant, General Medicine, Carbamazepine, Discontinuation, Anesthesia, Concomitant, Anticonvulsants, Drug Therapy, Combination, Autopsy, Drug Monitoring, Drug Overdose, business, Monte Carlo Method, medicine.drug
Abstract

The antiepileptic, carbamazepine, is extensively metabolized via hepatic enzymes in the cytochrome P450 family and is therefore subject to a myriad of drug interactions. Concomitant administration with phenytoin enhances carbamazepine metabolism thus reducing serum concentrations and necessitating the use of a higher maintenance dose. Removal of phenytoin therapy in the absence of anticipatory dose adjustments and careful monitoring of serum concentrations may result in catastrophic outcomes. Reported herein are the events leading to the death of a 23-month old child who suffered a fatal carbamazepine overdose following withdrawal of phenytoin therapy.

Published
2012

36. Predicting missing biomarker data in a longitudinal study of Alzheimer disease

Author

Mary M. Laubinger, Po H. Lu, M. Saleem Ismail, Alan J. Lerner, Paul Malloy, Daniel C. Marson, Pierre N. Tariot, Adam S. Fleisher, Neill R Graff-Radford Mbbch, Vernice Bates, Jeffrey M. Burns, Robert B. Santulli, Maria Kataki, Kris A. Johnson, Henry Rusinek, Nick C. Fox, Ronald C. Petersen, Matt A. Bernstein, Heather Anderson, Janet S. Cellar, Godfrey D. Pearlson, Mark A. Mintun, Karen Crawford, Stephen Salloway, Owen Carmichael, Kaycee M. Sink, Howard Chertkow, Jeff D. Williamson, Ann Marie Hake, Teresa Villena, Scott Turner, George Marzloff, Daniel Varon, Anil Nair, Martin R. Farlow, Yaakov Stern, Javier Villanueva-Meyer, Kathleen Johnson, Martha G. MacAvoy, Daniel H.S. Silverman, Marjorie E. Marenberg, Jacobo Mintzer, Ranjan Duara, Ronald A. Cohen, Munir Chowdhury, Bruce L. Miller, Charles DeCarli, Dzintra Celmins, Stephen Correia, Sonia Pawluczyk, Paul S. Aisen, Heather Johnson, Gaby Thai, Paul J. Wang, William J. Jagust, Anthony Gamst, Adrian Preda, Jaimie Toroney, Allyson C. Rosen, Chris Hosein, Michele Assaly, Neil Buckholtz, Christopher M. Clark, Hillel Grossman, Stephanie Reeder, Ging-Yuek Robin Hsiung, John A. Rogers, Wes Ashford, Scott C. Neu, Jennifer Richard, Karen S. Anderson, Michael Borrie, George Bartzokis, Marilyn S. Albert, Brian R. Ott, Barry A. Hendin, Dick Trost, Michael D. Devous, Ramon Diaz-Arrastia, Chuang-Kuo Wu, Helen Vanderswag, Jeffrey R. Petrella, Susan De Santi, Jeffrey Kaye, Randall Griffith, Howard Feldman, Catherine Mc-Adams-Ortiz, Bryan M. Spann, Donald Connor, Francine Parfitt, Ruth A. Mulnard, P. Murali Doraiswamy, Raj C. Shah, M.-Marsel Mesulam, Howard J. Rosen, Donna Munic, Marilyn Aiello, Robert C. Green, Laurel A. Beckett, Cynthia M. Carlsson, Marwan N. Sabbagh, Michael C. Donohue, John C. Morris, Donna M. Simpson, Peter A. Hardy, James B. Brewer, Charles Bernick, Cheuk Y. Tang, Leon Hudson, Sanjay Asthana, Alice D. Brown, Kristen Martin-Cook, David G. Clark, Amanda L. Benincasa, T-Y Lee, Seema Mirje, Charles D. Smith, Lon S. Schneider, Nancy Collins Johnson, Christopher H. van Dyck, Joseph F. Quinn, Steven G. Potkin, Sandra Jacobson, Ronald G. Thomas, Kelly E. Behan, Barry W. Rovner, Anders M. Dale, Norbert Schuff, Howard Bergman, Arthur W. Toga, Andrew Kertesz, Horacio Capote, Keith A. Johnson, Mony J. de Leon, Sandra E. Black, Dan Bandy, Karen L. Bell, Leylade Toledo-Morrell, Allan I. Levey, Connie Brand, Paul M. Thompson, Julia Pedroso, Scott Herring, Dana Nguyen, Oscar L. Lopez, Judith L. Heidebrink, Curtis A. Given, Reisa A. Sperling, Simon P. Graham, Danielle J Harvey, Earl A. Zimmerman, Sara Dolen, John Kornak, Walter Martinez, Ronald J. Killiany, Smita Kittur, Holly Soares, Paula Ogrocki, Joanne L. Lord, Jared R. Tinklenberg, Lawrence S. Honig, Kewei Chen, Carl H. Sadowsky, Joel P. Felmlee, Magdalena Korecka, Jessica Englert, Peggy Roberts, Michelle Rainka, Clifford R. Jack, Annapurni Jayam-Trouth, Alexander Norbash, Sterling C. Johnson, Curtis B. Caldwell, MaryAnn Oakley, Gene E. Alexander, Dorene M. Rentz, Tatiana Foroud, James J. Lah, Cassie Pham, Virginia M.-Y. Lee, Franklin Watkins, T. J. Montine, Douglas W. Scharre, Sam Gandy, Thomas O. Obisesan, Steven Potkin, Li Shen, Jessica Nunez, Andrew J. Saykin, Raymond Y. Lo, Evan Fletcher, Sarah Walter, Stacy Schneider, Rob Bartha, and Rachelle S. Doody

Subjects
Oncology, medicine.medical_specialty, Longitudinal study, Patient Dropouts, tau Proteins, Neuropsychological Tests, Logistic regression, Developmental psychology, Cohort Studies, Alzheimer Disease, Fluorodeoxyglucose F18, Risk Factors, Internal medicine, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, Longitudinal Studies, Homocysteine, Amyloid beta-Peptides, Dementia, Vascular, medicine.disease, Missing data, Magnetic Resonance Imaging, Peptide Fragments, Logistic Models, Research Design, Positron-Emission Tomography, Biomarker (medicine), Neurology (clinical), Alzheimer's disease, Psychology, Biomarkers, Alzheimer's Disease Neuroimaging Initiative, Cohort study
Abstract

Objective: To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD). Methods: The Alzheimer9s Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI. Results: CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ 42 . Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD. Conclusion: The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.

Published
2012

37. Treatment options for multiple sclerosis: current and emerging therapies

Author

Kristen M. Gawronski, Francis M. Gengo, Michelle Rainka, and Malti J. Patel

Subjects
Central Nervous System, medicine.medical_specialty, Multiple Sclerosis, chemistry.chemical_compound, Daclizumab, Teriflunomide, medicine, Humans, Immunologic Factors, Pharmacology (medical), Intensive care medicine, Clinical Trials as Topic, business.industry, Multiple sclerosis, Antibodies, Monoclonal, medicine.disease, Fingolimod, Clinical trial, chemistry, Immunology, Alemtuzumab, Rituximab, business, Laquinimod, Immunosuppressive Agents, medicine.drug
Abstract

Multiple sclerosis is a chronic autoimmune disease affecting the central nervous system, more specifically, the myelin sheath covering of nerve fibers in the brain and spinal cord. This disease requires lifelong disease-modifying therapy, and all of the currently available first-line disease-modifying agents are parenteral formulations only. To date, eight drugs have entered or completed phases II and III clinical trials, four of which are oral drugs. These include five immunomodulators--cladribine, fingolimod, laquinimod, teriflunomide, and dimethyl fumarate--and three monoclonal antibodies--alemtuzumab, daclizumab, and rituximab. Although comparing these new drugs with available therapies is difficult, they do show promise as potential first-line agents for the treatment of multiple sclerosis. This marks a new frontier in the treatment of this disease, as the advent of new oral drugs will lead to increased patient compliance and contribute to longer sustained symptom-free periods and less marked disability.

Published
2010

38. Prevalence of platelet nonresponsiveness to aspirin in patients treated for secondary stroke prophylaxis and in patients with recurrent ischemic events

Author

Alan Forrest, Maurice Hourihane, Michelle Rainka, Michael F. Gengo, Vernice Bates, Francis M. Gengo, and Matthew J. Robson

Subjects
Blood Platelets, Male, medicine.medical_specialty, Ticlopidine, Time Factors, Platelet Aggregation, Ischemia, Anti-Inflammatory Agents, Coronary Artery Disease, Gastroenterology, chemistry.chemical_compound, Recurrence, Internal medicine, Odds Ratio, Medicine, Humans, Pharmacology (medical), Platelet, Treatment Failure, Stroke, Aged, Pharmacology, Aspirin, Arachidonic Acid, business.industry, Age Factors, Odds ratio, Dipyridamole, medicine.disease, Confidence interval, Clopidogrel, chemistry, Ischemic Attack, Transient, Anesthesia, Ambulatory, Arachidonic acid, Drug Therapy, Combination, Female, Collagen, business, medicine.drug
Abstract

To determine the prevalence of platelet nonresponsiveness to aspirin treatment for secondary stroke prophylaxis, the authors studied consecutive patients during a 29-month period. Information regarding their ischemic events, risk factors, and medications was collected. Platelet aggregation in response to collagen and arachidonic acid was used to determine platelet responsiveness to aspirin. A total of 653 patients were evaluated. Of these, 129 patients (20%) were determined to be nonresponsive to aspirin based on continued platelet aggregation in response to collagen, arachidonic acid, or both. A total of 87 (13%) of the 653 patients were clinical aspirin failures (ie, presented with new focal cerebral ischemic symptoms while taking aspirin). Of the patients with new cerebral ischemic symptoms, 57 (66%) were determined to be platelet nonresponsive to aspirin. The odds ratio for platelet nonresponsiveness to aspirin in patients who suffered a recurrent ischemic event while taking aspirin was 14.25 (95% confidence interval: 8.5-23.7; P < .5). Continued platelet aggregation despite aspirin treatment occurred in 20% of ambulatory patients treated for secondary stroke prophylaxis. The prevalence of nonresponsiveness to aspirin was statistically higher in those patients who suffered recurrent cerebral ischemia while taking aspirin (P < .5) compared with patients who remained without new ischemic symptoms.

Published
2008

39. Population pharmacodynamic modelling of aspirin- and Ibuprofen-induced inhibition of platelet aggregation in healthy subjects

Author

Michelle Rainka, Vernice Bates, Ying Hong, Donald E. Mager, and Francis M. Gengo

Subjects
Adult, Naproxen, Time Factors, genetic structures, Platelet Aggregation, Analgesic, Population, Administration, Oral, Ibuprofen, Pharmacology, Models, Biological, medicine, Humans, Pharmacology (medical), Cyclooxygenase Inhibitors, Single-Blind Method, Antipyretic, education, Aspirin, education.field_of_study, Arachidonic Acid, Cross-Over Studies, Chemistry, organic chemicals, Drug interaction, Middle Aged, Pharmacodynamics, Collagen, Monte Carlo Method, Platelet Aggregation Inhibitors, medicine.drug, Half-Life
Abstract

The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination.Ten healthy volunteers were enrolled in a single-blinded, randomized, three-way crossover study. Treatments consisted of single doses of oral aspirin (325 mg) and ibuprofen (400 mg) and concomitant administration of aspirin (325 mg) and ibuprofen (400 mg). Ex vivo whole blood platelet aggregation induced by collagen (1 microg/mL) or arachidonic acid (0.5 mmol/L) was measured by impedance aggregometry. Model development and population parameter estimation were performed using nonlinear mixed-effects modelling implemented in NONMEM.Relatively complete inhibition of platelet aggregation was achieved following aspirin treatment (approximately 77% inhibition within 2 hours), and return to baseline values occurred within 72-96 hours after dosing. In contrast, treatment with ibuprofen alone or in combination with aspirin produced transient inhibition of platelet aggregation, with complete recovery observed in 6-8 hours. The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (kout) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h(-1) and 0.152 (mg/L)(-1).h(-1), with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration.A mechanism-based pharmacodynamic model has been developed that characterizes the antiplatelet effects of aspirin and ibuprofen, alone and concomitantly, and predicts a significant inhibition of aspirin antiplatelet effects in the presence of a typical ibuprofen dosing regimen.

Published
2008

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